API 原料药的验证 PDF

Validation of Active
Pharmaceutical
Ingredients
Second Edition
Edited by
Ira R. Berry and Daniel Harpaz
informa
healthcare
New York London
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2001 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works

Version Date: 20130325
International Standard Book Number-13: 978-1-4200-2597-2 (eBook - PDF)
This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have
been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal respon-
sibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or
opinions expressed in this book by individual editors, authors or contributors are personal to them and do not neces-
sarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for
use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other
professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and
the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice
on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the drug
companies’ printed instructions, and their websites, before administering any of the drugs recommended in this book.
This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ulti-
mately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to
advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of
all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has
not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify
in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or uti-
lized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopy-
ing, microfilming, and recording, or in any information storage or retrieval system, without written permission from the
publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://
www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923,
978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For
organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for
identification and explanation without intent to infringe.
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
CONTENTS
PREFACE 2001 xvii
AUTHOR BIOGRAPHIES xix
1. INTRODUCTION 1
Daniel Harpaz
GMP Concepts 2
Regulatory 3
FDA Site Inspections 4
References 7
2. THE LEGAL FRAMEWORK FOR THE REGULATION

OF ACTIVE PHARMACEUTICAL INGREDIENTS 11
David F. Weeda, Arthur Y. Tsien,
Neil F. O'Fiaherty, and Robert A. Hahn
The Regulatory Status of APis 12
AP/s and BPCs 12
AP/s as "Drugs" 13
AP/s as "New Drugs" or "New Animal Drugs" 14
API Adulteration 14
cGMP Noncompliance 15
Validation as Part of cGMPs 16
Other Forms of Adulteration 19
API Misbranding 20
iii
iv Validation of Active Pharmaceutical Ingredients
API Inspections 21
History of API Inspections 21
Reasonable Inspections Under Section 374(a) 22
Scope of FDA lnspectional Authority over APis 23
Inspection Priorities: Active Drug Substances Versus Excipients 25
Foreign Versus Domestic Plant Inspection 26
Other Inspection Issues 30
Enforcement Tools Against APis 32
Administrative Tools 32
Judicial Tools 34
FDA Import/Export Authority over APis 37
Drug Master Files for APis 42
DMFTypes 42
DMF Holder Obligations 43
Status of DMFs as Records 44
Conclusion 45
Notes 45
References 52
3. THE LEGAL BASIS FOR VALIDATION 55

Irving L. Wiesen
Current Good Manufacturing Practices 55
The 1962 Food and Drug Amendments 56
Challenges to the cGMPs 59
FDA's Analysis of cGMPS 59
Judicial Analysis of cGMPs 61
MOpen-Endedness" of the cGMP Framework 63
Failure to Comply with cGMPs Constitutes Product Adulteration 65
Active Pharmaceutical Ingredient Standards 66
Validation 67
FDA's Validation Guideline of 1987 69
Validation of Active Pharmaceutical Ingredients 70
The Barr Laboratories Decision 70
Conclusion 76
Notes 76
References 81
4. DRUG MASTER FILES 83

Arthur B. Shaw
Regulatory Basis for DMFs 84
Guideline 84
Relationship Between Holder and Applicant 84
Filing and Referencing a DMF 85
Review of a DMF 87
Contents y
Approval of DMFs 89
Types of DMFs 89
Manufacturing Performed at More Than One Site 91
Intermediates 93
Rereview of DMFs for APis 93
Changing the Manufacturing Procedure in a DMF 95
Summary 96
5. THE FDA's PERSPECTIVES ON ACTIVE PHARMACEUTICAL

INGREDIENT MANUFACTURING, cGMP CONTROLS,
AND VALIDATION 97
Edwin Rivera Martinez
Development of the FDA's API GMP Draft Guidance 98
"What to Do" Versus "How to Do" in the FDA's API Guidance 100
cGMP Deficiencies Uncovered by the FDA's Inspections Abroad 101
Scope of the FDA's Draft API Guidance 105
Application of cGMPs to API Processes 106
Defining and Identifying the Starting Material 107
API Process Validation 110
Defining and Identifying Critical Process Steps 113
Defining Critical Process Parameters 115
Types of Process Validation 116
Equipment Cleaning and Validation 118
Process Water 120
Review of Batch Production and Control Records 123
Reprocessing and Reworking 123
Impurity Testing and Impurity Profiles 124
Initiatives to Develop an Internationally Harmonized
GMP Guidance for APis 127
Conclusions 129
References 130
6. DOMESTIC AND FOREIGN API MANUFACTURING

FACILITY AUDITS AND FINDINGS 133
Peter D. Smith
Quality Assurance Functions and Systems 133
Standard Operating Procedures 134
Batch Release Procedure 136
Deviation and Failure Investigations, Reports 136
vi Validation of Active Pharmaceutical Ingredients
Reworking and Reprocessing 137

Change Control System 138
Annual Product Quality Reviews 139
Raw Materials Handling and Controls/Warehousing 140
Qualification 143
API Production Equipment 145
Equipment Cleaning 146
Commonly Found Problem Areas 146
Equipment Calibration 148
Labeling Controls 149
Recovered Solvents 149
Master Production and Control Records 150
Batch Production and Control Records 151
Personnel Training and Training Program 153
Quality Control Laboratory Operations 154
Common Adverse Observations 155
Research and Development (R&D) 160
Process Validation 161
Reference 162
7. VALIDATION OF APis: A CASE STUDY 163

Nirma/ Khanna
The FDA and the History of Validation 164
What Is Validation? 164
A Successful Validation Program 165
API Validation-A Case Study 166
Manufacturing Operations 166
Quality Assurance Systems 167
Validation Program 168
Retrospective Reviews 169
Master Plan 169
Retrospective Review Effort 170
Concurrent/Prospective Validations 172
Master Plan 174
Validation Protocols 175
Summary Report 175
Cleaning Operations 176
Cleaning Validation-Concurrent or Prospective Validation 178
Computer Control Systems 179
Concurrent Validation 179
Contents vii
Executive Summary-Concurrent/Prospective Validations 180

Validation File 181
Maintaining a "Validation State" 181
Concurrent or Prospective Validation Effort 182
Conclusions 184
Reference 185
Additional Reading 186
Acknowledgments 186
Appendices
7.1: What Is Concurrent Validation?
What Is Prospective Validation? 187
7.2: Events and U.S. Regulations 188
7.3: SOPs-Operations, IDEAL Corp. 189
7.4: Batch Records-A Validation Viewpoint 191
7. 5A: Miscellaneous Activities-Prospective Validation
(Support Systems) 192
7. 58-Miscellaneous Activities-Prospective Validation
(Process Equipment) 195
7. 5C-Miscellaneous Activities-Prospective Validation
(Computer System Validation) 197
7.6: Outline of a Typical Retrospective Protocol 198
7. 7: Outline of a Typical Concurrent or Prospective Validation Protocol 199
7.8-Key Instruments Used in OQ Activities 200
7. 9A-Retrospective Example 201
7.98-Prospective Example: Process Equipment, Train 8 (/Qs, OQs) 210
7.9C-Concurrent Example: Controlled Environment (IQ, OQ) 220
7.90-Concurrent or Prospective Example: Supreme Process (PQ) 227
7.9E-Concurrent or Prospective Example: Cleaning 233
7.9F: Concurrent or Prospective Example: Micronization 242
7.9G: Concurrent Example: DCS Summary Report 252
8. ACTIVE PHARMACEUTICAL INGREDIENT VALIDATION:

AN OVERVIEW AND COMPARATIVE ANALYSIS 261
Max S. Lazar
FDA Focus 262
Industry Reaction 262
Validation: A Comparison of Dosage Versus APis 263
Development Documents 264
Considerations During Development 265
Technology Transfer 266
Change Control 266
Defined Critical Steps 267
Well-Defined Purification 267
Types of Validation 268
Retrospective Validation 268
viii Validation of Active Pharmaceutical Ingredients
Prospective Validation 269

Concurrent Validation 269
The Future Horizon 269
References 270
9. IMPURITIES IN DRUG SUBSTANCES AND DRUG PRODUCTS 271

Stephen R. Byrn and Joseph G. Stowell
Quality 272
A Typical USP Monograph 272
USP Descriptions of Impurities 273
Foreign Substances 273
Toxic Impurities 273
Ordinary Impurities 273
Other Impurities 274
Signa/Impurities 274
Organic Volatile Impurities 274
Concomitant Components 275
ICH Documents on Impurities 275
Specifications 276
Qualification of Impurities 276
Analytical Procedures for Degradation Products or Drug-Excipient
Reaction Products 278
Specification Limits for Degradation Products or Drug-Excipient
Reaction Products 279
Impurities in Drug Products in Abbreviated New Drug
Applications (ANDAs) 279
Validation 280
Impurity Issues Related to Manufacturing, Processing, or
Holding Drug Substances (APis) 282
Enantiomers as Impurities 285
Polymorphs as Unwanted Components 285
BACPAC 287
Summary and Conclusion 289
References 290
10. INVESTIGATING PROCESS DEVIATIONS 293

Frank J. Golden
Process Deviations 294
Regulatory Considerations 295
Process Deviation Principles 297
Problem Description 297
Classification of Deviation 297
Contents ix
Examination of Data Available 298

Review Procedures Utilized 298
Materials Used 298
Suitability of Facilities 298
Suitability of Equipment 299
Employee Training 299
Extent of Deviation 300
Validation Impact 300
Equivalency 300
Testing Required 300
Regulatory Impact 301
Results of Investigation 301
Corrective Action 301
Preventive Actions 301
Conclusions 302
Documentation 302
Signatures and Approvals 302
Periodic Review 302
Investigating Quality Problems 302
Process Deviation Examples 304
Example 1 304
Example 2 305
Example 3 307
References 308
11. TECHNOLOGY TRANSFER:

ACTIVE PHARMACEUTICAL INGREDIENTS 309
B. J. Evanoff and K. L Hofmann, Jr.
Preliminary Considerations 310
The Role of Marketing 310
Defining the Process 311
Categories of Technology Transfer 312
New Chemical Entities 312
Changes to Established Processes 312
Process Development Report 313
Organization for Technology Transfer 317
Technology Transfer Team 317
Intracompany Project 318
External Technology Transfer Project 319
Considerations for Plant Scale-Up 319
Raw Materials 320
Plant Equipment and Utilities 320
Process Control Parameters 321
Process Equipment 322
Cleaning Validation 323
Analytical Methods 324
x Validation of Active Pharmaceutical Ingredients
Ancillary Issues 326

API Container/Closure 326
Stability 327
Regulatory Issues 327
Summary 327
References 328
12. POSTAPPROVAL CHANGES TO BULK DRUG SUBSTANCES 329

Eric Sheinin, Eric Duffy,
Kasturi Srinivasachar, and John Smith
BACPAC I 331
Scope 331
Filing Mechanism 332
Assessment of Change 333
Manufacturing Site, Manufacturing Scale, and Equipment Changes 335
Specification Changes 336
Process Changes 336
BACPAC II 337
Scope 338
Principles of Equivalence 338
Filing Mechanisms 339
Types of Changes 339
Summary 339
Conclusion 340
13. VENDOR QUALIFICATION AND CERTIFICATION 343

Ira R. Berry
Definition of Terms 344
Purpose of Vendor Qualification and Certification 345
Qualification/Certification Procedure Overview 346
How to Qualify a Vendor 34 7
Certifying a Vendor 351
Monitoring a Vendor 352
Vendor Audits 353
Philosophy of Pharmaceutical GMP Compliance 354
Documentation 354
Quality Assurance Program 355
Standard Operating Procedures Manual 355
Change Control Procedure 356
Personnel Training 356
Out-of-Specification Data Handling/Failure Investigation 356
Written Master Production and Control Records with
In-Process Controls 357
Contents xi
Reprocessing and Rework 357

Process Validation Program 357
Analytical Methods Validation 358
Stability Program 358
Control of Suppliers 358
Distribution Records 359
Recall Procedure and Capability 359
Product Complaint Handling Procedure 359
Returned Goods Procedure 359
Safety Program 360
Current Drug Master Rle 360
Internal/External Audit Program 360
Calibration Program 361
Facilities and Equipment Preventive Maintenance Program 361
Materials and Labeling Control 362
The Auditors 362
Be Prepared 363
Some Common Plant Issues 363
Preparation Aids 365
References 366
14. QUALITY ASSURANCE SYSTEMS 369

Fred C. Radford
Definition and Decision 375
FDA Requirements Are Central 380
The Inspection Focus 381
Beyond the Manufacturing Instruction 383
Tangent Considerations 385
Plan, Do, Study, Act 388
References 395
15. CLEANING FOR ACTIVE PHARMACEUTICAL

INGREDIENT MANUFACTURING FACILITIES 397
William E. Hall
Regulatory Requirements 397
Multiple Use Versus Dedicated Equipment 399
The Unique Nature of APis 401
Multiple Levels Approach to Cleaning 402
Level 1 Cleaning 402
xll Validation of Active Pharmaceutical Ingredients

Philosophy of Cleaning 403
Nature of Contaminants 404
Product Groupings and Selection of a Worst Case 405
Cleaning Techniques 406
Sampling 407
Analytical Methods 409
Visual Examination 411
Analytical Techniques for Biotechnology Cleaning Validation 412
High Performance Liquid Chromatography 412
Microbial and Endotoxin Testing 413
Total Organic Carbon Analysis 413
Limits and Acceptance Criteria 414
Calculation of Limit Based on Smallest Therapeutic Dose 416
Calculation of Limit Based on Toxicity 417
Cleaning Validation Documentation 420
Protocols 421
Final Validation Report 425
Emerging Trends in Cleaning in the Pharmaceutical Industry 425
References 427
16. VALIDATION OF STERILE APis 429

Robert V. Kasubick
Regulatory Aspects 431
Validation Protocol Format 431
General Manufacturing Process Description 432
Facility 432
Room Classification 434
Airflow Patterns and Pressure Differentials 435
Pe~onneiRow 437
Material Row 439
Support Systems 439
Water Systems 439
Air Systems 442
Equipment Sterilization 444
Clean Steam System 445
Filtration Systems 445
Heat Exchange~ 44 7
Vacuum Systems 44 7
Manufacturing Process Validation 44 7
Validation Maintenance 449
References 449
Contents xiii
17. VALIDATION OF BIOTECHNOLOGY ACTIVE

PHARMACEUTICAL INGREDIENTS 451
Rob Murphy and Robert J. Seely
Master Planning 452
Equipment Qualification 453
Installation Qualification 453
Operational Qualification 454
Performance Qualification 454
Equipment Sterilization 456
Timing 458
Process Variables 459
Impurity Profile 462
Additional Studies 463
The Rna/ Package 463
Process Monitoring 464
Change Control 466
Revalidation 468
References 469
Appendix 17.1: Process Validation Protocol PV-08 471
18. MICROBIOLOGICAL ATTRIBUTES OF ACTIVE

PHARMACEUTICAL INGREDIENTS 475
Karen Zink McCullough and John Shirtz
Preliminary Issues 478
Standard Operating Procedures 478
Microbiological Quality of Water 4 79
Validation/Qualification and Maintenance of the Water Purification,
Storage, and Distribution System 482
Bioburden 484
API Processing 486
Facility and Equipment Considerations for the
Production of Sterile APis 488
Use of Isolator Systems to Minimize Human Contact
with Sterile APis 493
Containment 493
Monitoring the Environment in API Manufacturing Facilities 494
Monitoring of Classified and Critical Areas: Manufacturing and
Support for Products and APis Produced Aseptically 495
Monitoring of Unclassified Areas: Nonsteri/e Dosage Forms
and APis 496
Site Selection and Frequency of Testing 496
xiv Validation of Active Pharmaceutical Ingredients
Microbiological Monitoring of Air 497

Microbiological Monitoring of Surfaces 499
Microbiological Monitoring of Operators 501
Trending Data Obtained from Environmental Monitoring 501
Microbiological Testing of Finished Sterile APis 502
Sterility Testing 502
Testing of APis for the Presence of Endotoxin 503
Endotoxin Limits 506
Summary 510
Glossary 511
References 514
19. EXCIPIENTS: FACILITY, EQUIPMENT, AND

PROCESSING CHANGES 519
Irwin Silverstein
Identification of Significant Process Change 524
Facility 531
Equipment 534
Processing 537
Conclusion 540
Glossary 541
References 542
20. API TERMINOLOGY AND DOCUMENTATION 543

Robert A. Nash
Active Pharmaceutical Ingredient 548
Compendia! Standards 549
Chiral APis 550
Chemical Control Regulations 551
The Validation of APis 553
Process Validation Options 554
Process Description 554
Impurity Profile 559
Retrospective Validation 559
Revalidation 560
Change Control 560
Bulk Actives Postapproval Changes 561
Reprocessing 562
Contents XV
Validation Master Plan 563

Explosion Suppression Validation 566
Validation Documentation 566
Recommended Reading 569
References 570
INDEX 573
PREFACE 2001
Since publication of the first edition, there has been continuous activity in
the subject areas of bulk pharmaceutical Good Manufacturing Practice (GMP)
and validation. The basic philosophy and principles of GMP and validation
have not changed. New terminology has been introduced, and old terminol-
ogy has been better defined so as to improve the understanding of related
concepts and principles. For example, the term active pharmaceutical ingredi-
ent (API) has been introduced to replace the older term bulk pharmaceutical
chemical (BPC).
The continuous activity referred to has resulted in considerable new in-
formation and global regulatory guidance that has been made available in
the form of guidances and guidelines written by the U.S. Food and Drug Ad-
ministration and by ICH (International Conference on the Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use).
These guidances and guidelines cover current Good Manufacturing Practices
(cGMPs), stability, product quality requirements, and postapproval changes
-all of which are discussed in this book.
This second edition includes updates to the chapters in the first edition
and several additional chapters on pertinent subjects, including postapproval
changes, technology transfer, international cGMP guidelines/FDA guidance
progress and fadlity inspectional issues. The book is intended to provide bet-
ter clarity and understanding of the regulatory process so as to facilitate com-
pliance by the regulated pharmaceutical industry.
Spedal thanks are given to the contributing authors, who have given of
their personal time to write this book, while continuing their very busy work
schedules. These people have provided extensive effort to create this
book and to help maintain the high quality of products that the industry
manufactures, while also striving to create a more productive regulatory
environment.
Ira R. Berry
Daniel Harpaz
xvii
AUTHOR BIOGRAPHIES
BOOK EDITORS
Ira R. Berry
Ira R. Berry is executive vice president of Wockhardt Americas Inc. He is
responsible for global regulatory affairs and quality assurance, the U.S. oper-
ation, and establishing new manufacturing and technical operations world-
wide. He has a BS in biology and chemistry from Queens College of the City
University of New York, an MA in biology from Hofstra University, and an
MBA from Adelphi University.
Previously, Mr. Berry was a manager at Pfizer, Inc., in product and
process development and production. At Denver Chemical Manufacturing
Company, he held several positions in production and product development,
regulatory affairs, and quality assurance. Before joining Wockhardt, Mr. Berry
was corporate vice president for technical affairs at Banner Pharmacaps Inc.
Mr. Berry's professional experience covers pharmaceuticals, nutritional
supplements, diagnostic products, medical devices, and cosmetics. He is cred-
ited for patents in antacid formulation, controlled release, foaming bath oil,
and chewable gelatin shell capsules. He is a member of the Regulatory Affairs
Professionals Society, the Pharmaceutical Quality Control Association, the
American Academy of Pharmaceutical Sciences and the National Association
of Pharmaceutical Manufacturers (on the Board of Directors). Mr. Berry has
published more than 25 papers on GMP, softgels, validation, and nutritional
supplements. He is coeditor for a second edition of Pharmaceutical Process Val-
idation and coeditor of Validation of Bulk Pharmaceutical Chemicals.
xix
xx Validation of Active Pharmaceutical Ingredients
Daniel Harpaz
Daniel Harpaz is president of Harpaz Consulting Services, a firm that provides
global regulatory and technical advice to FDA regulated industries. He holds
a BS and MS in chemical engineering, an MBA, and a PhD in industrial
pharmacy.
With over 30 years of experience in the pharmaceutical industry, Dr.
Harpaz has held senior positions in research and development, quality con-
trol, and engineering and has handled diversified programs for his employees
and clients, domestically and internationally. He presents and publishes on
GMP and validation issues, is on the editorial board for the Journal of Valida-
tion Technology, and is a member of many professional and trade associations.
CONTRIBUTING AUTHORS
Stephen R. Byrn
Stephen R. Byrn is the Charles B. jordan Professor at Purdue University's
School of Pharmacy and Pharmacal Sciences. He is also head of the Depart-
ment of Industrial and Physical Pharmacy and director of the Center for AIDS
Research at Purdue University. He received his BA from DePauw University
and his PhD in chemistry from the University of Illinois at Champaign-
Urbana. He was a postdoctoral fellow at UCLA. Dr. Byrn's research focuses on
the solid-state chemistry of drugs and has emphasized the application of X-
ray crystallography and solid-state nuclear magnetic resonance spectroscopy
to pharmaceutical problems. He is committed to educating scientists to bring
a wide range of analytical techniques to bear on solid-state problems. Dr.
Byrn has extensive experience as a consultant in the pharmaceutical indus-
try, currently serves on the Chemistry III, Dissolution, and Excipients sub-
committees of the U.S. Pharmacopeia, and is the chair of the Drug Substance
Technical Committee for PQRI.
Eric Duffy
Eric Duffy holds a PhD in synthetic organic chemistry from Tufts University.
He has a decade of experience in drug discovery and development, regulatory
affairs, and specialty chemicals manufacturing. This experience led to posi-
tions within the U.S. Food and Drug Administration in the Office of Generic
Drugs (reviewing antibiotics, anti-infectives, and antifungals), the Office of
New Drug Chemistry (team leader), and the Division of Oncology Drug Prod-
ucts. Dr. Duffy has served on many committees and working groups, includ-
ing BACPAC I, BACPAC II, the Drug Substance Committee (chairperson), the
Author Biographies xxi
rONA Metabolites Working Group, the New Drug Substance Source Working
Group, and International Conference on Harmonisation Q3A/Q6A Working
Groups.
Barbara J. Evanoff
Barbara J. Evanoff is a regulatory affairs analyst for Bristol-Myers Squibb Co.
She has a BA in chemistry. Ms. Evanoff has 10 years of experience in manu-
facturing process development and analysis and 10 years of experience in
drug regulatory affairs, primarily in the area of bulk pharmaceuticals and in-
termediates. She is a member of the American Chemical Society.
Frank J. Golden
Frank J. Golden is the manager of supplier quality assurance and internal au-
dits at Glaxo Wellcome Inc. He has an AAS in biological technology, a BS in
biology, and an MBA. Mr. Golden was an FDA investigator and compliance
officer for 13 years and for the last 10 years has served in quality assurance
and compliance groups in the pharmaceutical industry. As a Certified Qual-
ity Auditor from the American Society for Quality, he routinely provides GMP
and audit training to Glaxo Wellcome staff, contractors, and other industry
personnel. Mr. Golden is a member of the Parenteral Drug Association, ASQ,
and the North Carolina Regulatory Affairs Forum.
Robert A. Hahn
Robert Hahn is an associate attorney at Olsson, Frank, and Weeda, P.C. He has
a BA magna cum laude, Phi Beta Kappa, from Brown University, a law degree
from Columbia University Law School; and an MA in public health from the
Harvard School of Public Health. Mr. Hahn was admitted to the New York
State Bar in 1985. Previously, he was director of legal affairs at Public Voice
for Food and Health Policy (now merged with the Consumer Federation of
America); vice president and counsel at Manufacturers Hanover Trust Com-
pany; and an associate in the Guangzhou, China, office of Lewis, D' Amato,
Brisbois, Bisgaard, Buxbaum & Choy.
William E. Hall
Dr. William E. Hall is an international expert on cleaning validation in the
pharmaceutical industry. He holds a BS from the University of Arkansas and
an MS and a PhD from the University of Wisconsin. With more than 40 years'
xxii Validation of Active Pharmaceutical Ingredients
experience, he consults for approximately 250 companies worldwide since

forming his own consulting company in 1995. Prior to 1995, Dr. Hall was
with Glaxo Wellcome for 22 years and a professor at the University of North
Carolina School of Pharmacy for 7 years. He has published extensively in
journals and textbooks on the subject of cleaning and serves on the Editorial
Advisory Board for the Journal of Validation Technology. He is also a member of
the IVT Validation Hall of Fame. Dr. Hall has given hundreds of presentations
on the importance and activities of process validation, cleaning validation,
and quality assurance.
Karl L. Hofmann
Karl L. Hofmann, Jr., is director of quality assurance at Bristol-Myers Squibb
Co. He holds a BS and an MS. Mr. Hofmann has over 25 years of experience
in pharmaceutical manufacturing and quality assurance. He is a member of
the Parenteral Drug Association, the Pharmaceutical Research and Manufac-
turers of America Bulk QC Work Group, and the International Society for
Pharmaceutical Engineering. He is the author of several papers and text chap-
ters dealing with the manufacture of sterile pharmaceuticals and GMP for the
manufacture of bulk pharmaceuticals. Mr. Hofmann has also lectured at the
Center for Professional Advancement on the topic of sterile filtration.
Robert V. Kasubick
Robert V. Kasubick is vice president of operations and regulatory affairs at
Oakwood Laboratories. He has a BS from Pennsylvania State University, an
MS from Connecticut College, and a PhD from Purdue University. Dr. Ka-
subick's experience includes a variety of positions in research, quality control,
pilot plant operations, manufacturing, and regulatory affairs at Pfizer, Bristol-
Myers Squibb, Wyeth Ayerst, and Ben Venue Laboratories. He has a strong
background in the formulation and manufacturing of tablets, capsules, and
sterile injectables.
Nirmal K. Khanna
Nirmal K. Khanna is a full-time consultant to the director of chemical opera-
tions at Hoffmann-La Roche. He holds a BChE from liT (Delhi), an MChE
from New York University, and an MS in industrial and management engi-
neering from Columbia University. Mr. Khanna has more than 25 years of
experience in development, manufacturing, and engineering related to fine
chemicals, APis, and biotechnology products. As a consultant, he has executed
Author Biographies xxiii
several retrospective reviews and concurrent and prospective validations

and has written investigation reports for these reviews/validations. Mr.
Khanna is a member of the American Institute of Chemical Engineers and the
International Society for Pharmaceutical Engineering.
Max Lazar
Max S. Lazar is Vice President of FDA and DEA Compliance at Hoffmann-La
Roche. His undergraduate degree is from Brooklyn College of the City Uni-
versity of New York. During his 34 years' professional working experience
with Hoffmann-La Roche, Mr. Lazar has held positions as laboratory analyst,
quality control laboratory supervisor, quality control manager, and quality
control director. At the company's largest bulk manufacturing site in the
United States, he has been director of process development and director of
engineering. Mr. Lazar was the founder of the Pharmaceutical Research and
Manufacturers of America's Quality Control Committee Work Group on APis.
He is vice chairman of the USP Expert Committee and a topic leader for the
International Conference on Harmonisation Q7 Expert Working Group for
the development of an international guideline for Good Manufacturing Prac-
tice for APis. He has published numerous papers and addressed many orga-
nizations on the subjects of API and FDA compliance issues.

Mr. Rivera-Martinez is a compliance officer in the Center for Drug Evaluation
and Research's Office of Compliance. He has a BS in chemistry and an MBA
with a concentration in management. He worked as a bench chemist for the
pharmaceutical industry in Puerto Rico before initiating his career with the
U.S. Food and Drug Administration. In 1978, he specialized in the inspection
and investigation of complex, state-of-the-art bulk drug and finished phar-
maceutical production facilities. From November 1987 to April 1990, he
served as a consultant to the Pan American Health Organization (regional of-
fice of the World Health Organization), organizing and presenting pharma-
ceutical cGMP training courses as part of a FDA/PAHO cooperative program
to strengthen national drug regulatory agencies and improve the quality of
pharmaceuticals in Latin America. Since his appointment as the active phar-
maceutical ingredient contact in the Office of Compliance in August 1993,
he has reviewed numerous recommendations for regulatory and administra-
tive action involving GMP and validation issues for APis. He serves as the pri-
mary division representative for public presentations and training in this area
and is an active member of the FDA's API GMP task force charged with de-
veloping an industry guidance document for the manufacture, control, and
xxiv Validation of Active Pharmaceutical Ingredients
validation of APis. He is a technical expert on the ICH Q7 A Expert Working

Group charged with developing an internationally harmonized GMP guid-
ance for APis.
Karen Zink McCullough

Karen Zink McCullough is owner and principal consultant of MMI Associ-
ates, specializing in consulting for pharmaceutical quality control. She has a
BA in bacteriology from Douglass College of Rutgers University and an MS in
molecular biology from the University of Oregon. Previously, Ms. McCul-
lough was supervisor of microbiology at Beecham Laboratories. She is a fre-
quent speaker at training courses and scientific symposia in the United States,
Canada, and Europe. She is a member of the Parenteral Drug Association and
teaches courses in the United States and Europe for the PDA, the Center for
Professional Advancement, and Pharmanet.
Rob Murphy
Rob Murphy is a senior manager in quality assurance at Amgen Inc. He re-
ceived a BS in biochemistry from the University of Missouri. He has six years
of experience in validation and has worked on the licensure of three manu-
facturing facilities and four different products. He has made numerous pre-
sentations concerning validation and preapproval inspections to the
Parenteral Drug Association, the Pharmaceutical Research and Manufacturers
of America, and the U.S. Food and Drug Administration.
Robert A. Nash
Robert A. Nash is a consultant and adjunct professor of industrial pharmacy
and cosmetic science at St. John's University. He was formerly director of
pharmaceutical development of the Purdue Frederick company as well as
manager of pharmaceutical product development at Lederle Laboratories and
a research associate of Merck, Sharp, and Dohme Research Labs. Mr. Nash has
published widely in the fields of pharmaceuticals and cosmetic science and
holds nine U.S. patents. He is also coeditor of Pharmaceutical Process Valida-
tion and a member of the editorial advisory board of the Journal of Validation
Technology. He is an active member of International Sodety for Pharmaceuti-
cal Engineering, the Academy of Pharmaceutical Research and Science, the
American Chemical Society, and the American Association of Pharmaceutical
Scientists.
Author Biographies xxv
Neil F. O'Raherty
Neil F. O'Flaherty is a principal at Olsson, Frank, and Weeda, P.C. He received
a BA from the University of Notre Dame and a JD from Loyola University of
Chicago School of Law. He was admitted to the Illinois Bar in 1990 and the
District of Columbia Bar in 1991. Mr. O'Flaherty concentrates his practice in
the area of FDA regulation of medical devices. He has spoken and written ex-
tensively on device-related topics, including FDA regulation of in vitro diag-
nostics and blood bank software and FDA device inspection and enforcement
authority. Over the years, Mr. O'Flaherty's device work has included assis-
tance to the Advanced Medical Technology Association, the largest trade as-
sociation for the medical device industry in the United States, including
assistance on device tracking, medical software, and device reclassification
matters. His practice also includes legal matters relating to other FDA-regu-
lated products.
Fred C. Radford
Fred C. Radford is the president of Alert Consultants, Inc., a firm specializing
in human and veterinary drug and medical device submissions and the es-
tablishment and auditing of quality assurance systems. He has a BA in Eng-
lish from Western Michigan University, a BS with high honors in chemistry
from Grand Valley State University, plus graduate studies in business. Mr.
Radford is a Regulatory Affairs Certified professional. Prior to the formation
of Alert Consultants, Mr. Radford held various supervisory positions at Per-
rigo Company (Allegan, Mich.) as it grew from a dozen products to over 800
products and 20,000 product configurations, including quality control su-
pervisor, R&D supervisor, compliance manager, quality assurance director,
business development director, and export and international director. He has
developed a variety of manual and electronic systems that are still being used
today. Mr. Radford is a corporate representative for the the Nonprescription
Drug Manufacturer's Association, the Council for Responsible Nutrition, the
National Association of Pharmaceutical Manufacturers, and other organiza-
tions. He is also a member of many professional organizations, including the
Regulatory Affairs Professional Society, the Food and Drug Law Institute, the
American Association of Pharmaceutical Scientists, the Parenteral Drug Asso-
ciation, the Drug Information Association, and the American Society for
Quality.
Robert J. Seely
Robert Seely specializes in downstream processing, scale-up, troubleshooting,
and validation of recombinant therapeutic protein processes at Amgen. He
has a BS from Oregon State University, an MS in biochemistry from the
xxvi Validation of Active Pharmaceutical Ingredients
University of Colorado Medical School, and a PhD in biochemistry from Col-

orado State University. Prior to Amgen's acquisition of Synergen (1995), he
was a pharmaceutical researcher at Upjohn and an industrial specialist at
Great Western Sugar Company and BioGas of Colorado. Beginning in 1985
with Synergen, he has participated in the successful scale-up and validation
of a very large-scale multiproduct biotechnology clinical manufacturing fa-
cility.
Arthur B. Shaw
Arthur B. Shaw serves as an expert in Drug Master Files. He has a BS from the
City College of New York and a PhD in biochemistry from Cornell University.
After postdoctoral work, he joined Revlon Health Care Group's Protein
Chemistry Research and Development Group. He began work at the FDA in
the Division of Gastrointestinal and Coagulation Drug Products in 1990. Af-
ter serving as chair of the Drug Master File Technical Committee, he was rec-
ognized as the FDA's Expert in DMFs in 2000.
Eric B. Sheinin
Eric Sheinin is vice president for general policies and requirements at the
United States Pharmacopeia. Formerly he was the deputy director of the Of-
fice of Pharmaceutical Science of the Center for Drug Evaluation and Re-
search of the Food and Drug Administration. He has a BS in zoology from the
University of Illinois at Champaign-Urbana and a PhD in chemistry from the
University of Illinois at Chicago Medical Center. Previously he held leader-
ship positions in the Office of New Drug Chemistry in the Office of Pharma-
ceutical Science; the Division of New Drug Chemistry III in the Office of New
Drug Chemistry; the Division of Medical Imaging, Surgical and Dental Drug
Products; and the Division of Oncology and Radiopharmaceutical Drug Prod-
ucts. He was also chief of the Drug Standards Research Branch and a research
chemist in the Division of Drug Chemistry of the Center for Drugs and Bio-
logics. Author or coauthor of over 30 publications, he has presented papers
at over 75 scientific conferences. He is a member of the American Association
of Pharmaceutical Scientists, the American Chemical Society, and the USP
Committee of Revision. He is currently a member of the AAPS/APQ Com-
pendia! and Regulatory Affairs Committee.
John Shirtz
john Shirtz is manager of quality control microbiology at Catalytica Pharma-
ceuticals. He has a BS in biology from the State University of New York at Al-
bany and an MS in molecular biology/biotechnology from East Carolina
Author Biographies xxvii
University. Prior to joining Catalytica Pharmaceuticals, he was department

head of quality assurance microbiology at Glaxo Wellcome, coordinator of
sterile operations validation at Burroughs Wellcome, and various positions
with Bristol-Myers Squibb. Mr. Shirtz specializes in compendial microbiolog-
ical requirements and chemical requirements for both sterile and nonsterile
product validation. He has authored several journal articles and book chap-
ters on the various aspects of microbiological testing. He is a member of the
Parenteral Drug Association.
Irwin Silverstein
Irwin Silverstein is a quality assurance specialist at International Specialty
Products, supporting cGMP compliance for the pharmaceutical products
manufactured by the firm, primarily excipients. He has a PhD in chemistry
from New York University. He led the effort that achieved ISO 9002 certifica-
tion in 1991 and assisted in the development of the cGMP compliance pro-
gram. He is a Certified Quality Auditor and Certified Lead Auditor for ISO
9000.
Dr. Silverstein was a founding member of the International Pharmaceu-
tical Excipients Council GMP Committee and was instrumental in the devel-
opment of their Good Manufacturing Practices Guide for Bulk Pharmaceutical
Excipients. He chaired the IPEC committee that developed significant change
and impurity profile guides and helped to develop the recently completed
manufacturer and distributor audit guides.
John Smith
John Smith is a review chemist for the U.S. Food and Drug Administration.
He holds a BA in chemistry from Rutgers University and a PhD in chemistry
from the University of Minnesota. Prior to joining the FDA Office of Generic
Drugs and the Office of New Drug Chemistry, he was a process research and
development chemist with Merck & Co., Inc., and a technical service chemist
in the enhanced oil recovery group at OXY USA, Inc. Dr. Smith has served on
numerous technical committees within the Center for Drug Evaluation and
Research, including the Chemistry, Manufacturing, and Controls Coordinat-
ing Committee; the Packaging Committee; and the Drug Substance Techni-
cal Committee. He is presently the chairman of the Drug Substance Technical
Committee and the BACPAC II Working Group.
Peter D. Smith
Peter D. Smith is director of international compliance services at KMI/Parexel
LLC. He has a BS in biology from Roger Williams College (Bristol, Rhode
xxviii Validation of Active Pharmaceutical Ingredients
Island). Early in his career, Mr. Smith was an investigator for the Food and
Drug Administration, specializing in GMP inspections at drug production fa-
cilities, at API manufacturers, and medical device manufacturers, along with
GLP and clinical study audits. From 1986 to 1984, he was associate director
of the FDA's International and Technical Operations Branch within the Office
of Regulatory Affairs, where he was responsible for foreign field inspections
in human and veterinary pharmaceutical plants. In 1994, Mr. Smith joined
Kemper-Masterson, Inc. (now called KMI/Parexel LLC), where he specializes
in GMP compliance issues. His primary expertise is in the fields of API man-
ufacture, preapproval inspections, nonsterile dosage forms, GMP quality sys-
tems, and FDA regulatory issues. He is a member of the International Society
for Pharmaceutical Engineering and the Parenteral Drug Association.
Kasturi Srinivasachar
Kasturi Srinivasachar is a chemistry team leader in the Division of Cardio-Re-
nal Drug Products of the Center for Drug Evaluation and Research. He has a
PhD in organic chemistry from the University of Chicago. After postdoctoral
appointments at the Swiss Federal Institute of Technology (Zurich), the Uni-
versity of California (Irvine), and the University of Kansas (Lawrence), Dr.
Srinivasachar joined the National Institutes of Health in 1986 to work in the
area of immunotoxins. He was involved in the development of targeted drug
delivery systems using new acid cleavable cross-linking agents for conjugat-
ing toxins like ricin and diptheria toxin to monoclonal antibodies. Dr. Srini-
vasachar joined FDA in 1993 prior to becoming a chemistry team leader. In
addition to his regulatory activities at the Center for Drug Evaluation andRe-
search, he has been engaged in research on antisense oligonucleotides at the
Center for Biologics Evaluation and Research.
Joseph G. Stowell
joseph G. Stowell is director of laboratories for the School of Pharmacy and
Pharmacal Sciences at Purdue University. He has an AB in chemistry from the
University of California at Irvine and a PhD in organic chemistry from the
University of California at Davis, specializing in natural-product synthesis.
Dr. Stowell joined the staff of Purdue University's School of Pharmacy and
Pharmacal Sciences after two years in technical services at Eli Lilly and Com-
pany. Dr. Stowell's research interests encompass the chemistry of pharmaceu-
tical solids, computational chemistry, and pharmaceutical manufacturing.
Author Biographies xxix
Arthur Y. Tsien
Arthur Y. Tsien is a principal at Olsson, Frank, and Weeda, P.C. He has a BS
magna cum laude from Tufts University and a JD from the University of
Washington. He was admitted to the Washington Bar in 1978 and the Dis-
trict of Columbia Bar in 1987. Currently he is a member of the District of Co-
lumbia Bar and the Washington State and American Bar Associations. Mr.
Tsien served as law clerk to Chief Judge Frank D. James of the Washington
Court of Appeals from 1978 to 1980 and as associate chief counsel for veteri-
nary medicine and enforcement at the FDA from 1980 to 1985. He concen-
trates his practice in FDA regulatory issues and litigation.
David F. Weeda
David F. Weeda is a principal of Olsson, Frank, and Weeda, P.C. He has a BA
cum laude from St. Thomas University, Miami, and a JD from the Loyola Uni-
versity of New Orleans School of Law. Mr. Weeda served as associate chief
counsel for biologics and enforcement at the FDA from 1976 to 1981. He
served as adjunct law professor at the Columbus School of Law at Catholic
University of America from 1985 to 1989. He applies his expertise primarily
to assist manufacturers of pharmaceutical and biological products in ap-
proval, regulatory, compliance, and legal matters. He has also defended com-
panies and individuals charged with violating the Federal Food, Drug, and
Cosmetic Act, the Controlled Substances Act, and related federal criminal
laws. He is a frequent lecturer before trade and professional groups and is gen-
eral counsel to the National Association of Pharmaceutical Manufacturers.
Irving L. Wiesen
Irving L. Wiesen is a food and drug law attorney specializing in all areas of law
affecting the pharmaceutical industry, including all areas of FDA regulation-
drug approvals, drug research, Good Manufacturing Practices, FDA proceed-
ings, and promotion and marketing regulations. In addition, his law practice
includes licensing, research, sales and manufacturing agreements, general
commercial and marketing issues, antitrust, personnel, and litigation. Mr.
Wiesen is a graduate of the New York University School of Law, where he was
was also an editor of the Journal of International Law and Politics. Mr. Wiesen is
employed by Ullman, Shapiro, and Ullman, was formerly a partner at Bass and
Ullman, and served for many years as division counsel for Boehringer Ingel-
heim Pharmaceuticals, Inc. Mr. Wiesen has also lectured before all the major
professional organizations serving the pharmaceutical industry and has pub-
lished in periodicals and books on topics relating to FDA regulation.
1
INTRODUCTION
Daniel Harpaz
Harpaz Consulting Services
Suffern, New York
The subjects of Good Manufacturing Practice (GMP) and validation are not
new to the pharmaceutical industry (Berry and Nash 1993; Tetzlaff et al.
1993; Berry 1988; Reisman 1995; Agalloco 1995; FDA 1987, 1994a, 1993a;
Tetzlaff 1992a, 1992b; Tetzlaff 1993; Harpaz 1996; Amer 2000). There have
been discussions on the subject and controversies have arisen and been re-
solved since the 1960s (Gold 1996; Nash 1993; Sharp 1995; Simmons 1997;
Selby 1999; Chapman et al. 2000). For years these issues have been directed
toward the dosage form sector of the pharmaceutical industry. Since 1991, fo-
cus has also been directed toward the manufacturers of active pharmaceutical
ingredients (APis) as evidenced by the U.S. Food and Drug Administration's
(FDA's) increased effort in inspections of domestic and foreign API manufac-
turing facilities and their agents (FDA 1991, 1994b, 1998a; Gold Sheet 1993;
Falcone 1999). In the mid-1990s, the term active pharmaceutical ingredient was
introduced by the FDA instead of bulk pharmaceutical chemical (BPC).
In its Guideline to Inspection, the FDA set the following criteria to identify
an industrial chemical as a BPC (FDA 1991):
• When there is no recognized nondrug commercial use for the

chemical
• When it reaches the point in its isolation and purification such
that it is intended that the substance will be used in a drug product
• When the manufacturer sells the product or offers it for sale to a
pharmaceutical firm for use in a drug product
1
2 Validation of Active Pharmaceutical Ingredients
Active chemical ingredients and excipients used in drug products may, there-
fore, be considered as BPCs. These materials can be made by chemical synthe-
sis, fermentation, enzymatic reactions, recombinant DNA, recovery from
natural materials, or a combination of the above.
One basic problem that has evolved is that the FDA has not issued GMP
regulations for BPCs as it did for drug products (21 CFR Parts 210 and 211), for
medical devices (21 CFR Part 820), and for foods (21 CFR Part 110). After issu-
ing a revised Guideline to Inspection of Bulk Pharmaceutical Chemicals in 1991,
FDA spokespersons assured the bulk chemical industry that GMP regulations
were to follow. However, with the change in the political environment in
Congress in 1994, the FDA changed its direction and decided to issue a guide
to industry, spelling out specific GMP requirements and clarifying the con-
cepts of process validation for APis, instead of specific GMP regulations. The
first such document was issued in August 1996, where the FDA introduced the
term active pharmaceutical ingredient, or API, instead of BPC. Since the majority
of the APis for U.S. consumption were produced in Europe, the European
Pharmaceutical Inspection Conference (PIC) introduced its own version of
GMP regulations as a guidance document (PIC 1997). In response, the FDA re-
vised its guidance to industry and agreed to develop internationally harmo-
nized GMP regulations (FDA 1998b). The International Conference on
Harmonisation (ICH) API guidance document, known as Q7a, was issued for
public comments at presstime. There are no significant differences between
Q7a and the FDA's 1998 guidance (Rivera Martinez 2000). Details about the
development of GMP regulations for APis are covered in Edwin Rivera-
Martinez's chapter, "The FDA's Perspectives on Active Pharmaceutical Ingredi-
ent Manufacturing, cGMP Controls, and Validation."
As part of the ongoing harmonization for new drugs, the FDA issued nu-
merous guidance documents related to API quality, i.e., specifications, impu-
rities, and stability (FDA 1996, 1997, 1999a; FR 1997, 2000).
The purpose of this book is to provide some food for thought in estab-
lishing guiding principles, and a number of concepts will be developed in this
regard, for example, process validation, cleaning validation, quality assur-
ance, technology transfer, microbial controls, biotechnology, and so on.
GMP CONCEPTS
GMPs, in most simplistic terms, are the minimum requirements that a manu-
facturer must satisfy in producing drugs. The legal ramifications of not com-
plying with GMP and the extension of the GMP regulations for finished
pharmaceuticals to APis are described in the chapter by David Weeda, Arthur
Tsien, Neil O'Flaherty, and Robert Hahn, "The Legal Framework for the Regu-
lation of Active Pharmaceutical Ingredients." Validation is a concept that is
part of the GMP regulations that involves documentation as evidence that a
manufacturing process is in control. Irving Wiesen's chapter, titled "The Legal
Introduction 3
Basis for Validation," explains the relations between GMP and validation. To
clarify its position on validation, the FDA issued a revision to the GMP regu-
lations in May 1996 (FR 1996c) and expanded it in its latest API Guidance
(FDA 1998a, 1998c). The concepts of process validation for nonsterile drug
products are still open to interpretation and are not implemented alike by the
industry (Amer 2000; Chapman and Harpaz 2000). A number of chapters ad-
dress in detail how to validate properly.
Additional terms have been incorporated into the everyday language of
people in the dosage form industry and are significant to those involved with
the API industry. Robert Nash's chapter, API Terminology and Documenta-
11
tion," defines and expands on these terms.
REGULATORY
APis are considered components of drug products, and therefore are subjected
to FDA regulations (Harpaz 1996). These are numerous and cannot all be cov-
ered in this book. However, those regulations that are related to GMP are
worth mentioning.
Site Registration is a filing process notifying the FDA that a site is being
used for manufacturing, packaging, labeling, and distributing drug. This reg-
istration process applies to domestic and foreign sites, yet distributors of for-
eign-made drugs must register the site of manufacturing and name a U.S.
agent. The U.S. agent will assist the FDA in communication with the foreign
establishment (FR 1999). In addition to informing the FDA about the site,
the drugs must be listed. Drug Listing is a process of submitting appropriate
forms describing the drug product and drug substance that are distributed
(21 CFR Part 207). The distribution of drugs in the United States requires
FDA approval; new drug products and new drug substances (new molecular
entities) are subject to the filing and approval of New Drug Applications
(NDAs). Generic drug products are subject to the filing and approval of
Abbreviated New Drug Applications (ANDAs). Antibiotics are subject to Ab-
breviated Antibiotic Drug Applications (AADAs) (21 CFR Part 314). Drug sub-
stance, intermediate, and excipient manufacturers are expected to submit to
the FDA Drug Master Files (DMFs) (21 CFR Part 314.420). A DMF is a compi-
lation of technical data describing the manufacturing, quality, and controls
of the material. A DMF is not reviewed by the FDA upon application, and it
does not undergo a formal approval process. This confidential and extensive
document is designed to create an open file for review by the FDA only when
an NDA or ANDA is filed by a dosage form manufacturer making reference to
the material described in the DMF (FDA 1989). It is very important that a
DMF holder maintains the currency of the DMF, because it will be examined
for its relevancy during a site inspection by the FDA investigator. In his
chapter, Dr. Arthur Shaw describes in detail the FDA review process for
DMFs.
For economic or other reasons, frequent changes do occur in the API in-
dustry. In recognition, the FDA issued guidance documents regarding changes
made postfiling (FR 1997b; FDA 1998d, 1999). These are covered in the chap-
ter by Eric Sheinin, Eric Duffy, Kasturi Stinivasachar, and John Smith, "Postap-
proval Changes to Bulk Drug Substances."
FDA SITE INSPECTIONS
Domestic and foreign manufacturers of drug substances and drug products

that distribute in the United States are subject to the Federal Food, Drug, and
Cosmetic Act (FD&C Act) and to regulations promulgated by the FDA. Section
501 of the act, titled "Adulterated Drugs and Devices," requires conformity
with current Good Manufacturing Practice (cGMP).
Section 704 of the FD&C Act, "Factory Inspection," authorizes desig-
nated FDA employees to enter and inspect sites where drugs are manufac-
tured, processed, packed, or held. The objective of such inspections is to
assure compliance with the act, which among other requirements calls for
conformance with GMP
In order for a manufacturing site to satisfy the FDA investigator that it
operates with conformance and with acceptable manufacturing practices, the
site should be able to demonstrate the following aspects:
• A commitment to quality by the entire organization, including top

management
• A written Quality System Program that assures adherence to the basic
principles of GMP
• A proactive GMP Compliance Program designed to achieve constant
upgrading and correction of deficiencies
• An ongoing Personnel Training Program that assures that employees
are routinely trained in GMP and in Standard Operating Procedures
(SOPs) pertaining to their activities
The GMP regulations require manufacturers to establish written operat-

ing procedures for all of the critical activities at the site (21 CFR Parts 210 and
211). The regulations, however, do not spell out how a site is to carry out
these activities; it is the responsibility of the manufacturing site to establish
procedures that are appropriate for its activities. Once such procedures are
written and approved, it is essential that the users be trained in these proce-
dures. These procedures then become the "laws" of the manufacturing site
and, therefore, must be adhered to precisely. FDA investigators frequently cite
companies for not following their own SOPs and/or for deviating from the
Introduction 5
practices described in their current DMFs. Fred Radford's chapter, "Quality As-
surance Systems," and Ira Berry's chapter, "Vendor Qualification and Certifi-
cation," describe some of the systems that are required to conform to GMP
regulations. Peter Smith describes his observations in the chapter "Domestic
and Foreign API Manufacturing Facility Audits and Findings." An area of con-
cern to the FDA is a poor change control program and a lack of adequate in-
vestigations. Frank Golden's chapter, "Investigating Process Deviations,"
addresses these issues.
In 1992, the FDA implemented a new policy for the approval of NDAs
and ANDAs. This policy calls for a preapproval inspection (PAl) of the dosage
form manufacturing site to assure compliance with GMP and verification of
the accuracy and completeness of the data presented to the FDA (FDA 1992).
The PAl policy was extended to cover API manufacturers. This event triggered
a large number of inspections of foreign manufacturers (Gold Sheet 1993).
During an inspection of an API manufacturing site, the FDA investigator re-
views compliance with GMP with emphasis on the following areas (21 CFR
Part 314; Avallone 1992a; Anisfeld 1997; FDA 1998a; Falcone 1999)
• Impurity Profile
• Solvent Recovery
• Polymorphism
• Reprocessing
• Change Control
• Cleaning Validation
• Process Validation
• Stability (determination of degradation products and establishing
retest dates)
• Development Reports
Process validation is another area of concern to the investigator (Barr et

al. 1993; Lazar 1993; Gold 1992; Brocklenbank and Deo 1996; PhRMA 1995,
1996, PIC 1999; EMEA 1999; Amer 2000). For drug products, all manufactur-
ing steps in the creation of the final product, including cleaning, weighing,
measuring, mixing, blending, filling, packaging, and labeling, must be vali-
dated. For APis, the FDA does not require validation of all the manufacturing
steps but accepts validation of the critical processing steps (Seely et al. 1999;
Rivera Martinez 1996, 1994; FDA 1998b; FR 2000a). This means that the ini-
tial processing steps in a multistep, batch-type chemical synthesis may re-
quire fewer controls than the final steps. Therefore, it is the responsibility of
the API manufacturer to determine when process validation should begin.
This determination can be done only by having a thorough knowledge of the
chemistry of the API. Max Lazar's chapter, "Active Pharmaceutical Ingredient

Validation: An Overview and Comparative Analysis," makes a comparison be-
tween the validation of APis and the validation of drug products. Nirmal
Khanna's chapter, "Validation: A Case Study," describes in detail the valida-
tion process for APis and compares Prospective Validation with Retrospective
Validation. The FDA expanded the requirements for process validation to in-
clude the cleaning process, as evidenced by its Guide to Inspection of Validation
of Cleaning Processes (FDA 1993b) and in the proposed revisions to the GMPs
(FR 1996) and the ICH Guide (FR 2000a). The concept of Cleaning Validation
is described in detail in William Hall's chapter.
Drug substances that are used in sterile drug products are subject to
tighter GMP regulations (FDA 1994b; FR 2000a). Sterile APis are synthesized
in the same mode as nonsterile APis except that the end step is followed by a
procedure such as aseptic filtration. Thereafter, in an aseptic environment,
crystallization, separation, drying, filling, and packaging take place. Robert
Kasubick's chapter, "Validation of Sterile APis," and the chapter by Karen Mc-
Cullough and John Shirtz, "Microbiological Attributes of Active Pharmaceuti-
cal Ingredients," describe the manufacturing and controls of sterile APis. The
validation of APis manufactured by biological processes is outlined in Rob
Murphy's and Robert Seely's chapter.
Developmental Reports are documents that are written in preparation for a
PAl (Hoekstra 1996). The FDA investigator reviews these reports to confirm that
th~ following have been established: the source and specifications for intermedi-
ates, determination of the manufacturing processes and substantiation of critical
process parameters, equipment and operating ranges, control of residual sol-
vents, and determination of impurities. Barbara Evanoff's and Karol Hoffman's
chapter, "Technology Transfer," describes the content of Development Reports.
Processing impurities in a drug substance is another area of concern to
the FDA (Avallone 1992b; Boehlert 1997). The FDA issued guidelines for the
identification and reporting of impurities in new drug substances. This guide-
line defines an impurity as any material, organic or inorganic, other than the
new drug substance, that is present at a level above 0.1 percent. All impurities
above this level must be identified and reported in the new drug filing (FDA
1997; FR 2000c). Similar regulations apply to APis used in the manufacturing
of generic drug products (FDA 1999e). Stephen Bym and Joseph Stowell de-
scribe in their chapter the impact of impurities on drug substance quality.
Registrations for APis should also include information regarding the
solid-state forms of the drug substance. Crystal forms of the drug substance
should be controlled. If bioavailability is affected by the polymorphic, hy-
drated, or amorphous forms of the drug substance, the FDA requires the man-
ufacturer to demonstrate the suitability of the control methods (Byrn et al.
1995; Chowhan 1994; DeCamp 1999; Ressler 1999).
Excipients are used to formulate a drug substance to an acceptable drug
product. The FDA considers such excipients as BPCs but has not issued spe-
cific GMP regulations for such. However, the International Pharmaceutical
Introduction 7
Excipient Council (IPEC) issued a proposed GMP for Excipient BPCs in 1995,
and a guide on "Significant Change for Bulk Pharmaceutical Excipients in
2000" (IPEC 1995; IPEC-Americas 2000). Irwin Silverstein describes how to
manage changes in manufacturing in his chapter, "Excipients: Facility, Equip-
ment, and Process Equipment Changes."
This introduction chapter was written to acquaint the reader with the
regulatory requirements for APis. The chapters to follow were written by ex-
perts in their fields and provide more detailed information about the manu-
facturing and control processes of APis.
REFERENCES
Agalloco, J. 1995. Validation: An unconventional review and reinvention. PDA f.
Phann. Sci. & Tech. (July).
Amer, G. 2000. Process validation issues: A discussion with C. Coleman, USFDA. f. Val-
idation Tech. (May).
Anisfeld, M. 1997. Implementation of U.S. GMPs in the manufacture of active ingredi-
ents: A case study of implantation, costs and benefits. Phann. Tech. (April).
Avallone, H. L. 1992a. GMP Inspections of drug-substance manufacturers. Phann. Tech.
(June).
Avallone, H. L. 1992b. Drug substance purity. Phann. Tech. (December).
Barr, D. B., W. C. Crabbs, and D. Cooper. 1993. FDA regulation of bulk pharmaceutical
production. Phann. Tech. (September).
Berry, I. R. 1988. Process validation: Practical applications for pharmaceutical prod-
ucts. Drug Dev. Ind. Phann. 14 (2 and 3).
Berry, I. R., and R. A. Nash, eds. 1993. Phannaceutical process validation. New York: Mar-
cel Dekker, Inc.
Boehlert, J.P. 1997, Impurities-where are we now. Phann. Tech. (June).
Brocklenbank, M.P., and P. V. Deo. 1996. GMP issues for bulk pharmaceutical chemi-
cal plants. Phann. Eng. (January/February): 8-26.
Byrn, S., and R. Pfeiffer. 1995. Pharmaceutical solids: A strategic approach to regulatory
considerations. Phann. Res. (July).
Chapman, K. G., and D. Harpaz. 2000. Proposed validation standard VS-1: Nonaseptic
pharmaceutical processes, introduction and preamble. f. Validation Tech. (February).
Chowhan, Z. 1994. Drug substance physical properties and their relations to the per-
formance of solid dosage forms. Phann. Tech. (March).
DeCamp, W. H. 1999. The impact of polymorphism on drug development: A regulator's
viewpoint. Presented at the Congress of the International Union of Crystallogra-
phy in Glasgow, UK (August).
EMEA. 1999. Note for guidance on process validation. London: European Agency for the
Evaluation of Medicinal Products.
Falcone, M. 1999, Drug preapproval inspection program 1998 results. Presented at the
Twenty-Third International Good Manufacturing Practices Conference in Athens,
Ga. (March).
FDA. 1987. Guideline on general principles ofprocess validation. Rockville, Md., USA: Food
and Drug Administration, Center for Drugs and Biologics.
FDA. 1989. Guideline for Dmg Master Files. Rockville, Md., USA: Food and Drug Admin-
istration, Center for Drug Evaluation and Research.
FDA. 1991. Guide to inspection of bulk pharmaceutical chemicals: Reference materials and
training aids for investigators. Rockville, Md., USA: Food and Drug Administration,
Center for Drug Evaluation and Research.
FDA. 1992. Pre-approval inspection/investigation. Compliance Policy 7346.832.
Rockville, Md., USA: Food and Drug Administration.
FDA. 1993a. Recommendations for submitting documentation for sterilization process vali-
dation in application for human and veterinary dmg products. Rockville, Md., USA:
Food and Drug Administration, Center for Drug Evaluation and Research.
FDA. 1993b. Guide to inspection of validation of cleaning processes. Rockville, Md., USA:
Food and Drug Administration, Division of Field Investigation.
FDA. 1994a. Guide to inspection of oral solid dosage form pre/post approval issues for devel-
opment and validation. Rockville, Md., USA: Food and Drug Administration, Divi-
sion of Field Investigation.
FDA. 1994b. Guide to inspection of sterile dmg substance manufacturers. Rockville, Md.,
USA: Food and Drug Administration.
FDA. 1996. Guidance to industry, QlB: Photostability testing of new drug substances and
products. Rockville, Md., USA: Food and Drug Administration.
FDA. 1997. Guidance to industry, Q3B: Impurities in new dmg products. Rockville, Md.,
FDA. 1998a. Active pharmaceutical ingredients. Compliance Program Guide 7556.002F.
FDA. 1998b. Guidance for industry-manufacturing, processing or holding active pharma-
ceutical ingredients. Rockville, Md., USA: Food and Drug Administration.
FDA. 1998c. Global harmonization task force study group #3-draft process validation guid-
ance. Rockville, Md., USA: Center for Devices and Radiological Health.
FDA. 1998d. BACPAC I: Intermediates in dmg substances synthesis/bulk active postapproval
changes: Chemistry, manufacturing, and controls documentation. Rockville, Md., USA:
Food and Drug Administration.
FDA. 1998e. Guidance for industry ANDAs: Impurities in dmg substances. Rockville, Md.,
USA: Food and Drug Administration, Center for Drug Evaluation and Research.
FDA. 1999. Guidance for industry, changes to an approved NDA or ANDA. Rockville, Md.,
Introduction 9
FR. 1996. Current good manufacturing practice: Amendment of certain requirements

for finished pharmaceuticals; proposed rule. Federal Register 61:20104.
FR. 1997a. International Conference on Harmonization; guidance on impurities:
Residual solvents. Federal Register 62:67377.
FR. 1997b. Changes to an approved application: Guidance to industry: Changes to an
approved application for specified biotechnology and specified synthetic biologi-
cal products and biological products. Federal Register 62:39889.
FR. 1996c. Current Good Manufacturing Practice: Amendment of certain requirements
for finished pharmaceuticals; proposed rule. Federal Register 61:20104.
FR. 1999. Foreign establishment registration and listing. Federal Register 64:26330.
FR. 2000a. International Conference on Harmonization; Draft guidance on good man-
ufacturing practice for active pharmaceutical ingredients: Availability. Federal Reg-
ister 65:46936.
FR. 2000b. International Conference on Harmonization; Draft revised guidance on Q1A®:
stability testing of new drug substances and products. Federal Register 65:21446.
FR. 2000c. International Conference on Harmonisation. Draft Revised Gudance on impu-
rities in New Drug Substance. Federal Register 65:45085.
Gold, D. H. 1992. GMP issues in bulk pharmaceutical chemical manufacturing. Pharm.
Tech. (April).
Gold, D. H. 1996. Validation: Why, what, when, how much. PDA 1- Pharm. Sci. & Tech.
0anuary-February).
The Gold Sheet 1993. (September).
Harpaz, D. 1996. Bulk pharmaceutical chemicals. Regulatory Affairs 1- Oanuary).
Hoekstra, M. S. 1996. A guideline for transferring bulk pharmaceutical chemical tech-
nology from chemical development to manufacturing. Pharm. Tech. (October).
IPEC. 1995. Good manufacturing practices guide for bulk pharmaceutical excipients. Inter-
national Pharmaceutical Excipients CounciL
IPEC-Americas. 2000. Significant change guide for bulk pharmaceutical excipients. Interna-
tional Pharmaceutical Excipients CounciL
Lazar, M. S. 1993. Concepts for the process validation of bulk pharmaceutical chemi-
cals. Pharm. Tech. (December).
Nash, R. A. 1993. Response to the validation editoriaL 1- Parenteral Sci. Ouly).
PIC. 1997. Draft-internationally harmonized guide for active pharmaceutical in-
gredients: Good Manufacturing Practice." Geneva: Pharmaceutical Inspection
Convention.
PIC. 1999. Recommendation on validation master plan: Installation and operational
qualification, nonsterile process validation, cleaning validation. Geneva: Pharma-
ceutical Inspection Convention.
PhRMA. 1995. PhRMA guideline for the production, packaging, repackaging, or hold-
ing of drug substances, part L Pharm. Tech. (December).
PhRMA. 1996. PhRMA guideline for the production, packaging, repackaging, or hold-
ing of drug substances, part II. Pharm. Tech. Uanuary).
Reisman, H. B. 1995. Eight rules to live by for successful validations. f. Validation Tech.
(August).
Ressler, R. 1999. Batch crystallization-a good solid solution to tough solids problems.
Pharm. Eng. (September).
Rivera-Martinez, E. 1994. An FDA perspective on bulk pharmaceutical chemical GMPs,
control, and validation. Pharm. Tech. (May).
Rivera-Martinez, E. 1996. Update on international inspections/latest guidance on
GMPs. Paper presented at NAPM BPC Workshop in New York (March).
Rivera-Martinez, E. 2000. FDA's international API inspections-update on ICH Q7 A.
Paper presented at the Synthetic Organic Chemical Manufacturers Association's
Annual Conference in Washington, D.C. (May).
Selby, D. 1999. Can validation improve the bottom line? Pharm. Eng. (November-
December).
Seely, R. ]., et al. 1999. Defining critical variables in well-characterized biotechnology
process. Biopharm (April).
Sharp,]. 1995. Validation-how much is required? PDA f. Pharm. Sci. & Tech. (May).
Simmons, S. ]. 1997. GIPA's bulk audit template. Pharm. Tech. (October).
Tetzlaff, R. F. 1992a. Validation issues for new drug development: Part I. Pharm. Tech.
(September).
Tetzlaff, R. F. 1992b. Validation issues for new drug development: Part II. Pharm. Tech.
(October).
Tetzlaff, R. F. 1993. Validation issues for new drug development: Part III. Pharm. Tech.
Uanuary).
Tetzlaff, R. F., R. E. Shepard, and A.]. LeBlanc. 1993. The validation story: Perspectives
on the GMP inspection approach and validation development. Pharm. Tech.
(March).
21 CFR Part 207. Registration of producers of drugs and listing of drugs in commercial
distribution.
21 CFR Parts 210 and 211. Current Good Manufacturing Practice in manufacturing, pro-
cessing, or holding of drugs: General.
21 CFR Part 314. Application for FDA approval to market a new drug or an antibiotic drug.
21 CFR Part 314.420. Drug Master Files.
2
THE LEGAL FRAMEWORK

FOR THE REGULATION OF
ACTIVE PHARMACEUTICAL
INGREDIENTS
David F. Weeda
Arthur Y. Tsien
Neil F. O'Fiaherty
Robert A. Hahn
Olsson, Frank and Weeda, P.C.
Washington, D.C.
This chapter provides a broad overview of and perspective on the legal frame-
work by which the U.S. Food and Drug Administration (FDA) regulates active
pharmaceutical ingredients (APis). While validation of APis has recently be-
come a very important FDA regulatory requirement, it is only one of many
API manufacturer obligations under the much broader statutory concept of
current Good Manufacturing Practices (cGMPs). Moreover, while cGMPs are a
very important aspect of the FDA's regulatory control over APis and their
manufacturers, they do not represent the full scope of FDA legal authority
over such products and the companies that make them. While a detailed ex-
position of all of the legal aspects of FDA regulation of APis is beyond the
scope of this brief chapter, we attempt to provide the reader with useful in~
sight into how APis fit into the statutory scheme of the Federal Food, Drug,
and Cosmetic (FD&C) Act, as amended, 21 U.S.C. § 301 et seq., and how the
FDA typically regulates APis in the normal course. We highlight many of the
11
legal requirements imposed on APis and their manufacturers, as well as the

regulatory tools that the FDA has at its disposal to enforce these requirements.
We especially emphasize those requirements and enforcement tools that bear
a relationship to API validation issues. Finally, we put forth our own views on
how API manufacturers can most efficiently work within the FDA regulatory
scheme.
THE REGULATORY STATUS OF APis
APis and BPCs

An "active ingredient" is any component that is intended to furnish pharmaco-
logical activity or any other direct effect in the diagnosis, cure, mitigation, treat-
ment, or prevention of disease. It also can be intended to affect the structure or
any function of the body of man or other animals. The term also includes any
components that may undergo chemical change in the manufacture of a drug
product and that are present in the product in a modified form intended to fur-
nish such activity or effect [21 CFR § 210.3(b)(7)]. Since the term used for active
ingredients in international circles is active pharmaceutical ingredients, the FDA has
adopted this term for its guidance documents (FDA 1998a). Active ingredients
also are known as "drug substances." At times, the FDA also refers to drug sub-
stances as "bulk drug substances" or "bulk drugs." The terms are synonymous.
The term active pharmaceutical ingredient is thus of relatively recent vin-
tage. The FDA formerly used the term bulk pharmaceutical chemical (BPC),
which emcompasses active ingredients, inactive ingredients or "excipients,"
and "intermediates" used in the synthesis of active ingredients but not ap-
pearing in the finished drug product (FDA 1994, 3). APis can therefore be un-
derstood as a subset of BPCs.
Although the FDA now uses the term API, many FDA regulatory docu-
ments refer to BPCs. Although this chapter uses the term API, most of the reg-
ulatory requirements discussed apply to all BPCs. 1
A vast array of substances can be or are used as APis. According to the
FDA, they can be of animal, botanical, synthetic, or microbiological origin,
including components produced with rDNA (recombinant deoxyribonucleic
acid) technology. They are incorporated into human and veterinary drug
products as well as biological products. The FDA takes the position that APis
can even be for use in placebos with no therapeutic effect (FDA 1994, 3).
The point at which a chemical becomes an API can be difficult to deter-
mine. The term active pharmaceutical ingredient, like the older term bulk phar-
maceutical chemical, is not specifically defined in the FD&C Act or in the FDA
implementing regulations. At times, the FDA and industry disagree over
whether a particular product or in-process substance amounts to an API. All
parties agree, however, that there is no easy answer or "bright line" test for
The Legal Framework for the Regulation of APis 13
when a processed chemical substance becomes an API. The FDA has acknowl-
edged that "[t]he question of when an industrial chemical becomes an [API]
can be complex, and there is no satisfactory answer" (FDA 1994, 2). Despite
this uncertainty, the FDA has enumerated three criteria that can be used to
identify when a chemical has become an API:
1. When there is no recognized non-drug commercial use for the

chemical;
2. When the chemical reaches the point in its isolation and purifica-
tion where the intended use of the substance is a component in a
drug product; and/or
3. When the manufacturer sells the product or offers it for sale to a
pharmaceutical firm for use in a drug product (FDA 1994, 2).
While these criteria may seem straightforward at first blush, they can
prove most difficult to apply in specific cases. Chemical manufacturers should
consider developing reasonable, "good faith" rationales as to when or if cer-
tain of their products become APis. This may be especially prudent for prod-
ucts for which the manufacturer and the FDA may disagree as to whether the
products are APis or as to when they become APis. Persuasive positions
against treating a particular product as an API (or as an API too soon) may
help to properly minimize the scope and scrutiny of FDA oversight of a chem-
ical manufacturer's operations. API firms may wish to enlist the help of legal
counsel with expertise in FDA regulatory issues in developing such positions.
APis as "Drugs"
Under the FD&C Act, the FDA has authority to regulate, among other articles,
"drugs." The FD&C Act, in relevant part, defines a "drug" as an article
• Recognized in the official United States Pharmacopeia [USP], offi-

cial Homeopathic Pharmacopeia of the United States, or official Na-
tional Formulary [NF], or any supplement to any of them;
• intended for use in the diagnosis, cure, mitigation, treatment, or
prevention of disease in man or other animals;
• intended to affect the structure or function of the body of man or
other animals (other than food); or
• intended for use as a component of any of the above articles
[21 u.s.c. § 321(g)(1)].
Obviously, falling under this definition are FDA-regulated prescription med-
ications and over-the-counter (OTC) products. The agency classifies such
items as "drug products" (i.e., products in a finished dosage form) [21 CFR
§ 210.3(b)(4)]. Consistent with the FD&C Act, the FDA considers APis to be
components of drug products (FDA 1994, 2-BPC Guide). As such, APis meet
the definition of a "drug" under the FD&C Act. They are "articles intended for
use as a component of" a drug product [21 U.S.C. § 321(g)(1)(D)].
APis as "New Drugs" or "New Animal Drugs"

Under the FD&C Act, a "new drug" for human use is defined as a drug that is
not generally recognized by qualified experts as safe and effective for its in-
tended use [21 U.S.C. § 321(p)(1)]. Except for investigational products, new
drugs cannot be shipped in interstate commerce unless they are the subject of
an approved New Drug Application (NDA) or Abbreviated New Drug Applica-
tion (ANDA) [21 U.S.C. § 3SS(a)]. In practice, most prescription human drugs
(including antibiotics) and some newer OTC human drugs are regulated by
the FDA as "new drugs."2
The regulatory scheme for "new animal drugs" (including veterinary an-
tibiotics) is similar; except for investigational products, new animal drugs are
deemed adulterated if they are not the subject of an approved New Animal
Drug Application (NADA) or Abbreviated New Animal Drug Application
(ANADA) [21 U.S.C. § 321(w), definition of new animal drug;§ 351(a)(S), "un-
safe" new animal drugs are deemed adulterated; and § 360b(a)(1)(A), unap-
proved new animal drugs are deemed "unsafe"].
The FDA's view is that if an API is intended for use as a drug substance
(i.e., the active ingredient in a finished drug product that would be regarded
by the FDA as a "new drug" or a "new animal drug"), then the API itself is re-
garded as a "new drug" or a "new animal drug."
API ADULTERATION
Among other things, the FD&C Act is intended to protect the public against
unsafe, ineffective, and/or otherwise violative drug products. There are two
main categories of violative products under the FD&C Act: "adulterated" and
"misbranded" products. Under the FD&C Act, among other things, it is illegal
to introduce, or deliver for introduction, into interstate commerce any drug
that is adulterated or misbranded [21 U.S.C. § 331(a)]. Generally, a drug is
adulterated if there is or may be a compositional defect that makes it unsafe
and/or ineffective or potentially unsafe and/or ineffective. As this book gener-
ally deals with the topic of API validation, we primarily limit our discussion of
violative product categories to circumstances in which an API, as a drug, is
rendered adulterated (e.g., through lack of cGMP compliance generally or
proper validation specifically). However, API manufacturers should be aware

that improper or insufficient labeling and other deficiencies can render their
products misbranded. (See below for a brief discussion of API misbranding.)
cGMP Noncompliance
There are several ways an API, as a drug, can become adulterated. Probably the
most common means of adulteration is through noncompliance with the
cGMPs. Under the FD&C Act, a drug is deemed to be adulterated if
[T]he methods used in, or the facilities or controls used for, its
manufacture, processing, packing, or holding do not conform
to or are not operated or administered in conformity with cur-
rent good manufacturing practices to assure that such drug
meets the requirements of this Act as to safety and has the
identity and strength, and meets the quality and purity char-
acteristics, which it purports or is represented to possess
[21 U.S.C. § 351(a)(2)(B)].
The FDA has promulgated regulations enumerating cGMPs for the com-
mercial manufacture of finished dosage form drug products at 21 CFR Parts
210 and 211. The cGMP regulations describe the FDA's expectations regarding
all aspects of pharmaceutical manufacturing. These include organization and
personnel, buildings and facilities, equipment, components (raw materials),
production and process controls, packaging and labeling controls, storage and
distribution controls, laboratory and testing controls, record keeping and re-
porting, and controls for returned and salvaged product. The cGMP regula-
tions require that product complaints be expeditiously investigated and that
appropriate corrective action be taken quickly when warranted. The cGMP
regulations also contemplate that company management will adopt and pre-
serve a corporate philosophy of quality assurance and control that extends to
all FDA-regulated activities of the firm. In short, the cGMP regulations require
pharmaceutical manufacturers to establish and maintain policies and proce-
dures that give reasonable assurances that every commercially manufactured
product batch shipped for human or animal use meets its predetermined
specifications (e.g., strength, purity, quality, stability, etc.).
Legally speaking, APis are not subject to the FDA cGMP regulations be-
cause these regulations technically apply only to finished dosage form drug
products [21 CFR § 211.1(a)]. However, because of the statutory provision
against cGMP noncompliance [21 U.S.C. § 351(a)(2)(B)], API manufacturers
still have a legal obligation to implement and follow some form of cGMPs. As
the FDA has noted, "there are many cases where GMPs for dosage form drugs
and [APis] are parallel" (FDA 1994, 3). As such, the FDA looks to many of the
requirements of 21 CFR Parts 210 and 211 as guidelines for the inspection of
API manufacturers' cGMP operations. The BPC Guide identifies and interprets
for FDA investigators those portions of Parts 210 and 211 that should be used
as a "regulatory yardstick" in measuring the acceptability of an API manufac-
turer's cGMP operations:
This document [BPC Guide] does not supersede the GMP regu-
lations, rather it provides general guidance to inspectional
personnel as to the extent and point of application of some of
the concepts of Parts 210 and 211 to [API] production (FDA
1994, 3).3
There are also guidelines being developed by trade associations repre-

senting API manufacturing interests that attempt to articulate cGMPs for
APis. If industry guides are used as a framework for implementing cGMPs, we
recommend that they be compared with the FDA's expectations for cGMP
compliance as found in the BPC Guide to avoid any potential regulatory prob-
lems. In this regard, it may be prudent to enter into a dialogue with the FDA
on any proposed industry voluntary standards to obtain its input and concur-
rence prior to final implementation.
The FDA has invested time and manpower toward drafting proposed reg-
ulations that would enumerate cGMPs for APis. In 1994 and the first half of
1995, FDA representatives speaking at industry conferences and seminars an-
nounced their impending arrival. The industry was hopeful, on one hand,
that such regulations would clarify the long-standing, nebulous cGMP obliga-
tions of API manufacturers, but also feared burdensome overregulation. In the
middle part of 1995, the issuance of proposed regulations appeared immi-
nent. There were reports that the proposal potentially was bound for finaliza-
tion through a negotiated rule-making process between the FDA and industry
representatives. However, a proposal was never issued, and the FDA has stayed
the initiative. Although the FDA remains interested in issuing proposed cGMP
regulations for APis, the Republican-dominated Congress and the Clinton ad-
ministration's "Reinventing Government" initiatives have created a political
climate in which more administrative regulation is viewed critically. However,
as history has shown, the political climate in Washington changes as Con-
gresses and presidential administrations come and go. In the proper political
climate, the proposal for cGMP regulations for APis could resurface.
Validation as Part of cGMPs

Obviously, process validation is an important component of cGMPs. Accord-
ing to the FDA, "process validation" means establishing documented evidence
that provides a high degree of assurance that a specific process will consis-
tently produce a product meeting its predetermined specifications and quality
attributes (FDA 1987, 2). In recent years, the FDA has increasingly emphasized
the need for such validation in the context of API manufacturing operations.
In June 1992 the FDA summarized its general views on API process validation
in its Compliance Program No. 7346.832 (Preapproval Inspections):
Process validation requirements for the manufacture of [APis]

differ somewhat from those involving dosage forms. The
Guide to Inspection of BPCs issued in 1991 states that [API]
manufacturers are expected to adequately determine and doc-
ument that significant manufacturing processes perform con-
sistently. The type of [API], the range of specifications and
other factors determine the extent of the process development
and documentation required. The documentation system re-
quired for early process steps must provide a chain of docu-
mentation, and while it need not be as comprehensive as in
the latter parts of the process, the manufacturer is required to
identify and control the key steps in the process.
This language clearly demonstrates the FDA's position that process valida-
tion becomes increasingly important as the API manufacturing process pro-
gresses. It also shows the FDA's realization that the stringency and type of
process validation appropriate to fulfill cGMP obligations is a function of many
factors, including the complexity and intended use of the API in question.
The FDA also appears to realize that process validation is a fairly new con-
cept and a rather significant undertaking for many API manufacturers. There-
fore, it has tailored its expectations and related regulatory actions accordingly:
Many [API] manufacturers have recently initiated validation

programs and we recognize that not all [APis] can be validated
simultaneously. Therefore, we do not anticipate taking legal
action where a firm has an adequate program in place, includ-
ing reasonable milestones. Regulatory action should be rec-
ommended where there is a lack of validation and evidence of
a significant number of failed batches (Compliance Program
No. 7346.832).
Yet, the FDA will not hesitate to withhold drug product marketing application
approval for those referencing an API where its manufacturer has an inade-
quate validation plan or repeated failures. The FDA enunciated this policy as
follows:
Based on recent emphasis by FDA, the industry has begun to

formally validate the manufacturing processes for [APis]. The
[FDA] district [office] should recommend withholding ap-
proval of an application [for a drug product] based upon lack
of process validation for the API where:
A. The [API] firm has not established or is not following an

adequate plan to validate all [APis]; or
B. The process is not valid, as demonstrated by repeated

batch failures due to manufacturing process variability
not attributable to equipment malfunction or operator
error (Compliance Policy Guides [CPG] § 490.100).
These FDA statements unmistakably manifest the high priority the FDA
places on API process validation and the FDA's increasing expectation that
API manufacturers fully meet the FDA's validation policies or face adverse ac-
tion for themselves and their finished drug product customers. The FDA's ex-
pectation can already be seen in the string of Warning Letters that have been
issued to API manufacturers over process validation deficiencies since 1992.
(See "Warning Letter," pp. 32-33, and Note 10 for more details.) However,
these statements also manifest the FDA's intent to give the API industry time
to digest and implement its expectations regarding process validation.
Process validation does not end with the FDA's approval of a new drug or
new animal drug. Postapproval manufacturing changes must be validated to
the extent that their effect on the identity, strength, quality, purity, and po-
tency of the drug may affect the drug's safety and effectiveness. Depending on
the nature of the change, the dosage form manufacturer may be required to
obtain FDA prior approval before implementing the change. If a change is
deemed by the FDA to be a "major manufacturing change" (i.e., a change de-
termined by the FDA to have "substantial potential" to adversely affect the
identity, strength, quality, purity, or potency of the drug as these relate to the
drug's safety or effectiveness), the holder of the approved application must
submit, and the FDA must approve, a supplemental application for the
change. For nonmajor changes, the FDA may require a supplemental applica-
tion or merely a report, but the change may be implemented without prior
approval. The supplemental application or report must include information
on the validation of the change and such other information as the FDA may
require [21 U.S.C. § 356a].
In addition, the FDA has issued a draft guidance document recommend-
ing that certain postapproval changes in APis relevant to the performance of
the finished dosage form should be documented, reported to the FDA, and
subjected to chemical, manufacturing, and control tests. 4
Finally, it is worth noting that validation, as a cGMP concept, should not
stop with and be applied only to API production processes. Consistent with
FDA expectations, it also should be applied in other cGMP areas, such as
equipment cleaning and analytical methods. In the BPC Guide, the FDA
opines that cleaning of multiuse equipment is an area where validation must
be carried out. The FDA recommends that the API manufacturer determine
the degree of effectiveness of its cleaning procedure for each API or interme-
diate used on a particular piece of equipment (FDA 1994, 9). According to the
FDA, validation data should verify that the cleaning process will remove
residues to an acceptable level:
The residue limits established for each piece of apparatus
should be practical, achievable, and verifiable. When review-
ing these limits, ascertain the rationale for establishment of
that level. The manufacturer should be able to document, by
means of data, that the residual level permitted is scientifi-
cally sound (FDA 1994, 10).
Additionally, in discussing laboratory controls to be employed by API manu-
facturers, the FDA comments that "analytical methods should be validated."
The FDA considers this necessary with respect to analytical methods used to
determine an API's conformance to specifications as well as for analytical
methods used to determine levels of remaining residues on equipment (FDA
1994, 23).
Other Forms of Adulteration

Besides through cGMP noncompliance, there are several other ways and cir-
cumstances by which an API, as a drug, can become adulterated. An API is
adulterated by law if it consists in whole or in part of any filthy, putrid, or de-
composed substance [21 U.S.C. § 351(a)(1)]. For instance, dirt, insect parts, or
rodent droppings inadvertently commingled with an API batch would most
likely adulterate it. If an API has been prepared, packed, or held under unsan-
itary conditions whereby it may have been contaminated with filth, or
whereby it may have been rendered injurious to health, it is also adulterated
under the FD&C Act [21 U.S.C. § 351(a)(2)(A)]. For example, the FDA could
deem all API lots from a plant to be adulterated based on inspecting the plant
and finding it unsanitary, even if individual API lots have not been sampled
and tested for actual adulteration. Moreover, the FDA could even consider
them adulterated if testing indicates the lots' conformance to specifications.
An API container composed in whole or in part of a poisonous or delete-
rious substance that may cause its contents to become injurious to health also
renders the API therein adulterated by law [21 U.S.C. § 351(a)(3)]. For instance,
a container substance posing a health risk, which could migrate from the con-
tainer into the API, causes the product's adulteration. Moreover, if an API con-
tains a color additive that has not been approved by the FDA, it is considered
adulterated [21 U.S.C. § 351(a)(4)). More generally, an API is adulterated if it
has been mixed or packed with a substance that reduces its quality or strength
[21 U.S.C. § 351(d)(1)). This is often referred to as "economic adulteration."
The USP/NF contains official monographs for pharmaceutical ingredi-
ents and products that, among other things, set forth standards for the
strength, quality, and purity of such items. The Homeopathic Pharmacopeia
of the United States sets forth similar standards. If an API purports to be or is

represented as a drug, the name of which is recognized in one of these official
compendia, and its strength differs from, or its quality or purity falls below,
the standards set forth in such compendium, the API is adulterated. s How-
ever, no drug defined in an official compendium is deemed to be adulterated
because it differs from the standard of strength, quality, or purity established
by the compendium if its differences are plainly stated on its label [21 U.S.C.
§ 351(b)]. This provision manifests Congress' intent and the FDA's view that
compliance with an applicable compendium standard should be the rule and
not the exception. Moreover, in practice many APis are without mer-
chantability if they do not meet an applicable compendium standard.
An API is adulterated if its strength differs from, or its purity or quality
falls below, that which it purports or is represented to possess [21 U.S.C.
§ 351(c)]. For example, if an API's labeling represents the product as having a
higher level of purity or quality than it actually has, the API would be adul-
terated under this provision.
API MISBRANDING
A drug, including an API, is generally misbranded if there is something wrong
with its label or labeling that will or could lead to unsafe or ineffective use. For
instance, an API is misbranded if its label or labeling is false or misleading in
any particular (e.g., an untrue representation as to its quality, strength, or pu-
rity) [21 U.S.C. § 352(a)]. In addition, an API is misbranded if its labeling does
not bear adequate directions for use [21 U.S.C. § 352(£)(1)]. Generally, an API
is exempt from bearing adequate directions for use (and thus is not mis-
branded on this basis) if its label bears the statement Caution: For manufactur-
ing, processing, or repacking [21 CFR § 201.122]. However, generally speaking,
this exemption does not apply if the substance is intended for use in manu-
facturing, processing, or repacking operations that cause the finished article to
be a "new drug" or a "new animal drug" unless there is an approved or pend-
ing premarket approval application in effect [21 CFR § 201.122(a)]. An API
also can be exempt from bearing adequate directions for use if it is approved
for investigational use and its label bears the following statement: Caution: For
manufacturing, processing, or repacking in the preparation of a new drug or new an-
imal drug limited by federal law to investigational use [21 CFR § 201.122(b)].
An API also can be misbranded due to circumstances not directly linked
to its label or labeling. An API that purports to be a drug, the name of which
is recognized in an official compendium, is misbranded unless it is packaged
and labeled as prescribed therein (unless the FDA has consented to some
modification) [21 U.S.C. § 352(g)]. In addition, if an API is a bulk drug sub-
stance and its manufacturer is not registered as a manufacturer and/or has not
listed the product with the FDA, the API is considered misbranded [21 U.S.C.
§ 352(o)].
API INSPECTIONS
History of API Inspections

Historically, the FDA's purpose in inspecting API manufacturers has been to
evaluate the compliance status of the API industry as a whole and to assess
the status of processes and controls used to manufacture APis. Traditionally,
the enforcement of cGMPs relative to APis was rare or nonexistent. Prior to
1991, the FDA issued no Regulatory Letters (one predecessor to Warning Let-
ters) on cGMPs to API manufacturers. As Edmund M. Fry, former director, Di-
vision of Drug Quality Compliance, National Center for Drugs and Biologics,
commented in a speech at a 1983 conference:
We are comfortable ... that there is not a general problem

with the bulk pharmaceutical chemical industry, and there-
fore this industry is not a high priority target for increased reg-
ulatory attention, additional regulations, or guidelines ....
The bulk pharmaceutical industry is, in fact, policed very
effectively by its own customers. FDA is not privy to the
wealth of quality assurance information, but it undoubtedly
contributes to a continual awareness of the need to maintain
high quality standards ....
I would also caution you and the industry not to over-
look your responsibility to maintain awareness of the state of
the art in your field. The cGMP regulations, as you are well
aware, are profusely sprinkled with the words adequate and ap-
propriate and the concept of what was appropriate five years
ago may be woefully behind the times this year.
Starting in the late 1980s (and primarily resulting from the generic drug
scandal that forced the FDA to rethink its regulatory philosophy related to the
approval of new brand name and generic drugs), the FDA tightened its con-
trols applicable to the manufacture of all drugs, including APis. At approxi-
mately the same time, the FDA was recording less than satisfactory
inspectional results in overseas cGMP audits of API manufacturers exporting
products to the United States. During 1989, the FDA found cGMP deviations,
resulting in adverse inspectional observations, in about 60 percent of all for-
eign bulk firms inspected. One in five (20 percent) of those inspected were
judged by the FDA to have violations of such a magnitude as to make them
unacceptable as suppliers to the U.S. pharmaceutical market.
The FDA's concerns were also heightened by FDA reviewer findings of re-
current problems with drug product applications in the raw materials area. In
a study completed in 1990, the FDA found inadequate information on raw
materials to be the most common problem cited in "not-approvable" letters
issued to ANDA sponsors. The intensive application auditing conducted
by FDA field offices as part of the generic industry investigations and the
then-new preapproval inspection program also increased the FDA's concern

with API suppliers. As a result of all of these factors, stricter control over API
manufacturing operations became one of the new components in the FDA's
drive to assure that representations and commitments regarding API chem-
istry, manufacturing, and related controls, as contained in drug marketing ap-
plications, were met.
Because of this new increased focus on API cGMP controls, FDA investi-
gators are inspecting for and discovering problems with API manufacturing
operations (e.g., poor or no process validation, lax record keeping on pro-
cesses and laboratory testing, and insufficient oversight of production/
manufacturing changes). Customers, meanwhile, are keeping step with the
FDA by strengthening their own bulk supplier auditing programs.
Reasonable Inspections Under Section 374(a)

The principal means by which the FDA monitors the safety, quality, and pu-
rity of APis and other FDA-regulated drugs and articles is through establish-
ment inspections. The FDA is authorized by 21 U.S.C. § 374(a) to conduct a
regulatory inspection at reasonable times and in a reasonable manner of any
factory, warehouse, or establishment in which drugs (including APis) are
manufactured, processed, packed, or held for introduction into interstate
commerce or after such introduction. The FDA is also authorized to enter con-
sulting laboratories where drugs are manufactured, processed, packed, or
held. Entering any vehicle used to transport such drugs in interstate com-
merce is also authorized [21 U.S.C. § 374(a)].
It is a prohibited act to refuse to permit rightful entry or inspection by
the FDA or to refuse to permit FDA access to or the copying of records re-
quired to be kept under the FD&C Act [21 U.S.C. §§ 331(e) and (f)]. While
very rare, such a refusal could lead to criminal prosecution of a domestic
drug company and its officials [21 U.S.C. § 333] or influence the FDA to seek
an injunction against the domestic firm to permit inspection [21 U.S.C.
§ 332]. (See "Injunction and Criminal Prosecution," pp. 35-37, for a more
detailed discussion of 21 U.S.C. §§ 332 and 333.) In practice, the FDA more
likely would seek to obtain an administrative inspection warrant against the
domestic firm. (See "Inspection and Search Warrants," pp. 30-31 for more in-
formation on such a warrant.) However, the FDA seeks very few of these war-
rants. Alternatively, on refusal to allow FDA inspection or access to required
records, the FDA could refuse to approve any drug product applications
where the applicant's drug substance supplier was the refusing firm. If a for-
eign establishment refused inspection or access to records, the FDA's likely
response would be to bar entry of the establishment's drugs into the United
States (see "FDA Import/Export Authority over APis: Import Authority of the
FDA," pp. 37-39). In addition, the FDA again could refuse approval of drug
product applications where the foreign drug substance supplier has refused
inspection or prohibited FDA access to required records.
For drugs generally, the FDA's inspection authority extends to a com-

pany's factories; warehouses; establishments; vehicles; and all pertinent
equipment, finished and unfinished materials, containers, and labeling in the
company's establishment [21 U.S.C. § 374(a)]. For all human drugs and all
prescription animal drugs, the FDA's inspectional authority also extends to all
things within the factory, warehouse, or establishment, including records,
files, papers, processes, controls, and facilities, that bear on whether a drug is
adulterated, misbranded, or otherwise in violation of the FD&C Act [21 U.S.C.
§ 374(a)].6
There are only a small number of records excluded from this very broad
inspectional power for human drugs and prescription animal drugs (but not
OTC animal drugs). The FDA's inspection authority does not extend to finan-
cial data, sales data (other than shipment data), pricing data, personnel data
(other than data as to qualifications of technical and professional personnel
performing functions subject to the FD&C Act), and research data (other than
research data related to new drugs and new animal drugs subject to reporting
and inspection requirements by regulation) [21 U.S.C. § 374(a)]. For instance,
in the context of a drug product, while the FDA would not have authority to
review research and development (R&D) records for the drug product gener-
ally, it is authorized by regulation to inspect and copy Investigational New
Drug (IND) and Investigational New Animal Drug (INAD) study records of a
drug product undergoing clinical investigation. (See 21 CFR §§ 312.58 [in-
spection of IND sponsor's records and reports], 312.68 [inspection of IND in-
vestigator's records] and 511.1 [INADs]).
Scope of FDA lnspectional Authority over APis

By statute, a registered drug manufacturer (including an API firm) is required
to be inspected routinely every two years [21 U.S.C. § 360(h)]. In practice, the
time between statutory inspections can be more than two years due to the
FDA's limited resources and public health priorities. Drug firms also can be in-
spected in special circumstances (e.g., to verify drug product application rep-
resentations as part of the drug product approval system, following receipt of
complaints about possibly violative product or a significant number of ad-
verse reaction reports, follow-up inspections, etc.).
Most prescription drug products and some OTC drug products are "new
drugs" or "new animal drugs" that require FDA preapproval for marketing,
and the FDA will conduct preapproval inspections of API suppliers as part of
the review process:
As soon as the district becomes aware of any significant ad-

verse [API] inspectional, analytical, or other information
which could or should affect the agency's new product deci-
sions with respect to a firm, the district should immediately
notify HFC-120, Medical Products Quality Assurance Staff, via
EMS or fax, and they will, in turn, convey the information by

fax or equivalent expeditious means to the appropriate center
regulatory units (Compliance Program No. 7356.002F).
Although not specifically required by statute, the FDA typically conducts
a preapproval inspection of every drug manufacturer (including the API man-
ufacturer) before approving a marketing application. From our experience, it
is often the case that the FDA will withhold drug marketing application ap-
proval where significant API inspectional deficiencies are found.
In response to the generic drug scandal of the late 1980s, the FDA has ex-
panded and strengthened its preapproval inspection program. First, the FDA
has expanded the list of criteria that will trigger a preapproval inspection to
include the following: the date of the applicant's last biennial inspection, the
applicant's cGMP compliance history, results of recent inspections covering
the same class of drug product, recalls by the applicant, regulatory actions
against the applicant, and complaints against the firm. The FDA may also
conduct a preapproval inspection for drug products that have a narrow thera-
peutic range, are difficult to manufacture, are among the top 200 most pre-
scribed drugs, are New Chemical Entities (NCEs), or represent the first
prescription drug product or a new dosage form product from the particular
applicant. This list is not intended to be inclusive (see Compliance Program
No. 7346.832; FR 1991; FR 1993).
Second, the FDA has required that applicants filing NDAs, ANDAs,
amendments, and supplements that provide for a change other than a change
in labeling must submit an additional "field copy" of their application,
amendment, or supplement to enable FDA investigators to check application
statements against actual manufacturing practices. This is intended to facili-
tate the detection of fraudulent practices by an applicant during the preap-
proval inspection. The field copy must include a certified copy of the
chemistry, manufacturing, and controls section (chemistry section) of the ap-
plication, each amendment thereto, and each chemistry supplement. It must
be filed with the applicant's home FDA district office. Third, the FDA has de-
cided that preapproval inspections should include an audit of the manufac-
turing and controls records relating to the batches used to conduct
bioavailability, bioequivalence, and stability studies, and the FDA has re-
quired the chemistry section of an NDA or ANDA to include certain informa-
tion about such batches (FR 1993).
As previously noted, based on the language of§ 374 and the definition of
a "drug," the FDA has broad inspectional authority over an API firm's drug com-
ponent operations and records. The BPC Guide assumes FDA investigators have
the ability to inspect several categories of API records, including the following:
• Manufacturing process flow diagrams
• Batch production records
• Testing records
• Product failure/rejection, investigation, and complaint records

• Product purity data
For preapproval drug products, the FDA may inspect and copy R&D docu-
ments that support process validation; these documents often are known in
the trade as technology transfer documents or development reports. As is evi-
denced by the BPC Guide, the FDA appears fairly intent on conducting, as it
deems appropriate, a review of certain product records as part of an API facil-
ity inspection.
API firms must remember that FDA investigators may ask to review
records that they have no legal authority to inspect, such as R&D records not
related to an IND or INAD. However, legal authority or not, once a firm con-
sents to disclosure of records, the investigator's review and inspection of them
is legitimate under the law. API firms need to know the scope of the FDA's in-
spectional authority over product records so they can make informed deci-
sions about disclosure on an FDA investigator's request. When in doubt, a
firm may wish to contact legal counsel with FDA regulatory expertise to dis-
cuss the risks and benefits of disclosing any record.
Inspection Priorities: Active Drug Substances Versus Excipients

As would be expected, the FDA's main focus in terms of BPC inspections is the
active drug substance, the API. Compliance Program No. 7356.002F specifi-
cally states:
This program circular applies only to those BPCs which are in-
tended for use as active components of drug products, and the
manufacture of which requires registration under§ 510 of the
Act [21 U.S.C. § 360].
As a general rule, the FDA does not regularly inspect the operations of estab-
lishments that produce BPCs for use as excipients in finished drug products. 7
According to the FDA, inspections of inactive ingredient operations are gener-
ally discretionary. However, such firms can always be inspected "for cause"
(FDA 1994, 3).
An API company's regulatory history and circumstances can greatly af-
fect the level of scrutiny with which the FDA will approach an establishment
inspection. Depending on the perceived status of a particular bulk active
drug substance, the FDA may choose to conduct an abbreviated or full in-
spection of the manufacturer's operations. As an initial matter, the first in-
spection of any API firm is deemed to require a full inspection under FDA
policy (Compliance Policy No. 7356.002F). A full inspection consists of a
complete inspection of all systems and processes of the firm, including the
following:
• Buildings and equipment

• Personnel training, qualifications, and experience
• Component controls
• Manufacturing controls
• Laboratory controls
• Packaging and labeling controls
• Recordkeeping practices
In contrast, an abbreviated inspection consists of
• a brief inspection of the physical facility;

• a review of master and batch records for a representative number of
the firm's products (including products that have a history of previ-
ous problems);
• a spot check of a limited number of analytical tests to assure
batches are being subjected to adequate testing for conformance to
specifications; and
• a review of packaging and labeling controls.
According to the FDA, an abbreviated inspection is not appropriate for a

firm that "has a past history of fluctuating into and out of compliance" (Com-
pliance Policy No. 73S6.002F). Moreover, the following circumstances war-
rant subjecting an API firm to full inspection:
• New potentials for cross-contamination arising from changes in the

firm's manufacturing process
• Use of significantly new equipment or facilities requiring new
expertise
• A pattern of product complaints
• Records of internal rejection or reworking of batches, indicating
possible weaknesses in the firm's processes, systems, or controls
• Observed inadequate packaging or labeling controls
Foreign Versus Domestic Plant Inspection

The 1990s brought a heavy emphasis on FDA inspection of foreign API firms.
This emphasis resulted from an alleged disparity over the years between the
FDA's treatment of U.S. and foreign API firms. Domestic industry alleged that
it was held to higher standards and more inspections. As a result, the FDA
initiated a concerted effort to conduct more intense but fair inspections of

foreign API facilities. Many of these inspections have resulted in FDA Warning
Letters being issued to these firms. (See below for a fuller discussion of Warn-
ing Letters.) The FDA recognizes that many of the drug substances used by
U.S. finished drug manufacturers are sourced from overseas. Under the FDA
Modernization Act (FDAMA), drug (including API) manufacturing establish-
ments located in foreign countries are now required to register with the FDA
and to provide the FDA with the name of their U.S. agent [21 U.S.C. § 360(i)].
The FDA has published a proposed rule implementing the registration re-
quirement for foreign drug manufacturing establishments (FR 1999b). Be-
cause of the perceived or realized problems with foreign API firms, the FDA
has intensified its inspectional approach toward them. Given the FDA's broad
authority to bar import entry of regulated products (discussed in more detail
below), foreign API firms should acknowledge this increased FDA scrutiny
and be prepared for it.
Despite the increase in foreign inspections, the FDA has been unable to
inspect foreign firms at a rate it considers satisfactory, and the FDA recognizes
that it cannot increase foreign inspections at a pace that would keep up with
the rapidly growing number of imported products. This reality has spawned
an interest within the FDA in achieving mutual recognition of some foreign
pharmaceutical inspection systems, so that the FDA might rely on foreign reg-
ulatory authorities, at least in certain countries, to ensure that drug products
manufactured abroad meet acceptable quality standards. As early as 1968, in
fact, the FDA signed a Mutual Recognition Agreement (MRA) with Switzer-
land, under which the United States would recognize Swiss inspections of
bulk drug facilities as equivalent to FDA inspections. In the years following
the Swiss MRA, the FDA also reached an agreement with Sweden providing
for mutual recognition of drug facility inspections, and an agreement with
Canada under which the two countries exchange drug facility inspection in-
formation. In 2000, the FDA signed a Cooperative Agreement with Australia
that provides for exchange of inspection and other information regarding hu-
man pharmaceutical facilities. The FDA continues to state publicly that it be-
lieves that "developing more effective international agreements with foreign
regulatory counterparts would help to maximize FDA's limited inspection and
surveillance resources" (House Committee, Oversight Hearing). As the FDA
has explained,
[a]ppropriate foreign regulatory peers can share the responsi-

bility for assuring the safety of products offered for entry to
the U.S. from companies under their jurisdiction. Greater con-
fidence in the validity of product certifications and inspection
reports produced by foreign inspectors can assist FDA with its
public health protection responsibilities and optimize FDA's
constantly dwindling resources (House Committee, Oversight
Hearing).
Other than these four agreements, however, little progress has been made in
harmonizing regulatory requirements with other countries or reaching agree-
ments for mutual recognition of product approvals or cGMP inspections.
The FDA has taken the position that it cannot rely on a given foreign
regulatory authority unless and until it is satisfied that the regulatory scheme
in that particular country is equivalent to the regulatory scheme enforced by
the FDA. These concerns were reinforced by a 1995 report by FDA's Foreign
Inspection Working Group, which found that a higher percentage of signifi-
cant cGMP problems had been observed at foreign facilities in comparison
with domestic facilities.
Because of these concerns, the FDA's policy statements on harmoniza-
tion endorse the concept of mutual recognition in theory but stress that such
recognition can come only when it is assured that regulatory systems abroad
are equivalent to its own system. As the Foreign Inspection Working Group
explained, "FDA's most important criterion for such agreements must be de-
termining the equivalence of foreign regulatory programs to FDA's programs"
(FDA 1998c). Consistent with this philosophy, the FDA's 1995 Compliance
Policy Guide on International Memoranda of Understanding (MOU), which
sets forth the FDA's overall policy for developing, initiating, and monitoring
MOUs with agencies of foreign governments or international organizations,
stated that before accepting the procedures and activities, including enforce-
ment methods, of foreign governments as equivalent to its own, the FDA will
seek assurance that such activities provide the same level of product quality,
safety, and effectiveness that is provided under the FD&C Act, the Fair Pack-
aging and Labeling Act, the Public Health Service Act, and any other relevant
law of the United States. The FDA may find it necessary to confirm by on-site
review or other appropriate means that the foreign government agency has
the necessary authorities, product standards, capabilities, and infrastructure
to successfully achieve the proposed terms of the MOU and, therefore, that a
determination of equivalence can be made.
The FDAMA included specific provisions directing the FDA to proceed
with efforts to achieve harmonization with Europe. The FD&C Act, as
amended by FDAMA, now requires the FDA to "support the Office of the
United States Trade Representative, in consultation with the Secretary of
Commerce, in efforts to move toward the acceptance of mutual recognition
agreements relating to the regulation of drugs, biological products, devices,
foods, food additives, and color additives, and the regulation of good manu-
facturing practices, between the European Union and the United States"
[21 U.S.C. § 383(c)(2)]. The FDAMA also required the FDA to "participate
through appropriate processes with representatives of other countries to re-
duce the burden of regulation, harmonize regulatory requirements, and
achieve appropriate reciprocal arrangements" and to "make public a plan that
establishes a framework for achieving mutual recognition of good manufac-
turing practices inspections" no later than 180 days after the date of the law's
enactment [21 U.S.C. §§ 383(c)(4), 903(b)(3)].
The U.S. Trade Representative and the Department of Commerce have

been negotiating with the European Community (EC) since the late 1980s to
conclude an MRA that would allow products approved under European regu-
lations to be accepted in the United States without further regulatory review,
and vice versa. In 1997, an MRA was achieved that includes a general um-
brella agreement and a number of product category-specific annexes. At the
conclusion of negotiations, the FDA published a proposed rule on the MRA in
the Federal Register soliciting comments (FR 1998a), and a final rule in No-
vember 1998 (FR 1998d). The MRA was signed in London on 18 May 1998
(FR 1998d).
One of the annexes to the MRA covers post- and preapproval cGMP in-
spections for human drugs, animal drugs, and certain biological products.
The annex describes procedures under which the participating parties and
regulatory authorities will exchange information and describes how the
equivalent authorities will regard information that they receive from one an-
other. Under the annex, a three-year transition period began immediately af-
ter the MRA entered into force. During the transitional period, the FDA will
participate in equivalence assessment activities with its counterpart pharma-
ceutical regulatory authorities in the EC Member States; 8 these activities will
include information exchange, joint training, and joint inspections. These ac-
tivities are intended to enable the FDA to evaluate the equivalence of its coun-
terpart regulatory authorities and to enable those authorities to assess the
equivalence of the FDA. The FDA and EC Member State regulatory authorities
will assess equivalence according to certain criteria specified in the annex.
During this transitional period, the authorities will develop an alert system
and will develop means of exchanging information on confirmed product re-
ports, corrective actions, recalls, rejected import consignments, and other reg-
ulatory and enforcement problems for products subject to the annex.
At the end of the three-year transition period, the FDA will assess the in-
formation that it has obtained. The EC regulatory authorities that carried out
equivalence assessment activities will, likewise, assess the information they
have obtained. Representatives from the FDA and the EC will then meet in a
Joint Sectoral Committee to discuss which regulatory authorities will be deter-
mined to be equivalent. The FDA will make available for public review the com-
plete record on which each equivalence assessment and determination is based.
During the operational period, preapproval and postapproval cGMP in-
spection reports for products covered by the annex will be transmitted to the
regulatory authority requesting the report. Once an authority receives an in-
spection report from an equivalent authority (pre- or postapproval reports),
the receiving authority will "normally endorse" the report. Normal endorse-
ment will occur "except under specific and delineated circumstances" and
will be "based on the detemination of equivalence in light of the experience
gained." This language allows the FDA to make final determinations as to
compliance with U.S. cGMP requirements. The FDA expects to be able to ac-
cept most findings in inspection reports received from authorities listed as
equivalent. The annex provides, however, that "under specific and delineated
circumstances" including "serious concern in relation to product quality or
consumer safety," the regulatory authority of the importing party may seek
more information regarding an inspection report and, if not satisfied, carry
out its own inspection.
APis would be covered by the annex on pharmaceutical cGMPs to the
extent that they are regulated by the authorities of both the United States and
the country in which the facility is located. Where the manufacture of APis is
not regulated by the country in which an API manufacturer is located, the
FDA will continue to require that the FDA itself inspect and pass the facility,
as a precondition for permitting importation of either the APis or a finished
product made from those APis.
Other than the individual agreements with Sweden, Switzerland, Can-
ada, and Australia, and the new MRA with the EC, there are no other signifi-
cant efforts underway to harmonize inspection systems for drugs, including
APis. APis manufactured domestically for use in other countries will likely
have to conform to the requirements of the country of destination, unless
that country unilaterally recognizes the U.S. regulatory scheme. Manufactur-
ers of APis in such countries who wish to import their products into the
United States (or sell their products to finished dosage form manufacturers for
importation into the United States) will have to comply with U.S. cGMPs and
will have to permit FDA inspection.
Other Inspection Issues

Common Carrier Authority
If a firm has its own trucking or shipping facilities, additional FDA inspec-
tional authority is relevant. The FDA has authority to access or copy interstate
shipping records of common carriers or other persons receiving or holding
drugs during or after shipment in interstate commerce. Upon special written
request by the FDA, such carriers or persons must allow FDA investigators ac-
cess to and copying of all records showing such interstate shipment, receipt,
or holding as well as the quantity, shipper, and consignee involved. It is un-
lawful to refuse FDA investigators access to and copying of such records when
the FDA's request is accompanied by a written statement specifying the nature
or kind of drug (including an API) to which the request relates [21 U.S.C.
§ 373]. In practice, the FDA rarely, if ever, uses this authority. One reason is
because a firm that provides records under 21 U.S.C. § 373 basically obtains
immunity from prosecution. If the FDA obtains records pursuant to a written
request under 21 U.S.C. § 373, the records cannot be used against that firm in
any subsequent criminal prosecution.
Inspection and Search Warrants

The FDA may conduct routine regulatory inspections under 21 U.S.C. § 374(a)
without an administrative inspection warrant. However, the FDA utilizes such
a warrant under certain circumstances. Practical considerations may lead the
FDA to seek a court-issued administrative inspection warrant (e.g., after a
refusal by a firm to be inspected or in anticipation of such a refusal) in order
to carry out an inspection in a timely and effective fashion. Although the
FD&C Act makes no explicit provision for administrative inspection warrants,
courts have concluded that the FDA can apply for, and obtain, such warrants
(e.g., United States v famieson-McKames Pharmaceuticals, Inc. [651 F2d 532, 540
(8th Cir 1981)]. When the FDA conducts an inspection pursuant to an ad-
ministrative inspection warrant, its inspectional authority is the same as (and
not broader than) its inspectional authority under 21 U.S.C. § 374(a) {In re
Medtronic, Inc. [500 F Supp 536, 540-41 (D Minn 1980)]}.
Besides such civil warrants, any federal enforcement officer, including an
FDA criminal investigator, can seek a criminal search warrant. A U.S. magis-
trate typically issues a criminal search warrant when the FDA shows "probable
cause" to believe that a facility holds evidence of a crime (Fed. R. Crim. P. 41).
Such a showing is usually supported by an affidavit of an FDA investigator or
another appropriate officer. A criminal search warrant authorizes the seeking
and seizure of any evidence specified in it, including records that would not
be available to the FDA under 21 U.S.C. § 374(a). However, a company can
still assert its right to withhold privileged records (e.g., written attorney-client
communications).
Grand Jury Subpoenas

A criminal search warrant is not the only means by which the federal govern-
ment can obtain records beyond its ability under 21 U.S.C. § 374(a). As part of
an ongoing criminal investigation, a grand jury subpoena may be issued, de-
manding a company or other person to whom it is directed to produce the
books, papers, documents, or other objects designated in the subpoena [Fed.
R. Crim. P. 17(c)]. A grand jury subpoena can seek records that would not be
available to the FDA for inspection under the FD&C Act. The presiding court,
on motion made promptly, may quash or modify a grand jury subpoena if it
finds that it would be unreasonable or oppressive to expect the company or
person in question to comply with it [Fed. R. CrimP. 17(c)]. For instance, as
with a criminal search warrant, a grand jury subpoena cannot violate a valid
privilege, whether established by the Constitution, statutes, or the common
law (e.g., attorney-client privilege) {United States v Calandra, 414 US 338, 347
(1974)]; see also In re Grand fury Subpoenas (803 F2d 493 (9th Cir 1986)]}. In
other words, a company that has been issued a grand jury subpoena can move
to quash production of documents over which it can assert a valid privilege of
nondisclosure.
There is precedent for grand jury subpoenas being issued concerning

possible FD&C Act violations by foreign firms doing business in the United
States. The procedures for serving an enforceable U.S. subpoena on a foreign
national firm are complex and based upon bilateral treaty commitments, the
extent of the foreign firm's holdings in the United States, and the nature of
the potential charges. Obviously, the enforceability of U.S. subpoenas abroad
is handled on a case-by-case basis, and further exposition of this issue is be-
yond the scope of this chapter.
ENFORCEMENT TOOLS AGAINST APis
Administrative Tools
Form FDA 483
At the end of an establishment inspection, if the FDA investigator has ob-
served what he or she regards as significant violations, the investigator will
generally issue to the inspected firm a list of inspectional observations,
known as a "Form FDA 483." 9 While not required, it is considered extremely
prudent to respond to a Form FDA 483 in writing. The response should ad-
dress any factual inaccuracies in the observations and explain what the firm
intends to do to address each legitimate observation, including a description
of any relevant corrective action plan. Inspected companies receiving a Form
FDA 483 should respond to the FDA promptly. While there is no required
time frame for a response, we suggest attempting to respond within 10 work-
ing days (or 2 weeks) of receiving the inspectional observations. If more time
is needed to respond adequately, we suggest contacting the relevant FDA of-
fice or district to acknowledge that the firm takes the Form FDA 483 seriously
and is working on a response to fully address FDA observations, giving an es-
timate as to when a response will be submitted. There have been several in-
stances in which a firm has not responded to a Form FDA 483 within 30 to
45 days and the firm's response has crossed in the mail with an FDA Warning
Letter, as discussed below.
Warning Letter
Oftentimes, if a firm neglects to or is late in responding to a Form FDA 483, or
the FDA is not satisfied with the company's response, the FDA will issue a
Warning Letter to the firm. A Warning Letter constitutes an FDA communica-
tion notifying an individual or firm that the FDA considers one or more prod-
ucts, practices, processes, or other activities to be in violation of the FD&C
Act, or other acts, and that failure of the responsible party to take appropriate
and prompt action to correct and prevent any future repeat of the violation
may result in administrative and/or regulatory enforcement action without

further notice (FDA Regulatory Procedures Manual [RPM], ch. 4, p. 79). Unlike a
Form FDA 483, which represents an individual investigator's observations, a
Warning Letter represents FDA conclusions concerning violations based on
the review of FDA compliance staff.
A Warning Letter usually states that a firm has 15 working days to re-
spond and explain what it plans to do to correct the alleged violations. While
the FDA allots 15 working days for a response, we recommend a prompter re-
ply if it is possible to adequately respond in a shorter time period (e.g.,
10 business days). If a timely response is not possible for whatever reason, the
firm should contact the FDA and inform them of the reason for the inability
to respond in timely fashion, as well as the time by which a response is antic-
ipated. A Warning Letter should never be ignored.
The FDA's position is that Warning Letters should be issued only for vio-
lations of "regulatory significance" (i.e., those violations that may actually lead
to stronger enforcement action if not promptly and adequately corrected)
(RPM, ch. 4, pp. 79-80). Under many circumstances, a Warning Letter can be
issued at the discretion of an FDA district director without concurrence from
the relevant FDA center (e.g., Center for Drug Evaluation and Research
[COER]). However, a Warning Letter involving alleged cGMP violations relative
to bulk drug substances must receive concurrence from COER before being is-
sued by an FDA district office. Alternatively, such Warning Letters can be issued
directly from CDER headquarters in Rockville, Maryland (RPM, ch. 4, p. 81).
Many of the API manufacturers for the U.S. market are foreign compa-
nies. In general, the same principles for issuance of a domestic Warning Letter
apply with regard to foreign companies. Warning Letters to foreign drug com-
panies, including API manufacturers, are issued from COER. Specifically, the
FDA has stated:
For foreign manufacturers of drugs and drug products,

CDER/OC [Office of Compliance] issues Warning Letters based
on their review and concurrence with recommendations by
FDA investigators in the foreign inspection reports (RPM,
ch. 4, p. 85).
Therefore, the importance of foreign API companies being in cGMP compli-

ance for purposes of FDA inspections cannot be overstated.
We have compiled a lengthy list of cGMP deficiencies that the FDA has
cited in Warning Letters to API companies between 1992 and 1998. The list
provides insight into many of the areas in which an API firm can expect re-
view by the FDA on establishment inspection. Moreover, it provides insight
into the types of cGMP deficiencies that, alone or in tandem with other qual-
ity system problems, can trigger a Warning Letter. As the list shows, 10 some of
the most cited Warning Letter deficiencies for API firms are lack of proper
process validation; no or insufficient batch testing, record keeping, complaint
handling, equipment calibration, and maintenance; deviations from product

specifications or USP standards; cross-contamination problems; and no or in-
adequate control of raw materials. These Warning Letter observations demon-
strate the vast array of cGMP requirements the FDA will inspect for
compliance. The observations also show how closely the FDA's concerns rela-
tive to quality assurance in API manufacturing can mirror its concerns relative
to finished pharmaceutical production.
Recall
Besides issuing Forms FDA 483 and Warning Letters, the FDA can also,
through publicity or otherwise, attempt to pressure a firm to conduct a vol-
untary recall. While the FDA has no legal authority to require the recall of
drugs, such pressure is often effective given that the FDA could alternatively
seek seizure and condemnation, an injunction, and/or criminal prosecution
to address the existence of violative distributed product. The FDA has issued
guidelines for conducting voluntary recalls in 21 CFR Part 7. A "recall" is de-
fined as a firm's removal or correction of a marketed product that the FDA
considers to be in violation of the laws that it administers and against which
the FDA would initiate legal action (e.g., seizure) [21 CFR § 7.3(g)]. A "correc-
tion" means a repair, modification, adjustment, relabeling, destruction, or in-
spection (including patient monitoring) of a product without its physical
removal to some other location [21 CFR § 7.3(h)]. In short, a company's con-
duct of a voluntary recall is often viewed as the "nonlegal" alternative to the
FDA's seeking to institute a legal proceeding to address distributed product
that is in violation of the FD&C Act.
Judicial Tools
The FD&C Act gives the FDA authority to take more serious actions against
adulterated or misbranded drugs in U.S. commerce and their companies and of-
fidals, beyond Forms FDA 483 and Warning Letters. 11 Through recommenda-
tion to the U.S. Attorney, the FDA can seek to have certain legal actions initiated
in federal district court. The actions are brought by the U.S. Attorney because
the FD&C Act provides the FDA with no independent litigation authority. Due
to the serious nature and possible ramifications of FDA legal actions, it is essen-
tial for defendants to retain legal counsel to represent their rights.
Seizure and Condemnation

Through the U.S. Attorney, the FDA can initiate a proceeding in federal dis-
trict court to seize and condemn allegedly violative drugs, including APis
[21 U.S.C. § 334(a)]. In a seizure action, the violative product seized is the
defendant in the case (i.e., it is an in rem legal action). In such an in rem ac-
tion, the federal government seeks to condemn the FDA-regulated article and
declare its forfeiture due to a violation of the FD&C Act. Any interested party,
owner, or agent may appear to claim the article by filing a verified claim stat-
ing the nature of his/her/its interest in the article. The interested company or
individual can then defend the article against condemnation and forfeiture in
court.
Usually, a seizure will be preceded by prior notice by the FDA to respon-
sible company officials that their product(s) is in violation of the laws en-
forced by the FDA. For instance, the FDA might issue a Warning Letter prior to
commencing a seizure action. However, the FDA does at times proceed with-
out prior notice if it perceives the violation is intentional or flagrant, involves
willful fraud, or presents a reasonable possibility that someone might be in-
jured or die (RPM, ch. 4, pp. 79 and 174).
Injunction
Through the U.S. Attorney, the FDA can also initiate a legal action in federal
district court to enjoin a drug firm and its responsible officials from violating
the FD&C Act (e.g., promoting and distributing allegedly violative drugs, in-
cluding APis) [21 U.S.C. § 332]. The purpose of an injunction is to halt the
flow of violative products in interstate commerce and to correct conditions
that caused the violation to occur. It is not mandatory to demonstrate that
the law has been violated to seek an injunction. It is only necessary to show
that there is a likelihood that it may be violated if an injunction is not
entered. According to the FDA, an injunction should be considered for
any significant "out-of-compliance" circumstance, but particularly when a
health hazard related to the violation has been identified (RPM, ch. 6, p. 187).
The FDA may consider an injunction to be appropriate when violations
are pervasive and affect many different products (e.g., significant cGMP viola-
tions).
Criminal Prosecution
The FDA, through the U.S. Attorney, can also initiate criminal proceedings in
federal district court against a drug company and/or its officers and employ-
ees as individuals for violating the FD&C Act. To be convicted of a misde-
meanor violation of the FD&C Act, criminal intent (mens rea) is not required
[21 U.S.C. § 333(a)(1)]. Misdemeanors are punishable by a maximum of one
year incarceration, a maximum fine of $100,000 for individuals (and
$200,000 for corporations) per offense, or both [21 U.S.C. § 333(a)(1);
18 U.S.C. § 3571(b) and (c)].l 2 To be convicted of a felony violation of the
FD&C Act, the activity must involve an "intent to defraud or mislead" or be a
repeat FD&C Act offense. Felony violations are punishable by a maximum of
three years incarceration, a maximum fine of $250,000 for individuals (and

$500,000 for corporations) per offense, or both [21 U.S.C. § 333(a)(2);
18 U.S.C. § 3571(b) and (c)]. Alternatively, a defendant can be required to pay
twice the pecuniary gain derived from (or the loss caused by) the violative
conduct [18 U.S.C. § 3571(d)].
According to FDA policy, the FDA generally will seek to prosecute only
companies that and individuals who exhibit an ongoing disregard for the
FD&CAct:
With the exception of prosecution recommendations involv-

ing gross, flagrant, or intentional violations, fraud, or danger
to health, each recommendation should ordinarily contain
proposed criminal charges that show a continuous or repeated
course of violative conduct. This may consist of counts from
two or more inspections, or counts from separate violative
shipments at different points in time. This is because the
agency ordinarily exercises its prosecutorial discretion to seek
criminal sanctions against a person only when a prior warn-
ing or other type of notice can be shown. Establishing a back-
ground of warning or other type of notice will demonstrate to
the U.S. Attorney, the judge, and the jury that there has been
a continued course of violative conduct and a failure to effect
correction in the past (RPM, ch. 6, pp. 202-203).
Before a violation of the FD&C Act is reported by the FDA to any U.S. At-
torney for institution of a criminal proceeding, the prospective defendant
must be given appropriate notice and an opportunity to present his or her
views, either orally or in writing, with regard to such recommendation for
prosecution [21 U.S.C. § 335]. Therefore, companies that and individuals
whom FDA is considering for prosecution have an opportunity to persuade
the FDA not to proceed further with a criminal action. Representation by legal
counsel is essential at this preprosecution stage.
It is important to remember that corporations can be held accountable
for the actions of their employees and agents acting within the scope of their
employment or agency, even if the wrongful acts are committed by lower-
level employees or representatives. Moreover, company officers can be held
personally responsible for FD&C Act violations in criminal proceedings. The
standard of liability for corporate officers under the FD&C Act was construed
in United States v Park, 421 US 658 (1975). Under the Park case, a corporate of-
ficer may be convicted of a misdemeanor under the FD&C Act if the prosecu-
tion demonstrates that the officer "had, by reason of his position in the
corporation, responsibility and authority either to prevent in the first in-
stance, or promptly to correct, the violation complained of, and that he failed
to do so." Criminal liability is not based merely upon actual "awareness of
some wrongdoing" or "conscious fraud" (United States v Park [421 US at
673-674]). This is because "the [FD&C] Act imposes not only a positive duty to
seek out and remedy violations when they occur but also, and primarily, a
duty to implement measures that will insure that violations will not occur."
Although the U.S. Supreme Court in Park recognized such a standard created a
great burden on corporate officers, it explained that such a standard is "no
more stringent than the public has a right to expect of those who voluntarily
assume positions of authority in business enterprises whose services and prod-
ucts affect the health and well-being of the public that supports them" (United
States v Park [421 US at 672]).
A corporate officer's guilt may not, however, be based solely on his or
her corporate position. A corporate officer may defend himself/herself on the
basis that he/she was "powerless" (i.e., lacked authority) to prevent or correct
the violation. In making such a claim, the officer has the burden of producing
evidence, but the ultimate burden still lies with the government, which must
prove the officer's guilt beyond a reasonable doubt, "including his power, in
light of the duty imposed by the [FD&C] Act, to prevent or correct the pro-
hibited condition" (United States v Park (421 US at 672-673]).
FDA Import/Export Authority over APis

Import Authority of the FDA
The FDA has authority to regulate the import of drugs, and therefore APis and
other BPCs, into the United States. The FD&C Act authorizes the FDA to sam-
ple, detain, and/or refuse entry into the United States of drugs offered for im-
port. Such articles can be detained and/or refused admission if they appear to
be adulterated, misbranded, or otherwise violative [21 U.S.C. § 381(a)]. An ac-
tual determination of adulteration or misbranding is unnecessary. This stan-
dard for FDA action is lower than the standard for seizure of domestic product
(i.e., actual adulteration or misbranding).
The results of inspections of foreign API manufacturers can directly af-
fect the status of their products when offered for entry into the United States.
For example, APis could be sampled, detained, and/or refused entry into the
United States, if an inspection of their foreign manufacturer's establishment
revealed that the manufacturer was not complying with cGMPs. In addition,
the FDA could do the same if a foreign bulk chemical facility refused the FDA
access to relevant records. This could also be the case if the APis demon-
strated actual adulteration or misbranding upon sampling and testing. As the
FDA has stated, "firms are placed on automatic detention because of repeat-
edly offering violative products for import" (RPM, ch. 4, p. 85). 13
Sampling and Related Procedures. Under its§ 381 authority, the FDA can
sample FDA-regulated articles, including APis, offered for import. Upon sam-
pling product for testing, the FDA will issue a "Notice of Sampling" (Form
FDA 712) to the owner or consignee of the product. If the shipment is found
to be in compliance after examination, the FDA will issue a "Release Notice"
(Form FDA 717) to the owner or consignee. If sample examination indicates
the article appears to be in violation, the FDA will issue a "Notice of Detention
and Hearing" (Form FDA 718). In that notice, the FDA will specify the nature
of the violation and set a place at which the owner or consignee can provide
oral or written testimony as to the admissibility of the article into U.S. com-
merce. Generally, the notice allots a time period of 10 working days during
which testimony may be offered. Extensions can be granted when reasonable
(RPM, ch. 9, p. 41). After the hearing, the FDA will issue either a Release No-
tice or a "Notice of Refusal of Admission" (Form FDA 772). If a refusal notice
issues, the notice will provide that the prodl!ct must be destroyed or exported
under the U.S. Customs Service's supervision within 90 days of the notice
(RPM, ch. 9, p. 41). The owner or consignee can also attempt to bring an arti-
cle into compliance with the FD&C Act or to remove it from the FDA's juris-
diction by timely submitting a "Request for Authorization to Relabel or
Perform Other Acts" (Form FDA 766). Such reconditioning (e.g., converting
product from drug use to another use) can avoid the need for product de-
struction or reexportation.
Automatic Detention/Import Alert. The FDA also has the authority to auto-
matically detain imported product (i.e., to place the product on "Import
Alert"). Under FDA policy, automatic detention should be recommended
whenever there is information that indicates that future shipments of a prod-
uct or products offered for entry into the United States appear violative
within the meaning of 21 U.S.C. § 381(a). An Import Alert may cover a spe-
cific manufacturer, or geographic area or country, if information supports
such a broad Import Alert (RPM, ch. 9, p. 347).
There are many circumstances and situations that could lead the FDA to
institute automatic detention through issuance of an Import Alert. An API
could be placed on automatic detention based upon one violative sample
where use of the product may lead to adverse health consequences, or where
the product is violative in a way that is likely to continue because of the prod-
uct's ingredients or formulations (e.g., due to unapproved color additives or
because the API's composition does not meet an applicable standard of iden-
tity) (RPM, ch. 9, pp. 347-348). Automatic detention recommendations also
can be based on multiple violative samples. In relevant part, under FDA policy
the FDA considers recommendations for automatic detention to be appropri-
ate for the following:
• A specific product from an individual manufacturer or shipper for

violations that do not pose a significant public health hazard when
there have been at least 3 detentions in a recent 6-month pe-
riod or less; and
these detentions represent at least 25 percent of total ship-

ments of that product examined in the applicable time period
as known to the recommending FDA district or unit.
• Multiple products from a manufacturer or shipper when
there are at least 6 detentions in a recent 6-month period or
less; and
these detentions represent a variety of products and constitute
at least 25 percent of the total shipments examined from that
firm during the applicable time period as known to the rec-
ommending FDA district or unit (RPM, ch. 9, pp. 348-349).
Moreover, where an establishment inspection of a foreign manufacturer, in-

cluding an API firm, reveals significant deviations from cGMPs, unsanitary
conditions, or other practices that result in the firm's product, as manufac-
tured at its facilities, appearing to be adulterated, misbranded, or otherwise in
violation of the FD&C Act, the FDA considers a recommendation for auto-
matic detention of articles offered for import from such a manufacturer to be
appropriate. An Import Alert in such a case may identify a product from mul-
tiple locations of one firm, and one or more products of that firm, as appro-
priate for automatic detention. A "string" of bad establishment inspections in
a particular country or geographic region can lead to that country or region
being placed on automatic detention for some or all FDA-regulated articles
exported from there (RPM, ch. 9, p. 349).
When a product is placed on Import Alert, the FDA presumes it is viola-
tive upon offer for import, and the burden of showing otherwise falls on the
importing party (e.g., submitting test results on individual lots or production
codes of product to demonstrate they are not violative).
Automatic detention is not necessarily a permanent condition for a firm.
The following guidelines, in relevant part, have been established by the FDA
for removal from automatic detention:
• In the case of a specific product from an individual manufacturer,

the last 5 shipments have been documented to be in compliance
with the FD&C Act; and
• In the case of multiple products from a specific manufacturer, the
last 12 shipments have been established to be nonviolative and
constitute a representative range of products normally entered by
the firm or represent each of the products covered by the automatic
detention if only certain products are covered under the Import
Alert (RPM, ch. 9, pp. 351-352).
In cases where a foreign establishment inspection has revealed cGMP

deficiencies, unsanitary conditions, or other violative practices of a firm,
reinspection, establishing that the appearance of the violation(s) has been re-
moved, is usually required before the Import Alert will be canceled for that
firm (RPM, ch. 9, p. 350).
Import of Drug and Biological Components

to Manufacture Products for Export
The FD&C Act permits the importation of drug and biological components
(such as APis) that otherwise cannot be imported into the United States, if the
components are intended for manufacturing a product for export. Generally,
the importer must provide notification to the FDA at the time of initial
import and must maintain records that account for the use or destruction of
the imported components [21 U.S.C. § 381(d)].
Export Authority of the FDA

APis, as drugs, that are not adulterated, misbranded, or otherwise in violation
of the FD&C Act, can be freely exported from the United States in general. Ex-
portation of drugs that do not meet U.S. requirements for commercial use or
marketing in foreign countries is governed by 21 U.S.C. §§ 381(e) and (f) and
382. Depending on the nature of an API, it may be subject to the require-
ments of 21 U.S.C. § 381 or§ 382.
Under§ 381(e)(1), a drug intended for export "shall not be deemed to be
adulterated or misbranded," even if it does not meet U.S. requirements, and
may be exported if it
• accords to the specifications of the foreign purchaser;

• is not in conflict with the laws of the country to which it is in-
tended for export;
• is labeled on the outside of the shipping package that it is intended
for export; and
• is not sold or otherwise offered for sale in domestic commerce. 14
The provisions of§ 381(e)(1) apply to the export of unapproved new animal
drugs unless banned in the United States [21 U.S.C. § 381(e)(3)J.
Drugs exportable under§ 381(e) may be labeled in accordance with the
requirements of the country of destination if also labeled in accordance with
FDA requirements. However, the labeling must state that any conditions of
use unapproved in the United States have not been approved by the FDA
[21 u.s.c. § 381(f)J.
Section 381(e) does not govern the export of unapproved new drugs for
human use and unlicensed biological products. These products are governed by
21 U.S.C. § 382.15 Section 382 provides three alternative mechanisms for
exporting unapproved new drugs and unlicensed biologicals for foreign
commercial use. First and most importantly, any unapproved product may be
exported to any country without FDA export approval, if the product is lawful
in the country of destination and has been approved for marketing in one of
the following 25 listed countries: Australia, Canada, Israel, Japan, New Zealand,
Switzerland, South Africa, and countries in the European Union or the Euro-
pean Economic Area. 16 Second, any unapproved product may be exported,
without FDA export approval, to a country not listed above, if the product is
lawful in the country of destination and the FDA determines that the destina-
tion country has adequate requirements concerning drug product safety and
effectiveness, GMPs, adverse reaction reporting, and drug labeling and promo-
tion. Third, a petition process is available for persons seeking to export a prod-
uct under conditions that do not comply with either the first or second
criterion set forth above [21 U.S.C. § 382(b)]. Exporters of unapproved new drugs
and unlicensed biologicals under§ 382(b) must provide the FDA with a "simple
notification" at the time of first export, identifying the drug (and the country, if
not one of the 25 listed countries). Exporters must also maintain records of the
products being exported and the destination countries [21 U.S.C. § 382(g)].
Certain other provisions of § 382 govern the export of unapproved new
drugs and unlicensed biologicals for investigational and manufacturing uses.
Such new drugs and biologicals may be exported for investigational use to any
of the 25 listed countries in accordance with the laws of the relevant foreign
country and without FDA export approval or compliance with the FDA's IND
requirements [21 U.S.C § 382(c)]. Although notification to the FDA is not tech-
nically required for such exports, an FDA draft guidance advises that "firms
that export a product in anticipation of market authorization ... notify the
FDA when they export the product" (FDA 1998a). An unapproved new drug or
unlicensed biological intended for formulation, filling, packaging, labeling, or
further processing in anticipation of marketing approval in any of the 25 listed
countries may be exported pursuant to the relevant foreign country's laws,
without FDA export approval or notification to the FDA [21 U.S.C. § 382(d)].
If an API is an unapproved new drug for human use or an unapproved
new animal drug for animal use, it is subject to the requirements of§ 382 for
purposes of export. Other BPCs (e.g., inactive ingredients or excipients,
FDA-approved APis, and APis for use in OTC drug products subject to FDA
promulgated monographs) can be exported pursuant to 21 U.S.C. § 381 if
they do not comply with the FDA requirements (i.e., they are adulterated,
misbranded, or otherwise violative).
The export provisions of§§ 381 and 382 were revised in April and Au-
gust 1996, and it is unclear how certain provisions apply to APis. For example,
the bulk active ingredient for an unapproved new drug is treated as an unap-
proved new drug by the FDA. However, in applying this concept to the export
of such a bulk active ingredient for further processing in a listed country un-
der§ 382, the result appears to be that the FDA must be given export notifica-
tion if the unapproved finished dosage new drug is approved in the foreign
country [21 U.S.C. § 382(b) and (g)], while notification is recommended but
not required if approval is anticipated [21 U.S.C. § 382(d)]. In June 1998 the
FDA issued a draft guidance document titled Draft Guidance for Industry on Ex-
ports and Imports Under the FDA Export Reform and Enhancement Act of 1996,
setting forth its interpretations of the export provisions of§§ 381 and 382 and
addressing certain inconsistencies in the provisions (FDA 1998a).
DRUG MASTER FILES FOR APis

One other area of great relevance to API manufacturers is the FDA's system for
Drug Master Files (DMFs). FDA regulation 21 CFR § 314.420 governs DMFs.
A DMF is a submission to the FDA that may be used to provide confidential
detailed information about facilities, processes, or articles used in the manu-
facturing, processing, packing, and storing of one or more human drugs
[21 CFR § 314.420]. The submission of a DMF is not required by law or FDA
regulation. A DMF is submitted solely at the discretion of a company or indi-
vidual. The information contained in a DMF may be used to support an IND,
NDA, ANDA, another DMF, an Export Application, or amendments and sup-
plements to any of these. 17 A DMF is not a substitute for an IND, NDA,
ANDA, or Export Application, and it is not approved or disapproved.
The technical contents of a DMF are reviewed only in connection with the re-
view of an IND, NDA, ANDA, or Export Application. DMFs are generally cre-
ated to allow a person, other than the holder of the DMF, to reference
material of the holder, without the holder having to disclose to the person
proprietary information. Instead, the proprietary information is maintained
in the DMF.
DMFTypes
There currently are five types of DMFs:18
1. Type !-Manufacturing site, facilities, operating procedures, and

personnel
2. Type 11-Drug substance, drug substance intermediate, and materi-
als used in their preparation, or drug product ·
3. Type III-Packaging material
4. Type IV-Excipient, coloring, flavor, essence, or materials used in
their preparation
5. Type V-Other FDA-accepted reference information
The FDA published a guideline titled Guideline for Drug Master Files (FDA
1989), which provides recommendations on the format and content of
various forms of DMFs. Adherence to this guidance is highly recommended in

preparing any DMF, as it minimizes the likelihood that the submission will be
found administratively unacceptable by the FDA.
DMF Holder Obligations

There are five responsibilities of which an API company should be aware as a
DMF holder:
1. Any addition, change, or deletion of information in a DMF is re-
quired to be submitted to the FDA. An original and one copy
should be submitted [21 CFR § 314.420(c)]. The submission should
adequately cross-reference previous submissions. The submission
should reference dates, volumes, sections, and/or page numbers of
the DMF affected.
2. If an API company adds, changes, or deletes any information in a
DMF, it must notify in writing each company or individual autho-
rized to rely on the DMF. However, a DMF holder does not have to
provide the text of the addition, change, or deletion to the com-
pany or individual. The purpose of a DMF is to permit the holder to
authorize others to rely on its DMF information to support a drug
product or study application to the FDA without its having to dis-
close the information to the others [21 CFR § 314.420(c)]. The FDA
has stated that a DMF holder's notification about changes in a DMF
does not have to be so specific that the confidentiality of informa-
tion in the file is compromised (FR 1985). In light of this, if an API
company ever revises a DMF, it should notify companies and indi-
viduals affected that an addition, change, or deletion has occurred
and describe the general nature of the revision. It should also state
whether the revision affects information in the DMF on which the
company or individual relies. For example, if the holder changes a
component of its API and revises its DMF, a drug company, which
has relied on the API composition, should be told that the change
significantly impacts the company's reliance on the DMF. On the
other hand, if the DMF holder appoints a new quality assurance
manager and revises its DMF, the drug company should be told the
change does not affect its reliance on the DMF.19
3. A DMF holder must provide an annual update report for each DMF
on the anniversary date of its original submission to the FDA. This
report must contain a complete list of persons authorized to rely
on information in the DMF (discussed below) and should identify
all additions, changes, and deletions of information in the DMF
since the previous annual update report. If the DMF has not
changed, the holder should provide a statement that the DMF is

still current.
4. A DMF is required to contain a complete list of companies and in-
dividuals authorized to rely on information in the DMF [21 CFR
§ 314.420(d)]. A DMF holder must update the list in its annual up-
date report. The list should identify the information that each com-
pany or individual is authorized to rely on and give the location of
that information by date, volume, and page number in the DMF. If
the DMF holder restricts authorization to particular drug products,
the list must include the names of the products and their corre-
sponding application numbers if known [21 CFR 314.420(d)]. The
holder must also identify any company or individual that has lost
authorization during the previous year in the annual update report.
If the list has not changed on the anniversary date of the DMF
submission, the holder should submit a statement in the annual
update report that the list is still current. A company can submit
and the FDA will accept a DMF without a list when the company
desires to establish a DMF before authorizing companies or individ-
uals to rely on it. However, once companies or individuals are au-
thorized to rely on DMF information, an authorization list should
be submitted to the FDA as an amendment to the DMF.
5. Besides submitting the authorization list, a DMF holder must sub-
mit to its relevant DMF a letter of authorization permitting the FDA
to reference the DMF before the FDA can review DMF information
in support of a drug product or study application. An original and
one copy must be submitted.
Failure to update a DMF, or to assure the FDA annually that previously
submitted materials and the authorization list in the DMF remain current, can
cause delays in the FDA's review of a pending drug product or study applica-
tion. Additionally, the FDA can close or terminate the DMF in extreme cases.
Status of DMFs as Records

Finally, it is worth noting that DMFs are voluntary records not required to be
maintained under the FD&C Act. Moreover, in practice, the FDA has a copy of
any DMF accepted for filing by the FDA in its own records. In light of these
factors, from a legal perspective, the FDA arguably could not penalize an API
firm for refusing to provide it access to a DMF during an establishment in-
spection. (See 21 U.S.C. § 331(e); it is only a violation of the FD&C Act to pro-
hibit access to required records.) However, as stated before, practical
considerations (e.g., loss of business) may influence firms to allow the FDA ac-
cess to and copying of on-site DMF records during establishment inspections.
CONCLUSION
APis are actively regulated articles under the FD&C Act. Increasingly, the FDA
has used its authority over "drugs," as given in the FD&C Act, to monitor, reg-
ulate, and enforce the quality, strength, and purity of APis for use in human
and animal drug products, as well as biologics. The FDA views APis as having
a significant and direct impact upon the safety and effectiveness of the fin-
ished drug products and biologics in which they are used. Currently, the FDA
appears to be heavily focused on the cGMP compliance status of both foreign
and domestic API manufacturers as a means of asserting tighter control over
the quality of the finished drug products and biologics in which they are
used. The FDA is conducting more frequent and more in-depth establishment
inspections of API manufacturers, both domestically and overseas, as a means
of more closely overseeing API cGMP compliance. The FDA's attention is
especially directed at issues concerning API validation. Increasingly, the FDA
is using Warning Letters to enforce cGMP compliance by API firms; but it
must be remembered that the FDA also has the ability to act more harshly
against noncompliant API manufacturers by seeking seizure and condemna-
tion of products, injunctions against manufacture and/or distribution, and
criminal prosecution of firms and their officers and employees. The FDA's
ability to regulate the import of APis into the United States for use in the
manufacture of finished drug products and biologics also gives the FDA a
strong enforcement tool against noncompliant foreign API manufacturers.
The FDA can use its import sampling, detention, and "refusal of admission"
authority to regulate the influx of foreign APis or to bar their entry when the
FDA has concerns regarding their quality or safety.
Finally, the FDA has established the DMF system by which API firms can
submit information regarding their products to the FDA, in support of drug
product and study applications, without having to divulge formulation, man-
ufacturing process, or other proprietary information to its applicant cus-
tomers. The quality of information and data submitted in an API
manufacturer's DMF, as well as the API manufacturer's ultimate conformance
to representations made in its DMF, can greatly impact on the fortunes of its
customers' drug product and/or study applications, often greatly contributing
to their approval or nonapproval.
NOTES
1. A company that makes BPCs that are not APis (i.e., excipients or in-
termediates) is not subject to the registration requirement and
therefore is not subject to mandatory biennial inspection [21 U.S.C.
§ 360(g); 21 CFR § 207.10; See 21 CFR § 207.3(a)(4)].
2. The Food and Drug Administration Modernization Act of 1997

(FDAMA), Pub. L. No. 105-115, subjected antibiotic drugs for hu-
man use to the FD&C Act's "new drug" premarket review and ap-
proval requirements, repealing the former certification requirement
for antibiotics. The FDA in 1998 issued regulations implementing
the FDAMA, which eliminated 21 CFR Parts 430 through 460, the
regulations that had governed antibiotic drug certification and had
included the FDA's antibiotic drug monographs (FR 1998b).
The FDAMA exempts certain "pharmacy compounded" drug
products from the FDA's "new drug" requirements. Under the
FDAMA amendments to the FD&C Act, drug products com-
pounded by a pharmacist or a physician on a customized basis for
an individual patient are exempt from the FD&C Act's new drug
provisions and certain adulteration and misbranding provisions,
provided that a number of requirements are met. One such re-
quirement pertains to the universe of bulk drug substances that
the compounder may use. Specifically, to qualify for FDAMA's
statutory exemptions, the bulk drug substance used in compound-
ing (1) must comply with an applicable USP or NF monograph;
(2) if a monograph does not exist, then the bulk drug substance
must be a component of an FDA-approved drug; (3) if a mono-
graph does not exist and the bulk drug substance is not a compo-
nent of an FDA-approved drug, it must appear on an FDA-
established list of bulk drug substances that may be used in com-
pounding [21 U.S.C. § 353a]. In January 1999 the FDA issued a
proposed regulation identifying the list of bulk drug substances
that may be used in pharmacy compounding under the FDAMA
exemptions (FR 1999a).
3. On 1 August 2000, the FDA announced the availability of a draft
guidance document titled Q7A ICH Good Manufacturing Practice
Guide for Active Pharmaceutical Ingredients that sets forth the FDA's
current thinking on cGMPs for the manufacturing of APis. The ICH
guidance applies to the manufacture of APis for use in human drug
products, including sterile APis, up to the point where the API is
rendered sterile (FR 2000b). ICH, which stands for International
Conference on Harmonisation of Technical Requirements for Regis-
tration of Pharmaceuticals for Human Use, works to harmonize
technical requirements for approval of pharmaceutical products
among the United States, the European Union, and Japan.
A guidance document represents the FDA's current thinking
on a particular topic. It does not create or confer any rights for or
on any person and does not bind the FDA or the public.
4. The FDA guidance document Bulk Actives Postapproval Changes:
Chemistry, Manufacturing, and Controls Documentation, commonly
referred to as "BACPAC I" (November 1998), deals with postap-

proval changes in site of manufacture, scale of manufacture, equip-
ment, specifications, or manufacturing process for intermediates
up to and including the final intermediate, with certain exclusions.
The draft guidance recommends that sponsors of NDAs, ANDAs,
NADAs, and ANADAs, and holders of Drug Master Files (DMFs) or
veterinary master files (see "Drug Master Files for APis," pp. 41-44,
for more details) should test, document, and file documentation
with the FDA on relevant postapproval changes. Recommended
testing should include an evaluation of any changes in the impu-
rity profile and physical properties of the intermediate. If equiva-
lence of the impurity profile cannot be established at any
intermediate stage, the FDA recommends testing of the drug
substance. If equivalence of the impurity profile and physical prop-
erties is not established by such testing, "the need for qualification
of impurities and studies to ensure bioequivalence of dosage form
should be considered." The draft guidance does not specify
whether this should be done by the dosage form manufacturer or
the intermediate manufacturer. The FDA has stated it will soon
issue a second related draft guidance document, BACPAC II, ad-
dressing postapproval changes to the final intermediate and manu-
facturing changes after the final intermediate (FDA 1998b).
5. However, the FDA has issued guidance documents for qualification
of impurities in drug substances which suggest that impurity levels
higher than those permitted in the USP may be qualified under cer-
tain circumstances. See Q3A(R) Impurities in New Drug Substances
(FR 2000a) (qualification of impurities in innovator drug products)
and Guidance for Industry: ANDAs: Impurities in Drug Substances (FDA
1999) (qualification of impurities in generic drug products).
6. For many years, the FDA's broad records inspection authority did
not extend to human OTC drugs. The Food and Drug Administra-
tion Modernization Act of 1997 (FDAMA) changed that, granting
the FDA authority to inspect records at all factories, warehouses, es-
tablishments, and consulting laboratories in which prescription
drugs or "nonprescription drugs intended for human use" are man-
ufactured, processed, packed, or held [21 U.S.C. § 374(a)(1)].
7. Such establishments are exempt from establishment registration
and drug listing under 21 CFR Part 207 [21 CFR § 207.10(e)].
8. The European Community Member States are Austria, Belgium,
Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxem-
bourg, The Netherlands, Portugal, Spain, Sweden, and the United
Kingdom.
9. The FDA investigator will also prepare an Establishment Inspection

Report (EIR). An ElR is a narrative summary of the inspection that
includes the inspection's purpose, the company's history and
organization, key personnel responsibilities and functions, person-
nel/management interviews, procedures and quality systems in-
spected and assessed, observations of violative conditions, and the
company management's attitude and commitments for corrective
action. Each EIR is incorporated into the official FDA records on a
regulated company. The FDA often depends on EIRs when deciding
whether it should institute an enforcement action against a com-
pany or its products. The Form FDA 483 is included as part of the
EIR. Beginning in April 1997 the FDA routinely provides an in-
spected firm with a copy of the final EIR, as soon as the FDA has de-
termined that the file on the inspection is "closed." In the event
that the FDA refuses to provide a copy of the EIR several weeks after
an inspection because the firm's file remains open, such refusal
may be an indication of serious problems.
10. The list is as follows:
• Failure to establish and follow adequate procedures to validate
manufacturing processes
• Failure to provide an adequate description of validation
methods
• Failure to provide data validating the adequate performance
of manufacturing processes
• Failure to initiate a revalidation of manufacturing processes
• Failure to validate sterilization process
• Failure to validate a reprocessing procedure
• Failure to validate water system used in production
• Failure to document complete validation of the computer sys-
tem used to monitor and control the production process
• Failure to track and validate computer hardware and software
modifications
• Failure to have adequate or effective validated equipment
cleaning procedures
• Failure to provide adequate information establishing clean-
ing validation
• Failure to provide adequate validation of test methods
• Failure to adequately test each batch for conformance to estab-
lished specifications, or release of product before test results
are known
• Failure to maintain adequate batch records; failure to have re-

view of batch production and control records by an indepen-
dent quality unit
• Failure to maintain adequate procedures for tracking com-
plaints and for sufficient investigation and subsequent action
on complaints
• Failure to assure complete investigations of product com-
plaints
• Failure to perform failure analyses
• Failure to calibrate testing equipment
• Failure to calibrate laboratory instruments
• Failure to maintain calibration records
• Failure to qualify manufacturing equipment
• Failure to establish and follow a written testing program de-
signed to assess stability characteristics of a product
• Failure to conduct adequate stability studies
• Failure to manage and utilize USP reference . standards
properly
• Failure to compare in-house standards against official USP ref-
erence standards
• Failure to perform full compendia testing
• Failure to assure that products meet applicable standards of
identity, strength, quality, and purity
• Failure to test purity and quality of water used as a component
in drug product
• Failure to develop appropriate specifications for products
• Failure to adequately address the potential for cross-contami-
nation
• Failure to design facilities to prevent cross-contamination
• Failure to establish microbiological specifications for water
used in manufacture
• Failure to establish and implement procedures covering the
reprocessing of lots that fail to meet product specifications
• Failure to prepare or complete production records for products
• Failure to maintain adequate laboratory records
• Failure to provide second person review of laboratory records
for accuracy, completeness, and compliance
• Failure to maintain adequate recordkeeping procedures

• Failure to maintain all data associated with laboratory testing
• Failure to follow procedures that describe the sampling fre-
quency of products
• Failure to have approved procedures for raw materials
acceptance
• Failure to identify raw materials in specifications properly
• Failure to conform raw materials testing and release to writ-
ten specifications
• Failure to test APis prior to use in manufacture of finished
drug product
• Failure to maintain accurate and complete raw material re-
ceiving records and finished product distribution records
• Failure to follow the master formula for production
• Failure to have written procedures for the issuance of labeling
• Failure to have a responsible person sign and date master
labels
• Failure to provide copies of case labels for packaging records
• Failure to use the lot coding system as set forth in the relevant
Drug Master File
• Failure to implement appropriate quality control for the test-
ing of finished product
• Failure to take appropriate corrective action when critical test
equipment was found to be out of calibration
• Failure to provide impurity profiles for finished products
• Failure to provide adequate environmental controls
• Failure to have sufficient separation controls to prevent mix-
up between quarantined and approved products
• Failure to maintain buildings in good state of repair
• Failure to provide laboratory staff with cGMP training
• Failure to establish appropriate time limits for completion of
each phase of production
• Equipment used to manufacture drug product also used in
manufacture of a pesticide chemical
The Legal Framework for the Regulation of AP/s 51
This is not intended to be an all-inclusive list of cGMP deficiencies

cited in FDA Warning Letters to API manufacturers.
11. Other than serving as notice to a firm of perceived violations by the
FDA, Forms FDA 483 and Warning Letters have no legal effect.
12. Under the explicit language of 21 U.S.C. § 333(a), a misdemeanor
violation of the FD&C Act is punishable by not more than one year
imprisonment or not more than $1,000, or both, while felony vio-
lations of the FD&C Act are punishable by not more than three
years imprisonment or not more than a $10,000 fine, or both.
However, Congress enacted Public Law 99-660 in 1986. Section 103
of Title I of Public Law 99-660, among other things, provides that,
for fines authorized to be imposed under 21 U.S.C. § 333, referral
should be made to 18 U.S.C. § 3571. The higher and alternative
fines discussed in this section are provided for in 18 U.S.C. § 3571.
13. The difficulties involved with manufacturing sterile bulk drugs
have led the FDA to pay particular attention to these operations
and products. Import Alerts have been imposed on bulk pharma-
ceuticals reporting to be sterile, while similar actions were not
taken against nonsterile forms of the same chemicals.
14. The requirement against prior sale or offer for sale in domestic
commerce refers to the particular unit of the article in question and
not the article generally.
15. Section 382 also governs the requirements for the export of unap-
proved new drug and unlicensed biological products for tropical
diseases [21 U.S.C. § 382(e)]. In conjunction with the Public Health
Service Act, Section 381 also governs the export of partially
processed biological products [21 U.S.C. § 381(e)(1); 42 U.S.C.
§ 262(h)].
16. The EU countries are Austria, Belgium, Denmark, Finland, France,
Germany, Greece, Ireland, Italy, Luxembourg, The Netherlands,
Portugal, Spain, Sweden, and the United Kingdom. The EEA coun-
tries are the EU countries, Iceland, Liechtenstein, and Norway. This
list of countries expands automatically if any country accedes to
the EU or becomes a member of the EEA (FR 1998c).
17. There are also Veterinary Master Files (VMFs) for supporting an
INAD, a NADA, an ANADA, another VMF or DMF, an Export Appli-
cation, or amendments or supplements to any of these. DMFs can
also be referenced to support these filings.
18. The FDA has proposed, but not finalized, a rule that would elimi-
nate Type I DMFs (FR 1995). According to the FDA, Type I DMFs
contain information that is outdated, duplicates information con-

tained in marketing applications, or is no longer relied on by FDA
review divisions. Under the proposed rule, the FDA would no
longer accept new Type I DMFs or updates to existing Type I DMFs,
and existing Type I DMFs could no longer be incorporated by refer-
ence into new applications, amendments, or supplements. In place
of a Type I DMF, foreign firms are now asked to submit a preinspec-
tion document package that includes current facility and product-
specific information.
19. According to the FDA's draft guidance document BACPAC I, if there
is a postapproval change in the manufacturing process and the
method of manufacture is described in the DMF, the DMF holder
should file documentation of the postapproval change with the
FDA as an amendment to the DMF and should notify all applicants
authorized to reference the DMF. Although details of the change
may be kept confidential, the DMF holder should at a minimum in-
form the applicants of the type of filing recommended for their re-
spective drug applications (FDA 1998b).
REFERENCES
Code of Federal Regulations, 21 CFR Parts 7, 20, 201, 207, 210, 211, 312, 314, and 511.
Compliance policy guides§ 490.100 (Process validation requirements for drug products
subject to pre-market approval). CPC no. 7132c.08; 30 August 1993. Rockville,
Md., USA: Food and Drug Administration.
Compliance program guide manual, Compliance program nos. 7346.832 (Pre-approval
inspections) and 7356.002F (Bulk pharmaceutical chemicals). Rockville, Md., USA:
FDA. 198 7. Guideline on general principles ofprocess validation. Rockville, Md., USA: Food
and Drug Administration.
FDA. 1989. Guideline for drug master files. Rockville, Md., USA: Food and Drug Admin-
istration.
FDA. 1998a. Draft guidance for industry on exports and imports under the FDA export reform
and enhancement Act of 1996. Rockville, Md., USA: Food and Drug Administration.
FDA. 1998b. Draft guidance for industry on bulk actives postapproval changes: Chemistry,
manufacturing, and controls documentation (BACPAC I: Intermediates in drug substance
synthesis). Rockville, Md., USA: Food and Drug Administration.
FDA. 1999. Guidance for industry: ANDAs: Impurities in drug substances. Rockville, Md.,
USA; Food and Drug Administration.
FDA Regulatory Procedures Manual: August 1997: Chapters 4 (Advisory Actions), 6 Oudi-
cial Actions), and 9 (Import Operations/Actions).
Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 301 et seq.
Federal Rules of Criminal Procedure Nos. 17 and 41.
FR. 1985. New drug and antibiotic regulations. Federal Register 50:7452, 7489 (Feb. 22,
1985).
FR. 1991. New drug and abbreviated new drug applications; proposed preapproval in-
spection requirements. Federal Register 56:3180 Oan. 28, 1991).
FR. 1993. New drug and abbreviated new drug applications; preapproval inspection re-
quirements. Federal Register 58:47340 (Sept. 8, 1993).
FR. 1995. New drug applications; Drug Master Files. Federal Register 60:34486 Ouly
3, 1995).
FR. 1998a. Mutual recognition of the FDA and European Community Member State
conformity assessment procedures; pharmaceutical GMP inspection reports. Fed-
eral Register 63:17744 (April10, 1998).
FR. 1998b. Removal of regulations regarding certification of antibiotic drugs. Federal
Register 63:26066 (May 12, 1998).
FR. 1998c. Draft guidance for industry; exports and imports under the FDA Export Re-
form and Enhancement Act of 1996. Federal Register 63:32219 Oune 12, 1998).
FR. 1998d. Mutual recognition of pharmaceutical good manufacturing practice inspec-
tion reports ... between the United States and the European Community. Federal
Register 63:60122 (Nov. 6, 1998).
FR. 1999a. List of bulk drug substances that may be used in pharmacy compounding.
Federal Register 64:996 Oan. 7, 1999).
FR. 1999b. Foreign establishment registration and listing. Federal Register 64:26330
(May 14, 1999).
FR. 2000a. International Conference on Harmonisation; draft revised gudiance on im-
purities in new drug substances. Federal Register 65:45085 Ouly 20, 2000).
FR. 2000b. International Conference on Harmonisation; draft guidance on Good Man-
ufacturing Practice for active pharmaceutical ingredients; availability. Federal Reg-
ister 65:46936 (Aug. 1, 2000).
House Committee on Commerce, Subcommittee on Oversight and Investigations,
Oversight hearing regarding: U.S.-EU (European Union) mutual recognition agreement on
drug inspections, 105th Congress, 2nd session, 1998, p. 4.
In re Grand Jury Subpoenas, 803 F2d 493 (9th Cir 1986).
In re Medtronic, Inc., 500 F Supp 536, 540-541 (D Minn 1980).
Public Health Service Act, 42 U.S.C. § 262.

Public Law No. 99-660, 99th Congress, 2nd session, Nov. 14, 1986.
Public Law No. 105-115, 105th Congress, 1st session, Nov. 21, 1997.
United States Code, 18 U.S.C. § 3571.
United States v Calandra, 414 US 338, 347 (1974).
United States v Jamieson-McKames Pharmaceuticals, Inc., 651 F2d 532, 540 (8th Cir 1981).
United States v Park, 421 US 658, 672-674 (1975).
3
THE LEGAL BASIS FOR

VALIDATION
Irving L. Wiesen
Attorney at Law
Stamford, Connecticut
The U.S. Food and Drug Administration's (FDA) emphasis on the validation
of the drug and device manufacturing process represents the continuation of
a lengthy progression of increasingly strict scrutiny over the process and con-
text of drug manufacture that has emerged in the regulatory, judicial, and
legislative realms. This progression, driven by a widely perceived need for the
strictest public protection, has been facilitated by the very flexibility and
open-endedness of the FDA's regulatory scheme, which has allowed its evo-
lution on the basis of providing a dynamic and progressive standard for drug
quality. This has resulted in a legal and regulatory framework far different
from that envisioned in the early food and drug statutes; it represents a con-
ceptual shift in the nature of the drug manufacturing process and its rela-
tionship to government and the consumer.
CURRENT GOOD MANUFACTURING PRACTICES

The validation of drug manufacturing processes is rooted in the current Good
Manufacturing Practice (cGMP) requirements of the FDA, as embodied in
FDA regulations and informal policies, as a means of determining the pre-
dictability and the consistency of results of those manufacturing processes.
Until the establishment of the Food and Drug Amendments of 1962, drug
product quality was viewed as a function of the status of the product itself,
55
rather than of its method of manufacture. Thus, the quality of a drug prod-
uct was historically determined on the basis of the conformity of the final
product with standards of drug quality, purity, and strength established for
each drug product. The first legislative initiative involving drugs, for exam-
ple, the Pure Food and Drugs Act of 1906, mandated merely that drugs listed
in an official compendium were required to meet the standards of quality, pu-
rity, and strength contained in that compendium, unless otherwise indicated
on the drug label. Similarly, standards of quality applied to the newly emer-
gent field of antibiotic drugs in the 1940s required testing of each batch of
manufactured product prior to its release for marketing.
The flaw in these approaches to drug quality was that standards applica-
ble only to the physical, final drug product could be satisfied only by testing
the final product to determine that it met the relevant quality standards.
Such a methodology, to be effective, necessarily required a large sampling of
final product in order to yield results sufficiently valid to be extrapolatable to
the batch or product run as a whole. Thus, the typical sampling sizes were not
statistically reliable as an indicator of the quality of the batch as a whole.
Moreover, it was difficult, if not impossible, to determine what percentage of
finished product defects would render the entire batch unacceptable. It even-
tually became apparent that no adequate statistical model for finished prod-
uct testing could be constructed that would not be economically prohibitive
but that could also provide an adequate measure of drug quality for the batch
as a whole. A new approach was needed to ensure product quality. 1
The 1962 Food and Drug Amendments

In the Food and Drug Amendments of 1962, Congress adopted a different
conceptual approach to ensuring drug quality, by reference to the method of
manufacture, not only to the results. While refraining from providing the de-
tails of which practices would, or would not, be appropriate, the Amend-
ments, nevertheless, mandated that drug manufacturers would be required to
produce their products in conformity with the cGMPs. The establishment
legislatively of standards applicable to the drug manufacturing process, as op-
posed to the drug products themselves, was a recognition that the quality of
the product was a function largely of its method of manufacture and that
control of its method would translate into greater quality control of the final
product itself. The focus on the manufacturing process, moreover, would
have been expected to yield exponentially greater results in quality, primar-
ily for two reasons:
1. Control of the manufacturing process would provide a means of qual-

ity control that would augment the statutory standards applicable to
the final product and compensate for its deficiencies.
The Legal Basis for Validation 57
2. By focusing on the process, there was imported into quality control a

notion of standardization whose very existence would itself intro-
duce predictability and consistency to the quality of the final
product.
Another effect of the 1962 Amendments was to further standardize the

methods of drug manufacture across company lines as well. As the FDA noted
in its Preamble to the Final Rule enforcing the cGMP provisions,
Congress was quite concerned about the uneven and sometimes un-
acceptable quality of drug products from some portions of the phar-
maceutical industry. The purpose of section S01(a)(2)(B) of the act is
to provide assurance that the drug product quality would not fall be-
low that which was feasible and available under contemporary tech-
nology (FR 1978).
The cGMP standards enacted into law in the 1962 statute that are ap-
plicable to drugs are described in Section 501(a)(2)(B) [21 U.S.C. 351(a)(2)(B)]
as relating to "[t]he methods used in, or the facilities or controls used for, its
manufacture, processing, packing, or holding." These methods, facilities, and
controls used in manufacturing, packing, or holding, the statute continued,
were to be
[o]perated or administered in conformity with current good manu-

facturing practice to assure that such drug meets the requirements of
this Act as to safety and has the identity and strength, and meets the
quality and purity characteristics, which it purports or is represented
to possess [21 U.S.C. 351(a)(2)(B)].
The statute determined that failure to meet this standard would cause the
drug product itself to be considered "adulterated" and subject to legal seizure
and sanction. Thus, in an important departure from the previous statutory
scheme, the 1962 Amendments determined the quality status of the final
product on the basis of the method of manufacture and storage, rather than
on the content and quality of the final drug product itself.
The reason for the shift in scrutiny back into the production process was
the perceived need to enact stricter controls over drug quality. As one semi-
nal court opinion noted,
[T]he GMP provision stems from congressional concern over the dan-
ger that dangerously impure drugs might escape detection under a
system predicated only on seizure of drugs shown to be in fact adul-
terated. In order to insure public safety, Congress determined in 1962
that it was necessary to regulate the means of production themselves
(United States v. An article of drug . . . George N. Bell Manufacturing
Chemists [484 F.2d 748, 749 (7th Cir. 1973)].2
As other courts have found, echoing the legislative history behind the 1962
Amendments,
(T]he 1962 amendments were intended to strengthen and broaden
the Act by effecting better, safer medicine and a more effective system
of enforcement (United States v. Bel-Mar Laboratories, Inc. [284 F.Supp.
875, 880-01 (E.D.N.Y. 1968], citing 1962 U.S. Code Cong. & Admin.
News, p. 2884).
More specifically, the court noted,
[t]he purpose of Section 3Sl(a)(2)(B) was to attack commerce in un-
safe and unreliable drugs in its incipiency by giving the Food and
Drug Administration (FDA) " ... additional authority to require that
sound methods, facilities, and controls be used in all phases of drug
manufacturing and distribution" (1962 U.S. Code Cong. & Admin.
News, p. 881).3
Advancing the quality control standards into the manufacturing process
was thus perceived as a better preventive quality measure that would better
prevent the marketing of unsafe products. As one court noted,
[T]he GMP provisions of the statute for devices and human drugs and
their implementing regulations, are prophylactic measures designed
to prevent the distribution of poorly manufactured drugs and devices .
. . . Simply put, the GMP regulations are intended to be preventive,
by requiring manufacturers to build quality into their devices, rather
than permit a defective device to be distributed and used to treat pa-
tients. (United States v. 789 Cases [799 F.Supp. 1275, 1285 (D. Puerto
Rico 1992)]). 4
An important feature of the cGMP standard embodied in Section SOl is
that it leaves open the question of what specific standards must be employed
in the manufacturing process, leaving that determination to the FDA and to
the evolution of industry standards, as these are developed and applied within
the industry. The FDA, taking the initiative from its Congressional mandate,
developed an extensive set of standards, which it codified in the Code of Fed-
eral Regulations (CFR), Title 21, Parts 210 and 211, containing its views of
those areas of a manufacturer's operations that must conform to the cGMPs.
These areas include facilities, personnel, production, process and package op-
erations, and controls as well as labeling, containers and closures, laboratory
procedures, and handling and control of records and documentation. 5
As noted, the statute was fashioned by Congress to be deliberately vague
on the precise standards that constitute the cGMPs, having determined that
the statutory purposes of quality assurance were best met by a flexible, chang-
ing, and FDA-determined set of standards. It is this very indeterminacy,
however, that laid the statute open to challenge as unconstitutional because
it allegedly provided insufficient notice to the affected industry concerning

the standards to which they were expected to adhere and that were enforce-
able by legal sanction. The legal status of the FDA's cGMP regulations was
thus the subject of early legal controversy between the FDA and some seg-
ments of the industry. The fact that Congress appeared to intend a degree of
open-endedness in what constituted a good manufacturing practice at any
particular time or circumstance, reflected, some argued, that the FDA regula-
tions authorized by the statute were merely interpretive, i.e., representing
merely the FDA's view of what it considered compliance with the statute-
and thereby in their particulars not legally binding on industry-rather that
substantive, legally binding regulations.
Challenges to the cGMPs

The issue of whether the cGMP regulations constituted binding rules on the
industry was discussed early on in the FDA's rule-making proceeding, with
much accompanying debate concerning the legislative history and intent. In
a lengthy consideration of the regulations published in the Federal Register,
the FDA considered the issue, noting that a number of comments received in
the context of its notice and comment rule-making proceeding proposed that
the FDA lacked statutory authority to issue binding regulations. Citing a Sen-
ate Committee Report underlying enactment of the 1962 Amendments, these
comments noted that the senators intended to authorize the FDA to issue
"interpretive" regulations that would constitute only prima facie evidence of
adulteration. The effect of such an interpretation of the FDA's authority
would be to permit companies found in violation of the cGMPs to show that,
in fact, their products comported with the relevant specifications notwith-
standing violations of the cGMPs. In addition, companies could rebut the
FDA's standards as well and attack their very embodiment of the cGMPs as er-
roneous. In effect, the FDA's regulations would provide merely a rebuttable
presumption, rather than a substantive standard of manufacturing whose
breach by the company would constitute a per se violation of the FDA's reg-
ulations and be subject to sanction by statute (FR 1978).
In addition to the cited legislative intent, these comments also con-
tended that the FDA lacked specific authority to issue binding regulations; in
the absence of a clear congressional mandate, it was beyond its authority in
doing so (FR 1978).
FDA's Analysis of cGMPs

Responding to this reading of the legislative history, the FDA noted that the
issue of whether its regulations would go beyond merely prima facie evidence
of adulteration was specifically discussed subsequent to the aforementioned
Senate Report in the Senate Judiciary Committee, which addressed a number

of amendments submitted by President Kennedy, one of the prime movers
behind the 1962 Amendments. Citing extensive congressional discussion of
this issue in both houses of Congress, the FDA showed that it was the clear,
congressional intent to establish firm rules of drug manufacture. Repeated
pronouncements by the legislators evidenced a strong desire to adopt rules
that would would not lend themselves to endless de novo litigation ... each
11
time there is enforcement action" (FR 1978), thus further buttressing the
FDA's position that binding rules were intended by Congress. Moreover, the
FDA showed, Congress looked to a streamlined procedure for the adoption of
the FDA's regulations, to avoid a lengthy and wasteful period of rule-making
before the new standards could be adopted. The FDA concluded,
[T]o the extent that a stronger Congressional mandate can be gleaned
from the various reports, amendments, and debates, it appears that
binding standards were to be issued by FDA and issued through ...
less cumbersome notice-and-comment rule making procedures.
(FR 1978).
In addition to its analysis of the legislative history, the FDA further ana-
lyzed the judicial precedent that established its authority to issue binding reg-
ulations under Section 701(a) of the Act. 6 Comparing its cGMP regulations
with other rule-making involving prescription drugs, in particular the FDA's
new drug" review procedures applied to over-the-counter (OTC) drugs, the
11
FDA found the same considerations at work as were cited by the courts in
support of the FDA's rule-making powers. 7 The binding nature of the FDA's
regulations, these courts observed, were based on the strong policy of public
protection that demanded strong standards, subject to reasonable, but not
paralyzing, judicial review. The FDA, summarizing the policy expressed in
these judicial opinions, noted,
[t]he statutory standard of current good manufacturing regulations"
11
can and should be particularized as a protective measure to identify

those manufacturing practices which are a minimum necessary to as-
sure drug quality (FR 1978).
Turning to the purposes of the FDA's regulations, the FDA noted that
[S]ubstantive regulations also provide greater certainty about the
agency's expectations because, in promulgating such regulations, the
agency must carefully distinguish standards it seriously intends to
enforce from those it finds desirable but not essential. The Commis-
sioner also stated in the 1976 proposal that binding cGMP regula-
tions would assist courts and expedite enforcement proceeding under
the act (FR 1978).
In addition to their substantive strength, the regulations were also de-

signed to be procedurally strong, to avoid paralyzing FDA and judicial review,
that, the FDA found, would similarly thwart the public interest. As with
the "new drug" determinations of the prior case law, the FDA's cGMP regula-
tions would, if subject to de novo review in each enforcement proceeding,
unduly burden the FDA and severely hamper its enforcement abilities (FR
1978).8 Therefore, the FDA concluded that both the legislative history and ju-
dicial precedent supported its authority to issue binding cGMP regulations
pursuant to the 1962 Amendments.
Judicial Analysis of cGMPs

Notwithstanding the FDA's analysis of its authority, the issue was further ad-
judicated in 1980-81, in the case of the National Association of Pharmaceutical
Manufacturers ("NAPM") v. FDA [487 F.Supp. 412 (S.D.N.Y. 1980), aff'd, 637
F.2d 877 (2d Cir. 1981)], in which the court held that the regulations, adopted
with notice and comment, were indeed substantive and legally binding on
the industry. In this case, the plaintiffs, two trade associations, argued that
the federal Food, Drug, and Cosmetic Act did not empower the FDA to issue
binding regulations enforcing the cGMP requirement of Section 501(a)(2)(B)
of the Act. The FDA's regulations issued, following a period of informal no-
tice and comment pursuant to Section 701(a) of the Act, were, the plaintiffs
contended, merely interpretive and lacked the binding effect of law. Exam-
ining closely the legislative history underlying the 1962 Amendments and
prior case law,9 the court determined that Section 701(a) indeed provided the
FDA with the authority to issue binding regulations, notwithstanding that
these may have been "interpretive" of the cGMPs. Accordingly, the court
held, these regulations bore the full authority and force of law and were bind-
ing per se on the industry.lO
The open-endedness of both the statute and the regulations also resulted
in legal challenges based on their inherent indeterminacy providing insuffi-
cient guidance on legal standards applicable to the affected parties. The plain-
tiffs charged with cGMP violations contended that it was precisely this
feature of the law-its indeterminacy-that rendered them unconstitution-
ally vague, in violation of the Due Process Clause of the Fifth Amendment to
the Constitution. The courts have articulated this constitutional standard as
follows:
It is established that a law fails to meet the requirements of the Due

Process Clause if it is so vague and standardless that it leaves the pub-
lic uncertain as to the conduct it prohibits or leaves judges and jurors
free to decide, without any legally fixed standards, what is prohibited
and what is not in each particular case (Giaccia v. Pennsylvania [382
U.S. 399, 402-403]).
In the case of United States v. An article of drug ... George N. Bell Manufac-
turing Chemists [484 F.2d 748-750 (7th Cir. 1973)], the defendant, charged
with violations of the cGMPs, attacked the statute as void for vagueness due
to the imprecision in the terms current and good. The court, rejecting this ar-
gument, noted that these terms presented no unconstitutional vagueness.
Defining the term current, the court held that it fulfilled a sufficiently precise
and definable purpose by differentiating obligations based on the time they
emerge into general acceptance as industry standards:
[t]he term current fixes the point in time when the acceptability of the
relevant production practices must be determined. Thus, the statute
does not permit prosecution for failure to follow safety practices which
were not recognized prior to the production of the subject drugs.
The term good, the court went on to say, was also meaningful, notwith-
standing the fact that many dictionary meanings could be found for the
word. Conceding, however, that the word was not precise, the court noted
that "[t]he Constitution requires only a reasonable degree of certainty in
statutory language." Quoting previous opinions of the U.S. Supreme Court
on this issue, the court declared that a certain degree of imprecision is not
only inevitable, but desirable as well:
[F]ew words possess the precision of mathematical symbols, most
statutes must deal with untold and unforeseen variations in factual
situations, and the practical necessities of discharging the business of
government inevitably limit the specificity with which legislators can
spell out prohibitions. Consequently, no more than a reasonable de-
gree of certainty can be demanded. Nor is it unfair to require that one
who deliberately goes perilously close to an area of proscribed con-
duct shall take the risk that he may cross ... the line (Boyce Motor
Lines, Inc. v. United States [342 U.S. 337, 340]). 11
Moreover, the Bell court noted, the statute could not be viewed separately
from the FDA's regulations that were specifically authorized and mandated by
the statute. Congressional intent in drafting the legislation contemplated
that the regulations would operate in tandem with the statute.
"[T]he Secretary's interpretative regulations as to good manufacturing
practice for purposes of judging the adequacy of the methods, facili-
ties, and controls," the court stated, quoting Congress, "would be
prima facie evidence of what constitutes current good manufacturing
practice in any proceeding involving 351(a)(2) of the Federal Food,
Drug, and Cosmetic (FD&C) Act as amended by the bill" (1962 U.S.
Cong. & Admin. News, p. 2890).
The court concluded the FDA's regulations themselves, in providing stan-
dards under the cGMPs, "considerably illuminate the statutory language"
and served, in effect, as the legal definition of the terms (United States v. An
article of drug . .. George N. Bell Manufacturing Chemists [484 p. 2d 750]).12
Other courts addressing the issue of the vagueness of the cGMPs have
pointed to the all-encompassing regulatory scheme that was a product of col-
laboration between the FDA and the drug industry, and that, accordingly,
provides substance and meaning to the term cGMPs. In United States v. Bel-
Mar Laboratories, Inc. [284 F.Supp. 875, 883 (E.D.N.Y. 1968)], the court noted
the term "is not strange to those in the trade to whom the subject section is
directed." Citing practices reaching back to 1948, the court traced early enun-
ciations of the cGMPs to a cooperative effort between the FDA and industry
in which a series of inspections of drug manufacturers was combined with ed-
ucational conferences to establish the more progressive industry practices as
"good manufacturing practices." This program was extended and institu-
tionalized by the 1962 Amendments as minimum requirements. Accordingly,
the court in Bel-Mar noted,
[t]his is not a case where there is no meaningful referent in business
practice or usage ... or where there are no regulations in point avail-
able for guidance.... Indeed, the drug industry has actively partici-
pated in the regulatory process, and the regulations emerging
therefrom have been carefully considered.n
Finally, the courts have noted, it was Congress' purpose in enacting the
cGMP standard that it be flexible and able to encompass the changing stan-
dards of ever-changing and improving product manufacturing. Thus, the
court noted in United States v. Morton Norwich Products, Inc. [1975-1977 Jud.
Rec. 169 (N.D.N.Y.)] that
[t]he term good manufacturing practice is and of necessity must be flex-
ible in its application to the manufacture of particular drugs. Fur-
thermore, considering the end to be accomplished (i.e., the identity,
strength, quality, and purity of the drugs being introduced into com-
merce for the purpose of use by human beings, improvements and
consequent change in what is cGMP is always to be anticipated as
well as a desired end.
Thus, for the foregoing reasons, the courts have consistently rejected the
"void for vagueness" constitutional attack on the cGMPs. 14
"Open-Endedness" of the cGMP Framework

As we have seen, case law from the early period of the statute determined
that the cGMP statute was not unconstitutionally void for vagueness in no
small part due to the need, as these courts indicated, to read the statute in
conjunction with the regulatory scheme that it expressly authorized. The
regulatory scheme developed by the FDA, following notice and comment
and the participation of industry, provided, these courts held, the requisite
particularity and specificity and also provided adequate notice and guidance
to the affected parties as to be constitutionally sound. In doing so, however,
a lacuna remained open and unremarked-that the cGMP scheme, even in-
cluding the degree of specificity embodied in the FDA regulations, must be
inherently open-ended if it is-as Congress intended-to embody a dynamic,
progressive, and "current" standard of manufacture for the drug industry.
Thus, irrespective of the greater specificity of the regulations in comparison
with the underlying statute, even the regulations must be sufficiently general
as not to ossify a manufacturing standard needing constant revision through
lengthy and contentious rule-making by the FDA.
This degree of open-endedness, though smaller than that of the statute,
provided an opening for further constitutional attack, in the case of the Na-
tional Association of Pharmaceutical Manufacturers (''NAPM") v. Department of
Health and Human Services [586 F.Supp. 740 (S.D.N.Y. 1984)], in which a
generic pharmaceutical trade association attacked the FDA's regulations as,
inter alia, insufficiently precise under the constitutional standard, not com-
portive with the statutory mandate, and not applicable to new drugs. This
case represents the last major judicial analysis of the constitutionality and ap-
plicability of the FDA's cGMP scheme and contains important pronounce-
ments on the legal basis for the cGMPs.
In NAPM, the plaintiffs argued that the cGMP statute applies only to
"old" drugs, not to "new" drugs, which require FDA approval via a New Drug
Application (NDA). So-called "old" drugs are drugs that can be marketed
without advance FDA approval because they were marketed prior to enact-
ment of the statute. Because these old drugs could be marketed without FDA
approval, their method of manufacture would otherwise be unregulated ab-
sent the application of the cGMP statute. In contrast, the NAPM argued,
"new" drugs require FDA approval prior to marketing of, inter alia, the man-
ufacturing methods used in production, and that also have their own en-
forcement mechanisms by which such approval could be withdrawn if the
manufacturing methods were later found to be inadequate, were therefore
not intended to be subject to the cGMP statute. The court soundly rejected
this argument on the basis of the legislative intent, judicial precedent, and
statutory construction. All of these, the court determined, supported-either
explicitly or implicitly-that the cGMP statute was intended to apply to new
drugs with equal force as to old drugs.lS The adulteration provisions of the
Act, the court noted, provide a significantly broader range of enforcement
mechanisms, such as seizure, as well as applicability to individual lots of a
given product. Thus, if a particular lot of product was found to be adulter-
ated, regulatory action could be limited to the particular lot at issue. In con-
trast, the new drug provisions permit or prohibit marketing of a drug product
per se by rendering the application valid or invalid. Action that is more lim-
ited than product-wide invalidation is thus not possible under the new drug
provisions of the Act, which provides a rationale for the application of the
cGMP regulations to new drugs, notwithstanding the remedy already con-

tained in the new drug provisions.
With respect to the vagueness of the regulations, the court noted, fol-
lowing the precedent set for the statute in United States v. Bel-Mar Laboratories,
Inc. [284 F.Supp. 875, 883 (E.D.N.Y. 1968)] that the considerations applied to
the statute apply to the regulations as well. Where conditions-even if ex-
pressed in terms such as "adequate" and "proper"-are conjoined to specific
goals relating to the safety and purity of drugs, then those regulations are ad-
equately specific to provide guidance to the industry satisfactory to the con-
stitution. Nor, the court further maintained, did the broadly worded
regulations lend themselves to the possibility of abuse of discretion, because
the Administrator of the Act is provided broad discretion to enable him to
perform his duties fairly.
Failure to Comply with cGMPs

Constitutes Product Adulteration
The new emphasis on the manufacturing process as a determinant of prod-
uct quality was given legal sanction as well by the courts, who have deter-
mined that failure by a manufacturer to adhere to cGMPs in the
manufacturing process would, by itself, provide sufficient basis for an in-
junction against the manufacturer, even without a showing that the products
themselves were, in fact, of unacceptable quality. Thus, the courts held, a
showing by the FDA that products were not manufactured in accordance
with the cGMPs established a prima facie showing of product adulteration
under the statute, thereby shifting the burden of proof to the drug company
to prove that its products were in compliance with the statute. This standard
was applied early on, in the case of United States v. Medwick Laboratories, Inc.
[416 F.Supp. 832, 834 (N.D. Ill. 1976)], in which the U.S. government re-
quested injunctive relief to enjoin Medwick Laboratories from introducing
into interstate commerce articles of drugs that it contended were not manu-
factured in accordance with cGMPs. In that case, the court granted the gov-
ernment a temporary restraining order even though, the court noted,
[t]he government has not contended that any of the articles of drug
already manufactured and presently on hand are in fact dangerous to
the health and well-being of potential users. Nor has the government
shown that the safety, identity, quality, and purity of inventory drugs
could not be assured by appropriate sample testing and assay proce-
dures.l6
The action of the court in Medwick became the basis for the new legal
framework applied to the cGMPs. A subsequent case, United States v. Undeter-
mined Quantities ... Larson Laboratories, Inc. [1978-80 FDLI ]ud. Rec. 109
(W.O. Penna. 1979)], applied this principle to a condemnation proceeding
brought by the government to seize and destroy various drug products that
were not manufactured and tested in accordance with the cGMPs. Failure to
meet the cGMPs, the court stated, caused the drugs to be "adulterated" under
the Food and Drug Statute, 21 U.S.C. 351(a)(2)(B). The regulations, the court
noted,
[d]efine and interpret the meaning of the phrase good manufacturing

practices as found in 21 U.S.C. 3Sl(a)(2)(B), ... contain the criteria for
determining whether the manufacture, processing, or holding of a
drug conform to or are operated or administered in uniformity with
current good manufacturing practices. 17
In response to claims by the defendant drug company that its products were
actually in compliance with the statute, the court noted that the burden of
showing finished product compliance was now on the defendant:
[T]o prevail on a charge of adulteration for failure to conform to cur-
rent good manufacturing practices, the government need not estab-
lish that any article of drug actually was contaminated. IS
These court rulings have been embodied in the FDA's policy, as contained
in the FDA's "Standard Drug GMP Paragraph," standard language that the
FDA utilizes in its regulatory letters to manufacturers found deficient in
cGMPs during the course of an FDA inspection. "A drug," the FDA states in
its standard language, "is adulterated regardless of whether it is physically de-
ficient in some respect. The purpose of the good manufacturing practice pro-
vision of the Act is to control the process of drug manufacturing and to attack
the production of unreliable drugs in its incipiency, not after the fact."
Since the 1962 Amendments, the FDA has continued to shift its focus in
drug quality toward manufacturing operations. If the 1962 Amendments es-
tablished, as it were, endpoints relating to aspects of the process of manufac-
turing itself, the FDA extended this to mandating specific segments of the
manufacturing process 19 and, further, establishing controls to determine that
those processes are operating as expected. In fact, so extensively has the FDA
shifted its attention to the manufacturing process side, that the idea has been
raised as to whether, in view of the degree of control and testing over the
manufacturing process, endproduct testing might even be eliminated (Davis
1994).
ACTIVE PHARMACEUTICAL INGREDIENT STANDARDS
It is worth noting, however, that the FDA's cGMP regulations apply to "drug
products," which are defined in the regulations as a "finished dosage form"
(i.e., a capsule, tablet, solution, etc., which is the final manufactured form of
the product provided to the consumer). Thus, the regulations technically do

not explicitly refer to the manufacture of active pharmaceutical ingredients
(APis), previously known as bulk pharmaceutical chemicals (BPCs), a growing
and increasingly important segment of the pharmaceutical industry. How-
ever, although the regulations refer only to manufacture of the drug product,
as a practical matter, for the reasons explored here at length, the manufacture
of APis has been held by the FDA to standards similar, if not identical, to
those employed with respect to finished dosage forms. If it is acknowledged
that there exists a need to regulate the manufacture of drugs farther back into
the process of manufacturing in order to assure adequately the quality of the
finished product, then there should not rationally exist any distinction be-
tween the manufacture of finished product versus the manufacture of APis.
Conceptually, these two aspects of drug manufacture should be viewed as
part of a continuous process, even when performed by different companies.
As noted above, were only the narrowly construed manufacturing process for
finished dosage forms subject to the cGMPs, one could not adequately assure
the quality of the finished product if the active ingredient was similarly not
manufactured in accordance with the cGMPs. Mere testing of active ingredi-
ents by the finished product manufacturer would be subject to the same va-
garies of testing that Congress and the FDA found inadequate in the rationale
for enacting the cGMP requirements in the first instance. Thus, implement-
ing the cGMP scheme intended by Congress and the FDA truly and com-
pletely would require adherence to the cGMPs in the manufacture of active
ingredients no less than in the manufacture of finished dosage forms.
Thus, the FDA has taken the position that the good manufacturing pro-
visions of the FD&C Act, Section 501(a)(2)(B) [21 U.S.C. 351(a)(2)(B)], apply
to the manufacture of both finished and bulk drugs (FR 1993a; FDA 1991).
Accordingly, the FDA has held that, while its good manufacturing regulations
do not explicitly refer to APis, they do have significant applicability to active
ingredient manufacture.
VALIDATION
Concomitant with the new focus on the quality of drug manufacturing as a
guarantor of product quality came concepts of controls to verify the consis-
tency of the manufacturing process itself. The idea of finished product test-
ing as a check on product quality was similarly extended backward into the
manufacturing process in the form of testing the manufacturing process itself
at various critical points to determine that it was performing as expected.
In the mid-1970s, roughly contemporaneous with the FDA's rule-making
regarding cGMPs, the issue was raised within the FDA whether finished prod-
uct testing of sterile products was adequate to determine the sterility profile
of an entire batch of product. Out of this concern was born the idea that
some form of verification mechanism would need to be applied to the man-

ufacturing process to achieve results in quality assurance that could be mean-
ingfully extrapolated to an entire batch of drug product. As a result, the FDA
began to require that manufacturers "validate" the effectiveness of their man-
ufacturing procedures within the manufacturing process itself, as opposed to
merely at the finished product endpoint. Validation requirements, therefore,
began with sterilization procedures used in the manufacture of injectable
products, to be followed shortly thereafter with processes involved in the
manufacture of solid oral dosage forms (Davis 1994).
The FDA has established process validation as a requirement of the Cur-
rent Good Manufacturing Practices Regulations for Finished Pharmaceuticals,
21 CFR Parts 210 and 211, and the Good Manufacturing Practice Regulations
for Medical Devices, 21 CFR Part 820.
The scheme outlined by the FDA in the cGMP regulations includes the es-
tablishment of "written procedures for production and process control" that
are "designed to assure that the drug products have the identity, strength,
quality and purity they purport or are represented to possess" [21 CFR
211.100]. More specifically, the cGMPs require that
[t]o assure batch uniformity and integrity of drug products, written

procedures shall be established and followed that describe the in-
process controls, and tests, or examinations to be conducted on ap-
propriate samples of in-process materials of each batch. Such control
procedures shall be established to monitor the output and to validate
the performance of those manufacturing processes that may be re-
sponsible for causing variability in the characteristics of in-process
material and the drug product. Such control procedures shall include,
but are not limited to, the following, where appropriate:
1. Tablet or capsule weight variation;
2. Disintegration time;
3. Adequacy of mixing to assure uniformity and homogeneity;
4. Dissolution time and rate;
5. Clarity, completeness, or pH of solutions [21 CFR 211.110(a)].
By means of such in-process controls and tests, the manufacturing process
can be "validated," that is, determined to perform as expected and in a con-
sistent fashion, thereby producing products that meet their specifications.
In addition to controls and tests of the manufacturing process, the prod-
uct itself and its components are required to be tested at various points in the
process for such characteristics as identity, strength, quality, and purity.
These tests are required at each significant phase of the manufacturing
process, including after lengthy periods of storage [21 CFR 211.110(c)]. Eval-
uation of which points in the manufacturing process are considered critical
is relegated to the drug manufacturer, who is considered by the FDA to be

most knowledgeable and best situated to evaluate the validation process in
their plant.
In short, the FDA has defined process validation as
[e]stablishing documented evidence which provides a high degree of
assurance that a specific process will consistently produce a product
meeting its pre-determined specifications and quality characteristics
(FDA 1990).
FDA's Validation Guideline of 1987

In its guideline on process validation first issued in 1987, the FDA elaborated
on the general principles and practice that were of general applicability and
acceptable to the FDA but which the FDA indicated were not "legal require-
ments." In this document, the FDA provided its views of validation as re-
quiring validation of equipment and installation, process performance, and
product performance, as well as the various types of validation that may be
acceptable in various circumstances.
Initially, the FDA reviewed the by-then well-settled legal basis for valida-
tion as clearly embodied in numerous regulations in 21 CFR Parts 210 and
211, both generally as well as specifically. The purpose of the guideline, how-
ever, was to significantly elaborate on the procedures and methods to be fol-
lowed in validation studies, to provide guidance to the industry in the area.
The document, while considerably more specific than the FDA's regulations,
continues to preserve the open-endedness and flexibility characteristic of the
cGMP analysis. Thus, the FDA points out in its "preliminary considerations,"
that
[a] manufacturer should evaluate all factors that affect product qual-
ity when designing and undertaking a process validation study. These
factors may vary considerably among different products and manu-
facturing technologies and could include, for example, component
specifications, air and water handling systems, environmental con-
trols, equipment functions, and process control operations. No single
approach to process validation will be appropriate and complete in
all cases; however, the following quality activities should be under-
taken in most situations.
The specifications used by a firm in its validation testing are, therefore, de-
rived by the company itself, in its research and development (R&D) phase,
where the product's physical, chemical, and performance characteristics are
°
determined. 2 Full documentation of the validation program is required, and
the FDA further requires that approval and release of the process for routine
manufacturing be made only on the basis of a full and in-depth review of the
validation documentation from beginning to end (i.e., from equipment vali-
dation, process performance qualification, to product and package testing).
The FDA's guideline also described the kinds of validation that were ac-
ceptable and the parameters for their use. Validation, the FDA noted, could
be prospective as well as retrospective. Prospective validation is a study of the
manner in which the manufacturing process conforms with a predetermined
set of criteria and specifications developed on the basis of R&D on the prod-
uct, prior to the beginning of commercial manufacturing. This is the
standard means of validation now required of all products. Nevertheless, the
FDA recognized circumstances in which so-called "retrospective" validation
might be appropriate and might yield valuable data, on the basis of the in-
spection of data available for a product after the manufacturing process has
been under way for a substantial period of time. 21 Detailed finished product
test results, the guideline noted, could be statistically analyzed in terms of the
degree of variance observed, in comparison with the degree of variance that
might be expected from the process. This form of validation permitted cer-
tain conclusions regarding the manufacturing process to be reached on the
basis of finished product specifications and, therefore, represented a throw-
back to pre-cGMP conceptions of product quality.
Validation of Active Pharmaceutical Ingredients

As noted above, notwithstanding its absence from the FDA regulations, the
FDA has applied concepts of Good Manufacturing Practice (GMP) to active in-
gredient manufacturing by virtue of the statutory mandate underlying the
cGMPs. As a result, the FDA's requirement of manufacturing validation-an
outgrowth of cGMP requirements-has similarly been held applicable to ac-
tive ingredient manufacturing. While recognizing that process validation re-
quirements for active ingredient pharmaceutical chemicals differ in some
respects from those required for dosage form products (FDA 1991), the FDA
has established process validation requirements for APis as a condition for the
approval of all drug applications (Compliance Policy Guide 7132c.08). In addi-
tion, the FDA has drafted a guidance, "Manufacture, Processing or Holding of
Active Pharmaceutical Ingredients" first released for discussion in 1996, which
specifically sets forth detailed requirements for the validation of APis.22
The Barr Laboratories Decision

One of the most detailed judicial considerations of the FDA's validation re-
quirement was the case of United States v. Barr Laboratories [812 F.Supp. 458,
474-475, 477 (D.N.]. 1993)], which addressed a broad-ranging FDA attack on
the manufacturing practices of the defendant, Barr Laboratories, a generic
drug company. Among the deficiencies cited by the government as a reason

for prohibiting any further distribution of drug product by the company was
the lack of validation of the company's manufacturing processes. The court,
addressing this issue, noted that the FDA's validation requirement requires
that in-process testing be conducted on both in-process materials as well as
the manufacturing process itself. In-process materials, the court noted,
should be tested for identity, strength, quality, and purity "and approved or
rejected by the quality control units during the production process (e.g., at
commencement or completion of significant phases or after storage for long
periods)." In-process testing includes such testing as assay, content unifor-
mity, and dissolution testing.23 Validation studies, the court indicated, are
made up of assay and content uniformity testing at the blend stage and assay,
content uniformity, and dissolution testing at the finished product stage. 24
This testing, moreover, is required to be set out in writing and verified.
Quoting from the FDA's regulations, the court declared that the purpose of
these written procedures is "to monitor the output and to validate the per-
formance of those manufacturing processes that may be responsible for caus-
ing variability in the characteristics of in-process material and the drug
product."
In addition, the court noted, three types of validation were available to
the manufacturer: prospective validation, which requires the manufacturer to
produce at least three consecutive batches under closely controlled condi-
tions prior to marketing of a new drug, with all appropriate studies and test-
ing; concurrent validation for existing products, also based on testing of at
least three consecutive batches; and retrospective validation, which is essen-
tially an extrapolation for existing products, based on lengthy past experi-
ence with manufacturing batches consistently meeting specifications. In Barr,
the FDA charged that Barr's products could not be retrospectively validated
due to numerous failures and that, consequently, its manufacturing processes
were invalid. The court, analyzing Barr's practices, focused on the deficiencies
in its testing program, including such practices as omitting failing testing re-
sults, omitting failing batches, and insufficient batches for validation.
With regard to Barr's practice of omitting failing testing results from its
retrospective validation studies, the court noted that such omissions were im-
proper without an appropriate failure investigation. In addition to omissions
of failing testing results, the court also examined Barr's practice of omitting
failing batches from consideration and determined that all batches within a
predetermined time frame must be included for validation. However,
the court noted, batches considered for validation must be representative of
the manufacturing process. Accordingly, batches manufactured under a dif-
ferent process could be omitted from consideration. The court instructed that
any batches omitted must be accompanied by an explanation and that Barr
document the reasons for exclusion "through a failure investigation if the
problem is an operator error, or a written explanation of the process and its
modifications if different processes are used."
The court in Barr also addressed one of the more vexing problems in-
volved in validation (i.e., the number of batches required to perform a proper
retrospective validation study). In contrast to the government's contention
that a series of 10 batches would be appropriate, Barr argued that by means
of statistical analysis, a smaller number of batches might be appropriate. The
court, reviewing the various figures provided by the experts, ranging from
somewhere above 5, and up to 20 or 30, declined to settle on a precise num-
ber of studies applicable in all cases. Rather, the court determined that, in the
absence of definitive guidance from the FDA's regulations, the "general rule"
in retrospective validation should be to test 20-30 batches in a retrospective
validation study, but a firm can depart from this number provided it can sup-
port any such departure with statistical or other evidence that supports vali-
dation. The court noted, however, that because a 10 percent failure rate is
unacceptable, if one batch fails, a minimum of 10 batches would be required
to support a retrospective validation study.
The court's decision-making with respect to the number of batches re-
quired for validation reveals an attempt to comport with the deeper, under-
lying goals and purposes of validation, while simultaneously attempting to
provide the definitive decision-making sought by the adversaries before it.
The court, having been importuned by the litigants to determine whether the
Barr practices comported with the cGMPs and, hence, whether Barr's prod-
ucts could be marketed, was required to make definitive determinations even
as the issues before it stemmed from a statute and regulations cast in vague
terms precisely to permit the flexible and subtle scientific distinctions that
courts are typically ill-suited to make. Accordingly, the court wisely chose in
a number of critical areas to preserve the open-endedness of the cGMP
scheme by providing guidance based on the expert testimony before it, while
allowing flexibility to a company to act otherwise, provided it could show ad-
equate justification for doing so.
The court adopted such a flexible approach in other areas of validation,
by suggesting appropriate standards and methods as a "general rule," while
leaving a case-by-case determination to the company and to its ability to jus-
tify its decision-making. For example, on the issue of sampling during the
manufacturing process, the court was called upon to adjudicate Barr's prac-
tice of sampling from drums of blended product, as opposed to sampling
from the mixer itself during the blending step, as urged by the FDA. Deter-
mining content uniformity, the court rightly observed, was appropriate for
the blending stage, where uniformity problems in the manufacturing process
will likely be discovered. In contrast, sampling from drums of blended prod-
uct is not qualitatively different from sampling of the final product, which is
no longer within the realm of testing for process validation. Accordingly, the
court determined that the mixer was the most appropriate point for sampling
as a general matter, but if Barr wished to sample from the drum, it must
demonstrate the appropriateness of the technique.
In addition to preserving elements of open-endedness embedded in the

regulatory scheme, the court also recognized the desirability of preserving the
FDA's role in the cGMP area and specifically declined to make adjudications
while maintaining the FDA's judgment and discretion were important. Thus,
for example, the court was asked to adjudicate the adequacy of Barr's valida-
tion of its testing methods. This form of validation is designed to determine
that analytical methods used in laboratory procedures that measure attrib-
utes of the product or raw material against prescribed specifications are reli-
able and consistent means of measurement. Under the FDA's regulatory
scheme, the company is required to establish the reliability of its testing
methods by reference either to the U.S. Pharmacopeia (USP) or other stan-
dard reference, or by reference to a method approved in the drug application,
or by reference to some other method that the company is able to validate
through a validation study. 2 5 In this case, the government conceded that
Barr's methods conformed with the USP but were not current with the most
up-to-date, revised USP methods. The court, declining to adjudicate the ade-
quacy of the methods employed by Barr, determined that "[b]ecause Barr's
analytical methods conform to the USP, the CFR or Barr ANDAs [Abbreviated
New Drug Applications], they are entitled to a presumption of validity." Nev-
ertheless, the court observed, "[t]he government's reservations, however, can-
not be disregarded lightly." Accordingly, the court held that Barr and the
government should review Barr's raw data on the issue and come to agree-
ment on whether Barr met the validation standards and what further infor-
mation would be required to do so. The court concluded its consideration of
the issue on a note of optimism:
In light of Barr's former willingness to update its methods in confor-
mance with USP revisions ... the Court is confident that the parties
will be able to resolve any subsequent disagreements without judicial
intervention.
Notwithstanding these examples of the court's unwillingness to settle on
a degree of regulatory specificity deliberately left open by the statute and reg-
ulations, the court, in some instances, could not evade definitive pro-
nouncements on the cGMP standards when these were squarely set before it
for adjudication. One such case was the highly controversial FDA require-
ment of the validation of cleaning procedures utilized by manufacturers. This
form of validation essentially required the company to determine that the
procedures utilized for cleaning its equipment were sufficient to eliminate
any residue from previous use. Three issues relating to cleaning validation
were placed before the court, based on Barr's practices: (1) whether Barr is re-
quired to identify the cleaning agents used in its cleaning procedures; (2) the
extent to which Barr is required to test for cleaning agent residues; and
(3) the number of times a cleaning procedure must be run in order to demon-
strate the reproducibility of the cleaning procedure. On these issues, the
court delivered specific instructions: 21 CFR 211.67, which requires a "de-

scription in sufficient detail" of the methods and materials used in cleaning,
requires identification of the cleaning agents used; that in view of the afore-
mentioned identification, there is a reduced need to test for cleaning agent
residues "unless Barr chooses to clean with a substance known to have such
difficulties"; and one run-through of the cleaning procedure, in the absence
of problems, "is not insufficient for validation."
Having analyzed Barr's practices and the complaints of the government,
the court turned to the issue of fashioning a remedy to address the issues
raised before it. Initially, the court determined on the basis of prior case law
that Barr's failure to comport with cGMP regulations caused products pro-
duced thereby to be adulterated under the statute. In addition, the court was
empowered to issue equitable relief, including injunction, to prevent further
wrongdoing by the company. The court concluded,
[W]ith regard to past violations, there can be no dispute that Barr has
violated the Act by failing to follow manufacturing practices that
comply with cGMP as required under section 351(a)(2)(B) and, there-
fore, has introduced adulterated drugs into commerce in violation of
section 331(a).
Barr's violative practices, the court determined, included failing to conduct

failure investigations, release of batches on the basis of selective data, and re-
fusal to validate its cleaning processes, in specific violation of 21 CFR
211.16S(a), 211.192, and 211.67. These violations rendered Barr's products
produced thereunder adulterated under the statute.
Product adulteration, however, the court found, is not the sole criterion
for entering an injunction against a defendant.[26) Injunctive relief requires,
the court noted, not only a finding of violation but also a "cognizable dan-
ger of recurrent violations." Turning to the question of Barr's future behavior,
the court examined Barr's past and present practices, concluding that "in-
junctive relief is necessary to safeguard the public interest" in this case. The
reason is that Barr's violative practices were contained in Barr's Standard Op-
erating Procedures (SOPs) and were vigorously defended by Barr's employees
at trial. In light of these, the court determined,
[O]nly through an injunction can the Court be confident that these

forbidden methods ... will be abandoned and the products made un-
der their auspices shielded from the public.
Accordingly, the court determined, injunctive relief was appropriate.

Having determined that injunctive relief was appropriate, the court then
addressed the question of the kind of relief required to address the issues be-
fore it. With respect to Barr's general cGMP violations, the court noted, Barr
had made extensive progress in bringing its operations into compliance.
Although yet incomplete, in light of these efforts, the court determined that
a general shutdown was inappropriate and unnecessary.
The question of noncompliance with product validation requirements,
however, was viewed as of greater concern:
[T]o the extent that Barr relied upon investigations which do not sat-
isfy section 211.192, as construed by the Court, to release batches or
to complete retrospective and prospective validation studies, these
actions and studies are invalid. Reliance on faulty methods cannot be
cured by subsequent compliance.
Moreover, the court noted, the many failures of Barr's batches itself demon-
strated that Barr's manufacturing procedures were not properly validated,
notwithstanding that the procedures may have been contained in Barr's
ANDAs and followed by the company. In such instances, failures in practice
were of greater importance than merely adhering to the ANDA procedure, be-
cause the ANDA procedure, the court observed, as often the result of testing
on smaller batches, may not evidence problems that might occur or be re-
vealed in scaled-up production. Accordingly, the court found that "[i]n order
to comply with cGMP, firms must correct any process that demonstrates its
own inadequacies in practice," and further validation studies were necessary
notwithstanding reliance on the procedures contained in the ANDAs. Barr,
the court held, was required to cease distribution of certain products that
were of particular concern to the government based on the degree of failures.
Other products, the court held, could be distributed only if concurrent or
prospective validation studies were performed, and the products tested in ac-
cordance with proper procedures. 27
Following issuance of the Barr decision and the ending of its judicial se-
quellae28, the FDA issued a lengthy analysis of the issues in Barr in which it
elaborated on the evidence in the case, and the basis for its decision-making
in light of the decision of the court (FR 1993b). In its analysis, the FDA
pointed to Barr's repeated exclusion of failing results and batches from its ex-
amination of its manufacturing processes as key to the FDA's view that its val-
idation program, such as it was, was fatally flawed. The exclusions included,
the FDA noted, out-of-specification test results from commercial batches,
out-of-specification results from in-process blend uniformity testing, finished
product assay testing, content uniformity testing, dissolution testing, and
stability testing. These exclusions, the FDA noted, which occurred both with
respect to Barr's prospective and retrospective validation studies, distorted
the results of the studies to the extent that no guidance could be extracted
with respect to the performance characteristics of the manufacturing
processes under examination.
In addition to the above, Barr's validation notebooks, which were sub-
mitted by Barr to validate its products retrospectively, were inadequate to
establish proper validation due to imprecision in testing data. Insufficient
data, averaged data, and missing data that characterized the documentation
rendered the notebooks insufficient to establish retrospective validation of
the manufacturing processes for Barr's products. Moreover, the FDA analyzed
a number of Barr's supplemental applications that contained changes that,
the FDA stated, could cause variability in the characteristics of the in-process
materials as well as in the finished products. These, the FDA found, required
validation prior to implementation.
Based on the foregoing, the FDA found Barr violative of a number of pro-
visions of the FD&C Act, specifically 21 U.S.C. 35S(j)(3)(A) [methods, facili-
ties, and controls inadequate to assure identity, strength, quality, and purity],
21 U.S.C. 357(a) [applicable to ANDAs], and accordingly determined to refuse
to approve applications of Barr under 21 U.S.C. 357(a), 355(c)(1)(B), (d)(3),
(j)(3)(A), and (j)(4)(C).z9
CONCLUSION
The history and progression of the FDA's legal basis for validation evidences
a steadily increasing reaching back into the process of drug manufacture, an
evolution fostered by the flexibility and open-endedness embedded in the
regulatory framework to provide the FDA with a dynamic, progressive stan-
dard for assessing product quality. This progression, deriving its impetus from
the particular exigencies of pharmaceuticals and their intimate relation to
human health and well-being, has as its endpoint the delivery of safe and ef-
fective drug products to a vulnerable consumer. There has thus emerged an
ever-widening fencing-in process, taking greater and greater areas of drug
manufacture into its ambit, subject to ever-greater scrutiny and control. It is
for this reason that the concern of drug and device legislation and regulation
has increasingly been with the context of drug manufacture, as opposed to
merely the product of that manufacture. 3D
NOTES
1. FDA officials conceded the inadequacy of finished product testing as a
means of assuring drug product quality as a reason for moving toward
process validation. A former FDA official who was at one time in charge
of the FDA's postmarketing sampling program, described the problems
as follows:
"Several attempts by my predecessor and by me were made to
have our statisticians design the program to give better reliabil-
ity of batch characteristics. All failed. The statisticians would
always get around to the troubling question, what level of de-

fects are you willing to accept? And then, of course, was the
number of units to be sampled. In most cases, to design a sam-
pling scheme to be statistically representative of a batch, say
1-5,000,000 units, would require sampling a quantity that is
economically prohibitive" (Davis 1994).
2. See United States v. Western Serum Co., Inc., 498 F.Supp. 863, 867 (D.Ariz.
1980) Aff'd, 666 F.2d 335 (9th Cir. 1982). "The Act is concerned with the
manner in which a drug is produced as well as its content."
3. A heightened degree of scrutiny and protection has long been attached
by the courts to legislation regulating the food and drug fields due to
the strong public policy of protecting the public health and welfare. See
United States v. Dotterweich [320 U.S. 277, 280], which describes the Food,
Drug, and Cosmetic Act as touching "phases of the lives and health of
people which, in the circumstances of modern industrialism, are largely
beyond self-protection." Accordingly, the courts will often provide
greater leeway in the food and drug field to a regulatory scheme de-
signed to protect the public, finding that marketers of drug products
should more properly bear the burdens of compliance because they
"have at least the opportunity of informing themselves of the existence
of conditions imposed for the protection of consumers before sharing in
illicit commerce, rather than to throw the hazard on the innocent pub-
lic who are wholly helpless" (1962 U.S. Code Cong. & Admin. News,
p. 285).
4. The parallel GMP provision of the Act relating to devices is at 21 U.S.C.
351(h).
5. The FDA issued its first set of regulations under Section 501(a)(2)(B) in
1963 (FR 1963) and a revised set of regulations in 1978 (FR 1978).
6. 21 U.S.C. Section 371(a): "The authority to promulgate regulations for
the efficient enforcement of this Act, except as otherwise provided in
this section, is hereby vested in the Secretary."
7. Most importantly, Weinberger v. Bentex Pharmaceuticals, Inc., [412 U.S.
645 (1973)] and National Nutritional Foods Ass'n v. Weinberger [512 F.2d
688 (1975)]. See also the cases cited in note 9.
8. judicial review, the FDA observed, is available for all regulations,
whether substantive or interpretive, under the Administrative Procedure
Act and is also available in any enforcement proceeding.
9. Significantly, the following seminal cases: Abbott Laboratories v. Gardner
[387 U.S. 136 (1967)], rev'g. Abbott Laboratories v. Celebreeze [352 F.2d
286 (3rd Cir. 1985)]; Gardner v. Toilet Goods Ass'n [387 U.S. 167 (1967)]
aff'g Toilet Goods Ass'n v. Gardner [360 F.2d 677 (2d Cir. 1966)]; and
Weinberger v. Hynson, Westcott & Dunning, Inc., [412 U.S. 609 (1973)];
CIBA Corp. v. Weinberger (412 U.S. 655 (1973)].
10. See also United States v. Articles of Drug ... Colchidne (442 F.Supp. 1236
(S.D.N.Y. 1978)], aff'd sub nom, United States v. Consolidated Midland
Corp. [630 F.2d 215 (2d Cir. 1979)]: "The Secretary's interpretive regula-
tions as to what constitutes good manufacturing practice concretize the
statutory language of 21 U.S.C. 351(a)(2)(B), eliminated the possibility
of vagueness, ... and have the binding force of law."
11. See also United States v. Bel-Mar Laboratories, Inc., (284 F.Supp. 875, 883
(E.D.N.Y. 1968)], wherein the court noted that "there are responsible
segments of opinion within the industry itself which oppose a greater
degree of specificity in this area."
12. Lest it be supposed that the defendant was merely churlish in its argu-
ments concerning these terms, the defendant in Bell actually cited pre-
vious U.S. Supreme Court decisions that held the terms current and good
to be unconstitutionally vague. The court in Bell differentiated those de-
cisions as specific to their factual contexts and inapplicable to the case
at bar.
13. See also United States v. Morton Norwich Products, Inc. (1975-1977 Jud.
Rec. 169 (N.D.N.Y.)] and United States v. Kendall Co. [324 F.Supp. 628)
D.Mass. 1971)].
14. See, e.g., United States v. Kendall Co. [324 F.Supp. 628 (D.Mass. 1971)],
which rejected the argument in the context of a criminal prosecution
for the introduction into interstate commerce of adulterated drug prod-
uct.
15. For example, in addition to finding explicit support in the legislative
history to support application of the statute to new drugs, the court also
endorsed the government's view that inclusion of new drugs should be
implied in the absence of any explicit exemption for new drugs. Such
an exemption should be read into the statute only if it is necessary "to
prevent absurd results or consequences obviously at variance with the
policy of the enactment as a whole" {National Assodation of Pharmaceu-
tical Manufacturers ("NAPM") v. Department of Health and Human Services
[586 F.Supp. at 750 (S.D.N.Y. 1984)]}.
16. That Congress intended legal sanction to apply to the drug manufac-
turing phase per se is evident from the legislative history underlying the
statute that deems adulterated any product not produced in conformity
with the cGMPs, irrespective of whether the drug product actually was
deficient in some respect. See 1962 U.S. Code Cong. & Admin. News,
p. 2890; United States v. Bel-Mar Laboratories, Inc. [284 F.Supp. at 881
(E.D.N.Y. 1968)].
17. See, e.g., United States v. Dianovin Pharmaceuticals, Inc., et al. [342 F.Supp.
724 (Puerto Rico 1972)].
18. See United States v. Undetermined Quantities of Various Articles [800 F.Supp.
499, 502 (S.D. Tex. 1992)]: "In order to prove a claim of adulteration of
a device based upon non-compliance with GMP regulations, the Gov-
ernment need not establish that the device is actually deficient as a result
of the GMP violation"; United States v. Lit Drug Company [333 F.Supp.
990, 998 (D.N.J. 1971)]: "Thus a drug may be pharmaceutically perfect
in content but still be regarded as adulterated under the law"; United
States v. 789 Cases [799 F.Supp. 1275 (D. Puerto Rico 1992)], which ap-
plies to the device context the above case law construing the effect of
the cGMPs and Section SOl in the area of drugs. Thus, the court, citing
the case law, held in the case of medical gloves kept under unsanitary
conditions that "the government is not required to prove any actual
contamination of the product to establish adulteration. . .. The gov-
ernment need only prove that there is a reasonable expectation that the
articles could become contaminated with filth" {United States v. Bronx
Drug Co .. .. Isaac Zonana [1969-74 FDLI Jud. Rec. 267 (S.D.N.Y. 1971)]}.
19. The requirement that nonanalytical methods be stability-indicating is
an example of increasingly specific forms of manufacturing processes
being mandated by the FDA.
20. Notably, the FDA suggests that any changes to the product specifica-
tions be made only in accordance with documented change control pro-
cedures.
21. This type of validation was allowed by the FDA on a limited basis for
products that had been marketed for a long time when it began to de-
velop its detailed validation program in the late 1980s. A continued role
for retrospective validation is viewed as primarily augmentative to
prospective validation (i.e., providing additional data to supplement
and support prospective validation data) and also to either build confi-
dence in a particular manufacturing process or impugn it as test results
are received.
22. The Guidance, which is detailed in its validation requirements for APis,
codifies many of the requirements previously enunciated by the FDA
and enforced in inspections. The Guidance, however, firmly establishes
the validation requirement for APis, noting, inter alia, that "[m]anufac-
turers should be actively engaged in a validation program for all
distibuted APis," and that "[v]alidation should extend to those steps de-
termined to be critical for the quality and purity of the final API."
23. Assay testing measures the potency (i.e., concentration of the active in-
gredients in the drug product). Content uniformity is a measurement of
the consistency and variability in potencies among different samples
and dosages of the drug product. Dissolution testing measures the rate at
which the drug will dissolve and thereby release its active ingredients
into the body.
24. Testing at the "blend" state, which is an intermediate manufacturing
process stage at which the various drug product ingredients are blended,
is a hallmark of validation testing, because it is performed on an inter-
mediate sample, prior to the finished product stage. It is designed to de-
termine that the blending of ingredients results in uniformity and
appropriate dispersion and integrity in the active ingredients at a criti-
cal step in the manufacturing product.
25. See 21 CFR Section 211.165(e); 211.194(a)(2). The regulation itself refers
to the requirement for the validation of testing methods and notes, par-
enthetically, that if the method of testing is contained in the USP or
other reference, or is contained in the NDA, a statement referencing this
method is sufficient [21 CFR 211.194(a)(2)]. ·
26. The government had sought an injunction from the court to shut down
the operations of Barr pending its correction of the problems found.
27. In addition to injunctive relief, the court ordered recalls of products that
were released on the basis of inadequate, or inconsistent, testing prior
to release.
28. A Motion for Clarification and/or Reconsideration filed by Barr, fol-

lowed by a Consent Order by the court three days afterward.
29. The series of the FDA enforcement and court actions culminating in
John D. Copanos et al. v. Food and Drug Administration et al. [854 F.2d 510
(D.C. Cir. 1988)] represent yet a further extension of the cGMP rubric,
by applying a company's history of compliance to negate the validity of
the drug application itself and not merely the process of its manufac-
turing. In this case, the FDA seized and condemned product, and ulti-
mately withdrew the company's NDAs, on the basis of serious and
repeated failure to manufacture the products in conformity with ap-
plicable cGMPs.
30. Counterparts to this concern for context may be found (e.g., in the
FDA's debarment authority, which debars persons and companies con-
victed of wrongdoing from being associated with the submission of drug
applications to the FDA).
REFERENCES
Compliance Policy Guide (Process Validation Requirements for Drug Products Subject to
Pre-Market Approval). CPG 7132c.08; August 30, 1993. Rockville, Md., USA: Food
Davis, J. S. 1994. Retesting and laboratory investigations. Journal of Pharmaceutical Sci-
ence & Technology 48:107.
FDA. 1990. Guidelines on general principles of process validation. Rockville, Md., USA:
FR. 1963. Federal Register 28:6385.
FR. 1978. Federal Register 48:45014-45024.
FR. 1993a. Current good manufacturing practices in manufacturing, processing, pack-
ing or holding of drugs; revision of certain labeling controls. Federal Register
58:41348.
FR. 1993b. Barr Laboratories, Inc., refusal to approve certain abbreviated applications,
opportunity for a hearing. Federal Register 58:31035.
4
DRUG MASTER FILES
Arthur B. Shaw
Division of Gastrointestinal and Coagulation Drug Products
Food and Drug Administration
The Food and Drug Administration (FDA) is charged with ensuring that safe
and effective drugs are available to the American public. In order for the FDA
to adequately review an application to market a drug, the application must
contain details on chemistry, manufacturing, and controls (CMC) as required
by 21 CFR 314.50. In addition, submissions to the FDA to ship unapproved
drugs for investigational use (Investigational New Drug Applications [INDs]),
covered under 21 CFR 312, must also contain CMC information [21 CFR
312.23 (a) (7)]. A number of years ago, the FDA recognized that it was desir-
able to provide a mechanism whereby manufacturers of bulk drug sub-
stances, excipients, and packaging materials could provide information for
review by the FDA without filing a formal application. This Drug Master File
(DMF) system was established so that companies submitting New Drug Ap-
plications (NDAs), INDs, and Abbreviated New Drug Applications (ANDAs)
could incorporate information in the DMFs by reference. This means that a
DMF holder does not have to submit the same information in each applica-
tion. (In the following discussion an "application" refers to an NDA, an IND,
an ANDA, an Export Application, or another DMF, while an "applicant" refers
to the individual or company that submits an application. A "holder" is an
individual or company that submits a DMF.) If an active pharmaceutical in-
gredient (API) manufacturer chooses to provide the details of its manufactur-
ing process in each application that uses the API, it may do so. However, most
firms prefer to keep the information in a DMF.
83
REGULATORY BASIS FOR DMFs

As stated above, an application is required to contain CMC information under
21 CFR 314.50 and 21 CFR 312.23(a)(7). Submission of a DMF, under 21 CFR
314.420, is an alternative mechanism to provide this information to the FDA.
DMFs are entirely voluntary and are not required by any law or regulation.
Guideline
Detailed information on the submission of a DMF may be found in the Guide-
line for Drug Master Files (DMF Guideline) published by the FDA in September
of 1989. Even though the guideline is in the process of being revised, most of
the basic features are not expected to change. This guideline, as well as other
guidelines and guidances mentioned in this chapter, may be obtained from
the Drug Information Branch using any of the following resources:
Telephone: 301-827-4573
Fax-on-Demand 800-342-2722 or 301-827-0577 (the DMF Guide-
(FOD): line is document 4001)
E-mail: druginfo@cder.fda.gov
Internet: http:/ /www.fda.govI cder I guidance/index.htm
The DMF Guideline contains information on how to organize and sub-
mit a DMF, but the details on the technical content of the DMF are found in
the guidelines for that particular technical area (drug substance, drug product,
etc.). For APis, the appropriate document is the Guideline for Submitting Sup-
porting Documentation in Drug Applications for the Manufacture of Drug Sub-
stances, also known as the "Drug Substance Guideline" (DSG). It should be
noted that guidelines were issued under 21 CFR 10.90(b), which provides for
the use of guidelines to state procedures or standards of general applicability
that are not legal requirements but that are acceptable to the FDA. Note that
new guidelines are called "Guidances." Guidance documents represent the
FDA's current thinking on a particular subject. They do not create or confer
any rights for or on any person and do not operate to bind the FDA or the
public. An alternative approach may be used if such approach satisfies the re-
quirements of the applicable statutes, regulations, or both.
RELATIONSHIP BETWEEN HOLDER AND APPLICANT

The information in a DMF is confidential and cannot be revealed by the FDA
to a third party. In particular, this means that the FDA will not disclose any in-
formation in the DMF to an applicant who incorporates the information in
the DMF by reference. If the applicant and the DMF holder choose to make an
Drug Master Files 85
agreement with each other to permit the applicant to obtain information

from the DMF holder, they may do so without FDA involvement.
A DMF holder and an applicant can be the same individual or company.
This is often done when the manufacturer of an API is a subsidiary of the ap-
plicant. For example, a new drug substance is sometimes used in a number of
different NDAs held by the same applicant. In this case, the applicant may
choose to keep information concerning the drug substance in a DMF to allow
for changes in the synthesis or testing of the drug substance without having
to include the details of each change in each NDA. In other cases, the appli-
cant may be planning to spin off the plant that is manufacturing the new
drug substance after the NDA is approved so that the drug substance manu-
facturer becomes a separate corporate entity or a subsidiary of another com-
pany. Having the manufacturing procedure already described in a DMF can
facilitate this process.
In the more common situation the DMF holder and the applicant are
different companies. In particular, there are a number of manufacturers of
APis that supply drug substances to applicants that have filed or plan to file
ANDAs for generic drug products.
FILING AND REFERENCING A DMF

The mechanism by which a DMF holder grants permission for the FDA to ex-
amine a DMF is by submitting a "Letter of Authorization" (LOA) to the DMF,
stating the specific portion of the DMF that is referenced. A copy of the LOA
must be filed with the application that references the DMF. The details that
should be included in an LOA are provided in the DMF Guideline.
The process for the handling of DMFs is summarized in Figure 4.1. When
a DMF is submitted to the FDA, it is examined by Central Document Room
(CDR) staff to determine whether the DMF is acceptable from an administra-
tive point of view. Since the CDR staff does not have technical training, no
technical review is done at this stage. The DMF is assigned a number, and the
holder is notified of the number. There is no fee for filing a DMF. The DMF
then remains on file in the CDR. The DMF holder is expected to provide an
annual update, including a list of firms that have been authorized to reference
the DMF. If there are no changes, the DMF holder is still expected to provide
a statement that there have been no changes. Although the LOA is expected
to contain a statement that the DMF is current, this is not a substitute for fil-
ing an annual update. If there is no DMF activity over a period of three years,
the DMF may be retired to the Federal Records Center, where it is not readily
accessible for review.
Figure 4.1 The Process for Handling DMFs
DMF returned
to Holder
DMF assigned
number and
placed In file
DMF maintained but not

reviewed
No
Yes
DMF
Reviewed
REVIEW OF A DMF
The FDA reviews a DMF only when it is referenced in an application (Figure
4.2). Some of the reasons for this policy are as follows:
• The information in the DMF must be reviewed in the context of the

characteristics of the drug product that utilizes the material de-
scribed in the DMF. These characteristics may include the dosage
form, the route of administration, and the dosing regimen.
• A DMF may be filed a number of years before it is used in support of
an application. For example, API manufacturers often file a DMF
for a drug substance before the exclusivity expires for the drug
Figure 4.2 Review Procedures for a DMF
Applicant not notified,

application may be approved
Holder not notified
Applicant notified that

deficiencies exist via IR, AE,
or NA Letter
Deficiency letter sent to

holder, detailing deficiencies
No Application
remains AE/NA
No review of DMF
amendment, application
remains AEINA
reviewed
product utilizing that active moiety. The FDA has an obligation to

review applications (particularly ANDAs) in the order in which
they are filed and within certain time constraints. Therefore, the
FDA cannot "prereview" DMFs.
• A DMF may be filed but never actually referenced. Since there is no
way of knowing at the time of filing whether a DMF will be refer-
enced, reviewing a DMF that never gets referenced would be an in-
efficient use of the FDA's resources.
After a DMF is reviewed, the review is filed with the DMF jacket. If there
are deficiencies, the DMF holder is informed of the deficiencies in a letter. The
applicant whose DMF is supported by the DMF is informed that there are de-
ficiencies, but the details are not provided to the applicant.
In general, an "Action Letter" (i.e., an approvable [AE], not approvable
[NA], or approval [AP] letter) is sent to an applicant when all the reviews (in-
cluding reviews of supporting DMFs) for that application are complete. How-
ever, depending on the timing of the review of the DMF relative to the "due
date" of the application and the progress of other reviews, the applicant may
be sent an "Information Request" (IR) or a discipline review (DR) letter, which
are not classified as an "action letters." This situation occurs more frequently
with NDAs than with ANDAs.
If there are no deficiencies in a DMF, neither the holder nor the appli-
cant is informed of this fact (see below).
When a DMF holder amends a DMF to correct the deficiencies, it should
notify the applicant whose application is supported by the DMF. The appli-
cant should then amend its application, informing the FDA that the DMF has
been amended. The DMF amendment will not be reviewed unless the appli-
cation that it supports is amended. The reason for this has to do with the de-
tails of the "review clock" for review of NDAs and ANDAs. The clock is
stopped by the issuance of the action letter (AE or NA) by the FDA and can be
restarted only by a complete response to the letter by the applicant. (In the
case where the applicant was notified of the DMF deficiencies in an IR or DR
letter, which are not classified as an agency "actions," the clock was not
stopped. However, the timing of the response to the IR or DR letter may effect
an extension of the review clock.) There are often situations in which an ap-
plicant receives an action letter and chooses to withdraw or otherwise sus-
pend activity on the application. In this case, any DMF amendment in
response to a DMF deficiency letter would not need to be reviewed. Therefore,
the review of a DMF amendment can occur only if the application that the
DMF supports is amended.
The difference in .the handling and storage of DMFs and applications
dictates that an added step should be followed when a DMF is amended.
When the review of a DMF is complete, the DMF jacket is returned to the
CDR. However, when the review of an application is finished, the application
jacket is returned to the reviewing division's document room. When an

amendment to an application comes in, the division document room staff
logs it into the division and distributes the amendment to the individuals
who are assigned to that particular application. On the other hand, when the
DMF is amended, the CDR staff does not notify the reviewer who last re-
viewed the DMF, since no individual is assigned to review a particular DMF. It
is the responsibility of the holder to notify the applicant and the reviewer
that the DMF has been amended. The holder should not submit the technical
details in the amendment directly to the reviewer.
In some cases, the holder may choose to submit a response to the defi-
ciency letter directly to the applicant, without amending the DMF. It is im-
portant that all communications concerning the DMF be placed in the DMF
itself. If the holder does not submit an amendment to the DMF, the next re-
viewer will see that there is an outstanding deficiency with no response from
the holder, and any new application supported by that DMF cannot be ap-
proved. Therefore, DMF holders should submit all amendments to the DMF.
APPROVAL OF DMFs
The FDA neither approves nor disapproves DMFs. These would be agency "ac-
tions." In addition, the FDA believes that it is important to retain the flexibil-
ity to review DMFs for drug substances that may be used in different drug
products having different characteristics (e.g., dosage form, route of adminis-
tration). Therefore, the FDA only issues a letter listing deficiencies in a DMF.
In order to avoid any inference that the DMF has been "approved," the FDA
does not inform the holder when there are no longer any deficiencies. This
aspect of the DMF review process as it applies to APis will be discussed more
fully below.
TYPES OF DMFs
Several types of DMFs are provided for in 21 CFR 314.420. These distinctions
originally were made mainly for administrative purposes. However, as the
FDA has developed guidelines and policies concerning the submission and re-
view of DMFs, the types of information submitted in the different types of
DMFs are more clearly defined.
Many API manufacturers are told by their customers or consultants that
they need to file a Type I DMF, which covers "manufacturing site, facilities,
operating procedures, and personnel" [21 CFR 314.420 (a) (1)]. Under an
amendment to the CFR (65 FR 1776, January 12, 2000), the FDA no longer
accepts Type I DMFs for either foreign or domestic sites. Since many API
manufacturers with foreign plants have been filing Type I DMFs for their sites,
they are affected by this change. It is also unnecessary to update or reference
existing Type I DMFs.
Since the Center for Drug Evaluation and Research (CDER) reviews in-
formation about sterile manufacturing facilities, both foreign and domestic, it
is still necessary to have that information available for review. Therefore, in-
formation about sterile manufacturing facilities (usually for finished drug
products) can be maintained as Type V DMFs, which are defined as contain-
ing "FDA-accepted reference information."
The type of DMF that is of primary concern to API manufacturers is the
Type II DMF, which covers the "drug substance, drug substance intermediate,
and materials used in their preparation, or drug product" [21 CFR 314.420 (a)
(2)]. Detailed guidance on what should be included in a Type II DMF for drug
substances and intermediates may be found in the DSG.
There are a number of aspects of the DMF system that have given rise to
some misunderstanding by DMF holders:
• A Type II DMF should cover only one topic. For instance, separate
DMFs should be submitted for different drug substances, even if
they appear to be closely related. If there are a number of APis in an
existing DMF, the holder should consider resubmitting each API in
order to facilitate review of the individual APis.
• An API and a drug product manufactured from the API should be
submitted in separate DMFs.
• All DMF holders should submit an annual report, specifying any
changes that have taken place since the last update and a list of all
companies authorized to refer to the DMF (authorized applicants).
The list of authorized applicants should contain a specific reference
to the portion of the DMF to which the company may make refer-
ence. If there have been no changes since the last update, the
holder may simply submit a letter stating that fact, along with the
list of authorized applicants.
• In the DMF Guideline, Section V.A., there is a list of items that
should be included in an LOA. Item 8 states that the LOA should
contain a "statement of commitment that the DMF is current and
that the DMF holder will comply with the statements made in it."
This statement is not a substitute for the submission of an annual
update.
• When an amendment or annual report is submitted, a transmittal
letter containing the following information should accompany it:
A statement identifying the submission as an amendment
The DMF number and subject
Drug Master Rles 91
TypeofDMF
Type of amendment
• Annual update
• Response to agency letter
• New information or revision (not in response to FDA
letter)
• Administrative changes
• Other (specify)
A list of the specific changes or information in the amend-
ment, including the affected section and/or page numbers of
the DMF
The name and address of all applicants authorized to reference
a portion of the DMF being amended
The number of each application that relies on the subject of
the amendment for support, if known
Signature of the holder or the authorized representative
Typewritten name and title of the signer
(Note: This list is slightly expanded from the list found in Section
IV.A.2 of the DMF Guideline.)
In addition, the holder should issue new LOAs identifying the date
of the amendment or annual report, which may be incorporated by
reference.
• Each page of each copy of the DMF should be dated and consecu-
tively numbered. An updated table of contents should be included
with each submission.
MANUFACTURING PERFORMED AT
MORE THAN ONE SITE
In some cases a firm may have all or part of the manufacturing procedure per-
formed at more than one plant, either at another plant owned by the firm or
using an outside contractor.
If a firm uses its own plants and/or processes to manufacture the same
material, a separate DMF for the manufacturing process at each location may
be submitted or one DMF can cover the manufacturing at all sites. Table 4.1
provides recommendations on how this information should be filed.
Table 4.1 Recommendations for Rling DMFs at Multiple Locations

Same Process (Minor Differences)* Multiple Processes
Same Site One DMF-Identify any differences One DMF-Identify any differences
Multiple Sites One DMF-Identify any differences Separate DMFs
*Example: Differences in climate at different sites may require different controls on moisture and
temperature during manufacturing.
If a firm contracts out most or all of a manufacturing procedure to an-

other company, the firm performing the actual manufacturing should submit
the DMF. However, if a manufacturing procedure is performed by a subsidiary
of a firm, the parent company may hold the DMF. In this case, the relation-
ship between the companies should be clearly defined in the DMF.
If a DMF holder contracts out one or two steps in a manufacturing pro-
cedure, it is not necessary for the contractor to submit a DMF, as long as a
complete description of these steps is provided in the DMF for the main part
of the manufacturing procedure. Only the DMF holder is required to submit
an LOA. The plant performing the manufacturing steps under contract may
be subject to inspection under the FDA's Preapproval Inspection (PAl) pro-
gram, depending on the nature of the manufacturing procedure. It is recom-
mended that the following information be provided in the DMF:
• A complete description of the operation, including in-process con-
trols and release specs.
• All of the addresses of the sites and companies engaged in the man-
ufacturing process. These addresses should be provided in any sub-
mission that references the DMF.
• All information concerning the shipment of any materials (inter-
mediates, final product) between the different sites, including the
release specifications and tests at the sending site, the acceptance
specifications and tests at the receiving site, and a description of
the containers and storage conditions. Adequate controls to ensure
the stability of the material should be described.
• A signed statement from each company participating in the manu-
facturing procedure, certifying that the information they have pro-
vided to the DMF holder is current and that they will comply with
the statements therein.
If a company is performing a common operation (e.g., fermentation) un-
der contract to a number of different DMF holders, the company performing
the contract work should submit its own DMF.
INTERMEDIATES
There has been a good deal of confusion about whether a DMF is required
for the preparation of an intermediate or a starting material. This is not
strictly a DMF issue, since the policy concerning the information about in-
termediates and starting materials is covered in the DSG and is the concern
of the Drug Substance Committee at CDER. Any questions about this matter
should be directed to this committee. If it is determined that a particular
chemical is an intermediate whose preparation should be fully described, as
outlined in the DSG, then a DMF may be filed for that intermediate. An LOA
from the DMF holder for the preparation of the intermediate should be sub-
mitted in the application that uses the active drug substance prepared from
the intermediate, if possible. This will permit the reviewer to know which
DMFs need to be reviewed in support of a particular application. If the API
manufacturer believes that the nature of the intermediate is a trade secret
that it would prefer not to reveal to the applicant, it is not necessary for the
intermediate manufacturer to submit an LOA permitting the applicant to in-
corporate the information by reference. However, the intermediate manufac-
turer should submit an LOA to the DMF for the API. The plant where the
intermediate is prepared may be subject to inspection, depending on the na-
ture of the intermediate.
REREVIEW OF DMFs FOR APis

As stated above, DMFs are reviewed only when they are referenced in an ap-
plication. CDER has adopted a policy in the Manual of Policy and Procedures
(MAPP) 5015.4 that limits the rereview of a DMF when it is referenced in a
subsequent application (see Figure 4.3). This policy, which is available at
www.fde.gov/cder/mapp.htm, is designed to apply to chemistry reviewers in
both the Office of Generic Drugs and in the Office of New Drug Chemistry. A
standard review format has been adopted in both offices. Note that the review
format may be used as a guide for organizing a Type II DMF for an API.
A review will not be performed if the DMF holder has not provided assur-
ances that the DMF is up-to-date. This is to ensure that time and effort are not
wasted in reviewing a manufacturing process or specification that is obsolete.
The rereview policy states that a DMF for a drug substance that has been
reviewed and found to have no deficiencies can be rereviewed only if certain
conditions are met. Note that there is a distinction between review of addi-
tional, previously unreviewed information in a DMF and rereview. In the lat-
ter case, the reviewer reviews information that was reviewed previously and
found acceptable. For example, an additional review is performed if the previ-
ous review of the DMF did not address a specific requirement for the drug sub-
stance. A review of the manufacturing procedures (e.g., milling) and controls
Figure 4.3 DMF Rereview Procedures
Yes
No
DMF NOT REVIEWED
of the drug substance in the DMF may be necessary. On the other hand, a
rereview is performed when there is a reason to reassess information that was
previously evaluated by a reviewer. For instance, if the only previous review
was done to determine whether there was a safety concern in an IND, a
rereview may be necessary. Many times a DMF for a new drug substance is
referenced in an IND and the initial review is done only to determine if the
preparation of the drug substance meets the minimal requirements for the
initiation of safety studies in a Phase I clinical trial. This review often is not
done in as great a depth as is required for a DMF in support of an NDA. For
more details on the CMC requirements for an IND see Guidance for Industry:
Content and Format of Investigational New Drug Applications (INDs) for Phase 1
Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived
Products, published in November 1995 (FOD number 0804).
If a reviewer determines that a rereview should be conducted and the
conditions listed above do not apply, the reviewer must document the reason
for the rereview and obtain supervisory concurrence.
It is felt that adoption of the above policy should eliminate or minimize
the number of rereviews for the same DMF.
CHANGING THE MANUFACTURING

PROCEDURE IN A DMF
An API manufacturer may change its manufacturing process for a number of
reasons (e.g., to meet environmental regulations, to use a new supplier of an
intermediate, or to improve the efficiency of a synthesis). The DMF holder has
the responsibility of reporting to applicants whose applications rely on the
DMF that changes have been made. The DMF holder does not have to reveal
the specific details of the change to the applicant. The applicant who relies on
a DMF for a description of the manufacturing process for an API has the re-
sponsibility for reporting that change under the regulations for reporting
postapproval changes (21 CFR 314.70). These regulations are in the process of
being revised. In the interim, a guidance has been issued to address the re-
porting requirements for different types of changes (Changes to an Approved
NDA or ANDA, issued 11/1999). In general, postapproval changes may be clas-
sified as major, moderate, or minor. The classification depends on whether the
change is considered to have a substantial, moderate, or minimal potential to
have an adverse effect on the identity, strength, quality, purity, or potency of
a product, as these may relate to the safety or effectiveness of the product. A
major change requires a prior approval supplement, a moderate change re-
quires a "changes being effected" supplement, and a minor change may be re-
ported in an annual report.
In addition, the FDA is preparing a guidance titled "Bulk Active Chemi-
cals-Postapproval Changes (BACPAC)."
Manufacturers of APis are advised to stay current in their knowledge of
the regulations and guidances related to post-approval changes. Neither the
regulation nor the Guidance for Changes to an Approved NDA or ANDA specifies
in detail the actual information to be reported to support a particular change.
SUMMARY
DMFs provide a convenient process by which API manufacturers can submit
confidential information for review by the FDA in support of a number of ap-
plications. Changes in the FDA's review procedures should streamline the re-
view process so that the American public can continue to have access to safe
and effective drugs at reasonable prices.
5
THE FDA's PERSPECTIVES

ON ACTIVE PHARMACEUTICAL
INGREDIENT MANUFACTURING,
cGMP CONTROLS, AND
VALIDATION
This chapter discusses the U.S. Food and Drug Administration's (FDA's) cur-
rent expectations regarding the manufacturing, control, and validation of ac-
tive pharmaceutical ingredient (API) processes. It provides a broad overview
of the FDA's draft Guidance for Industry Manufacturing, Processing, Holding Ac-
tive Pharmaceutical Ingredients-its development, scope, and factors the FDA
considered in determining how much specificity to include in the guidance.
In addition, the spectrum of Good Manufacturing Practice (GMP) controls in
API production and how manufacturers should apply validation concepts to
API processes is discussed. The chapter also examines several controversial ar-
eas in API manufacturing for which the FDA received extensive comments
and how the FDA addressed these in its March 1998 draft API guidance.
Finally, the author includes a brief update on the International Confer-
ence on Harmonisation's (ICH's) Q7 A initiative to develop a GMP guidance
for APis. However, this chapter does not address the consensus achieved to
date in the ICH Q7 A API negotiations. Once the guidance reaches Step II of
the ICH process, the Q7 A Expert Working Group (EWG) will most likely re-
vise it based on worldwide comments received on the latter.
97
For purposes of this chapter, the terms active pharmaceutical ingredient,

bulk drug substance, drug substance, and bulk drug are synonymous, all referring
to the active raw material used to formulate drug products. The term bulk
pharmaceutical chemical (BPC) also is used, referring to both active and nonac-
tive (excipient) ingredients utilized to manufacture dosage form drugs.
DEVELOPMENT OF THE FDA's

API GMP DRAFT GUIDANCE
Unknown to many, the FDA publicly committed to development of a current

Good Manufacturing Practice (cGMP) regulation for bulk drugs on 29 Sep-
tember 1978, when the amendments to the cGMP regulations (Title 21 of
the Code of Federal Regulations [CFR], Parts 210 and 211) were published in
the Federal Register. Page 45050 of the preamble to this final rule stated
that the cGMP regulations "apply to finished dosage form drugs (under
§§ 210.3(b)(4) and 211.1) and are not binding requirements for chemical
manufacturing." It further explained that the cGMP regulations for finished
pharmaceuticals "can serve as useful guidelines in the manufacture of chemi-
cals" and specified that "the agency plans to develop specific cGMP regula-
tions on production of bulk drugs."
In April 1984 the FDA published its Guide to Inspection of Bulk Pharma-
ceutical Manufacturing (currently titled Guide to Inspection of Bulk Pharmaceu-
tical Chemicals). The FDA revised this guide in February 1987 to include
changes submitted by the Pharmaceutical Manufacturers Association (PMA;
now Pharmaceutical Research and Manufacturer's of America [PhRMA]).
The FDA revised the guide again in September 1991 to incorporate com-
ments from the Center for Drug Evaluation and Research (COER), the
agency's Field Drug Committee, field investigators, and the PMA. Reformat-
ted in May 1994 with minor editorial changes, the document provides gen-
eral guidance on how to apply cGMP controls and validation concepts to
BPC processes and clarifies the FDA's position on impurities and impurity
profiles.
Mter issuance of the revised BPC inspection guide in 1991, industry of-
ficials speculated the FDA would promulgate a cGMP regulation for APis. This
initiative began in mid-1994 when the FDA formed a task force to draft a
GMP regulation specific to APis. The task force, headed by the Office of Pol-
icy in the FDA's COER included representatives from the latter, the Center for
Biologics Evaluation and Research (CBER), the Center for Veterinary Medi-
cine, the Office of Regulatory Affairs (ORA), and the Office of the General
Council.
Despite the changing political environment in 1994, the FDA task force
worked for over a year on a draft API regulation. This group produced four
drafts of a regulation intended for publication as 21 CFR Part 212. The fourth
The FDA's Perspectives on API . .. Validation 99
draft even included extensive preamble language that would have been pub-
lished with the new regulation.
However, reality eventually set in. On 7 July 1995, FDA senior manage-
ment recognized the difficulty of developing and issuing a new API regulation
because of the prevailing deregulatory climate. Thus, the FDA decided to
cease efforts to develop an API regulation and to draft an industry guidance
instead. This important task was assigned to the Division of Manufacturing
and Product Quality in COER's Office of Compliance.
The Office of Compliance circulated the first draft of the API GMP guid-
ance for comments within the FDA in March 1996. On September 20, 1996
the FDA unveiled an August 1996 discussion draft of the industry guidance at
an international API conference in Canberra, Australia, sponsored by the
Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-
operation Scheme (PIC and PIC/S). The draft was reviewed along with other
API GMP documents prepared by the European Chemical Industry Council/
European Federation of Pharmaceutical Industries' Association (CEFIC/
EFPIA), PhRMA, PIC and PIC/S, and other organizations.
On 1 October 1996, the FDA distributed the discussion draft at the Par-
enteral Drug Association's (PDA's) annual PDA/FDA conference in Bethesda,
Maryland. On 8 November 1996 COER's Office of Compliance distributed the
discussion draft to pharmaceutical trade associations for comment. Subse-
quently, the FDA posted the draft on COER's Web site with a request for com-
ments by 10 December 1996. The FDA later extended the deadline for
submitting comments on the draft guidance to 31 January 1997.
The FDA received more than 2,000 comments on the August 1996 API
draft guidance from 17 manufacturers, 2 consulting firms, and 1 FDA re-
viewer. Comments were also submitted by 7 pharmaceutical associations, in-
cluding the National Association of Pharmaceutical Manufacturers, the
National Pharmaceutical Alliance, the Generic Products Industrial Associa-
tion, the PDA, the PhRMA, the German Association of Research Based Phar-
maceutical Companies, and the CEFIC/EFPIA.
From March to July 1997 a working group convened in COER's Office of
Compliance classified and summarized the comments received on the draft
guidance. From August to October the group reviewed the comments and
made appropriate changes to the guidance.
COER's Office of Compliance recirculated the revised guidance for inter-
nal FDA comments on 25 November 1997. On 15 January 1998 COER sub-
mitted for FDA clearance a draft Federal Register Notice of Availability and
revised guidance incorporating final comments from COER, CBER, and ORA.
However, at a 5 February 1998 meeting of the ICH at Tyson's Corner, Vir-
ginia, the FDA supported the decision to develop an internationally harmo-
nized GMP guidance for APis. At this meeting, the FDA also announced the
decision to issue its API GMP document as draft guidance.
The FDA released its revised draft API guidance (dated March 1998) for
public distribution on 17 April 1998, by publishing a Notice of Availability in
the Federal Register. The FDA has received 881 comments from 28 organiza-
tions on the March 1998 draft. COER's Office of Compliance has entered the
comments into a database and is currently reviewing the comments.
The FDA's March 1998 Guidance for Industry Manufacture, Processing or
Holding Active Pharmaceutical Ingredients can be viewed and downloaded from
the COER guidance Web site at http://www.fda.gov/cder/guidance/index.htm.
After connecting to the Web site, look for the document under "Compliance
(Draft)." The API guidance is the third document listed under this category.
Although this guidance is identified as "Draft-Not for Implementation," it
represents current FDA thinking and expectations on the manufacture and
control of APis.
"WHAT TO DO" VERSUS "HOW TO DO"

IN THE FDA's API GUIDANCE
As with any guidance, there has been much debate regarding the specificity or
"how to do" language incorporated in the FDA's draft API guidance. Many in-
dustry officials maintain that greater specificity often leads to a guidance that
is easier to understand and avoids misinterpretation by regulatory inspectors.
Other industry officials, however, caution that this approach may hinder de-
velopment of new technologies and provide less flexibility in improving API
processes. Too many "how to do elements" could also increase compliance
costs if regulators interpret the guidance too narrowly.
The FDA's draft API guidance attempts to address both views, in that the
overall guidance is general in nature and more specific in addressing contro-
versial areas where industry has asked the FDA for more guidance. The guid-
ance attempts to balance the needs of many in industry who for years have
been saying, "FDA, give us more guidance in the API area" and others who
have said, "FDA, just tell us what needs to be done, not how to do it."
The FDA considered four important factors when determining how
much specificity to include in the API guidance. First, the document is guid-
ance for industry, not a regulation. As manifested in the FDA's Good Guidance
Practices, which was published in the Federal Register on 27 February 1997,
guidance documents are prepared to establish clarity and consistency in FDA
policies, regulatory activities, inspection, and enforcement procedures. Guid-
ance documents reflect the FDA's current thinking on issues and are intended
to provide assistance to the pharmaceutical industry. They do not legally bind
the FDA or the public. Thus, unlike regulations, which traditionally are void
of "how to specifics," guidance documents contain recommendations and
more specifics about how best to accomplish certain tasks.
Second, the FDA expects this guidance to have a significant impact on
the API industry abroad, since about 70 percent of APis used in innovator
drugs (New Drug Applications [NDAs]) in the United States and 80 percent of
APis for generic drugs (Abbreviated New Drug Applications) come from
The FDA's Perspectives on API ... Validation 101
oversees. The FDA foresees that the guidance will be beneficial to API manu-
facturers in developing countries that currently market or intend to market
APis in the United States. In these countries, the API industry has long wanted
and expects inclusion of more "how to elements."
Third, the draft API guidance also addresses the manufacture and control of
APis for drug products not covered by applications. Although the FDA does not
routinely inspect manufacturers of APis intended solely for over-the-counter
(OTC) drug products, the FDA expects the cGMP concepts and expectations em-
bodied in this industry guidance to apply to these API manufacturing operations.
Fourth, but just as important, is the FDA's desire and need to provide ad-
ditional guidance in problem areas or deviations most cited during inspec-
tions of API facilities.
cGMP DEFICIENCIES UNCOVERED BY

THE FDA's INSPECTIONS ABROAD
Table 5.1 shows the types of human drug establishments inspected by the FDA
abroad during fiscal years 1995 through 1999. The U.S. federal government's
fiscal year begins each October, so this table includes data on international in-
spections conducted from 1 October 1994 to 30 September 1999. Notice the
large number of international inspections that covered the production of APis.
Of 1,322 human drug inspections conducted abroad during the 5 fiscal years,
706 (54 percent) involved inspections of API manufacturers, and 171 (13 per-
cent) involved inspections of both API and finished dosage manufacturers. In
contrast, only 324 (25 percent) involved inspections of dosage manufacturers.
Table 5.1 FDA's International Inspections, Fiscal Years 1995-1999
Firm Type FY95 FY96 FY97 FY98 FY99
API Manufacturers 166 177 145 107 111

Both APijDosage Manufacturers 41 29 33 40 28
Dosage Manufacturers 50 62 70 78 64
Contract Labs 14 18 20 26 10
Contract Micronizers 5 2 1 1 3
Contract Sterilizers 1 0 1 1 1
Drug Repackers 2 4 3 5 1
Pharmaceutical Warehouses 0 1 1 0 0
Total Inspections 279 293 274 258 218
Figure 5.1. depicts the countries that were hosts to the largest number of
API inspections during fiscal years 1995 through 1999. During this period the
FDA conducted 128 inspections of API manufacturers in Japan, followed by
91 inspections in Italy, 57 in France, 47 in China, and 42 in the United King-
dom. Inspections of API manufacturers in these 5 countries accounted for
52 percent of the FDA's API inspections worldwide during the 5 years. There-
maining 48 percent of the FDA's API inspections abroad were conducted in
Ireland, Germany, India, Spain, and Switzerland.
Figure 5.2 shows the types of API processes the FDA inspected overseas
during fiscal years 1995 through 1999. Inspections of nonsterile APis derived
Figure 5.1 API Manufacturers Inspected Abroad, Fiscal Years 1995-1999
Figure 5.2 Processes Covered Durlng Inspections of API Manufacturers, Fiscal

Years 1995-1999
l!'ennentation
Nonsterile
12%
Chemical Synthe'b Crude Bulk NEC

Nonsterile 6%
72%
Plant/Animal
Extra(' lion
4%
Sterile
2%
Others_//
2% Fermentation
Control Testing Lab
Sterile
1%
1%
from chemical synthesis processes accounted for 72 percent of all API inspec-
tions, followed by nonsterile APis derived from fermentation processes
(12 percent), crude bulk not elsewhere classified (NEC; 6 percent), and APis
produced from plant/animal extraction processes (4 percent). Sterile APis pro-
duced from chemical synthesis and fermentation pr9cesses accounted for
2 percent and 1 percent, respectively, of the inspections in the 5-year period.
Crude bulk NEC includes inspections of bulk intermediates and API microniz-
ers. Plant/animal extraction APis includes manufacturers of human
menopausal gonadotropins, follicle simulating hormone, and human chori-
onic gonadotropins.
Figure 5.3 shows the most common cGMP deficiencies cited during the
FDA's inspections of API manufacturers abroad in fiscal years 1995 through
1999. Notice that laboratory controls accounted for the largest percentage of
GMP deficiencies (16 percent), followed by records/reports (14 percent),
process controls (12 percent), equipment cleaning (9 percent), process valida-
tion (7 percent), water systems (7 percent), and API stability programs (7 per-
cent). Deficiencies in written procedures, control of raw materials and
intermediates, reprocessing/reworking of APis, and building/facilities ac-
counted for 13 percent of the deficiencies cited during the five-year period.
The large percentage of deficiencies in the laboratory may be attributed
to the FDA's intensified inspectional focus in this area in the last several years.
Laboratory controls are important at API facilities since inadequate testing by
the API manufacturer can result in production of dosage products with impu-
rities or other contaminants that the dosage manufacturer may not detect.
Figure 5.3 Most Common cGMP Deficiencies Cited During Inspections of API Man-
ufacturers, Fiscal Years 1995-1999
Written Raw Materials & Reprocessing &

Buildings &
Intermediates Reworking
Facilities
4% 4% 3%
2%
Others
-----14%
Lab Controls
16%
Process
Validation
7% Records/Reports
Equipment 14%
Process Controls
Cleaning
12%
9%
The most frequently cited deficiencies in the laboratory included use of un-
validated test methods, failure to perform equipment suitability tests, failure
to investigate abnormal or missing analytical data, retesting without appro-
priate investigations, and laboratory data not reviewed for accuracy by a sec-
ond person. FDA inspectors also identified use of secondary reference
standards without comparing against official standards as a significant prob-
lem in developing countries where USP primary standards are expensive or
difficult to obtain.
The most prevalent documentation problems found during the FDA's in-
spections abroad were incomplete batch records or records that did not reflect
actual operations; activities often documented before actual completion; re-
lease of API batches before completing the review of production records; and
lack of equipment use, cleaning, and maintenance records. In addition,
changes to API processes beyond preestablished limits without approval by
the quality unit or without addressing these through the firm's change con-
trol system were frequent problems at API manufacturers.
The most common Form FDA 483 citations regarding equipment clean-
ing included inadequate equipment cleaning and validation protocols, inade-
quate sampling and testing of equipment surfaces, failure to establish the
specificity and sensitivity of analytical methods, and failure to establish
residue limits. In addition, FDA inspections uncovered many instances in
which manufacturers were not testing for residues of solvents (i.e., organic
volatile impurities) used in API production.
Deviations noted with respect to process controls included failure to
identify and monitor critical process parameters, failure to set expected yields
for critical process steps, inadequate in-process testing and batch testing of in-
termediates and APis, and blending of out-of-specification API batches with
batches that have passed specifications. Inadequate facilities, utilities,
and controls to prevent cross-contamination was also frequently cited at API
facilities and API contract micronizers. Occasionally, FDA inspections uncov-
ered common micronizing equipment used to process pharmaceuticals of
varying therapeutic significance, toxic non pharmaceutical materials, and pes-
ticides.
Despite all the articles and chapters published regarding water systems,
problems with process water are quite prevalent at API manufacturers. The
most common deficiencies noted included process water not shown to be suit-
able for its intended use, specifications not established for chemical/microbial
quality, inadequate investigations and corrective actions following recurring
abnormal microbiological test results, and reliance on point-of-use filters to
clean up water while ignoring the production and distribution system. FDA
inspections also found that water used in the final isolation and purification
steps of APis intended for use in formulating sterile drug products was
not routinely tested for bioburden or endotoxins. This is significant, since
the sterilization and subsequent processing steps in sterile drug production
will not remove endotoxins that may be present in the API or other raw
materials.
Regarding raw material controls, FDA investigators uncovered instances

in which raw materials received with a Certificate of Analysis were not sub-
jected to a specific identity test, nor were the supplier's analytical test results
verified at established intervals. Sampling of raw materials often was con-
ducted in open, uncontrolled warehouses, and bulk intermediates isolated for
further processing were not adequately packaged and stored to ensure their
suitability for later use.
SCOPE OF THE FDA's DRAFT API GUIDANCE
The FDA's draft API guidance applies to the production and control of drug
and biologic APis for use in human and veterinary drug products. Based on
recommendations received from industry during the initial comment period,
the FDA clarified the scope in the March 1998 draft by adding the following
sentence: "The guidance applies to the later chemical isolation and purifica-
tion steps of APis derived from biological or fermentation processes" (FDA
1998). Fermentation and biological processes usually include measures to pre-
vent or minimize contamination when pure cultures are inoculated in the
laboratory onto selected agar media and with each subsequent transfer of the
stock culture. Inclusion of this statement in the scope does not imply that
cGMPs do not apply to fermentation or biotech processes. The statement sim-
ply recognizes that these processes are unique and may require more compre-
hensive guidance than that provided in the draft API guidance.
In addition, the FDA clarified that the guidance applies to the synthesis
stages of a sterile API up to the point where the API is rendered sterile. In the
United States, sterilization of the API and subsequent aseptic processing steps
are subject to the cGMP regulations for finished pharmaceuticals (21 CFR
211). Why? Sterile APis are usually aseptically filled into the final dispensing
container without additional purification steps.
In response to many recommendations from industry, the FDA also in-
cluded a new section that identifies cGMPs for the manufacture of APis used
to produce drug products for clinical trials. This includes language similar to
that found in the PhRMA Guidelines for the Production, Packing, Repacking, or
Holding of Drug Substances.
The FDA also received several comments from industry inquiring
whether the draft API guidance applied to the manufacture and control of ex-
cipients. Recognizing there are many similarities between the manufacture of
APis and excipients, the FDA added a statement to the scope stating, "Al-
though this document focuses on the manufacture of APis, much of the guid-
ance provided may be useful for the manufacture of excipients." However, the
FDA may have to revise this statement based on the most recent comments
received on the March 1998 draft.
The draft API Guidance does not apply to medical gases, bulk-packaged
drug products, and radiopharmaceuticals.
APPLICATION OF cGMPs TO API PROCESSES
Since April 1984, with the first publication of the Guide to Inspection of Bulk
Pharmaceutical Chemical Manufacturing, the FDA has acknowledged that there
are "basic differences" between the processes used for the production of BPCs
and those used for finished drug products. BPCs, both actives and inactives,
usually are produced by chemical synthesis, recombinant DNA technology,
fermentation, enzymatic reactions, recovery from natural materials, or com-
binations of these processes. The production of BPCs typically involves signif-
icant changes of starting materials or intermediates by chemical, biological, or
physical processing steps. Purification is the ultimate objective.
In contrast, finished drug products are formulated from bulk raw materi-
als the quality of which can be measured against established specifications by
dosage manufacturers. Most important, the manufacturing processes for fin-
ished pharmaceuticals typically do not involve purification steps.
The FDA has long recognized that the "GMP concepts" embraced in the
cGMP regulations for finished pharmaceuticals are valid and can be applied to
API processes. These concepts include control of raw materials; building, not
testing, quality into a product; in-process testing and controls; process valida-
tion; and others. In fact, such concepts can be applied in any manufacturing
process, whether it involves constructing an automobile or airplane, or man-
ufacturing a computer chip or a medical device. Notwithstanding, API manu-
facturers frequently ask, "At what processing step and to what extent should
GMP controls be applied in an API process?"
In the April 1984 BPC inspection guide the FDA acknowledged that in
many bulk processes "it is neither feasible nor required to apply rigid controls
during the early processing steps." Page 4 of the guide explains that GMPs
"should be increasingly tightened according to some reasonable rationale," as
processing proceeds from early intermediate steps to final isolation and pu-
rification steps. Beginning "at some logical processing step, usually well be-
fore the final finishing operation," manufacturers should impose appropriate
GMP controls and maintain these throughout the remainder of the process.
At what processing step should GMPs begin to apply? Since 1984, the FDA has
maintained that GMP controls become applicable at that point where a "start-
ing material" is introduced into the process. Page 3 of the FDA's April 1984
BPC guide states the following:
Many elements and simple compounds that will ultimately

comprise the molecule of a BPC originate from botanicals,
mines, oil wells, and sea water. It would be ludicrous and un-
realistic to expect drug product GMP concepts to apply to the
production of these progenitors. As a general rule, it appears
reasonable to expect GMP concepts to come into play at that
point where a starting material enters a biological or chemical
synthesis or series of processing steps, where it is known that
the end product will be a BPC.
This statement was revised slightly in the September 1991 version of the
BPC inspection guide by deleting "ludicrous" from the second sentence and
rewording the third sentence to read as follows: "As a general rule, however, it
is reasonable to expect GMP concepts to start to become applicable at that
point where a starting material enters a biological or chemical synthesis or se-
ries of processing steps, where it is known that the end product will be a BPC."
The FDA's March 1998 API guidance embodies this important concept. The
third paragraph in the introduction of the guidance explains that the "FDA
expects appropriate cGMPs to be applied to all steps in the manufacturing
process, beginning with the use of starting materials."
Figure 5.4 shows the spectrum of GMP controls in a typical API process.
Once the starting material is introduced into the API process, manufacturers
should increase GMP controls according to some reasonable and scientifically
sound rationale as processing proceeds from early process steps to final syn-
thesis, isolation, and purification steps. Of course, how much control depends
on the process and manufacturing stage.
DEFINING AND IDENTIFYING THE STARTING MATERIAL

Page 7 of the FDA's April 1984 BPC inspection guide defined a starting mater-
ial as
A substance which, after undergoing various chemical or bio-

logical reactions, eventually becomes a BPC ... For purposes of
this guide, a starting material is a substance that is intended
to result in a BPC. This distinction removes from considera-
tion those starting materials destined to become non-BPC
products.
Figure 5.4 Spectrum of cGMP Controls in API Manufacturing
Apply controls to all

manufacturing steps, beginning
with the use of starting
materials
Controls increase Degree of controls, tests,

as process proceeds and documentation
to final synthesis, depends on process and
isolation and manufacturing stage
purification steps
However, the definitions section was deleted in the September 1991 revision
of the BPC inspection guide and this early definition of "starting material" re-
ceived little attention from the API or pharmaceutical industry.
The FDA's March 1998 API guidance includes a definition for a starting
material that is almost identical to the definition found in the ICH Harmo-
nized Tripartite Q3A Guideline, Impurities in New Drug Substances. It simply
substitutes API for the term drug substance as shown below:
A material used in the synthesis of an API, which is incorpo-

rated as an element into the structure of an intermediate
and/or API. Starting materials are normally commercially
available, and of defined chemical and physical properties and
structure.
Although this harmonized definition for a starting material has been rec-
ognized among the ICH parties since the Q3A guidance was recommended for
adoption at Step 4 of the ICH process in March 1995, the term remains con-
troversial and is still the subject of much debate today. In the European Union
(EU), for example, the term starting material has raised concerns because it is
widely used in Europe to refer to raw materials, both actives and excipients,
for manufacturing drug products. Beyond the EU, many industry officials
claim that the FDA and ICH Q3A definitions are too restrictive, since both
definitions limit starting materials to those that are "normally commercially
available." Some API manufacturers maintain that the definition is too vague
and is not applicable to all API processes, such as APis derived from fermenta-
tion and biotechnology processes. Other manufacturers maintain that identi-
fying the starting material in API processes may be arduous, and that
additional criteria should be incorporated into the definition to help in the
identification process.
The FDA's February 1987 Guideline for Submitting Supporting Documenta-
tion in Drug Applications for the Manufacture of Drug Substances attempted to ad-
dress these concerns by including the following criteria for identifying a
starting material:
• It is incorporated into the new drug substance as an important

structural element.
• It is commercially available.
• It is a compound whose name, chemical structure, chemical and
physical characteristics and properties, and impurity profile are
well defined in the chemical literature.
• It is obtained by commonly known procedures (this applies princi-
pally to starting materials extracted from plants and animals, and
to semisynthetic antibiotics).
The drug substance guidance explains that the starting materials will fre-
quently meet several of these criteria. If it does not meet any of the above cri-
teria, "it is probably not the starting material." It further explains that if the
starting material is not commercially available, it should meet the third crite-
rion. While helpful, the above criteria still did not address all situations,
prompting occasional meetings between FDA chemists and NDA applicants
to mediate the designation of the starting material in a new process. For some
API processes, such as semisynthetic antibiotics, the starting material itself is
often an active ingredient. In other instances, manufacturers subject an inter-
mediate produced in-house or received from a supplier to a final synthesis
and purification step to obtain the API and designate the intermediate as the
starting material.
One approach that may help identify the starting material involves
evaluating the actual or intended use of a material and where it is introduced
into the process. For example, does a material have both industrial and phar-
maceutical uses or is it sold or intended for use only in API production? Fig-
ure 5.5 shows how this approach can be applied in a multistep API process.
In this example, the first and second steps result in the production of mater-
ial "C" that has both industrial and pharmaceutical uses. A percentage of
material "C" is introduced into step three of the process and is further syn-
thesized and purified, resulting in the production of the API in step six. In
this example, the starting material is "C" and the API process begins with
step three where "C" is introduced into the chemical synthesis process that
results in production of the API. Steps one and two would not be considered
part of the API process, and would not be subjected to cGMP controls since
Figure 5.5 Designation of an API Starting Material in a Multi-Step API Process
INDUSTRIAL
Major Intermediate Extensive
•
USES
J Tests J In-process
I + + /Tests
= API USES
A - B - c •••• . . . n - E - F - API
I
API Starting Material
I
Minor
In-process
Final Intermediate
Key Intermediate
Tests
> API process begins with the use of Starting Material C to produce Intermediate D
> Level of control increases throughout synthesis of Intermediates E-F and API
> Control needed is highly dependent on the manufacturing process
these steps result in the production of a substance that has both industrial
and pharmaceutical uses. Like the original definition of starting material in
the FDA's April1984 BPC inspection guide, this approach removes from con-
sideration those materials not destined for use in API production. This
approach, however, may not be practical for all API processes, and manufac-
turers may need to develop additional criteria to help identify the starting
material.
The FDA recognizes that the "starting material" concept may not ade-
quately address all API processes, and that specific language may be needed to
address APis derived from fermentation, biotechnology, and other unique
processes. Whatever the outcome, one thing is certain. API manufacturers
should thoroughly understand their processes, exercise good judgment, and
adequately document the rationale used to determine the processing step
where cGMP controls begin to apply.
API PROCESS VALIDATION

Validation of API processes remains one of the most challenging issues facing
regulatory authorities and the industry today. Although most manufacturers
agree that validating API processes is necessary, they often question the ratio-
nale of applying validation concepts, well established in dosage manufactur-
ing, to API manufacturing operations. In addition, API manufacturers
frequently ask, "Should validation encompass all steps of the API process?" If
not, "at what point in the API process should validation begin?"
The FDA believes that the general principles of validation apply to any
process, and that these principles do not change from process to process. The
specific type of validation, or degree of validation, however, differs for active
pharmaceutical ingredient processes as compared with that required for fin-
ished pharmaceuticals.
In the production of dosage forms, all manufacturing steps in the pro-
duction of the final product, such as cleaning, weighing, measuring, mixing,
blending, filling, packaging, and labeling are encompassed by process valida-
tion. For API processes, the FDA does not expect validation of all manufactur-
ing steps, but accepts validation of critical process steps. Section XI.A. (page
32) of the March 1998 draft API guidance explains that "validation should
embrace steps in the processing of APis that are critical to the quality and pu-
rity of the final API."
The validation approach embodied in the FDA's API guidance is a diver-
gence from statements in previous FDA and industry publications. The FDA's
September 1991 BPC inspection guide (page 20) emphasizes "validation of the
BPC production at the stage(s) in the synthesis and purification steps used for
the bulk substance and/or the removal of impurities." Likewise, PMA's Concepts
for the Process Validation of Bulk Pharmaceutical Chemicals, which was published
in the December 1993 edition of Pharmaceutical Technology, recommends vali-

dation of the "processing steps in the later stages in the synthesis and purifica-
tion used for the formation of the bulk substance or the removal of
impurities." The August 1996 guide titled Good Manufacturing Practices for Ac-
tive Ingredient Manufacturers, published jointly by CEFIC and the EFPIA, pro-
poses validation of "critical steps at least, from the final intermediate."
What prompted this change in the FDA's expectations? Why did the
FDA select the "control all steps, validate critical process steps" approach? In
1994, the FDA GMP task force drafting a GMP regulation for APis considered
the following approaches to controlling and validating API processes:
• Control and validate all manufacturing steps.
• Control and validate all critical process steps.
• Control all manufacturing steps, validate critical process steps.
• Control and validate the final API step(s).
The advantages and disadvantages of each approach were summarized in an
internal FDA document titled Bulk GMPs for Drug Substances-Position Paper on
GMP Control and Validation (FDA 1994).
The task force agreed that the "control and validate all manufacturing
steps" approach would result in the highest quality assurance level for APis,
since the control and validation of each step after introduction of the starting
material would assure consistency and repeatability of the entire process.
However, the group concluded that validation of each step in the API manu-
facturing process was not necessary and would place considerable burdens on
API and intermediate manufacturers. This view was also expressed by PMA's
QC Section, Bulk Pharmaceuticals Committee, in their BPC process validation
concept paper. The latter explains that "although all steps in the production
of a BPC must be appropriately controlled, not all steps must be validated."
The "control and validate all critical process steps" approach would re-
quire identifying critical steps/control parameters during early process devel-
opment and generating appropriate data to show that a particular process
step is not critical to the quality of an API. Critical process steps could include
steps that introduce or remove impurities, introduce an essential structural el-
ement, where a physical change occurs, or steps that introduce a specific
stereochemistry. However, the task force agreed this approach minimized the
importance of cGMP controls over noncritical process steps.
The "control all steps, validate critical process steps" approach seemed
the most logical to the task force since it would require appropriate GMP con-
trols of all steps in the API process, beginning with the introduction of the
starting material, and identification and validation of process steps that influ-
ence the quality and purity of the API. This approach recognizes that the
process control needed is highly dependent on the manufacturing process
and increases throughout the synthesis as processing proceeds from early in-
termediate steps to final synthesis, isolation, and purification steps. Early pro-
cessing steps may only require elementary in-process monitoring, tests, and
documentation. However, critical process steps in subsequent synthesis, isola-
tion, and purification steps would require more sophisticated in-process con-
trols, tests, documentation, and, of course, validation. In addition, the group
agreed this approach would embrace critical steps before the final intermedi-
ate that result in important molecular structural changes or the introduction
and removal of impurities.
The "control and validate the final API step or steps" would provide the
minimum burden to industry and the lowest quality assurance for APis.
Although validation of the later synthesis and purification steps is the ap-
proach emphasized in the FDA's September 1991 BPC inspection guide, the
task force concluded this approach was not scientifically justified. It mini-
mizes control of earlier manufacturing steps that may be critical to API qual-
ity and is not consistent with the fundamental cGMP concept of assuring
quality by adequately controlling each step of the manufacturing process. In
addition, the group felt that this approach may actually promote the use of
dedicated "GMP" facilities that receive an intermediate from an outside
source and perform the final synthesis and purification steps.
After considerable discussion, members of the FDA GMP task force con-
cluded that the "control all steps, validate critical process steps" approach was
the most rational validation approach. Shown below are 10 reasons for sup-
porting this approach:
1. This approach requires appropriate GMP controls of all API produc-

tion steps, beginning with the use of starting materials, with vali-
dation of process steps determined to be critical to the quality and
purity of the final API.
2. It recognizes that many steps in an API process can be adequately
controlled by routine monitoring/testing for which validation may
be unnecessary.
3. It recognizes that validation of every step in an API process would
be unrealistic and burdensome to industry, without necessarily pro-
viding additional assurance regarding the quality or purity of
an API.
4. Critical process steps and critical process parameters would be de-
termined by API manufacturers. For new chemical entities, data
used to identify critical process steps and critical parameters would
be derived from research or pilot scale batches. For established API
processes this information could be obtained from previously man-
ufactured production scale batches.
5. Critical steps would not be limited to final synthesis and purifica-
tion stages and could include intermediate steps that introduce an
essential molecular structural element or result in a major chemical

transformation, introduce significant impurities, or remove signifi-
cant impurities.
6. This approach is consistent with the FDA's 1991 BPC inspection
guide, which explains:
[I]t is reasonable to expect GMP concepts to start to become
applicable at that point where a starting material enters a
biological or chemical synthesis or series of processing
steps, where it is known that the end product will be a BPC.
7. It is also consistent with the PMA's concept paper on BPC valida-
tion that maintains validation for a BPC "should be based on a
good working knowledge of the process," defining the BPC "in
terms of its critical quality attributes" and identifying the "critical
process parameters that could affect the critical quality attributes of
the BPC."
8. This approach takes into account the fundamental distinctions be-
tween the production of APis and the formulation of finished
dosage forms.
9. It increases emphasis on producers of intermediates performing
critical process steps as part of a multistep API process.
10. This approach will provide an acceptable and achievable level of
quality assurance for APis, without placing unnecessary burdens on
the industry.
DEFINING AND IDENTIFYING

CRITICAL PROCESS STEPS
One of the most difficult aspects of validating API processes is determining
critical process steps. Unlike dosage manufacturing, in which all process steps
may be critical, criticality may not factor into an API manufacturing process
until later synthesis, isolation, and purification steps.
Although identifying critical processes is a common practice when eval-
uating many production processes today, it is not a novel concept in API pro-
duction. The FDA's April 1984 BPC inspection guide included a synonymous
term, significant processing steps, defined as
Those steps in the total processing of a BPC, starting with the

initial starting materials and culminating with the desired
BPC, wherein the identity, strength, quality, and purity of the
finished BPC may be significantly affected.
The Good Manufacturing Practices Guide for Bulk Pharmaceutical Exdpients,

developed by the International Pharmaceutical Excipients Council (IPEC
1995), defines a critical process as "a manufacturing process step which may
cause variation in quality attributes." The August 1996 CEFIC/EFPIA GMP
guide for APis includes a definition for "critical" that reads as follows:
A material {e.g., raw material, packaging material, process aid,
intermediate), process step or process condition, test require-
ment or any other relevant parameter is considered to be crit-
ical when noncompliance with predetermined criteria directly
influences the quality attributes of the Active Ingredient in a
detrimental manner.
The FDA's March 1998 draft API industry guidance defines critical
process steps as "Process steps that must be controlled within established op-
erating ranges to ensure that the API or intermediate will meet specifications
for quality and purity." The FDA has received many comments from industry
suggesting that the definition be revised to read, "Process steps that must be
controlled within preestablished criteria to ensure that the API or intermedi-
ate will meet specifications for quality and purity." This revised definition
would be consistent with the CEFIC/EFPIA definition for "critical."
How can manufacturers determine what steps are critical in an API
process? Unfortunately, there is no easy answer to this question or specific
guidance that could be applied to all API processes. Since API processes vary
substantially in length and complexity, a thorough knowledge of each process
is essential in determining the steps or "unit operations" that affect API qual-
ity and purity.
The june 1996 Bulk Pharmaceutical Chemicals Baseline Pharmaceutical En-
gineering Guide, published by the International Society for Pharmaceutical En-
gineering, explains:
Each manufacturer should define the level of control, protec-
tion, and validation which are appropriate to each process,
based upon sound process understanding. They should deter-
mine the specific drug substance's characterization, and the
critical steps and critical parameters which will affect the char-
acterization chemically, physically or biologically.
Likewise, Section 3 of PMA's December 1993 BPC process validation concept
paper maintains:
Each process should be individually evaluated to determine

the point in the process after which process validation should
be applied to assure meeting the predetermined quality attri-
butes of the finished BPC. Determining this point should be
based on knowledge of the BPC and its critical quality attri-
butes, as well as the process and its capabilities.
The PMA concept paper also suggests that API manufacturers consider the fol-
lowing when determining which process steps should be validated:
• The points at which significant impurities may be introduced into

or removed from the process.
• The point after which no significant impurities will be removed
from the process.
• The point at which all the essential structural elements of the BPC
are present.
Another approach (Nash 1997) involves conducting "critical step analy-

sis" in which API manufacturers challenge the unit operations (i.e., a reaction
step, crystallization, centrifugation, etc.) during the process qualification
stage to determine "those critical process variables that may affect overall
process performance." This may be conducted using worst case analysis, "frac-
tional factorial design" studies, or other process studies that examine the ef-
fect of changes in control variables on API quality.
The FDA's March 1998 draft API guidance provides examples of process-
ing steps that could be defined as critical by the API manufacturer. These in-
clude phase changes (i.e., dissolution or crystallization), phase separation
(i.e., filtration and centrifugation), chemical reactions, and adjustments to
temperature or pH. Some process steps, such as crystallization, milling, and
micronizing, are very important to dosage manufacturers since they can im-
part changes in the surface area, particle size, bulk, and tap density of the API.
These changes in the API's physical properties may affect the bioavailability
and bioequivalence profiles of solid oral dosage forms and suspensions.
DEFINING CRITICAL PROCESS PARAMETERS

Critical process steps are usually determined by analyzing process parameters
(factors of the process that are controllable and measurable, either manually
or electronically) and their respective outcomes. Not all process parameters af-
fect the quality and purity of APis. Some parameters are controlled for
economic reasons, such as reducing energy consumption or raw material us-
age, whereas others are controlled for environmental or safety reasons. For
validation purposes, manufacturers should identify, control, and monitor crit-
ical process parameters that may influence the critical quality attributes of
the API.
The FDA's March 1998 draft API guidance defines critical process pa-
rameters as "process parameters that must be controlled within established
operating ranges to ensure that the API or intermediate will meet specifica-
tions for quality and purity." PMA's BPC validation concept paper defines a
critical process parameter as "a parameter that could affect a critical quality
attribute." PDA's Technical Report No. 18, Validation of Computer-Related

Systems, defines the term as "a process-related variable which, when out-of-
control, can potentially cause an adverse effect on fitness-for-use of an end
product or on process state-of-control." Similar definitions found in the liter-
ature include "those process parameters that are deemed important to prod-
uct fitness for use" (PMA 1985) and "factors which must be controlled to
ensure that acceptable product is produced" (Curtis 1996).
The temperature of a reaction is usually identified as a critical process pa-
rameter that must be controlled to ensure the production of acceptable APis.
If the temperature is too low, it may allow a competing reaction to form un-
wanted impurities or byproducts. If the temperature is too high, it may
prompt a decomposition reaction. Other critical operating parameters may
include reaction times, heating and cooling rates, pressure, oxygen/carbon
dioxide ratios, vacuum, and water content.
Critical process parameters should be determined by scientific judgment
and supported by appropriate documentation. For new API processes, data
used to identify critical process parameters are usually derived from research
or pilot scale batches. For established API processes, identification of critical
process parameters is often based on historical data.
TYPES OF PROCESS VALIDATION

One of the most frequent comments received on the FDA's August 1996 API
discussion draft concerned its exclusion of concurrent process validation. Al-
though other FDA guidance documents have discussed this approach without
using the term, the March 1998 draft API guidance is the first FDA guidance to
include a definition for concurrent validation. The guidance also openly dis-
cusses its utility when manufacturers cannot perform prospective validation
due to the unavailability of a sufficient number of batches to show consis-
tency of the process. This approach may be feasible for APis intended for clin-
ical or orphan drugs, APis produced infrequently due to limited market
demand, or APls produced by complex processes with long completion times.
Concurrent validation may also be useful when revalidating an API process
that deviates from a proven acceptance range for a critical process parameter,
and the process is revalidated at a new range.
Concurrent validation involves intensive in-process monitoring and
testing of each API batch to show that each production run results in an API
meeting its predetermined quality characteristics and specifications. Each
batch may be released and distributed based on the results of intensive in-
process monitoring and testing, but the manufacturing process would not be
considered validated until similar testing of replicate batches show consis-
tency and reproducibility of the manufacturing process.
The March 1998 draft API guidance specifies the conditions where con-
current validation may be employed. However, it cautions that "this
approach should not be viewed as a viable alternative when the number and
frequency of API production runs permit timely completion of validation
prior to API distribution." Although not mentioned in the API guidance,
manufacturers should consult with the FDA before attempting concurrent
validation for an API process.
The draft API guidance also clarifies FDA expectations regarding retro-
spective validation of established API processes. In the United States this ap-
proach is often considered when a manufacturer located abroad is referenced
for the first time in a drug application for an API it has manufactured for the
last 5 to 10 years for non-U.S. markets. Before attempting this approach, how-
ever, manufacturers should assure that the API process has not changed signif-
icantly and that there is sufficient production, testing, and control data on
past batches to show the process consistently produces acceptable API
batches. Inspections by the FDA have uncovered many instances in which
manufacturers have attempted retrospective validation of existing API
processes despite significant changes to the process, repeated batch failures
caused by process variability, or lack of impurity profile data. Retrospective
validation should be attempted only when
• critical quality attributes and critical process parameters have been

identified and documented,
• appropriate in-process specifications and controls have been estab-
lished and documented,
• there have not been excessive process failures or nonconforming
API or intermediate batches attributable to causes other than oper-
ator error or sporadic equipment failures (unrelated to equipment
suitability), and
• impurity profiles have been established for the existing API.
Prospective validation is the preferred approach for APis produced by a
new or modified process. This involves obtaining, documenting, and evaluat-
ing processing and analytical control information for multiple batches manu-
factured, sampled, and tested according to a preestablished validation
protocol. The FDA's March 1998 guidance articulates that "prospective valida-
tion should be completed prior to the commercial distribution of an API pro-
duced by a new or modified process." Several comments from industry
suggested revising this section to provide for processing of APis into the final
drug product while the API process was being validated. This would allow a
dosage manufacturer to initiate validation of a drug manufacturing process,
although the drug product would not be commercially distributed until vali-
dation activities for both the API and the dosage product had been completed.
Based on this recommendation, the FDA may revise the section to read as fol-
lows: "Prospective validation should be completed prior to the commercial
distribution of the final drug product manufactured from the API produced by
a new or substantially modified process."
The FDA's August 1996 API draft guidance did not include advice on the
number of production lots to include in process validation studies. The FDA
received many comments regarding this omission and corrected it in the
March 1998 version. For prospective validation the FDA recommends three
consecutive successful production lots as a guide, but cautions that additional
process runs may be warranted in some instances to show consistency of the
process. For retrospective validation the FDA recommends reviewing data on
10 to 30 consecutive batches to assess process consistency. However, fewer
batches may be examined if justified.
EQUIPMENT CLEANING AND VALIDATION
Development of equipment cleaning procedures and cleaning validation at

API plants is influenced by the uniqueness of API production. Since API pro-
duction often involves both chemical and biological reactions, generally
there are more concerns regarding potential contaminants. These may
include precursors, secondary reaction products, unreacted intermediates,
organic solvents, degradation products, cleaning agents, microbes, and endo-
toxins. In addition, equipment-related contaminants, such as equipment lin-
ings, gaskets, filtering agents, and lubricants, may pose problems and need to
be addressed in cleaning protocols.
Although the number and sources of contaminants are greater, API pro-
duction is unique in that residues and by-products from early steps often are
removed by purification steps in the later stages of the process. Because of
this, cleaning procedures may be more flexible in the early stages of the API
manufacturing process and less flexible in the later steps of the process. Con-
sequently, cleaning efforts and validation may be directed at later processing
steps in which the risk of cross-contamination and incidental carryover of
degradants is highest.
How did the FDA address this issue in their draft API guidance? The Au-
gust 1996 API discussion draft implied that process equipment should be
cleaned between successive batches despite whether equipment is dedicated to
a particular API. Section IV.D. of the March 1998 draft reads; "Equipment and
utensils should be cleaned, held, and where necessary, sanitized, at appropriate
intervals to prevent contamination or cross-contamination that would alter
the quality of the API beyond the official or established specifications." Dedi-
cated equipment should be cleaned at appropriate intervals to prevent the
buildup of objectionable material or microbial growth. These cleaning inter-
vals should be determined and justified by the manufacturer. Obviously,
nondedicated equipment should be cleaned between different APis and inter-
mediates to prevent cross-contamination. This revised language gives API man-
ufacturers greater flexibility to clean as necessary based on scientific studies.
The equipment cleaning validation section of the FDA's August 1996 API
discussion draft implied that all equipment cleaning methods should be vali-
dated. This drew many comments from industry and prompted the FDA to
rewrite the entire section. The March 1998 draft guidance states: "Equipment
cleaning methods should be validated, where appropriate." Overall, "cleaning
validation efforts should be directed to situations or process steps where cont-
amination or incidental carryover of degradants poses the greatest risk to API
quality and safety." If residues are removed by subsequent purification steps,
"it may be unnecessary to validate cleaning methods" in early synthesis steps.
Although not mentioned in the guidance, this approach may not be appropri-
ate for all API processes or cleaning procedures (e.g., cytotoxic API facilities).
In addition, the March 1998 draft guidance explains that cleaning valida-
tion should reflect actual equipment use patterns. If a family of APis (i.e.,
group of APis with similar toxicological and pharmacological properties) is
produced in the same equipment and the equipment is cleaned by the same
process, a worst case or "most difficult to remove" API may be selected to rep-
resent all APis processed in this manner. The API selected for this cleaning val-
idation study should be based on evaluating various characteristics of the API
family, such as potency, toxicity, solubility, stability, and difficulty of cleaning.
In response to industry recommendations, the March 1998 API guidance
also emphasizes the importance of routinely monitoring equipment cleaning
activities after cleaning validation. Section IV.E states: "Cleaning procedures
should be checked by appropriate methods after validation to ensure these
procedures remain effective when used during routine production."
What about cleaning validation for APis intended for clinical trials? Sec-
tion X.V. of the March 1998 API industry guidance does not specifically ad-
dress this issue. Typically, APis for clinical trials are produced in laboratory
facilities or pilot scale equipment that are often easier to clean than equip-
ment found in commercial production facilities. In addition, APis for clinical
trials often consist of a single or limited number of batches, which makes
cleaning validation difficult or inexact.
However, Section XV. C. of the API guidance states: "During all phases of
clinical development including the use of small-scale facilities or laboratories
to manufacture clinical API batches, procedures should be in place to ensure
that equipment is calibrated, clean, and suitable for its intended use." Proce-
dures for the use of facilities "should ensure that materials are handled in a
manner that prevents contamination and cross-contamination."
Although this language is quite general, the important point is that
manufacturers of APis for clinical trial drugs should ensure that equipment is
clean and suitable for its intended use. This may be accomplished by effective
cleaning and verification procedures that fall short of a cleaning validation
program that the FDA would expect to see in a nondedicated commercial
scale API facility.
PROCESS WATER
The quality and GMP expectations for process water also differ for dosage
forms and APis. USP 23 (Section 1231, Page 1984) prohibits the use of potable
water for manufacturing pharmaceuticals but allows its use in the production
of USP drug substances. Potable water generally has been recognized by both
industry and the FDA as the minimum quality water for the production of
APis, provided the water complies with established regulatory requirements
for source drinking water and data from periodic testing show compliance
with chemical and microbiological standards, including freedom from patho-
genic organisms.
Page 12 of the FDA's September 1991 BPC guide explains that "water
used in the production of BPCs in many instances (e.g., fermentation of an-
tibiotics) may be potable water obtained from wells or surface sources." The
FDA's August 1996 draft API guidance states: "Water for any API process
should, at a minimum, meet the standards for potable water, as stated in the
United States Environmental Protection Agency's (EPA) National Primary
Drinking Water Regulations (NPRDWR) set forth in 40 Code of Federal Regu-
lations, Part 141." This language was revised in the March 1998 draft (Section
V.F) to allow the use of drinking water meeting EPA standards "or comparable
standards of other authorities such as the European Union, Japan, or the
World Health Organization."
However, several organizations commented that if water not meeting
potable water standards is shown to be suitable for its intended use, this
should not be objectionable. They maintain that in many instances, water
used in early process steps need not be of drinking water quality, as the ag-
gressive nature of the process may destroy trace quantities of impurities lim-
ited in drinking water. In addition, they contend that starting materials
themselves often contain chemicals or impurities that are often limited in
drinking water.
From the FDA's perspective, a manufacturer would have to provide a
substantial amount of data to justify the use of water in API processing that
does not meet drinking water standards. This should include data to show
that the water supply is not contaminated by insoluble organic chemicals or
by compounds leaked into water sources from underground seepage or runoff
during increment weather. Furthermore, use of a lesser quality of water for
API processing would be difficult to justify when the International Pharma-
ceutical Excipients Council has adopted the use of potable water as the mini-
mum quality water for production of pharmaceutical excipients (IPEC 1995).
The quality of process water used during later isolation and purification
stages, particularly its microbial attributes, has generated even more discus-
sion and continues to be debated today. Review of technical literature, refer-
ences, and comments submitted to the FDA's August 1996 and March 1998
draft API guidance disclosed several opinions on this issue. Officials at some
API manufacturers contend that the microbial quality of water is irrelevant
because the manufacture of most synthetic APis involves use of strong acids
and/or bases, high temperatures and/or pressures, or reagents that themselves
are bacteriostats. These factors may preclude the buildup of microorganisms
in the API. Others maintain that potable water can be used in later isolation
and purification steps if the API manufacturer proves the water is suitable for
its intended use and shows that residual chlorine and other ions present in
potable water do not adversely alter API quality. Many API manufacturers re-
portedly prefer this latter approach rather than dealing with the potential
problems of microbial growth in deionizer, ultrafiltration, and reverse osmo-
sis systems used to produce purified water. Yet others, including FDA spokes-
persons in the early 1990s, advocated that the quality of water used in final
isolation and purification steps should be similar to that used for manufactur-
ing the dosage form incorporating the API (Avallone 1992).
Publications from the FDA, industry, and other sources have not ade-
quately addressed this issue. For example, the FDA's September 1991 BPC in-
spection guide states: "if the water is used in later processing steps such as for
a final wash of the filter cake, or if the BPC is crystallized from an aqueous sys-
tem, the water quality standards should be higher than normally specified for
purified water." However, as pointed out by the German BPC industry (Dem-
mer et al. 1994), "If purified water can be used routinely to manufacture oral
or topical drug products, it is difficult to justify a higher quality for the 1500 or
2000 L of water used just to wash the final crystals of a nonsterile BPC on a
centrifuge (presuming that the BPC will not be used in parenteral drug manu-
facture)."
Most recently, the Water for Pharmaceutical Purposes section of USP 24, of-
ficial as of 2 january 2000, states that "drinking water may be used in the
early stages of chemical synthesis and in the early stages of the cleaning of
pharmaceutical manufacturing equipment." This language could lead one to
conclude that drinking water should not be used in final isolation and purifi-
cation stages of a chemical synthesis process. However, USP 24 does not ad-
dress this in its discussion of the uses of purified water. It only states that
"Purified Water is used as an excipient in the production of official prepara-
tions; in pharmaceutical applications, such as cleaning of certain equipment;
and in the preparation of some bulk pharmaceutical chemicals."
The FDA's August 1996 draft API guidance included the following lan-
guage addressing the quality of water used in final isolation and purification
steps:
During critical manufacturing steps, such as final crystalliza-

tion and isolation of key intermediates and APis, higher
chemical and microbial water quality specifications should be
considered. For example, where the API needs to be of a high
microbiological purity, appropriate action levels for total mi-
crobial count, objectionable organisms and endotoxins may
need to be established and met. Higher specifications should
also be considered during early manufacturing steps if impuri-

ties may affect the quality of the product or their removal can-
not be validated in later steps.
Many organizations, however, commented that the examples given (e.g., final
crystallization and isolation) may not be critical for all API processes and that
only the manufacturer could determine this. Thus, the language was revised
in the March 1998 draft by substituting "critical manufacturing steps" with
"certain process steps" and rewording the section to read as follows:
Water of suitable quality, with tighter chemical and microbio-

logical quality specifications, should be used during certain
process steps (e.g., cell cultures, final crystallization and isola-
tion) and during early process steps if impurities that affect
API quality are present in the water and cannot be removed in
later steps. For example, if water is used for a final wash of a fil-
ter cake, or if the API is crystallized from an aqueous system,
the water should be suitably treated (e.g., deionization, ultra-
filtration, reverse osmosis, or distillation) and routinely tested
to ensure compliance with appropriate chemical and microbi-
ological specifications.
Although these changes were generally favorable to industry, some orga-

nizations commented that the language should be further clarified to suggest
that potable water may be appropriate for final isolation and purification
steps. Other manufacturers recommended that the FDA revise the section to
state that the quality of water used in different steps of API manufacturing
should be justified and controlled and should not have a detrimental effect
on the API or its fitness for use. Based on these and other recommendations,
FDA is considering revising the language to read:
If potable water standards are insufficient to assure API quality

and tighter chemical and microbiological water quality speci-
fications are necessary for certain steps, appropriate action
limits for chemistry, total microbial counts, objectionable or-
ganisms, and/or endotoxins should be established.
When establishing water specifications, API manufacturers should con-

sider the process, the stage in the process in which the water is used, and the
intended use of the API. If the API purports to be sterile or low endotoxin, or
will be used in preparing sterile drug products, water used in the final isolation
and purification steps should be routinely tested and controlled for bioburden
and endotoxins. Because of the large volumes of water required in API pro-
duction, API manufacturers often produce Water for Injection (WFI) quality
water by subjecting deionized or reverse osmosis water to ultrafiltration at the
last stage of preparation. This may be acceptable if the ultrafiltered water
meets compendia! specifications for WFI. This approach emphasizes the water
quality that should be met, not the method used to produce process water.
Obviously, when process water is treated to achieve an established qual-
ity (i.e., purified water, WFI), the treatment process and associated distribu-
tion systems should be qualified, validated, properly maintained, and
routinely tested following established procedures to ensure water of the de-
sired quality.
REVIEW OF BATCH PRODUCTION

AND CONTROL RECORDS
Another area where differences between the production of dosage forms and
APis influence cGMP expectations involves the review of batch production
and control records. In the United States the FDA's cGMP regulations for fin-
ished pharmaceuticals (21 CFR 211) mandate that the quality control unit re-
view all production and control records. Comments received on the August
1996 draft API guidance related to this section reported that the quality unit
in API facilities often reviews batch production records (BPRs) only for critical
or validated process steps, beginning with the first validated step and includ-
ing all subsequent manufacturing steps. Records for earlier, noncritical
process steps are often reviewed by qualified production personnel following
procedures approved by the quality unit.
Based on this fact and industry recommendations, the FDA revised the
draft API guidance to allow qualified production personnel to review BPRs for
noncritical steps following procedures approved by the quality unit. This ap-
proach is consistent with the fundamental concept embodied in the API guid-
ance: "The stringency of cGMP controls in API production should increase as
the process proceeds from early intermediate stages to final synthesis, isola-
tion and purification stages." In fact, the FDA recently allowed a major
API producer in the United States to implement such a procedure. As long as
the quality control unit maintains the responsibility for reviewing BPRs for
critical steps that influence the purity and quality of the API, review of BPRs
for noncritical steps by qualified production personnel would not be objec-
tionable.
REPROCESSING AND REWORKING

GMP expectations for reprocessing and reworking are also influenced by dif-
ferences in the manufacturing processes of dosage forms and APis. In dosage
manufacturing, no clear distinction exists between reprocessing and rework-
ing, and the two terms are often interchanged. However, this is not so in
API production, and recent FDA and industry guidance documents clearly dis-
tinguish the two terms.
The FDA's August 1996 discussion draft defined both reprocessing and
reworking as deviations from a "validated process." Based on many industry
comments, the FDA revised both definitions in the March 1998 draft by sub-
stituting "validated process" with "established process." This change is con-
sistent with PhRMA's definitions and would provide for reprocessing or
reworking of intermediates produced by noncritical process steps that may
not be validated.
The March 1998 draft API guidance defines reprocessing as "introducing
an intermediate or API that does not conform to standards or specifications,
back into the process and repeating one or more steps that are part of the es-
tablished manufacturing process." Recrystallizing using the same solvent is
the most common example of reprocessing, although other physical manipu-
lations, such as dissolution, filtration, and milling, are often employed.
Reprocessing is considered a frequent and commonly accepted practice
in the API industry. It is conducted primarily to increase yields, to obtain a
purer material, or to bring important attributes such as particle size distribu-
tion, bulk density, and tap density into conformance with established specifi-
cations. In contrast, reprocessing of a drug product is atypical and rarely
results in improving drug purity.
Reworking as defined in the FDA's March 1998 draft API guidance, in-
volves "subjecting an intermediate or API that does not conform to standards
or specifications, to one or more processing steps that are different from the
established manufacturing process." Recrystallizing using a different solvent
is a clear example of reworking. Reworking often alters the chemical structure
of the material and would include taking the molecular salt of the API back to
its base, although the subsequent step of converting the base into the salt is
part of the established process. Reworked batches should be subjected to ap-
propriate evaluation to show that the reworked API or intermediate is of
equivalent quality to that produced by the original process.
Again, the true difference between reprocessing and reworking is
whether the actions taken with the nonconforming batch deviate from the
established process. Reprocessing involves subjecting an intermediate or API
batch to a step or steps of the same process, whereas reworking involves sub-
jecting a nonconforming batch to a different process.
IMPURITY TESTING AND IMPURITY PROFILES
Assuring the purity of APis and testing for impurities has been and continues
to be a major concern of the FDA. In the last four decades, several incidents
have occurred in which the presence of precursors, by-products, or other im-
purities in APis used in dosage manufacturing resulted in serious patient side
effects and deaths. A classic example of this was the thalidomide tragedy in
the mid-1960s, when a change in the API manufacturing process, imple-
mented to improve yields, reportedly introduced a new impurity, the d-
isomer of the active. This d-isomer was not detected by routine in-process or
final testing and had not been previously consumed by humans. It apparently
caused fetal abnormalities and prompted the famous 1960-1962 U.S. Senate
Kefauver hearings and significant changes in U.S. Food and Drug Law.
In 1988 and 1989, changes in one manufacturer's bacterial fermentation
and purification steps for producing the amino acid L-tryptophan inad-
vertently introduced a trace contaminant, at a concentration of less than
0.1 percent. This contaminant was correlated with the outbreak of
eosinophilia-myalgia syndrome (EMS) in persons who repeatedly consumed
the amino acid as a dietary supplement. At least 27 people died of EMS di-
rectly or indirectly and more than 1,500 reported becoming ill before re-
searchers established a clear link between EMS and 13 tainted lots of
L-tryptophan produced by the modified process (Newton 1991). These inci-
dents clearly emphasize the importance of identifying and quantifying impu-
rities in APis and determining how the impurity profile is affected by changes
in the manufacturing process.
Establishing and maintaining impurity profiles is both a filing and a
cGMP issue. For a new active ingredient, establishing an impurity profile is an
important element of drug testing and development. API manufacturers are
expected to submit data on initial impurities identified along with toxicity
data in a drug master file or drug application. However, once the API process
is scaled up and commercial batches are produced, monitoring of impurities
becomes a significant cGMP issue because changes in the API's impurity pro-
file usually signal a change in equipment operating parameters, materials, or
processes. Most important, the appearance of an impurity in commercial size
API batches that was not present during the clinical stages presents serious
concerns regarding the stability, safety, and efficacy of the finished product
incorporating the API.
API manufacturers routinely conduct tests for ordinary impurities, re-
lated compounds, and organic volatile impurities if these are specified in the
USP monograph for the active ingredient. These tests are batch release specifi-
cations that must be met to comply with the USP monograph. Such testing,
however, does not substitute for impurity profile testing of APis nor do these
tests sufficiently characterize the purity of APis. The USP acknowledges that
compendia} methods may not be specific and are frequently inadequate, par-
ticularly for active ingredients obtained from multiple sources when each
source may use a different manufacturing process, resulting in distinct impu-
rity profiles. Page 7 of the General Notices and Requirements section of
USP 24 states:
While one of the primary objectives of the Pharmacopoeia is

to assure the user of official articles of their identity, strength,
quality, and purity, it is manifestly impossible to include in

each monograph a test for every impurity, contaminant, or
adulterant that might be present, including microbial con-
tamination. These may arise from a change in the source of
material or a change in the processing, or may be introduced
from extraneous sources. Tests suitable for detecting such oc-
currences, the presence of which is inconsistent with good
manufacturing practice, should be employed in addition to
the tests provided in the individual monograph.
Consequently, few USP monographs have acceptance criteria for individ-

ually identified impurities. However, USP adopted a 0.1 percent threshold for
identifying impurities when it revised the General Notices Section of the Sixth
Supplement to USP 23 (Page 3636), which became official on 15 November
1996. The revision proposed that impurities (0.1 percent level or greater) that
are not listed in the product monograph and cannot be reliably analyzed by its
methods should be named, quantified, and included on the certificate of
analysis of the official substance. This revision further emphasizes the need for
API manufacturers to monitor impurities beyond those specified in USP
monographs.
Impurities and impurity profiles have been addressed by the FDA in sev-
eral publications. The FDA's 1987 Guideline for Submitting Supporting Documen-
tation in Drug Applications for the Manufacture of Drug Substances recommends
that "impurities should not only be detected and quantitated, but should also
be identified and characterized when this is possible with reasonable effort." It
further clarifies:
Before or early in Phase 3, it is expected that all major impuri-

ties will have been isolated and identified. Levels of impuri-
ties, either individual or total, should be controlled.
The FDA's September 1991 revision of the BPC inspection guide discusses
the importance of characterizing and controlling impurities and outlines the
FDA's approach to evaluating API impurity testing during cGMP inspections.
Page 21 of the guide states: "It is important that manufacturers identify and
set appropriate limits for impurities and adequately control manufacturing
processes so that the impurities consistently meet established specifications."
Appendix A of the guide references the USP definition of an impurity profile
and clarifies that the FDA expects "the manufacturer to establish an appropri-
ate impurity profile for each BPC based on adequate consideration of the
process and test results." Most important, the guide directs investigators to
compare the impurity profile for the pilot batch material with that of the
commercial size BPC batches to determine if the profile has changed signifi-
cantly. Investigators should specifically ask "for current complete purity pro-
files, and these profiles should include the levels of solvents normally found
in the purified drug substance along with acceptable specifications."
Section IX.B. of the March 1998 draft API guidance states, "Impurity pro-
files should be established and maintained for each API that identify or quan-
tify each impurity observed." Impurity profiles are an important part of a
historic analysis and the FDA expects API manufacturers to establish appropri-
ate impurity profiles for each API as part of the process validation effort. This
should be "based on adequate consideration of the process and test results"
and include collecting data on (1) actual and potential organic impurities that
may arise during synthesis, purification, and storage of the API; (2) inorganic
impurities that may arise from the manufacturing process; and (3) organic and
inorganic solvents used during the manufacturing process known to carry
over to the API.
For new drug substances produced by chemical synthesis, ICH Q3A rec-
ommends the identification of all recurring impurities at or above 0.1 per-
cent. For established APis, the FDA's November 1999 Guidance for Industry
ANDAs: Impurities in Drug Substances recommends identification of all recur-
ring impurities at or above an apparent level of 0.1 percent in batches manu-
factured by the commercial process.
In summary, API manufacturers should ensure that appropriate and vali-
dated analytical methods are in place to detect and quantify recurring impuri-
ties in APis. Such testing, if conducted on a routine or batch-by-batch basis,
allows manufacturers to detect unanticipated changes by continuously com-
paring the impurity profile against the profile submitted in a Drug Master File
or drug application, or that shown by historical analysis. As voiced by
Boehlert (1987), apart from the primary concern of safety, few in industry
would argue that there are also very sound business reasons for knowing
the impurity profile of a drug substance or the degradation profile of a drug
product.
It is, perhaps, the best method for determining the impact of

change in any step of the drug substance manufacturing
process and plays a key role in assessing change in the drug
product.
INITIATIVES TO DEVELOP AN INTERNATIONALLY

HARMONIZED GMP GUIDANCE FOR APis
Although several API GMP documents were developed from 1987 to 1996, the
first formal attempt to harmonize GMP requirements for APis was launched at
a September 1996 meeting in Canberra, Australia, sponsored by the PIC and
PIC/S. This conference was attended by more than 80 government and indus-
try representatives from more than 30 countries. The conference brought to-
gether for the first time various organizations that had been independently
working on API guidance, including Canada's Health Protection Branch
(HBP), the Australian Therapeutic Goods Administration (TGA), the FDA, the
PhRMA, the EFPIA, the International Society for Pharmaceutical Engineering,

and the World Health Organization (WHO). At Canberra the group compared
the various API guidance documents available worldwide and generally
agreed that all the documents embodied the same concepts regarding GMP
controls in API manufacturing and validation of API processes. One primary
outcome of this meeting was the formation of an EWG composed of represen-
tatives from government regulatory bodies to draft a harmonized API industry
guidance. The EWG included representatives from the Swiss Intercantonal Of-
fice for the Control of Medicines, Australia's TGA, Canada's HPB, PIC and
PIC/S, the FDA, and China's State Pharmaceutical Administration.
The PIC and PIC/S EWG met in Geneva the first week of February 1997
to review a first draft of an API guidance. The second meeting was held 13-14
June 1997 in Helsinki, Finland, to review and revise a second draft. On 15 Sep-
tember 1997, the PIC and PIC/S issued their draft, Internationally Harmonized
GMP Guide for Active Pharmaceutical Ingredients, for public comments.
However, before comments on the PIC and PIC/S draft API guidance
were reviewed, the ICH agreed to adopt the topic of GMPs for APis. As men-
tioned earlier, this occurred during a February 1998 meeting in Tyson's Cor-
ner, Virginia. ICH has traditionally been involved in developing guidance
documents oriented to filing requirements for new drugs. The decision to de-
velop an API guidance (termed the Q7 A initiative) represents the first venture
of ICH into the GMP arena.
Initially, ICH limited the negotiations to the manufacture and control
of APis. After completing this first phase, ICH could propose to extend the
guidance or develop a separate guidance for excipients, source materials for
biological products, or target materials for radiopharmaceuticals.
At Tyson's Corner the ICH Steering Committee proposed a friendly
takeover of the PIC and PIC/S API GMP harmonization process launched fol-
lowing the September 1996 meeting in Canberra, Australia. The PIC and
PIC/S EWG reviewed 2,495 industry comments received on its September
1997 draft API guidance and revised the latter during a 1998 meeting in Paris
(20-28 April). This revised document was then presented at the first meeting
of the ICH EWG also held in Paris (29-30 April 1998).
The EWG tasked with developing the Q7 A API guidance consists of a
minimum of 20 members, including:
• two representatives from each of the six ICH members;

• three observers (WHO, Canada, and Switzerland);
• one representative from the generic drug industry (International
Generic Pharmaceutical Alliance);
• one representative from the OTC drug industry (World Self Medica-
tion Industry); and
• one representative each from Australia, China, and India.
During the April 1998 meeting, the ICH EWG reviewed the revised PIC
and PIC/S guidance along with the following API guidance documents:
• The August 1996 Good Manufacturing Practices for Active Ingredient

Manufacturers guideline prepared by CEFIC and the EFPIA
• The PhRMA Guidelines for the Production, Packing, Repacking, or Hold-
ing of Drug Substances, Part I and Part II, published in the December
1995 and January 1996 editions of Pharmaceutical Technology
• The FDA's March 1998 draft Guidance for Industry Manufacture, Pro-
cessing or Holding Active Pharmaceutical Ingredients released for pub-
lic comments on 17 April 1998
• The WHO guidance on APis that was published as Annex 1 of
WHO's Good Manufacturing Practices for Pharmaceutical Products
Thus, the ICH EWG initially had at their disposition two API documents pre-
pared by industry, two prepared by regulatory bodies that had gone through a
comment phase, and the WHO document. These documents provided excel-
lent building blocks from which to craft an ICH harmonized guide.
The EWG examined all five documents but could not achieve a consen-
sus on using one API document as a basis for the ICH initial draft. Thus, the
Rapporteurs agreed to draft the initial ICH guidance and drculate this to the
EWG by July 1998 for comments.
Comments on the initial draft were discussed by the EWG at the 31 Au-
gust to 3 September 1998 ICH meeting in Tokyo, Japan. To date, the Q7A
EWG has met on five other occasions. These include a meeting in London in
February 1999, Brussels in March 1999, Los Angeles in June 1999, and Wash-
ington, D.C., in October 1999. The last meeting was held 28 February to
3 March 2000 in Tokyo.
Since its inception in April 1998, the ICH EWG has produced seven
drafts, a substantial achievement considering this is the first time ICH has
been involved in developing a harmonized API GMP guidance. It is a long, de-
tailed process, and the EWG still has much ground to cover, but in the end,
the ICH harmonization process should result in an API guidance document
that will satisfy the needs of both industry and regulators.
CONCLUSIONS
This chapter has focused mainly on the FDA's current expectations regarding
the manufacturing, cGMP controls, and validation of API processes as embodied
in the FDA's draft Guidance for Industry Manufacture, Processing or Holding Active
Pharmaceutical Ingredients. Now that the FDA is involved in developing an inter-
nationally harmonized guidance on cGMPs through the ICH process, many
have asked why the FDA continues to discuss its draft API guidance at industry
seminars and forums and how the current draft is used by FDA investigators.
Clearly, the FDA is committed to the ICH Q7 A initiative and will do its
best to expedite the development of a harmonized GMP guidance that can be
implemented globally and that will provide greater assurance of the quality of
APis used to manufacture drug products. However, even if the ICH guidance
reaches Step II by the middle of the year 2000, it may take several months for
the EWG to review worldwide comments received on the document, revise it,
and resubmit it to the ICH Steering Committee for their approval and adop-
tion by the regulatory bodies. Thus, there may not be a final version of the
ICH harmonized guidance until late 2000 or early 2001.
Meanwhile, the FDA's inspections of API manufacturers, both domestic
and international, continue. The FDA is expected to clearly communicate its
cGMP expectations to the regulated industry. For manufacturers of APis,
these expectations are articulated in the FDA's March 1998 Guidance for Indus-
try Manufacture, Processing or Holding Active Pharmaceutical Ingredients. Al-
though identified as a draft, the industry guidance represents the FDA's
current thinking on the manufacturing and control of APis. Thus, it is usually
reviewed by FDA investigators when preparing for inspections of API facili-
ties. API manufacturers should also review the draft guidance and understand
the cGMP and validation concepts embodied in the document when prepar-
ing for FDA inspections.
REFERENCES
Avallone, H. L. 1992. GMP Inspections of Drug-Substance Manufacturers. Phann. Tech.
16 (6):46-55.
Boehlert, J.P. 1997. Impurities-Where Are We Now? Phann. Tech. Gune): 56, 58, and 60.
CEFIC/EFPIA. 1996. Good Manufacturing Practices for Active Ingredient Manufacturers.
Brussels, Belgium: European Chemical Industry Council/European Federation of
Pharmaceutical Industries' Associations.
CFR. 1978. Title 21, Part 211, Current Good Manufacturing Practice For Finished Phar-
maceuticals. Code of Federal Regulations. 43(190)
Curtis, E. A. 1996. Parameters and quality attributes. Paper presented at the Pharma-
ceutical Education & Research Institute, Inc. Bulk Pharmaceutical Chemical
Process Validation Course, September Wilmington, Del., USA.
Demmer, F., N. C. Franklin, S. Geussenhainer, H. Hausler, R. Kirrstetter, C. Rufer,
E. Walter, and F. Zimmermann. 1994. FDA regulation of bulk pharmaceutical
chemicals-an industrial commentary: part II. Phann. Tech. 18 (12):36-43.
FDA. 1994. Guide to inspection of bulk phannaceutical chemical manufacturing: Reference
materials and training aids for investigators. Rockville, Md., USA: Food and Drug Ad-
ministration, Office of Regulatory Affairs and Center for Drugs and Biologics.
FDA. 1987. Guideline for submitting supporting documentation in drug applications for the
manufacture of drug substances. Rockville, Md., USA: Food and Drug Administra-
tion, Center for Drugs and Biologics.
FDA. 1987. Guideline on general principles of process validation. Rockville, Md., USA:
Food and Drug Administration, Center for Drug Evaluation and Research, Center
for Biologics Evaluation and Research, and Center for Devices and Radiological
Health.
Office of Regulatory Affairs and Center for Drug Evaluation and Research.
FDA. 1994. Bulk GMP's for drug substances-position paper on GMP control and validation.
Rockville, Md., USA: Food and Drug Administration, Center for Drug Evaluation
and Research.
FDA. 1996. Draft guidance for industry: Manufacture, processing, or holding of active phar-
maceutical ingredients. Rockville, Md., USA: Food and Drug Administration, Center
for Drug Evaluation and Research, Center for Biologics Evaluation and Research,
and Center for Veterinary Medicine.
FDA. 1997. Good guidance practices (GGP's). Rockville, Md., USA: Food and Drug Ad-
ministration, 62 FR 8961.
FDA. 1998. Draft guidance for industry: manufacturing, processing, or holding active phar-
maceutical ingredients. Rockville, Md., USA: Food and Drug Administration, Center
for Drug Evaluation and Research, Center for Biologics Evaluation and Research,
and Center for Veterinary Medicine.
FDA. 1998. Active pharmaceutical ingredients (APis). Compliance Program Guide
7556.002F. Rockville, Md., USA: Food and Drug Administration.
FDA. 1999. Guidance for industry ANDAs: Impurities in drug substances. Rockville, Md.,
Hall, W. E. 1997. Cleaning for bulk pharmaceutical chemicals (BPCs): Validation of bulk
pharmaceutical chemicals. Buffalo Grove, Ill., USA: lnterpharm Press, Inc.
IPEC. 1995. Good manufacturing practices guide for bulk pharmaceutical excipients. Arling-
ton, Va., USA: International Pharmaceutical Excipients Council.
ISPE/FDA. 1996. Baseline pharmaceutical engineering guides for new and renovated facili-
ties, Vol. I, Bulk pharmaceutical chemicals. Tampa, Fla., USA: International Society
of Pharmaceutical Engineering and the Food and Drug Administration.
Nash, R. A. 1997. BPC Terminology and Documentation. In Validation of Bulk Pharma-
ceutical Chemicals, edited by I. R. Berry and D. Harpaz. Buffalo Grove, Ill., USA: In-
terpharm Press, Inc.
Newton, P. 1991. High performance liquid chromatography and the mystery of L-
tryptophan. LC-GC 9(3):208-213.
PhRMA. 1995. PhRMA guidelines for the production, packaging, repacking, or holding
of drug substances, part I. Pharm. Tech. 19 (11):22-32.
PhRMA. 1996. PhRMA guidelines for the production, packaging, repacking, or holding
of drug substances, part II. Pharm. Tech. 20 (1):50-63.
PhRMA. 1997. PhRMA guidelines for the validation of cleaning procedures for bulk
pharmaceutical chemicals. Pharm. Tech. 21 (9):56-73.
PMA Validation Advisory Committee. 1985. Process validation concepts for drug prod-
ucts. Pharm. Tech. 9 (9):78-82.
PMA Bulk Pharmaceuticals Committee. 1993. Concepts for the process validation of
bulk pharmaceutical chemicals. Pharm. Tech. 17 (12):32-40.
PDA. 1995. Technical Report No. 18: Validation of Computer-Related Systems. Bethesda,
Md., USA: Parenteral Drug Association.
Rivera Martinez, E. 1999. FDA's guidance for industry manufacturing, processing,
holding active pharmaceutical ingredients-Update on ICH Q7 A. Paper presented
at the Synthetic Organic Chemical Manufacturers Association's Annual Confer-
ence, May, Washington, D.C.
Rivera-Martinez, E. 1999. Fiscal year 98 update-FDA's international inspections. Paper
presented at PhRMA's 1999 Technical Symposium, june, Braselton, Ga., USA.
USP. 1995. Water for pharmaceutical purposes. In United States pharmacopeia 23, chap-
ter 1231. Rockville, Md., USA: United States Pharmacopeia! Convention, Inc.
USP. 1999. Water for pharmaceutical purposes. In United States Pharmacopeia 24, chap-
ter 1231. Rockville, Md., USA: United States Pharmacopeia! Convention, Inc.
6
DOMESTIC AND FOREIGN
API MANUFACTURING FACILITY
AUDITS AND FINDINGS
Peter D. Smith
KMI/PAREXEL
Rockville, Maryland
This chapter addresses current Good Manufacturing Practice (cGMP) func-

tions and systems emphasized by the Food and Drug Administration (FDA) as
applied to the production of active pharmaceutical ingredients (APis). Com-
monly found problems and failures of these systems are the primary focus of
this chapter, which also includes FDA expectations and measures that can be
taken to properly implement cGMPs in an API facility. The comments in this
chapter are based on the author's personal experience as an FDA investigator,
FDA manager, and an FDA/GMP compliance consultant.
QUALITY ASSURANCE FUNCTIONS AND SYSTEMS
The FDA expects regulated companies to have a strong and independent

quality control (QC) unit. The FDA defines a quality control unit as a person or
group having responsibility for the quality control of the drug product. This
incorporates the duties and responsibilities of the typical groups termed
"quality control" and "quality assurance" (QA). The FDA has decided not to
make a distinction between these two groups, since their functions are con-
sidered operational and the FDA would be dictating how some companies
133
must be structured. For the purpose of this chapter, however, the distinction
between QC and QA will be used as it is common industry practice.
Many GMP deficiencies encountered during FDA inspections and serious
regulatory problems experienced by the API industry could be reduced by a
strong and effective QA unit. Very often, especially in foreign API manufactur-
ing plants, the QA unit is limited in scope of responsibility and authority, and
sometimes the "QA unit" is a single person. Sometimes the QA director is a fig-
urehead, with no authority to halt the shipment of noncompliant products
and unable to influence GMP compliance and effect corrective actions. This
situation is a recipe for inspectional problems. Since many FDA inspection
techniques are based heavily on investigating from the QA perspective (such as
tracing a document trail, challenging systems, auditing documentation for
completeness), a competent QA group can provide a constant "FDA" direction,
preventing or recognizing and acting on compliance problems as they emerge.
Generally, FDA Investigators find that most systems operate well under
normal conditions and situations. For this reason, the FDA is always looking
for the exceptions and nonroutine events, assessing how these events are
handled and resolved. QA can play a large role in assuring these incidents are
dealt with correctly and consistently.
The FDA expects QA to be involved, and influential, in all operational
areas that effect product quality. This applies to the review and approval of
many documents and procedures, including validation protocols and reports,
material and product release, master/batch production records, Standard Oper-
ating Procedures (SOPs), change control, deviations and failure investigations,
and product quality reviews. The GMPs require written procedures describing
the authority, definition, organization, and responsibilities of the quality unit.
In a typical structure that is acceptable to the FDA, the QC manager (an-
alytical lab) answers to the QA director, who is equivalent in position and au-
thority to other department managers, such as the production director, and
answers to top management. In Europe, where there is a requirement to have
the position of Qualified Person (QP), the FDA does not automatically equate
the QP and QA. Even though the QP, by European requirements, releases
product, this may not be sufficient for the FDA, since the release procedure
must include additional activities that the QP may not always perform, such
as production record review and ensuring deviations are investigated.
The following briefly addresses QA-related areas where problems are
commonly found.
Standard Operating Procedures

Personal observation over the years reveals that most Form FDA 483s (List of
Observations) contain one or more items related to the failure of the Standard
Operating Procedure (SOP) system, including inadequate SOPs, lack of SOPs,
or SOPs not being followed.
Domestic ... API Manufacturing Facility Audits and Findings 135
It is clear that the FDA considers SOPs to be very important. The cur-
rent GMP regulation (21 CFR Parts 210/211, September 1978) contains 33
references to "written procedures/programs," that is, SOPs. SOPs are the only
way the FDA can receive assurance that operations that affect the quality of
the final product will be done according to the same approved process each
time. As such, every activity required by the GMPs and/or that affects prod-
uct quality should be covered in some SOP. The SOP system should be clearly
articulated, and most important, ensure that all procedures reflect actual
practices.
The FDA considers an incomplete SOP to be a problem and lack of an
SOP for an activity a bigger problem. But the worst offense is not following
an SOP. This is why SOPs must reflect actual practice. Therefore, a "good-
looking" SOP that is not followed can be a serious problem. From the audi-
tor's perspective, once one SOP is found not to be followed, doubt is cast on a
company's compliance with all written procedures. The inspector will then
begin to look for similar circumstances. lf other examples of SOPs not being
followed are discovered, a serious regulatory situation can develop.
To ensure that procedures are followed, the responsibilities for each ele-
ment required by SOPs must be clearly defined. Human nature dictates that
generally, if one understands his or her duties and tasks, there is a high prob-
ability that the duties and tasks will be completed. The reverse is that if re-
sponsibilities are not clearly defined and understood, there is a potential that
required tasks may not be completed. Many procedures require the input
from multiple individuals or groups. A "Responsibilities" section in each pro-
cedure should identify the responsible individuals or groups, and their duties
should be listed, preferably in bullet fashion, beginning wi~h a verb (for ex-
ample, ensure, review, approve, create).
A comprehensive SOP system should include or consider the following:
• SOP #1, the SOP for SOPs, is a very important cornerstone for the
entire system. It should describe all aspects of the system, including
generation, format, approval, distribution/retrieval, and revision.
• Establish a standard format for all SOPs such that each includes
headings for purpose, scope, responsibilities, definitions, related
SOPs, and the actual step-by-step procedure.
• Combine SOPs of the same subject or system. (This reduces redun-
dancies and contradictions and makes the SOP system easier to
manage.)
• Be sure all SOPs include clear step-by-step instructions and can be
followed easily, reflecting actual practices.
• Flowcharts should be made part of many SOPs. These are very use-
ful training tools and assist management and inspectors in seeing
the whole picture.
• Do not use words such as adequate or necessary unless the SOP de-
fines what is adequate or when something is necessary and the cri-
teria for making these decisions.
• There should be an SOP describing the meaning of review and ap-
proval signatures, that is, a description of what each person signing
a document actually did or reviewed.
• For foreign companies, an English translation of the SOP index that
describes by title the SOPs' content is very helpful to demonstrate
the scope and breadth of the SOP system.
Batch Release Procedure

The FDA is very concerned that a released product be properly tested and eval-
uated. Very often in API production, final product release is based solely on
acceptable analytical results, that is, the material meets the specification. The
final release for sale is often made by one individual reviewing only the final
results on a Certificate of Analysis, not a review of the actual test data, and
without any review of the production documentation. This individual also
may be responsible for the analytical testing (for example, the manager of the
QC laboratory).
The FDA expects an independent review of production and analytical
documentation as a prerequisite for batch release. It is necessary that the final
product release procedure combine review of analytical specification testing
and batch production records. The procedure must ensure that all deviations
occurring during production and all analytical out-of-specification (OOS) re-
sults are recognized, reported, and investigated. The final release decision
should not be made by the person who is also responsible for the analytical
testing. Final release should be made by the person responsible for QA, who is
independent from production and QC, and has the authority to reject or
withhold release and shipment of the API.
As mentioned earlier in this chapter, the European requirement for a QP
does not necessarily equate the QP to the QA. Unless the QP performs the
functions that the FDA requires for product release, and has the authority to
reject materials, the QP will not be an adequate substitute for traditional QA.
Deviation and Failure Investigations, Reports

Often, deviations that occur during production are not reported and not rec-
ognized either by production or QA. Therefore, they are not investigated and
resolved prior to batch release. Deviation and failure investigation reports are
often found incomplete in that:
• the investigation remains "open" for an excessive length of time,

• the root cause is not identified,
• there is no corrective action to prevent similar occurrences, and
• the investigation does not determine if other batches/products may
be involved.
Training and supervision must ensure that any unplanned departure

from approved procedures be documented, reported, and investigated. The
GMPs require all deviations to be investigated as a prerequisite to batch re-
lease. There should be one or more SOPs that clearly define the steps to be
taken when a deviation or product failure occurs. QA generally should man-
age the investigation.
Many companies use the term planned deviation when a change of some
sort is desired or needed (perhaps only a temporary change). "Planned devi-
ation" is a misnomer, as it actually is a change that should be handled
within the change control procedure. A deviation is an unplanned departure
from an approved process or procedure. Deviations are red flags to the FDA
investigator and tend to indicate an out-of-control event. Therefore,
planned deviations create the appearance of more uncontrolled events than
actually exist.
Very often the FDA will request lists or logs of rejected batches, failures,
or deviation reports and focus the inspection from that perspective. The FDA
realizes that, in general, routine events are managed correctly. However, the
FDA wants to determine how nonroutine events are handled, and these lists
provide the FDA with information needed to proceed.
Reworking and Reprocessing

Very often, reworking and reprocessing procedures for APis are not articulated
and justified. The industry uses the two terms interchangeably. The FDA does
not use the terms interchangeably, and the difference can be quite meaningful.
Regarding the use of the terms, companies must understand the FDA's
definitions and reference them correctly to avoid misunderstanding. The
FDA's March 1998 Guidance to Industry is quite clear. Reprocessing is subject-
ing a product to a repeat of a step or steps in the validated process (recycling).
Reworking is subjecting the product to a treatment outside the validated
process. The concern here is the potential formation of impurities and the
fundamental quality attribute for API purity. In most cases, repeating a step in
the validated process will not affect the established impurity profile. However,
subjecting the product to treatment outside the validated process does carry
the potential for impacting the impurity profile, perhaps to the extent of pro-
ducing new impurities.
Therefore, reprocessing is a lesser concern than reworking. However, any

reprocessing must be shown to have no adverse impact on product quality. If
reprocessing is frequently required, companies should consider introducing
the reprocessing step permanently to the validated process.
Reworking is a greater concern and carries an element of regulatory risk.
The FDA would like to see rework procedures approved and validated. This
can be difficult since potential rework situations cannot be predicted, and
true validation would require at least three batches, which hopefully would
not exist for a validated process. A practical approach when faced with a re-
work situation is to create a scientifically sound plan based on the individual
circumstances, execute the plan, and perform extra testing to demonstrate
that the rework process has not changed the quality or the characteristics of
the API. A clear documentation trail is important.
Change Control System

Change control is very important to the FDA, especially after systems are
qualified and processes and methods are validated. Change control must be
applied to any changes in facilities, equipment, processes, procedures, ana-
lytical methods, analytical equipment, and specifications. If change control
is handled by several procedures, there needs to be a high-level procedure
that expresses policy, general requirements, and responsibilities and logically
leads to the other SOPs. All changes, even those that appear to be minor,
must be covered by change control. The procedure must allow for emer-
gency changes. Those changes that are truly minor and do not affect product
quality, can be documented and dismissed. QA must at least review all
changes.
Common problems seen in the area of change control are as follows:
• Change control procedures often do not exist in API facilities, and

if they do exist, the procedures cover only process and equipment
changes. The procedures fail to cover changes in other GMP-
required systems, including raw materials, raw material suppliers,
documents, SOPs, buildings and facilities, utilities, cleaning meth-
ods, analytical test methods, and specifications.
• Procedures do not ensure the involvement of QA.
• Often some affected groups or departments are not included in the
change control process. These include maintenance/engineering
and regulatory affairs.
• Procedures do not ensure performance of change-related activities,
such as placement of product on the stability program, training, or
document revision.
Domestic . . . API Manufacturing Facility Audits and Findings 139
• There is lack of follow-up after change to ensure that change has

been properly implemented and other change-related activities.
The change control system must be user-friendly and be easy to apply in
order to encourage and facilitate the use of the procedure(s). It is suggested
that a coversheet form be created to capture concise information about each
change, approvals, and necessary actions. For each change, there should be a
documented determination regarding whether qualification, validation, cali-
bration, training, SOP modification, or stability testing is necessary following
the change.
There must be written procedures addressing all changes in the follow-
ing areas:
• Production processes
• Production equipment
• Facilities
• Utilities
• Raw materials
• Specifications
• Analytical methods
• Analytical instruments
• SOPs
• Computer-related systems
"Like-for-like" replacements and routine preventive maintenance should not

be included in the change control program. This is acceptable as long as the
documentation clearly demonstrates the replacement is actually like-for-like,
and the decision is endorsed by management. There also needs to be routine
QA audits of the work order decisions.
Annual Product Quality Reviews

Frequently, API manufacturers do not perform proper and complete Annual
Product Quality Reviews (APQRs), a basic GMP requirement. Often the APQRs
are simply a listing of the analytical results, and a conclusion that all is accept-
able because all batches met specifications. This is not sufficient for an APQR.
The APQR also must include review and assessment of cumulative
changes, process deviations, failures of intermediates, complaints, production
and testing procedures, trends involving critical process parameters, as well as
an overview evaluation to detect any trends that may be emerging.
RAW MATERIALS HANDLING AND

CONTROLS/WAREHOUSING
Many API warehouse facilities are found to be dirty, unorganized, and poorly
lighted, with the status of materials not clearly labeled, weather adversely ef-
fecting material containers, and unacceptable exposure of materials during
sampling and/or dispensing.
There is no reason why controls on raw materials and warehousing oper-
ations should not be fully compliant with GMPs. These functions are not
"rocket science" but are vitally important for several reasons. The primary rea-
son is that most FDA inspections and other audits logically begin "at there-
ceiving dock" and follow the flow of materials. Therefore, the warehouse
becomes the first operational area observed by the auditor. The impression de-
rived from observations in the warehouse serve to set the tone for the entire
inspection. The physical appearance and organization of the warehouse facil-
ities influence the auditor's impression of the maintenance program for the
entire plant. This is where SOPs may be first requested for review. This is
where an auditor may first encounter operator-level personnel. This is where
the inspector receives the first clues about general GMP compliance and man-
agement's attitude toward compliance.
The following elements need to be considered when establishing ware-
house operations:
• Cleanliness. Cleanliness, organization, and general appearance are
very important. Conditions to avoid include disorganized contain-
ers, pallets tipping under the weight of crushed containers, spills,
leaking containers, dented drums, unlabeled containers, and mate-
rials adversely effected by exposure to weather.
• Floors. Floors should be maintained in good condition (painted and
clean). The large expanse of floor is the area of the warehouse that
is first viewed and affects the impression of the entire facility. Any-
one entering the warehouse (or any other area) cannot avoid seeing
the floor and thus is affected, consdously or not.
• Lighting. Many warehouses have very poor lighting. This should be
avoided, as well lit areas can greatly improve the appearance and
provide sufficient lighting to see material identification and detect
any problems.
• SOPs. As mentioned earlier, an auditor may begin assessing the SOP
system in the receiving area by asking to see the SOPs that relate to
this operation. Very often a set of current SOPs is not immediately
available. The ensuing search creates a very poor impression, and if
the SOPs are not available for reference by operators, it is a GMP de-
viation. Current SOPs should always be available in the areas where
they must be used.
Domestic ... API Manufacturing Facility Audits and Findings ::1.4::1.
• Approved Sources. The receiving department should have a copy of

the current QA-endorsed list of approved qualified sources of all
materials. To ensure only materials from qualified suppliers are per-
mitted entry to the facility, a current list of approved suppliers
should be maintained by the receiving department.
• Status Identification. FDA Investigators are always watchful for
unidentified containers, whether in the production area, labora-
tory, or warehouse. The conventional system of identifying the sta-
tus of each raw material container using yellow/green/red sticker
labels is most acceptable, since the status of any material can be
readily known. Palletized bags that are film wrapped may be prop-
erly identified with a single label, which applies to the entire pallet.
However, this may become a problem when single bags are re-
moved from the pallet, as they would lack status identification. A
system must be established to avoid a situation in which individual
bags are not properly identified.
• Computer-Controlled Systems. Modern computer-controlled systems
(either using bar coding or location) often are linked to material in-
ventory and can eliminate the need to identify each container with
a status label. Walking through a warehouse and not seeing status
identification on containers gives the auditor an uneasy feeling.
This generally results in questions regarding appropriate controls
and challenges to the system. Validation of this system is absolute.
There also must be strict procedures on computer access and who
has the authority to change material status in the computer. QA
must be involved. These systems work very well, but there must be
adequate documentation to convince the FDA that safeguards are
in place and that materials are properly controlled. Additional
questions can arise when raw material containers are encountered
outside the warehouse environment without status identification
(such as in the production areas).
Computer systems used to track inventory, status, or physical
location must be validated. Many older systems are "unvalidata-
ble." In these cases, the company needs to conduct a function test
for each menu option and fully document that the system func-
tions correctly.
• Quarantine Control. As mentioned earlier, materials can be ade-
quately quarantined by computer controls. However, the FDA is
most comfortable with specific areas that are physically and visu-
ally segregated. In API situations where the amount of material un-
der quarantine varies greatly from time to time, a predetermined
quarantine area may not be practical. Flexible quarantine areas us-
ing movable posts connected with plastic chains (with identifica-
tion signs) can be used to surround the lot(s) under quarantine.
• Sampling Location. The FDA is very concerned about protecting all

materials and product from contamination by other materials and
the environment. Exposing raw materials to the uncontrolled envi-
ronment of a warehouse is no longer acceptable practice. An en-
closed area in which material containers can be opened for sampling
should be created. The enclosed area can be a room or a freestanding
booth and should be fitted with an air-handling system and con-
structed of readily cleanable materials. This is becoming the stan-
dard industry solution to the problem of protecting materials from
contamination.
• Stock Rotation. The FDA expects FIFO (first-in/first out) to be prac-
ticed, with reevaluation at designated intervals (usually annually
for most goods, more frequently for less stable materials).
• Storage Conditions. Raw materials should be protected from mois-
ture and temperature extremes, and in some cases, light. The FDA
expects warehouses to be monitored for temperature and humidity
conditions. Based on this, monitoring steps may need to be taken
to assure proper storage of some materials, such as coolers or even
heating/air conditioning the warehouse.
Often the "monitoring" is conducted at eye level (where the
instruments are easy to read), but materials are stored in rack shelv-
ing that may be six pallets or more high. This is not acceptable
since the area monitored is not reflective of actual material storage
conditions. The monitoring location should be the "worst case."
• Cleanliness of Material Containers. The FDA is very concerned about
chemical contamination, dirt, grease, debris, and other unknown
contamination being introduced to production areas on the exte-
rior of material containers. The FDA expects material containers to
be clean when brought into the production areas. For safety rea-
sons, outdoor storage is required for many API ingredients, such as
solvents. If not protected, the containers can become contami-
nated. Many companies are using covers over drum lids to main-
tain the lids free from dirt and debris. Whatever system is used,
procedures should require warehouse personnel to provide clean
containers, and production should not accept containers that are
not clean.
• Tank Farms. Many API manufacturers use tank farms for storage of
large volume solvents and other materials. Tank farms require spe-
cial attention regarding sampling, approval status/labeling, and
distribution piping.
• Drum Reuse. Reuse of drums is a practice that should be avoided.
The FDA has experience with serious contamination problems
resulting from improperly cleaned drums that were reused. If

drums are reused, they should be dedicated, as cleaning is difficult,
and should be clearly labeled as to the current contents. Any previ-
ous labeling should be completely removed or obliterated.
• Segregation for Rejected Materials. There should be a segregated,
restricted-access area for rejected materials. Often API warehouse
operations do not provide an acceptable reject area. However, as
with quarantine areas, space necessary to house rejected materials
must be flexible. Procedures that allow creation of a reject area us-
ing physical separation (movable chains) and placards is usually
sufficient to provide adequate security to assure materials will not
be accidentally used.
QUALIFICATION
The accomplishment of the equipment and utility qualification activities and
process and cleaning validations are vitally important. The FDA expects all
processes for marketed products to be validated, and those products that are
not validated are at regulatory risk. Any process qualification (PQ) accom-
plished using equipment that is not verified and documented as qualified, is
not sound. Qualification is a basic part of and prerequisite for validation.
Staffing to accomplish the validation work may need to be temporarily
increased, especially in a new facility. A possible solution would be to reas-
sign personnel from other areas, such as production, to work as part of the
validation team. The dual functions of personnel such as the maintenance
engineers, to accomplish qualification work and keep up with routine main-
tenance, hamper efficient completion of validation activities. Staff attached
to the validation team would provide dedicated individuals to accomplish
equipment qualifications in coordination with other validation work. The
separation would also allow routine maintenance to be conducted by a staff
dedicated to that purpose.
Common problem areas observed with regard to API equipment and fa-
cility qualification are as follows:
• Incomplete equipment qualification (design qualification [DQ], in-

stallation qualification [IQ], operational qualification [OQ])
• Lack of qualification of existing (old) equipment vs. new equipment
• Lack of accurate piping and installation diagrams (P&ID) for each
process configuration
• Computer-controlled or monitored (data collection) operations not
validated
• Utilities not properly qualified

air-handling system
water system maintenance procedures including sanitization,
sterilization, and regeneration.
brine system
com pressed air
nitrogen
• Insufficient staff to complete necessary qualification work
It is very important that instrumentation critical to manufacturing con-

trols and product quality are maintained and calibrated at the proper fre-
quency. It would be expected that the process validation activities would
identify the critical elements, which would include the critical equipment.
This classification would carry forward and be used by the maintenance
group to ensure that all critical equipment is maintained at the required fre-
quency. (All equipment requiring calibration must be maintained, but there is
less risk if critical equipment is given priority.)
For IQ it would be expected that the design specification, or the specifi-
cation of the equipment ordered, would be preprinted on the protocol forms.
This provides the acceptance criteria against which the qualification findings
will be judged. "As found" information that agrees with the acceptance crite-
ria is acceptable. The "as found" information that does not agree with the ac-
ceptance criteria is a deviation and must be evaluated to determine whether it
impacts product quality and whether correction is necessary.
Also, the concept of DQ should be introduced. DQ is the initial element
of qualification, in which the needs, functions, and specifications of an item
are determined prior to ordering the equipment.
Initially an inventory of all equipment should be prepared to identify
critical pieces of equipment. Qualification documentation should exist for all
critical equipment.
For older equipment, it is not possible to perform a traditional IQ. How-
ever, it is possible to create a specification for the function of the equipment,
and to locate and organize all information regarding the equipment. This
may include
• original purchasing information,

• supplier's manual or handbook,
• supplier's suggested maintenance or calibration,
• diagrams and schematic drawings,
• parts lists,
• maintenance history,
• recording of component models and serial numbers, and

• recording software versions.
OQ should document the operational capabilities over the entire range
of capacities for the equipment. OQ can be checked for any equipment at any
time, and the preventive maintenance should include a program to ensure
equipment operates in a continuous qualified state. Therefore, documenta-
tion to demonstrate OQ should exist for all critical equipment.
API PRODUCTION EQUIPMENT

Specific issues for API production equipment will be addressed here. Common
problems observed regarding API production equipment include the following:
• Lack of status labeling (e.g., clean, dirty, out of service)
• Lack of labeling to show identification of the batch in-process
• Lack of unique equipment number identification, especially for an-
cillary/portable equipment (pumps, filters, mobile carts, and mo-
bile vessels)
• Lack of labeling to show calibration of instruments (e.g., tempera-
ture and pressure gauges, flowmeters)
• Failure to have logs of equipment use, cleaning, and maintenance
• Failure to have an effective preventive maintenance program
• Poor management of material transfer hoses
Difficulty in distinguishing "clean" hoses from "to be cleaned"
Lack of permanent identification
Lack of cleaning records
Poor storage of "clean11 hoses with ends exposed (not covered)
Proving cleanliness of internal surfaces is nearly impossible
All of the above problems are observed frequently in API production fa-
cilities. They represent basic GMP requirements, and compliance should be
easy. During inspections, the FDA is constantly on the lookout for equipment
and containers that are not labeled with the contents and status. This applies
to the wide range of containers seen in a plant including reactor vessels,
pumps, drums, and bottles in the lab. Therefore, all production equipment
should be clearly labeled at all times to show the current contents and status
(clean, to be cleaned, under maintenance, batch in-process, last batch
processed, etc.). Most companies use a placard system for large equipment
and a tag system for smaller portable equipment.
All equipment must be identified with a unique number that is refer-

enced in production records, cleaning records, use logs, and maintenance
records. The number should be painted or otherwise clearly visible on the
equipment. Instances have been observed in which vessels have been re-
painted to improve appearance, but the identification has been painted over,
creating a GMP problem. Ancillary equipment such as portable pumps and fil-
ters is especially susceptible to problems with lack of complete and proper
identification. Often this type of equipment is not accompanied by equip-
ment logs and proper records of cleaning.
A frequent problem area is the management of material transfer hoses.
These hoses are clearly product contact elements. They often are not tracked,
monitored, or controlled in a systematic manner. Proving cleanliness of the
interior surfaces is difficult, if not impossible; therefore, dedication of these
hoses is recommended. Cleaned hoses should be fitted with end caps and
stored in a designated place, separated from unclean hoses.
EQUIPMENT CLEANING
The FDA's concern regarding minimizing the potential for contamination is
largely derived from experience with improperly cleaned equipment and con-
tainers. Several years ago, recalls in the United States resulted from use of im-
properly cleaned intermediate containers, which contaminated an API. The
API then contaminated milling equipment at a contract milling facility,
which in turn contaminated additional materials.
Cleaning is also a huge task for API manufacturers, who report that
equipment is often down for cleaning more time than it is operating to pro-
duce product. Well-designed and validated cleaning procedures can make this
task easier and eliminate potential regulatory problems. One almost certain
reason for inspection failure is inadequate, unvalidated cleaning procedures
in multiuse equipment.
Commonly Found Problem Areas

Lack of Written Cleaning Procedures
Some API companies have not established detailed written cleaning proce-
dures to ensure equipment is cleaned in the same manner each time. These
procedures are especially important when manual vs. automated cleaning
methods are used. Automated cleaning processes can be validated and con-
trolled to achieve uniform cleaning. Manual methods cannot be validated,
and uniformity can be achieved only through adherence to detailed instruc-
tions and personnel training.
Domestic . .. API Manufacturing Facility Audits and Findings 147
Dedicated vs. Nondedicated Equipment

Cleaning of equipment that is dedicated to a particular product or process is
far less problematic than cleaning of multiuse equipment. Dedicated equip-
ment must be cleaned to a level of visual cleanliness; that is, visual inspection
reveals no evidence of residual material. However, cleaning procedures must
be shown to be effective such that product is not adversely impacted by im-
purity or detergent residues or microbiological contamination.
Multiuse, nondedicated equipment must be cleaned to a level of "chem-
ical cleanliness." That is, cleaning procedures must be shown through perfor-
mance of validation to reduce residual levels to or below pre-determined
limits.
Inadequate Cleaning Frequency

Whatever cleaning frequency is chosen (each batch, each campaign, each
year, never), that frequency must be shown to have no negative effect on final
product quality. The potential problems are microbiological contamination or
excessive impurity residues. Testing must be conducted to demonstrate that
residual material does not contaminate, raise the level of level of impurities, or
cause new impurities to develop. Dedicated equipment has been encountered
that is "never" cleaned. This situation would not be acceptable to the FDA un-
less continuous testing is conducted to show there is no adverse effect. This
would be of major concern if the equipment were a final API dryer, when it is
not known if the residue is replaced with each use or if the residue remains
from the first batch. If the latter is the case, the residual material will be sub-
jected to many heating/cooling cycles and impurities could be concentrated
or created.
Fixed Vessels vs. Portable vs. Transfer Equipment

In general, cleaning records and status identification is adequate for large
fixed vessels such as reactors and dryers. However, this is not so for portable
equipment such as pumps, filters, and other mobile equipment. Often this
equipment lacks cleaning records (logs) and status identification.
Transfer hoses can be of particular concern since they are mobile, diffi-
cult to clean, impossible to verify as clean, often not dedicated, not identified
or adequately controlled, and not labeled. Batch records often do not require
documenting the identification of transfer hoses, which could be a valuable
piece of information for a failure investigation. Companies should establish a
policy and procedure for "hose management" that clearly defines the han-
dling, control, and storage of all hoses, including product transfer, solvent,
process water, and waste.
Cleaning Validation
The FDA expects that there are cleaning procedures for all product contact
surfaces. Validation must apply to all procedures for all products in all equip-
ment that are used for multiple products. It must include the "worst-case" sit-
uation, which is the most difficult to clean material with the greatest
potential for adversely effecting the final API. All validations must include
surface sampling (swabs). A validation totally based on analysis of rinse sam-
ples provides information regarding the material that has been removed, but
provides no information regarding residual material remaining on equipment
surfaces following the cleaning process. Validation must include a rational
limit for residues based on scientifically sound tests and reasoning.
The following cleaning validation failure is commonly seen during
preapproval inspections (PAis). The FDA performs a product specific preap-
proval inspection for product A in a multipurpose plant. The FDA inquires
about cleaning and cleaning validation. The company presents a complete,
well-reasoned and well-documented cleaning validation package for product
A. The FDA Investigator pushes the package aside. Why? At this moment, the
FDA is not concerned about how well product A can be cleaned but is con-
cerned about how well product B, product C, and so on can be cleaned. These
are the products that can precede product A in the equipment stream and
could potentially contaminate product A, the API of concern for this inspec-
tion. However, the cleaning of product A may be important to the FDA re-
garding the contamination potential for other products. That is why a
company should have a comprehensive cleaning validation program incorpo-
rating all products.
Postvalidation Monitoring of Cleaning

Once cleaning procedures are validated, many companies feel the require-
ment has been satisfied and do no follow-up monitoring. Automated cleaning
can be monitored by maintaining equipment in a qualified state, but this is
not the case for manual cleaning. There must be a program to confirm that all
operators are following the validated procedures and not taking shortcuts.
This can be accomplished by observing cleaning operations and having a
sampling plan.
EQUIPMENT CALIBRATION
Often critical instrumentation is not identified and labeled to show that it is
properly calibrated, and measuring equipment, such as balances and scales,
are not checked for reliability using an actual weight between formal calibra-
tion checks.
Instruments that monitor critical process parameters must be identified

and maintained in a calibrated condition. They should be marked to show
that they are calibrated and when recalibration is due. It is suggested that any
gauges that are "for reference only," and not intended to monitor process pa-
rameters, be marked with a sticker (green or yellow dot, for example) so that
it is clear that the gauge is not part of the calibration program. API manufac-
turers who do not distinguish between "critical" and "noncritical" instru-
ments run the risk of having such a great burden that all calibration cannot be
accomplished in a timely fashion. However, it is not sensible to have instru-
ments, regardless of any use, that cannot be relied on to provide accurate in-
formation. Therefore, it is best to calibrate all instruments.
Calibration must be performed such that it can be shown instruments
are properly calibrated when validation is conducted. Proper calibration of in-
struments must be demonstrated before and after validation studies.
Balances and scales (both analytical and production) are continuous
sources of adverse observations. The FDA expects frequent (generally each day
of use) checks of balances and scales with an actual weight. Internal calibra-
tion devices are not sufficient, as there is a potential that there could be dam-
age to this mechanism. Most companies keep a standard weight near each
balance, and the first person to use the equipment each day checks the mea-
sure and records the actual observed value in a notebook. The notebook
record is checked to ensure there is no drift in the measurement and there are
no unacceptable values.
LABELING CONTROLS
Control of labels in API production is not difficult but is largely ignored in the
industry. The FDA expects all labels and labeling operations to be controlled.
Labels should be stored in a secure, limited access location. Preparation and
issuance of labels should be controlled, and there should be a reconciliation
of labels issued, used, destroyed, and returned. API operations often use labels
that are preprinted, except for variable information (batch number, gross and
net weights, expiration date), which is completed by hand at the time labels
are applied. Storage of these labels and their preparation should be controlled
by an SOP and documented. Labels that are generated in-house by computer
must be controlled and documented in a similar manner.
RECOVERED SOLVENTS
Recovery of solvents in API production is a common and necessary industry
practice. The important issue with recovered solvents is the potential
carryover of impurities into steps or products for which there is no design in

the production process to remove such impurities. There are three sources of
solvents for recovery:
1. recovery from and reuse within the same step,
2. recovery from and reuse within the same product at different
steps, and
3. recovery from multiple streams and reuse in common distribution.
Recovery in the first situation has the least potential for harm, if impu-
rity carryover occurs. Recovery from the second situation does have the po-
tential for depositing impurities downstream of the step in which removal of
the impurity is accomplished. The last situation has the greatest potential for
carryover of impurities, perhaps many different residues from a number of
different process streams.
Solvent recovery processes must be shown to be effective and validated.
There must be specifications for recovered solvents. These specifications may
be different from those for the virgin solvent, but must be equivalent in terms
of the activity in the chemical process and must be shown to contain accept-
able levels for all potential impurities. There must be identification of con-
tainers of recovered solvent vs. virgin solvent.
MASTER PRODUCTION AND CONTROL RECORDS

A master/batch record system, frequently seen in the API industry is a vestige
of the chemical industry. The system consists of two separate records, a "mas-
ter" instruction sheet and a data sheet used to record various operating para-
meters. This arrangement is found primarily in API processes that run for
several days. However, this type of system often does not comply with GMPs
and carries regulatory risk. This system does not meet GMPs because batch
records are required to be accurate copies of the appropriate approved master
record. The data sheet, used as a batch record, does not meet this require-
ment, as well as other requirements of batch records.
Often the "master" is found to be not properly approved and the copies
seen in the production area have handwritten changes, which also are unap-
proved. The data sheets are almost never approved as part of the master.
The following elements frequently are lacking from API master produc-
tion and control records:
• Identification of critical process steps

• Revision number and date
• Data sheets not included as part of the approved master
• Step-by-step production and control instructions, acceptable oper-

ating ranges and conditions, specifications, and precautions to be
followed
• In-process sampling
• Limits on hold times (justified)
• Final blend procedures, lot definition

• Yield calculations at appropriate steps with comparison of actual
vs. theoretical yields
Since batch records must be copies of an approved master production

and control record, the recommendation is to avoid use of the master instruc-
tion/data sheet system. A master document that is similar to a traditional
pharmaceutical master/batch record should be prepared for each batch size of
each API product (the International Conference on Harmonisation (ICH) API
guidance document will relax this requirement, allowing batch sizes to be ad-
justed by calculation). The master should be a "rolling" record containing
step-by-step instructions, as well as other GMP-required elements (including
those listed above) and blank spaces to enter actual parameters achieved and
other operational comments. The master should then be copied for use as a
batch record.
BATCH PRODUCTION AND CONTROL RECORDS

As mentioned in the previous section, batch production and control records
(batch records) must be accurate copies of the appropriate master production
and control record.
The FDA expects batch records to be handled as controlled documents
and that they will not available for general production employees to copy or
obtain. There should be a system in which a designated person or group, in-
dependent of the individuals directly responsible for the production, holds
the original signed and approved master production and control record. To
prepare batch records for use by production, the person or group would pre-
pare photocopies of masters with individual batch numbers entered on each
page of the batch record. These copies are checked, dated, and signed as being
correct, complete, legible, copies of the appropriate master. The documents
are then issued to production with some sort of logging system maintained to
track records issued. Several prenumbered batch record copies could be issued
in packages to production management, so that records would be available
during nonstandard working hours.
Production management must be accountable for the records issued.
Should replacement copies be needed, production must make a request to the
document control group. The log would then show a second batch record was
issued for a particular batch.
The following are typical problems or omissions with regard to API batch
records:
• Batch records not prepared as copies of an approved master record

• Batch records issued without appropriate approvals and controls
• Executed batch records do not include
dates, times (start and stop)
list of raw materials
traceability of all subbatches
identification of all equipment, both major and minor
weights and measures of each raw material
calculations
in-process control results
key intermediates tested against control limits
laboratory results
performed by/checked by signatures for critical process steps
deviations reported, recognized, and evaluated
actual yields compared against theoretical yields
description of packaging materials
reference to sampling procedures
example final product API label
equipment cleaning confirmation
• Lack of clear record of blending
• Lack of traceability of intermediate batches
• Lack of documentation of the combining and addition of tailings
from other batches
• Lack of mixing following static drying operations
• Lack of proper documentation covering recrystallizations from sec-
ond crops
PERSONNEL TRAINING AND TRAINING PROGRAM
The FDA considers training to be a very important element of GMP compli-

ance. Some Investigators always cover the training program during inspec-
tions, and others may cover training only if there are indicators that the
training program may be ineffective. Indicators of ineffectiveness include
such things as forms consistently completed incorrectly or the same proce-
dure conducted differently by two people.
Problems observed regarding training programs include the following:
• Indicators of ineffective training

• Training documentation that does not demonstrate the training re-
ceived by individuals
• Training documentation that does not demonstrate who has been
trained on specific procedures
• Documentation not available to demonstrate training has occurred
following changes in processes or procedures
• Training program and responsibilities not clearly defined in written
procedures
• Lack of training effectiveness assessment
• Lack of GMP training documentation for top management
• Lack of training documentation for temporary and contract em-
ployees who perform GMP-related functions.
The GMPs require all staff who perform duties that may effect the qual-
ity of the final product to be adequately trained to do their jobs. The FDA
leaves the exact training requirements up to the individual companies. Com-
monly, the FDA expects three levels of training:
1. General GMP awareness training that all employees receive, includ-

ing top managers and contract employees who may be involved in
GMP activities.
2. Training specific to an individual's job (SOPs, manufacturing in-
structions, lab test procedures).
3. Training related to changes in procedures, instructions, and so on.
Training program features to consider include the following:
• There should be one or more written procedures describing the

company GMP training program in detail, including specific
responsibilities. Ensure that trainers have adequate credentials to

perform this function. Define who the trainers are (who trains the
trainers?). Many companies leave the actual implementation of
training to department supervisors. This can result in inconsistent
implementation and often failure of the training program.
• There should be documentation that clearly shows the training re-
ceived, including cumulative training hours for each employee.
• There should be documentation that demonstrates both an indi-
vidual's training record and indicates which personnel are trained
on individual procedures.
• Ensure that all top management (who are the individuals actually
responsible for GMP compliance) are included in the program and
have training files.
• Training can be a combination of education, previous job experi-
ence, internal and external training courses, and on-the-job train-
ing by colleagues and supervisors.
• The training program should demonstrate that training is on-
going; that is, there should be many short training sessions (an
hour or less) frequently, rather than one eight-hour session per year.
• A method of assessing training effectiveness should be developed.
It can be testing or job performance observation. One company has
established a system in which a set of pertinent questions is at-
tached as part of each newly drafted or revised SOP to be used for
training on the SOP.
QUALITY CONTROL LABORATORY OPERATIONS

In recent years, with the introduction of the PAl program (since the generic
drug scandal of the late 1980s), the FDA has focused heavily on QC laboratory
operations. Most PAis for dosage forms include an FDA analyst as part of the
inspection team, either a chemist or a microbiologist, depending on the prod-
uct inspected. Although not as consistently as with dosage form inspections,
FDA chemists are sometimes included on inspections at API manufacturers.
With the closure of many FDA laboratories, a number of FDA chemists have
converted to FDA investigators, as well. All this adds up to much more focus
and scrutiny of laboratory operations. There tends to be a large number of
FDA observations resulting from GMP deviations seen during inspections of
QC laboratories.
Common Adverse Observations

Poorly Controlled Samples Reception and Handling
Samples should be logged in and tracked until all tests are complete and ma-
terial disposition has been determined.
Lack of Specifications for Some Materials

Specifications must be developed and approved for all materials, including
raw materials, solvents, recovered solvents, intermediates, and final products,
and must include physical characteristics.
Materials Accepted Based on Manufacturer's Certificates of

Analysis (CofA) Without Validation of CofA Analytical Data
The GMPs and the FDA clearly allow reduced testing of raw materials and
other ingredients (e.g., solvents), provided that each lot and/or shipment is
accompanied by a CofA and at least one test is conducted on each lot to es-
tablish identity. The data presented on the manufacturer's CofA must be vali-
dated initially and checked periodically. The meaning of "periodically" is
open to interpretation. It can be annually, after a certain number of lots are
received, or some other frequency. Whatever frequency is used, it must be de-
fended by the company.
A major problem is the improper validation of the CofA data. Very often,
a company will think the data are validated by simply testing three lots that
meet the specification. However, this does not validate the data, and the only
fact learned is that three batches meet specification.
Correctly, to validate the data for each test, there must be predetermined
allowable ranges for the value on the CofA (acceptance criteria), without re-
gard for the actual specification range. For example, the pH value on three
CofAs are 6.2, 6.4, and 6.1. The example predetermined allowable range for
the pH value is ±0.4. Therefore, for the pH values on these CofAs to be vali-
dated, each of the values must be ±0.4 of the value stated on the CofA (or
5.8-6.6, 6.0-6.8, and 5.7-6.5). OOS results may be used for the CofA valida-
tion because the purpose of the validation is to confirm the accuracy of test
results, not to determine the acceptability of materials.
In-Process Control Testing Accomplished by Production Personnel

FDA's 1998 Guidance to the API industry addresses this issue by stating that
in-process tests can be conducted by production personnel rather than QC.
This accounts for the fact that many API processes run on a 24/7 basis, it is not
practical to staff QC labs for 24-hour operations. However, production per-
sonnel should use QC-approved procedures, perform tests on properly cali-
brated instruments, and receive documented training for the tests conducted.
Improper Raw Data Handling Practices

A major deficiency in the QC labs is the improper handling of raw data,
which can result in the FDA questioning the integrity of analytical data. Dur-
ing the generic drug scandal there were many instances of fraud regarding
analytical testing. As a result the FDA has advocated the use of a system of
controlled documents for recording raw analytical data. The use of uncon-
trolled photocopied worksheets to record raw data is unacceptable. Basically,
there are only two methods of documentation that meet FDA expectations.
No raw data should ever be discarded, even if it is found later to be incorrect
or inaccurate.
One acceptable method of documentation is the use of bound note-
books with prenumbered pages. The notebooks, or workbooks, must be is-
sued in a controlled fashion and are intended to be used to record all raw
data. Using scrap paper to record raw data for later copying neatly into the
workbook is a totally unacceptable practice, especially if the scrap paper is
discarded and not attached to the appropriate notebook page. In actuality,
the scrap paper is the raw data and the notebook becomes a fraudulent docu-
ment. Companies must have procedures that guide the use of these note-
books to assure the integrity of data. The use of notebooks has a major
limitation. Occasionally, the lab books must be removed from the immediate
possession of the analyst so that data can be checked by a second person or
an aberrant result can be investigated. This makes it difficult for the analyst
to continue, as results cannot be entered into the lab book. Lab management
must establish a system such that data are not recorded and then transferred
to the notebooks later.
The second acceptable method involves the issuance and control of ana-
lytical worksheets in a manner similar to the control of batch records. This is
most useful where computer systems are used to store specifications and test
methods and the computer generates worksheets for the required testing. The
generation, issuance, and accountability of the analytical document packages
must be handled by a person or group not directly responsible for the testing
itself, and issued for the specific testing of each lot or batch. The system must
be managed such that if the original worksheet package becomes unfit for use,
the second copy is issued with the authority and control of a top manager,
generally QA.
Lack of Check of Analytical Work by Second Person

Often there is a lack of quality checks of analytical records. In many compa-
nies, the procedure is to have the lab director perform these checks. This is
unnecessary and can create a bottleneck. It is perfectly acceptable to have
peers perform the check of routine analytical data. The primary value in this
check is to ensure the proper method was used and that all calculations are
correct. Nonroutine testing or OOS situations may require the involvement of
management.
API Impurity Profiles not Fully Developed

A major deficiency is the lack of an established impurity profile for an API.
The ultimate goal of API production is to produce a very pure chemical entity.
Therefore, impurities must be identified and controlled. The purity of an API
is a major criterion to judge whether changes have an effect on the material.
Analytical Methods Not Validated

Every noncompendial and altered compendia! analytical method must be val-
idated. The U.S. Pharmacopeia (USP) contains clear requirements for method
validation. Compendia! (USP/National Formulary [NF]) methods need not be
validated, but a lab must demonstrate that the USP method can be properly
employed which may involve some elements of methods validation such as
repeatability. Compendia! methods must be used exactly as described in the
USP. Any deviation from the prescribed method is cause for a validation and a
study to show that the altered method provides equivalent results.
Unapproved Changes Made to Analytical Methods Used

There have been many instances in which the copy of the approved analytical
method used at the bench by the analyst contains unapproved handwritten
changes. This can happen when a flaw exists in the original method, equip-
ment or instruments change, or an analyst believes "there is a better way."
The approved original method must be used by the analyst until a change is
properly approved and validated.
Laboratory Information Management Systems not Validated

Companies use laboratory information management systems (LIMS) to vary-
ing degrees, but any system used to perform a GMP-required function or that
makes decisions based on data entered must be validated. Some older LIMS
are difficult to validate, and some companies have decided to scrap them in
favor of an up-to-date LIMS. The Y2K problem provided the impetus for many
companies to upgrade.
Lack of Laboratory Equipment Qualification,

Especially "Older" Instruments
Most new instruments purchased, especially sophisticated equipment such as
gas chromatographs and high performance liquid chromatographs, come
with blank protocols and other documentation to qualify the instruments.
However, much of the older equipment still used has not been properly qual-
ified. Documentation of qualification also may be lacking following repairs.
There should be no distinction between new and old equipment regarding
qualification, although the approach may need to be different. IQ and OQ

should be handled similarly to the recommendations earlier in this chapter,
which refer to equipment qualification.
Reagents, Standard Solutions, Mobile Phases

Specific preparations are vital elements of an API QC lab. Often the following
deficiencies are observed:
• Lack of records of preparation

• Lack of a check of calculation for factors
• Incomplete labeling of containers
Because these solutions may effect the outcome of a test or be a root
cause of a test failure, records covering their preparation are very important.
The records may be contained in individual analysts' workbooks or in work-
books dedicated to that purpose. Either way, the records should show or refer
to the method of preparation, analyst name and date, lot number of ingredi-
ents, calculation of factors, and expiration date. Container labels should show
the name of solution, date prepared, expiration date, analyst, and factor,
if any.
Lack of or Improper Implementation of Laboratory Procedure

for Handling OOS Analytical Results
Handling OOS analytical results has merited intensified scrutiny since the
generic drug scandal. There have been instances in which companies were
not able to satisfactorily manufacture products consistently. Often these prod-
ucts were "tested into compliance." That is, tests were conducted until a pass-
ing result was obtained, and that passing result was accepted to approve the
batch, discarding all previous test data that was OOS. A court ruling prompted
FDA to emphasize the handling of data and OOS results. FDA has issued a
draft guidance document addressing handling of OOS results.
In general, any OOS result must be investigated to determine an assign-
able cause. It is totally unacceptable simply to conduct retesting and approve
material based on satisfactory results of the retests. The immediate actions fol-
lowing the discovery of an OOS result are to report the event to superiors and
conduct an investigation to determine if the cause was an error, instrument
failure, etc. If the cause is clearly explainable and documented, such as an ob-
vious analyst error or equipment malfunction, the original test results can be
disregarded and the test(s) redone. The investigation may lead to additional
testing, but this should be done in accord with an approved procedure, with
oversight by QA. All analytical data and records must be retained, including
records covering tests that are invalidated.
Unsatisfactory Stability Programs

Stability programs often are found unsatisfactory, primarily for one or more of
the following reasons.
• Improper or uncontrolled storage conditions. Samples on stability

study have been found stored in laboratory and warehouse areas
where the storage conditions (temperature and relative humidity)
were not controlled. The FDA has adopted the ICH Guidelines for
stability programs. The guidance provides specific information re-
garding controlled conditions for storage. In general, it is necessary
to have qualified chambers, with controlled temperature and rela-
tive humidity for stability samples. API manufacturers who do not
have such chambers may need to seek another company or labora-
tory that can assist with storage of samples.
• Lack of a stability indicating test. The FDA requires development
of a test(s) that can detect the degradation of an API. At times this
can be difficult, but it is not satisfactory to simply test API stability
samples for assay and total impurities, without a test that can de-
tect degradation. Stress testing can be used to force the appearance
of degradation impurities.
• Expiration dates not supported by data. Initially, it is acceptable to
assign an expiration period based on accelerated stability testing,
but there must be real-time shelf life data generated to support ex-
piration dating used.
• API stability samples not stored in simulated market containers .
Most APis are marketed in polylined fiber or plastic drums. Some
API manufacturers store stability samples in containers that do not
simulate these drums, using glass bottles or some other container
that may be "better" than drums. API manufacturers have pur-
chased miniature drums or placed premeasured, labeled packets of
multiple batches that are on study in full-size actual drums.
• Testing not done at required stations. Stability programs should
create a schedule of testing at the appropriate time stations (3, 6,
12 months, etc.). It is objectionable to the FDA if the stability test-
ing departs from the schedule, especially if samples are withdrawn
from the controlled conditions and then not immediately tested. It
would be acceptable to test stability samples ±10 days from the due
date. Short-term accelerated samples should be analyzed within
2 days of removal from the controlled environment. Since this lab-
oratory work can be scheduled in advance, the lack of availability of
lab resources should not be an issue.
• Samples not routinely (annually) placed on program. The GMPs re-

quire that at least one batch of each product in each package
configuration be placed on the stability program annually. Addi-
tional samples are required following changes, in accordance with
the change control program.
RESEARCH AND DEVELOPMENT (R&D)

R&D plays an important role in providing information to the development
report. Although the FDA and the GMPs do not require a development report
per se, the FDA does require a company to have information that supports
and justifies the manufacturing process. Industry coined the term "develop-
ment report," which is commonly used to describe the compilation of these
development documents. In general, a development report is a chronological
history of the product/process that not only describes the evolution of the
process, but also should include pitfalls and trials that were unsuccessful.
Information from R&D is also a necessary element to change control,
used when assessing the impact certain changes may have on final API qual-
ity, and when cleaning procedures are being developed.
An FDA inspection technique is to select a process step or parameter ran-
domly and request the company to provide development information that
justifies that step or parameter.
The FDA also requires sufficient documentation to demonstrate that
processes are adequately transferred and scaled up from R&D to commercial
production. The R&D department is typically responsible for providing this
data and documentation. Inadequate technology transfer documentation is
seen by the FDA as a GMP deficiency.
Often R&D facilities are responsible for producing API material that is
used in clinical trials. It should be noted that from a GMP perspective, the
FDA does not make a distinction between clinical supplies and commercial
product. The reason is that both clinical supplies and commercial products
are used in humans, which require GMPs to be applied in the manufacturing
processes.
The FDA requires that at least minimal controls be applied, which vary
depending on the exact process and situation. Minimal controls include at
least the following:
• Approved manufacturing instructions

• Approval of ingredients
• Qualification of production and laboratory equipment
• Calibration of equipment and laboratory instruments
• Documentation of the manufacturing process
Domestic . . . API Manufacturing Facility Audits and Findings 161
• Testing of intermediates and final API, especially to identify impurities

• Formal approval of product before release
PROCESS VALIDATION
Since the majority of this book is devoted to API process validation, only brief
details from the FDA perspective will be mentioned here.
Process validation has been in our vocabulary since 1978, but there is
still not a clear understanding throughout the API industry. Today, the FDA
expects all APis to be validated, even though the agency has not actively at-
tempted to seek compliance regarding "old" APis. Many of these old APis
have been manufactured for many years but have not been validated to in-
clude satisfactory support documentation. Although there are attempts to
validate most new APis, many fail to be accomplished properly. These inade-
quacies include lack of
• process justification,
• scale-up/biobatch vs. commercial size batch comparison,
• identification of critical parameters,
• special tests designed to demonstrate that critical parameters can be
achieved,
• acceptance criteria for these tests, and
• validation of blending processes.
Often the API production process is not completely defined and "frozen"
when material is produced for Phase III clinical trials. Validation cannot be
performed until the process is fixed. Development work must cease when val-
idation begins. Also, the FDA will find it objectionable if the API process for
Phase III studies differs from the commercial process filed in an Abbreviated
New Drug Application or New Drug Application.
The FDA encourages prospective validation, which may be conducted on
R&D or commercial size batches. If R&D-scale batches are used for process
validation, the process then can be scaled up (without changes) and trans-
ferred to commercial production, in which confirmatory testing would be
done. The FDA expects each process parameter to be justified (that is, to have
a development history that demonstrates the necessity and purpose of all
steps and parameters). All critical steps must be validated. It is the responsibil-
ity of the company to identify the critical steps or parameters. The criteria for
criticality should be based on the effect the step or parameter has on the final
API quality. In other words, a critical step is one that should it fail, may
have an adverse effect on the quality of the final API. Although the latter
production steps are generally more critical, early steps can be critical as well.
For example, if in an API process step 1 produces a toxic impurity that is in-
tended to be removed in step 2, and there is no subsequent step designed to
remove this impurity, then step 2 would be a critical step. Should step 2 fail,
the final API impurity profile could be adversely affected.
Retrospective validation is allowed, but discouraged, by the FDA because
of the limitations of this validation method. A minimum of 20 (preferably 30)
batches is necessary in a retrospective validation. All batches included must
have been produced by an identical process. If there were any changes, the
retrospective method cannot be used. Another limitation is that routine test-
ing on these batches may not have included tests that demonstrate critical pa-
rameters can be achieved.
REFERENCE
FDA. 1998. Guidance for industry, manufacturing, processing, or holding active pharmaceu-
tical ingredients [Draft]. Rockville, Md., USA: Food and Drug Administration.
7
VALIDATION OF APis:
A CASE STUDY
Nirmal Khanna
Consultant to Hoffman-LaRoche
Nutley, New Jersey
During the last five years, the industry has come a long way in understanding
and adapting validation in the manufacture of active pharmaceutical ingredi-
ents (APis). I believe the previous misgivings and confusion are now largely
behind us, and, generally speaking, validation has gained respect, at least
among all progressive manufacturers.
Technical literature has blossomed on this subject thanks to the Food
and Drug Administration (FDA), the International Society for Pharmaceutical
Engineering (ISPE), and the technical community, which have taken the chal-
lenge head-on by publishing on numerous validation topics, conducting sem-
inars, and developing key reference documents such as the Baseline
Pharmaceutical Engineering Guides. These documents now adequately sup-
port validation studies in the API manufacturing arena.
In this chapter, I present process validation as a case study for an API
manufacturer. The approach presented in the previous edition is updated to
accommodate the current regulatory environment. The objective is to illus-
trate the methodology for developing and executing a successful validation
program. In addition, this review includes examples of computer validation
and relocation of an API to another equipment train.
Today, a successful validation program must carry out either prospective
validation for a new drug substance or concurrent validation for an existing
drug substance (see Appendix 7.1). In the early 1990s, the FDA accepted ret-
rospective validation as a regulatory tool for a short period, but now this
163
approach should be used only for reviewing the manufacture of existing drug
substances and learning from it. Knowledge gained from retrospective reviews
can substantially benefit the company's concurrent validation program.
The ultimate company goal should be to minimize variability in manu-
facturing operations and consistently produce a quality drug substance. A suc-
cessful validation program must demonstrate that variability among the critical
parameters in production is under control. The validation program must use
common sense and technical sense at every step to accomplish that goal.
THE FDA AND THE HISTORY OF VALIDATION

At present, production of pharmaceuticals is governed by U.S. regulations
found in 21 CFR Part 211, which contains the minimum practices for meth-
ods, facilities, and controls to be used for the manufacture, processing, pack-
ing, or holding of a drug product. These also are referred to as current Good
Manufacturing Practices or cGMPs. These evolved in response to consumer
product safety needs after enactment of the Pure Food and Drug Act in 1906.
Now the cGMPs promote safe drug products that possess the identity,
strength, quality, and purity claimed for them.
Appendix 7.2 illustrates chronological events that brought about the is-
suance and subsequent revisions of pertinent FDA guidelines. The first refer-
ence to validation in regulatory documents was made in 1978 when the FDA
required manufacturers to perform validation studies on sterilization
processes. The term validation was then used only to describe assurance in
sterilization studies. A few years later, the scope was expanded, and the FDA
issued draft guidelines on process validation for drug products. In 1983, bio-
logical processes and bulk pharmaceutical chemicals (BPCs) were included in
the guidelines. BPCs were recently renamed APis.
WHAT IS VALIDATION?
Process validation is defined in the FDA guidelines (FDA 1987) as "Establish-
ing documented evidence that provides a high degree of assurance that a spe-
cific process will consistently produce a product meeting its pre-determined
specifications and quality attributes." The chosen process must consistently
produce a product to predetermined specifications and quality attributes
within each batch and between the batches. The end product must consis-
tently meet specifications and must be reliable, safe, and effective. Docu-
mented evidence means quantitative assessment, measurement, and conduct
of processes. A high degree of assurance is achieved through sufficient prod-
uct and in-process controls, verification procedures, personnel training,
Validation of AP/s: A Case Study 165
Standard Operating Procedures (SOPs), and quality control and assurance

involvement during execution of the manufacturing operations.
Validation is an ongoing process, not a single event. Quality, safety,
and effectiveness must be designed and built into the product by control-
ling variability from the beginning to the end of the manufacturing
process. The manufacturer must demonstrate control over process steps
that may be responsible for product variability, and such control must be
reproducible.
Ultimately, process validation helps in establishing and maintaining a
controlled process and provides necessary documentation to satisfy the regu-
latory requirements of the pharmaceutical industry. A controlled process de-
livers several benefits, including reduction of rejections and reworks;
improvement of yields; improvement in product quality; reduction of in-
process and or finished lot testing; easier investigation of process problems;
and, above all, employee quality awareness. In addition, the validation ap-
proach supports greater ability for worldwide product standardization.
A SUCCESSFUL VALIDATION PROGRAM

The practice of validation should begin at the project development phase and
continue through product end use, including continuous improvement and
change control to maintain the process in the validated state. Handling of the
project during the process development phase must be strengthened. All
process concerns such as failure limits, satisfactory operating ranges (includ-
ing normal operating ranges), yield expectations, and in-process checks (tests)
should be determined during this phase.
A successful validation program must employ a modular approach. Each
system should be divided into modules, with its functions defined. Critical
parameters in each module are identified. Operating ranges for each critical
parameter and control limits are established. Functional specifications are de-
termined, and acceptance criteria are established. Each module is validated in-
dividually, and, finally, all are proven to function reliably together.
Thus, validation is achieved through integration of the following:
• Qualified equipment
• Qualified facility and utility systems
• Qualified environment
• Qualified manufacturing steps and packaging processes
• Calibrated process controls
• Qualified analytical and microbiological test methods
• Qualified computers
• Qualified cleaning and sanitation methods

• SOPs
• Trained operators
• Proper documentation
• Continuous improvement and change control policy
• Preventive maintenance and calibration
• On-going monitoring and revalidation
API VALIDATION-A CASE STUDY

Let us assume that a company manufactures several drug substances using a
multistep synthesis that has not been validated so far. A new API is scheduled
for production in July 2000 in a dedicated train. Also, production of an exist-
ing API is moving to another building. This scenario presents many technical
challenges and options; nevertheless, I will attempt to present an approach
for developing and executing a successful validation program and show how
to produce the necessary documentation.
This exercise steps through a typical concurrent/prospective validation
program, which includes the validation team, the master plan, and various
validation activities, including cleaning validation, change control adminis-
tration, and ongoing monitoring and revalidation.
MANUFACTURING OPERATIONS
The API manufacturer has been producing several bulk actives since 1980 in a
few multiproduct equipment trains. These facilities are maintained and oper-
ated according to cGMP. A master validation program has been developed and
reviewed with the FDA district office for their blessings, and the validation
manager has been busy validating each product since 1996.
The typical bulk active is produced in four chemical synthesis steps. The
first two steps produce a prime intermediate from purchased materials, whose
quality is monitored. This prime intermediate is inventoried on-site and is re-
leased by Quality Control for production campaigns. In the third step, the
prime intermediate is reacted with another purchased material to produce the
basic chemical structure of the drug product. In the last step, another additive
that often modifies the chemical moiety slightly is added to produce the final
product.
A typical equipment train consists of several batch equipment modules
to complete the chemical synthesis and purification steps of the process. Also,
a few dedicated modules are provided, which meet the needs of a specific API.
The equipment train under validation was installed during 1980-1985. Re-
cently, two reactors were replaced. Dryer, cooling/heating system, and puri-
fied water units were installed. A Honeywell control system was added for
monitoring and controlling critical process parameters. Also, a rotary sifter
and a blender were installed in the packaging line to improve blend unifor-
mity. In addition, the drum filling room was rebuilt to Class 100 specifica-
tions for handling a parenteral product.
QUALITY ASSURANCE SYSTEMS

The API producer has in place the infrastructure of the various quality assur-
ance systems at this facility. The manufacturing operations follow cGMP
guidelines. The following quality assurance systems are identified as essential
to the success of any process validation program:
• SOPs and guidelines
• Technical and development reports
• Master batch records (manufacturing procedures)
• Cleaning procedures
• As-built process flow diagrams (PFDs) and piping and instrumenta-
tion diagrams (P&IDs)
• Raw materials/intermediate specifications and test procedures
• Variance reporting and change control system
• Validated analytical methods for in-process testing
• Validated analytical methods for finished lot testing
• Personnel training
• Facility and equipment maintenance program
• Instrument maintenance and calibration program
• Control testing and inspection operations
• Packaging and labeling practices
The items presented above in italic are not directly part of the validation
effort, but these are considered equally critical to the success of a process vali-
dation program. If a company lacks in any of the above documentation or
systems, efforts should be immediately directed to implement and upgrade
such systems to support a successful validation program on the site.
This API producer has written Guidelines and SOPs for several of the
above quality assurance systems (see Appendix 7.3). Every company may not
follow this example to the letter; however, the critical SOPs or Guidelines
must be adopted by a progressive manufacturing organization.
Good production batch records are extremely critical to the success of a
validation program. This API manufacturer has been improving its master batch
records since 1993. After completing a successful retrospective review and per-
formance history of the API, each critical parameter and specification has been
assigned an operating range. The batch records are written in clear and concise
format for the operating staff. Prior to initiating the validation effort, the vali-
dation manager or quality assurance personnel reviewed the master batch
records with the production manager to remedy any remaining inconsistency.
A validation viewpoint on this subject is included in Appendix 7.4.
In addition, as a minimum, as-built PFDs must be available to the operat-
ing staff and the validation team to facilitate the validation effort. The batch
records, PFDs, and P&IDs were updated by IDEAL Corp. with top priority to
support the validation effort. The company hired an outside contractor to up-
date its PFDs and as-built P&IDs. This work was completed during 1995-1996
for all production trains. Master batch records revision was completed in 1996.
VALIDATION PROGRAM
Following the FDA doctrine (FDA 1987), a validation program was developed
for the New Jersey manufacturing site. In addition, the company launched a
formal retrospective review program on all existing APis to identify opportu-
nities for improving production operations.
A validation manager was assigned to the job, who developed the work
teams and assigned responsibilities. Master plans were developed, meetings
were held weekly, and a schedule was developed for execution of all major
validation activities (see Table 7.1).
Table 7.1 Master Plans Schedule

Reports Person Assigned Time Taken
Retrospective Reviews:
Master Plan, Old APis (12) JM 8 weeks
Concurrent Validations:
Master Plan, Train A NK 8weeks
Master Plan, Train B NK 4 weeks
Master Plan, Train C JS 8 weeks
Master Plan, Train D JS 6 weeks
Prospective Validations:
Master Plan-New Dedicated Train E NK 8weeks
Master Plan-Old API moved to new site NK 6 weeks
Validation of APis: A Case Study 169
• Retrospective work team: key individual from validation (1) and

others on need basis, including production (1), quality assurance
(1), quality control (QC) (1), and development (1)
• Concurrent/prospective work team: key individual from validation
(1) and others on need basis, including production (2), quality as-
surance (1), QC (1), development (1), and engineering (1)
RETROSPECTIVE REVIEWS
Master Plan
IDEAL Corp. adopted a master plan for retrospective reviews to examine its older
API processes thoroughly. The purpose of this program was to demonstrate that
the production of each API at the New jersey facility has taken place in a satis-
factory and consistent manner according to the documented manufacturing
procedures. This review effort will document whether each process has consis-
tently met predetermined specifications regarding process parameters, in-process
control testing, and process yields. It will document that a product has met pre-
determined quality control specifications. It will establish that process documen-
tation is complete and accurate, each variance was satisfactorily investigated,
and findings were implemented. A typical master plan addressed the following:
• Scope ofprogram: This section included a list of candidates to be val-
idated and indicated priority, if any. The list identified processes
that will be prospectively validated or reasons for their exclusion.
• Time frame: This section indicated when preparation of the formal
reports will begin and included a realistic schedule.
• Personnel resources: This section listed the names of personnel who will
participate in writing the reports and the team of personnel who will
meet on a regular basis to review progress and manage the project. It
listed the experts from other departments who may be consulted.
• Scope of retrospective report: This section indicated the time frame of
the data that will be reviewed for each report. Typically, 20-30 con-
secutive lots of the most recent production were reviewed. When
fewer lots were available, such circumstances were clearly ad-
dressed. The scope described at what stage of the process retrospec-
tive validation will begin.
In general, the review began from the process step involving
the final chemical transformation forming the structural elements
of the API and continued downstream through subsequent isola-
tion/purification steps. However, if significant impurities were be-
ing introduced or removed at an earlier step, then the review team
often decided to initiate validation from that point in the process.
These operations were generally the most critical to the quality of

the final product and would be the steps that will be validated un-
der a concurrent/prospective validation program.
Each process was reviewed and exceptions to the scope, if nec-
essary and appropriate, were documented.
• Report contents: A retrospective report outline was included and de-

scribed in the master plan. Each retrospective report on a product
varied in content depending upon the nature of the process.
• Acceptance criteria: The API manufacturer adopted the following ac-
ceptance criteria for the retrospective review study. It stated that in
order for a process to be given a passing grade, the production and
quality control records must show the following:
At least 95 percent of the batches reviewed must have passed
quality control testing (excluding test failures caused by
equipment malfunction and or operator error).
Each key process parameter must have been within specified
ranges at least 90 percent of the time for batches reviewed (ex-
cluding variances caused by identified equipment malfunc-
tion and or operator error).
All in-process test failures and variances must be investigated
and documented satisfactorily. A retrospective investigation,
if necessary, should show that product quality was not ad-
versely affected.
Each in-process control test must have been within specifica-
tions at least 90 percent of the time for the batches reviewed.
If any of the above criteria were not met, then the process failed the
retrospective review. Problems associated with the process were de-
termined, corrective action was put in place, and that API was as-
signed an accelerated concurrent validation schedule.
RETROSPECTIVE REVIEW EFFORT

The IDEAL Corp. retrospective team had four core members. The core team
members were derived from the Validation, Production, and Quality Assurance
functions. Other personnel from the Process Development, Quality Control, and
Maintenance groups assisted the core team on need basis. Since the company
was short on manpower, two qualified temporary staff were hired as validation
engineers to gather data and write the 12 retrospective review reports. These can-
didates were chemical engineers with API manufacturing experience. Each
member was computer literate and possessed good analytical and writing skills.
To initiate the review effort, the validation engineer developed a good

working knowledge of the process by reading all technical, development, and
annual product review reports on the product.
All manufacturing batch records, in-process control data, QC records,
cleaning records, annual product reviews (performance summary), and main-
tenance and calibration records were reviewed for 20-30 sequential lots cov-
ering the most recent time period, 1993-1996. A template of an anticipated
report in table format was first prepared. The above data with comments and
footnotes were then efficiently summarized into the template's "table for-
mats" using a laptop computer and were later transferred into the desktop
computer by each writer. Since the data were dispersed with different groups
on the site, the laptop was a great help. Typically, the review began with the
final synthesis step, where moiety was first formed, and included all subse-
quent isolation/purification steps of the process.
The core team and the temporary staff initially met once a week for a
couple of hours to discuss issues in an informal atmosphere. As validation
policies were established and issues addressed, the two-hour meeting was re-
duced to only 30 minutes in the end. These meetings tracked the progress of
each project, provided guidance to temporary staff, resolved issues, and re-
viewed/edited the review reports. In addition, the temporary staff was en-
couraged to discuss any issue during the week with individual core members
and the extended team on an informal basis. Each report was somewhat
unique and was handled in depth by one person, who, on average, took about
10 to 12 weeks to complete it. The retrospective effort was concluded in 18
months.
Each report was signed by the author and the retrospective review team
members. Final approval was given by the heads of Chemical Operations and
Quality Control/Assurance.
Out of the 12 APis, only 4 received the passing grade. The remaining 8
products failed the tough retrospective review criteria for various reasons, and
these were then subjected to an accelerated concurrent validation schedule.
Among the 12 APis, 10 lots met QC specifications and in-process control
tests. A few failures occurred in 2 processes due to equipment malfunctions.
On process parameters, most deviations were small, and none had an adverse
impact on product quality; in some instances, additional/improved instru-
mentation and controls were recommended. On a few occasions, the valida-
tion team members uncovered unsatisfactory investigation of variances and
failure reports. This issue has been addressed. Each investigation is now care-
fully documented, backed with development work if necessary, and reviewed
by Quality Assurance personnel.
The retrospective review developed performance histories of all existing
APis. The review documents became a valuable performance reference and an
excellent tool for communication.
An outline and briefs of a typical retrospective review report are pre-
sented in Appendices 7.6 and 7.9A.
CONCURRENT/PROSPECTIVE VALIDATIONS
The concurrent/prospective validation studies had a much larger scope (see
Appendix 7.1). Besides monitoring the process and the cleaning, these valida-
tions documented a review of critical utilities, process equipment, and con-
trolled environment facilities.
Two validation engineers were hired to write, execute, and prepare sum-
mary reports for the various protocols. These chemical engineers were com-
puter literate, possessed good analytical and writing skills, and had
pharmaceutical industry experience. The core team members for this effort
also were derived from Validation, Production, and Quality Assurance func-
tions. And personnel from the Process Development, Quality Control, and
Maintenance groups assisted the core team on need basis.
To create validation documents, the validation engineer developed a
good working knowledge of the process by reviewing the batch records, PFDs,
and P&IDs, reading all technical, development, and annual product reviews
on the product. The work team participated in the review, execution, and ap-
proval of the various validation documents.
A typical concurrent or prospective validation review covered the fol-
lowing:
• Controlled environments facilities, such as dryer rooms, packaging
rooms, milling rooms (installation qualifications [IQs], operational
qualifications [OQs])
• All critical utilities, such as nitrogen, compressed air, and clean
steam (IQs, OQs)
• Deionized (DI) and purified water systems (IQs, OQs, performance
qualifications [PQs])
• Process equipment (IQs, OQs)
• Computer control systems (IQs, OQs)
• Process operations/steps (PQs)
• Equipment cleaning (PQs)
IQs documented that the equipment has been installed in accordance
with approved design and specifications, regulatory codes, and manufactur-
ers' recommendations. A typical IQ checklist included the equipment list, reg-
ular filter list, the HEPA filter list, the critical instrument list, noncritical
construction completion verification forms, the list of applicable SOPs/
Manufacturing Procedures (MFPs), materials of construction (product contact
surfaces), and the lubricant list.
OQs documented that the new equipment can operate as designed and
intended and is capable of operation over the entire range of process vari-
ables. The OQs were a testing process that evaluated the equipment/system
on start-up. Controls were adjusted, and performance trials were conducted to

verify that the equipment operated according to design specifications. As a
general rule, OQs focused on reviewing heating, cooling, turning, pressure,
and vacuum limits for the process equipment. This review also included criti-
cal utilities such as nitrogen and air, and noncritical utilities such as steam
and cold brine. Where feasible, water runs were completed in process equip-
ment to confirm design specifications and/or to confirm a match with the
performance needs of the manufacturing operations.
IQ/OQ activities for a new facility, which was being validated prospec-
tively, were completed with sufficient details prior to the commencement of
PQs. However, this rule was relaxed in concurrent validations of existing APis
when the process equipment already had a successful operation history and
satisfactory maintenance/calibration records. Overall, it is fair to add that a
commonsense approach was exercised in concurrent validation of an existing
API installation, and only value-added data were developed/monitored or re-
viewed (see Appendix 7.5).
PQs referred to monitoring of the production process that produced either
an intermediate, finished API, or critical raw material such as purified water. At a
minimum, three consecutive production runs were monitored during this test-
ing phase for successful validation. If a lot failed for reasons unrelated to process
performance, such as power failure or equipment breakdown, that lot was re-
moved from the validation scheme, and the fourth validation run was sched-
uled. Incidents of a lot failure or major process deviations were fully investigated,
and a formal investigation report was prepared and documented. After resolving
the issues, the API was scheduled for three consecutive production runs again.
The critical parameters were set at midvalue of the specified operating range
in each validation run. All in-process and final QC test results were reviewed and
documented. Where feasible, the validation team often recommended addi-
tional confirmatory in-process and QC testing during the validation runs. The
impurity profile in the API was fully characterized and documented.
In a multistep process, the validation team decided on the starting point
for validation after considering the following factors:
• The point in the synthesis at which significant impurities may be

introduced into or removed from the process.
• The point after which no significant impurities will be removed
from the process
• The point at which all structural elements of the API are present
• In all cases, the point at which the QC-released prime intermediate
is involved in the synthesis must be validated.
After the validation team declared an equipment train under validation, any
modification or change pertaining to the process or equipment thereafter was
documented under the change control policy of the organization. Each
change was reviewed appropriately by a designated group under this pol-

icy and its impact on validation activities was established, reviewed, and
acted on.
Master Plan
As a first step, master plans were prepared for all production trains. The key el-
ements of a typical prospective validation master plan for a multiproduct
train were as follows.
1. Introduction/scope: A brief overview of the project and scope of the
validation activities, which identified the validation team and spec-
ified individual and departmental project responsibilities.
2. Process/facilities description: A brief description of the manufacturing
process, the facilities, and equipment, including:
• Process synthesis description, in-process controls, and com-
puter controls;
• Utilities and support systems;
• PFDs, overall facility layout; and
• Packaging area, controlled environments, material/people
flow, and so on.
3. List of systems to be validated including purified water system, sol-
vent recovery, equipment cleaning, and so on; where necessary, ref-
erence was made to guidelines or SOPs on change control,
equipment maintenance, and calibration.
4. Validation approach: This section described an outline of the general
requirements and/or conditions for execution and acceptance. All
assumptions made, the sequence of activities, and the extent of val-
idation runs for PQs were covered. It stated that a minimum of
three consecutive successful API lots must be manufactured to
demonstrate that the process is validated (PQs). These lots must be
produced in the equipment train used for the manufacture of the
marketed product. The point in the process after which process val-
idation should apply was determined for each product and the val-
idation criteria for determining which steps must be validated was
documented in this section.
In general, only the process steps involving the final chemical
transformation forming the structural elements of the API and its
subsequent isolation/purification steps were included in the valida-
tion study. However, if significant impurities were being introduced
or removed at an earlier step, then the validation team often de-
cided to initiate validation from that point in the process.
5. Acceptance criteria guidelines: The master plan addressed the accep-

tance criteria clearly. The general guidelines for individual protocol
were addressed in this section.
6. Planning and manpower equipment: This section discussed typical is-
sues; specified who will prepare the master plan, protocols and so
on for a new facility; specified which department will perform IQs,
field testing, inspect cleaning, passivation, and welding, and so on;
specified which department will perform and document calibra-
tions; specified who will analyze samples; indicated any specialized
testing apparatus; specified which group will perform start-up
functions (lubricate drives, charge heating, ventilating, and air-
conditioning (HVAC) systems, test and balance air systems, certify
high efficiency particulate air (HEPA) filters; and specified training
needs and who will perform and document the training needs.
7. Approval: This section discussed approval procedures for protocols,
field documents, and summary reports.
8. Validation schedule: This section provided a validation schedule for
the validation project.
Each master plan was approved by the validation team and management
representatives from the Production and Quality Assurance departments.
The master plan presented a general overview and established guidelines
for conducting the validation program. This document provided an over-
view of the validation project. An outline of the master plan is presented in
Appendix 7.7.
Validation Protocols
Protocols were written for each train to qualify process, controlled environ-
ment facilities, process equipment, utilities, water systems, computer control
systems, equipment cleaning, and so on. Templates were created particularly
for the attachments. When solvent was recycled in the process, a solvent re-
covery protocol was added. These protocols were typically approved by the val-
idation team members (validation engineer, process manager, plant engineer,
and lastly by a quality assurance coordinator). An outline and a few concurrent
and prospective protocol briefs are presented in Appendices 7.4 and 7. 7.
Summary Report
After execution, a formal summary report was prepared for each validation
protocol. It provided an analysis of the data gathered and summarized the
findings. The summary report accurately documented the expected and
actual results. Discrepancies, if any, were appropriately discussed, and any fol-
low-up actions were included. An outline of a summary report is presented in
Appendix 7.9G.
CLEANING OPERATIONS
Two APis were often campaigned in the same equipment train. Each produc-
tion campaign often lasted about three months. At the conclusion of the
product run, an end-of-campaign cleaning was performed. Use of hot potable
water and 2 to S percent sodium hydroxide as cleaning agents, and occasional
use of detergents, was quite common. The rinse operations employed potable
water, DI water, or purified water and occasionally used solvents. For par-
enteral APis, the final rinse operations often used purified water and followed
up with solvent rinse.
A general master plan on cleaning, "Guidelines for Cleaning of Equip-
ment and Facilities," was issued to all production supervisors. Other support
documents included cleaning procedures/guidelines for key equipment such
as dryers, reactors, filters, centrifuges, mills, and dust collection equipment.
Each production supervisor used the guidelines for developing the manual
cleaning procedures for equipment systems in each train.
Each production supervisor was responsible for postproduction and pre-
production cleaning. Preproduction cleaning was enforced if (1) mainte-
nance had been performed between campaigns, (2) equipment remained
sealed for an extended period, (3) equipment was not adequately covered or
sealed and dusty/dirty operations had been performed since the last cleaning,
or (4) the next product to be manufactured was not known at the time of the
original cleaning and toxicological impact demanded more stringent clean-
ing requirements.
All cleaning procedures were reviewed and approved by Quality Assur-
ance. All cleaning procedures, like batch records, were written with sufficient
detail. These procedures defined which parts of the equipment train were to
be disassembled, and directed operator attention to "dead legs" in transfer
lines and so on during cleaning operations.
This facility had a generic SOP that required each cleaning procedure to
include (1) cleaning and sanitizing agents, amounts, volumes, and solvents;
(2) temperature and times; (3) conditions for disassembly of equipment and
piping; (4) rinses and final rinse volumes; (S) sampling and swabbing as re-
quired; and (6) inspection and testing. Other issues such as acceptance criteria
and intervals between cleaning were also addressed.
Written procedures were issued for cleaning and general housekeeping
of production facilities. These procedures included the methods, equipment,
and materials used for removal of residual product from floors, walls, and so
on. These procedures described how to sanitize general areas, maintain con-
trolled environments, and decontaminate pure packaging rooms. These pro-
cedures included monitoring for microbial control.
Cleaning guidelines enforced "how clean is clean" by recommending
the level of bulk active residue left in the process equipment that can be tol-
erated in the first production batch after cleaning. The maximum residue al-
lowed in the process equipment after cleaning was determined according to
the hierarchy in Table 7.2.
Since finished APis possessed varying degrees of toxicity, a multiproduct
train in this service was assigned the highest criticality in cleaning. Here, toxi-
cological and pharmacological properties of each API were taken into account
to determine the maximum allowable bulk active residue in each case. A family
of APis was defined as a group of products that possessed similar toxicological
and pharmacological properties based on their use, solubility, and toxicity.
The 25-ppm criteria was arbitrarily chosen. It was considered safe
enough and it helped in quantifying the "visually clean" criteria for the clean-
ing validation programs. Allowable residue, R, for finished APis with varying
toxicity/pharmacological properties was calculated using the following steps:
1. For API being cleaned, the lowest daily dose administered to SO-kg
adult was extracted from the Physician's Desk Reference (PDR) (A).
2. The next API batch to be processed was converted into total num-
ber of daily dosages using maximum daily dose from the PDR (B).
3. Safety factor (S): used 1/1000 for carcinogens, otherwise used 1/100
to determine acceptable exposure.
4. R =A X B X S.
Table 7.2 Hierarchy of Criticality

No. Product Types Processed on the Process Train Allowable Max. Residue in
Next Batch
1. Multiproduct train for finished APis, from point at which 25 ppm orR*, whichever
moiety first formed is smaller
2. Multiproduct train for family of APis, from point at which 25 ppm
moiety first formed
3. Multiproduct train for API intermediate 25 ppm
4. Dedicated equipment for intermediates and API product 25 ppm
5. Multiproduct trains for GRAS substances** 25ppm
* R-AIIowable residue based on toxicological/pharmacological properties.

** GRA5-Generally recognized as safe
Cleaning Validation-Concurrent or Prospective Validation

The intent of cleaning validation was to provide confidence that the cleaning
procedures assured equipment is acceptably clean for the next production
campaign. A minimum of three end-of-campaign cleaning runs was typically
performed, but two were acceptable for cleaning validation. If a cleaning
should fail for any reason unrelated to the performance of the equipment
cleaning procedures (e.g., a power failure or equipment breakdown), that
cleaning run was removed from consideration, and one additional cleaning
run was added.
Each equipment module was considered clean when its total residue
(TRi) was less than or equal to the established maximum allowable residue
(MARi). If the summation of all equipment module residues (ITRi) exceeded
the summation of maximum allowable residue (IMARi), the cleaning valida-
tion failed, and the cleaning procedures were amended as necessary.
Sampling for cleanliness utilized both the rinse and the swab methods.
An API facility often presented the following situations:
• The process equipment can hold the final rinse; a representative
rinse sample is available.
• The process equipment cannot hold the rinse; the rinse is always
running.
• The process equipment is totally enclosed/sealed, opening not
practical; therefore, swabbing is not feasible.
During validation, when equipment could hold the final rinse, its clean-
liness was verified by testing a final rinse sample (normal) and a confirming
swab sample (validation only). The swab sample was taken to confirm the suc-
cessful completion of the final rinse operation for the validation run. If process
equipment could not hold the final rinse, then its cleanliness was verified by at
least two swab samples. Where equipment was enclosed and swabbing was not
feasible, a minimum of two final rinses were required to verify its cleanliness.
The second final rinse sample was tested to verify the remaining residue.
The rinse and swab samples were tested during validation with validated
analytical methods. The concentrations of bulk active residues in the rinse
and swab samples were often determined via high performance liquid chro-
matography (HPLC). This procedure had a lower detection limit than the thin
layer chromatography (TLC) procedure.
TRi was calculated as follows:
Via Rinse Method

TRi = [Ci X Vi] X [3.7854 L/1 gal]
Via Swab Method
TRi =[average SRi x Ai x 144(in.2/ft2)]
Where
n n
MAR = L MARi = L TRi -::; xx.xx grams
1 1
MARi = Wi X MAR
MAR = maximum allowable residue on contact surfaces for train AA
MARi = maximum allowable residue on contact surfaces for operation i
TRi = total residue (mg) on contact surfaces for operation i
Ci = residue concentrations (mg/L or J.Lg/mL)
Vi= volume of rinse (gallons)
i = 1 through n, cleaning suboperations
Wi = weight factor for operation i
SRi = swab residue per inch 2 of contact surface for operation i
Ai = contact surface area (ft2) of equipment for operation i
To distribute the maximum allowable bulk active residue among the

equipment modules, the weight factors were often calculated as follows:
• Divide the product contact surface area of the cleaned equipment
module by the total product contact surface area of the train.
• Divide the estimated rinse volume of the cleaned equipment mod-
ule by the estimated total rinse volume of the equipment train.
This approach was often used for systems where final organic sol-
vent rinse was contained in equipment modules. This approach
eliminated the need to calculate contact surface areas of each
equipment module.
COMPUTER CONTROL SYSTEMS
Concurrent Validation
One of the equipment trains at the facility was operated with a distributed
control system (DCS). This system was installed in 1990 with selected Honey-
well TDC 3000 components and was dedicated to the operation and control
of a few critical unit operations in the equipment train. The DCS provided
centralized control and monitoring capabilities utilizing operator consoles
with a touch screen display. This DCS had an excellent performance history.
The validation for this existing system was based on retrospective review
of the current state of the technical documentation relating to system specifi-
cations and testing, procedural documentation, and records relating to opera-
tional environment (e.g., change management, user SOPs, security, user
training, etc.). Evidence of on-going correct operation was established. A few

critical loops were audited. The retrospective review included the traditional
IQ and OQ activities, and SOPs on existing computer systems guidelines were
followed.
The validation engineer and the control engineer jointly developed the
validation protocol, which was successfully executed with help from the Pro-
duction, Instrument and Control, and Maintenance departments. The valida-
tion team reviewed the protocol and, when needed, assisted during execution.
As part of IQs, key Honeywell documentation pertaining to hardware
and software were listed, and hard copies were assembled in the validation
file. All PFDs and P&IDs, equipment lists, instrument lists, and alarm lists,
along with alarm priorities and calibration records, were compiled. All inter-
locks in the system were identified. Interlock descriptions and logic block dia-
grams were included in the validation file. The current status of the history
module and its functioning were reviewed. The Y2k compliance was verified.
A list of the batch sequence programs was compiled. Each batch sequence
program was compared with written master batch records or continuous
manufacturing procedures to ensure that the DCS will control the manufac-
turing process as expected. Hard copies of the batch sequence programs were
deposited in the validation file.
Under OQs, the critical alarms were tested by simulating alarm condi-
tions. Computer security was verified. A loss of power test was simulated.
Backup and recovery procedures were tested. Functional testing of the soft-
ware (i.e., computer recipe vs. batch records description) was verified. Control
room environmental conditions with regard to temperature, humidity, dust,
and vibrations were monitored, and these were compared with vendor speci-
fications. An electrical ground test was completed on the computer hardware
enclosure. All testing and personnel training on the use of the computer sys-
tem was documented. Since this was an existing system with an excellent per-
formance history, only a few critical input/output (1/0) loops were audited,
and the performance of corresponding modulating control valves or sensors
was matched with expected results.
Executive Summary-Concurrent/Prospective Validations

After completion of the validation program, the validation manager issued an
executive summary on the project. This summary presented a brief overview
on the success/failure of the validation effort. This validation document was
often used to present the validation status of an API to customers and regula-
tory personnel. It summarized results of the overall validation effort and con-
firmed compliance with the master plan. The validation team, director of
technical operations, and director of quality assurance approved this sum-
mary report.
Validation File
All original validation documents were kept at the manufacturing site under
supervision of the documentation manager, and these were made available on
demand to interested personnel prior to any anticipated Inspection from the
regulatory agency.
MAINTAINING A "VALIDATION STATE"
After a system was validated, the system was maintained in the "validated
state" through implementation of calibration and enforcement of change
control policy by the organization.
To ensure the accuracy of the generated data, the calibration of manu-
facturing instruments was completed before the prospective or concurrent
validation testing began. In addition, regular calibration was conducted at
scheduled intervals throughout the life of the equipment.
Each equipment train had both critical and noncritical instruments.
Critical instruments had a direct effect on product quality, efficacy and yield,
operator safety, and the environment. Calibration of the critical instruments
was scheduled based on manufacturers' recommendations or the organiza-
tion's experience. Calibration procedures were traceable to U.S. National In-
stitute of Standards and Technology standards.
Readings from noncritical instruments (i.e., referenced instruments)
were generally not recorded in batch records. Typically, such instruments
were calibrated at the time of installation or on need basis at the production
manager's request.
IDEAL Corp. enforced a modification/change control and revalidation
policy at this manufacturing facility, which prevented unauthorized modifica-
tions to a validated system or a system under validation. It dictated how to im-
plement the proposed modification to a validated process. Such a change
control program addressed changes to processes, equipment, and raw materi-
als. This policy dictated that an assessment must be made before implementing
any modification or change to the validated systems to determine if revalida-
tion is needed. The modification/change control team reviewed the reason and
justification for the change and decided if revalidation was required.
Under the change control policy, emergency changes were allowed
when it was necessary to save product in process or protect operators and the
environment. Such changes can occur during unusual and/or unexpected cir-
cumstances. After the situation had stabilized, the normal change approval
process was initiated to ensure that all concerned parties were aware of the
measures taken to correct the situation, and the issue of validation testing and
documentation was appropriately addressed.
After the initial validation study was completed, if an API was not sub-
jected to any major change related to process or equipment or raw material,
then only one concurrent revalidation (process PQs only) was executed for
each batch size once every three years. Each API was supported by both a
sound change control and annual product review program, which provided
assurance that inherent minor raw material/process variability did not ad-
versely impact the validated state prior to the scheduled triennial revalidation.
If a critical piece of manufacturing equipment was replaced that was not
similar (i.e., this was not a like-for-like change), then three prospective valida-
tion batches were executed for each batch size. This revalidation covered IQs
and OQs for the new equipment and process PQs of the API. If the change was
not identical and not critical, then the rationale for doing less than the afore-
mentioned was concluded by the modification/change control team.
If no significant modifications to the process or related equipment had
been recorded, and the product continued to meet consistently the in-process
and QC specifications, then only one concurrent revalidation (process PQs
only) was executed for each batch size once every three years. In addition,
critical utilities such as compressed gases were retested for purity at least once
a year.
If there were frequent deviations in critical process parameters, in-process
tests, and product quality, the problems were resolved, and the API was immedi-
ately targeted for revalidation. If multiple minor changes were executed, a peri-
odic review of all change control forms may also indicate the need to revalidate.
IDEAL Corp. qualified suppliers of raw materials and excipients. Out-of-
specification raw materials were rejected and returned to the supplier. Change
of a supplier required that each raw material must meet the release and or U.S.
Pharmacopeia (USP) specifications. In addition, samples from three different
vendor lots were characterized, physically and chemically, and where neces-
sary tested microbiologically to determine the new raw material equivalency.
Any deviation from original specification in the new raw material was
considered a change and required a review and senior management approval
prior to use. If necessary, three qualification batches of API were produced and
placed on routine stability. The API was released for subsequent use only after
meeting all specifications.
Concurrent or Prospective Validation Effort

After completing the retrospective review, IDEAL Corp. initiated the concur-
rent/prospective validation effort. A master plan was prepared for each equip-
ment train that typically produced multiple APis. Validation protocols (IQs,
OQs, and PQs), including cleaning protocols, were written to execute the
qualification studies (see Table 7.3).
IDEAL Corp. created two teams for the concurrent/prospective valida-
tion effort. Each team had five core members, one from Validation, two from
Table 7.3 Protocols Executed for Concurrent Validation of Train A
Protocols Systems Validation Activity Completion Date
Master plan 6/98

A-PW-101 Purified water for parenteral API IQ, OQ, PQ Sept.98*
A-POT-102 Potable water IQ, OQ, PQ Oct. 98*
A-UTL-103 Utilities/process support services IQ, OQ 3rd qtr. 98
A-CGS-104 Compressed gases IQ,OQ 3rd qtr. 98
A-ENV-105 Controlled envs. {AB regular) IQ,OQ 3rd qtr. 98
A-ASC-106 Automated control system for the IQ, OQ 3rd qtr. 98
controlled environment
A-ENV-107 Controlled envs. {AB parenteral) IQ, OQ 4th qtr. 98
A-ASC-108 Automated control system for the IQ,OQ 4th qtr. 98
controlled environment
A-SAR-109 Product A regular PQ 4th qtr. 98
A-REC-110 Solvent recovery system PQ 4th qtr. 98
A-SAP-111 Product A parenteral PQ 4th qtr. 98
A-SBR-112 Product B regular PQ 4th qtr. 98
A-SBP-113 Product B parenteral PQ 1st qtr. 99
A-PEQ-114 Process vessels and equipment IQ,OQ 1st qtr. 99
A-BND-115 Blending IQ, OQ 1st qtr. 99
A-FIL-116 Drum filling IQ, OQ 1st qtr. 99
A-TDC-117 Computerized process control system IQ, OQ 3rd qtr. 98
A-CLN-118 Cleaning procedures for product A PQ 2nd qtr. 99
A-CLN-119 Cleaning procedures for product B PQ 2nd qtr. 99
* Completed in an earlier program
Production (the process manager and his day-shift supervisor), one from En-
gineering, and one from Quality Assurance. Other personnel from the Pro-
duction, Engineering, and Maintenance groups assisted the core team on
need basis. The responsibilities and functions of this validation team were as
follows:
• The validation engineer developed the necessary documents
(master plans, protocols, and summary reports) and shared leader-
ship of the validation team with the process manager. The valida-
tion engineer provided training to execute the protocols,
monitored the validation effort to ensure completion on sched-
ule, and prepared summary reports for final management ap-
proval. The validation team verified and approved all validation
documents.
• One member from the Engineering group assisted in supplying all

engineering documentation (procedures, data, manuals, drawings,
etc.) necessary for executing protocols (IQ, OQ) and provided addi-
tional personnel when needed to assist in the inspection and oper-
ation of equipment and equipment systems. The day-shift
supervisor and a helper from Production assisted in the execution
of all protocols (IQs, OQs, and PQs).
• One member from the QA/QC group monitored cGMP considera-
tions, contributed a QA/QC viewpoint during execution, and re-
viewed all executed protocols.
The validation team met regularly once every two weeks to discuss prob-
lem areas and issues connected with the validation effort. Total quality man-
agement concepts were followed in conducting meetings, and meeting
minutes were issued.
CONCLUSIONS
Overall, the validation effort at IDEAL Corp. helped to build employee quality
awareness and significantly reduced process and procedural deviations. This
effort helped to establish and maintain control over production processes and
provided management with validation documentation to meet the regulatory
requirements.
Validation is a team effort. The validation team must be familiar with
the process and validation principles, and all should be willing participants
for implementing a successful program.
A validation manager must be a good team player to accomplish the
task. He or she should possess team-building skills or should be given the ap-
propriate training to develop those skills. Prior to initiating the process vali-
dation effort, the validation manager must develop a good working
knowledge of the process. He or she should read technical documentation on
the facility and equipment and development reports, investigation reports,
and annual product reviews on the product. The knowledge gained from a
study of these reports is essential for developing validation protocols and di-
recting the overall validation effort.
The validation manager should be prepared to work against the bias and
attitudes of process and production personnel in the company. He or she
should be ready to face comments such as:
• Why are we doing this?
• What have we done wrong?
• We have made this product for the last 10 years.
• Are you saying we do not know how to make it?

• What is validation?
These questions must be softly handled through communications and train-
ing prior to initiating a validation effort.
Batch recipes should be included in the validation protocols (PQs) under
process description. IDEAL Corp. learned this lesson the hard way. An existing
drug substance manufacture was moved to a new building, and production
was restarted there under a prospective validation plan. The new master batch
records had a decimal error in the activated carbon dosage for the final step.
This error increased the use of activated carbon (10 times the normal weight)
and resulted in substantial yield loss. The drug substance was adsorbed into
the carbon, and the batch yield dropped from 80 percent (normal) to 20 per-
cent. Three very valuable batches were lost in this manner before the error
was discovered. If the validation protocol (PQ) had formally included the
batch recipe under the process description, then either the protocol writer or
the team would have had a chance to find such errors during the review
process.
Ranges for critical process parameters should be assigned with care in the
master batch records. One must take into account (1) operation history for ex-
isting products, (2) development work for new products, and (3) capability of
controls on the process equipment. A little care will avoid unnecessary vari-
ances and associated paperwork. Also, process parameters that are not critical
need not be included in the protocols.
API validation should be implemented using a life-cycle approach. It is an
ongoing process. To be under validation compliance, all critical utilities such as
compressed gases must be retested for purity at least once a year. A purified wa-
ter system should be placed under a continuous monitoring program. Con-
trolled environment systems (HVAC) should be recertified at least once a year. If
no significant modifications to the process or related equipment have been
recorded, and the drug substance continues to meet specifications, then con-
current validation (process PQs only) should be repeated once every three years.
REFERENCE
ADDITIONAL READING
FDA. 1993. Guide to inspections of validation of cleaning processes. Rockville, Md., USA:
FDA. 1998. Guidance for industry, manufacturing, processing, or holding active phar-
maceutical ingredients. Rockville, Md., USA: Food and Drug Administration.
ISPE/FDA. 1996. Pharmaceutical engineering guides for new facilities. In Bulk pharma-
ceutical Chemicals, vol. 1. Tampa, Fla., USA: International Society for Pharmaceuti-
cal Engineering; Rockville, Md., USA: Food and Drug Administration.
Lazar, M. S. 1993. Concepts of process validation of bulk pharmaceutical chemicals.
Pharmacetical Technology 17:32-40.
Lazar, M. S. 1995. Sterile bulk pharmaceutical chemicals, a PhRMA position paper.
Pharmacetical Technology 19:38-42.
ACKNOWLEDGMENTS
I wish to acknowledge A. Seminerio, former Director of Validation and Tech-
nical Operations, and Leo Chambers, current Director of Chemical Opera-
tions at Hoffmann-La Roche, Nutley, for their support and encouragement in
the preparation of this chapter. I have been executing validation studies un-
der their leadership since 1993. I also wish to acknowledge other colleagues
for their contributions.
APPENDIX 7.1
What Is Concurrent/Validation?
What Is Prospective Validation?
To meet the FDA regulatory requirements, the API manufacturer under cGMP
must execute either a concurrent validation program or a prospective valida-
tion program.
Concurrent Validation Program
• API is routinely manufactured in an existing facility and re-
leased to markets.
• API is routinely manufactured in an existing facility, and a few
like-for-like changes are executed.
Prospective Validation* Program
• New API manufacture in a new train-New Drug Application
(NDA) filed
• Existing API manufacture is moving to a new site.
• API is routinely manufactured in a facility where new equip-
ment was installed recently and a few process changes are be-
ing implemented under CBE (Changes Being Effected).
*Under prospective validation, the drug substance (API) and the drug product are not released until all
validation activities are successfully completed.
APPENDIX 7.2
Events and U.S. Regulations
Events U.S. Regulations

1906 Adulterated food, Pure Food & Drug Act:
several deaths
• prohibited interstate commerce
of adulterated food and drugs
• required labeling of the identity
and ingredients in the drug
1938 Product formulated in Food, Drug, and Cosmetic Act:
diethylene glycol, no • Required safety clearance
safety tests, several (tox data)
deaths
• Required approved NDA prior
to marketing drug product
• Required FDA to enforce the
law and authorized factory
inspections
1962 Thalidomide birth defects Drug Efficacy Amendment
in Europe; lack of safety and GMPs were added to the
and efficacy testing of Food, Drug, and Cosmetic Act:
the sleeping pill.
• Required manufacturers to
comply with GMPs
• Required proof of safety and
efficacy
• Required biannual inspections
of facilities
• Required reports of adverse
effects for new drugs
1970- Contaminated intravenous 1978 revision to GMPs:
1978 fluids; lack of validation
• Required validation of sterili-
zation processes. Use of
in-process controls to validate
manufacturing steps.
1983 Draft guidelines FDA draft guidelines on process
validation: Expanded to biologi-
cal processes and APis
1990- Integrated validation FDA recommends a
present philosophy validation life-cycle approach
APPENDIX 7.3
SOPs-Operations, IDEAL Corp.
Number SOP Title Effective Date

500-001 Preparing Manufacturing Procedures 2/4/97
500-002 Revising Manufacturing Procedures (MFPs) 2/4/97
500-003 Annual Review of Manufacturing Procedure 2/4/97
500-004 Control of Producton Operations Record Books 2/4/97
500-005 Drum Storage Areas 2/4/97
500-006 Gowning Procedures 2/4/97
500-007 Completing Batch Records 2/4/97
500-008 Permanent Process/Product Changes 2/4/98
500-009 Manufacture of Experimental Batches/Lots 2/4/97
500-010 Investigation of Chemical Product Rejections 2/4/98
500-011 Reprocessing/Rework of APis 2/4/98
500-012 Handling of Rejected In-Process Material 2/4/98
500-013 Assignment of Lot Numbers 2/4/97
500-014 Batch Records Review Process 2/4/97
500-015 Portable Purified Water System for API Production 2/4/98
500-016 Evaluation and Documentation of Manufacturing 2/4/98
Variances
500-017 Modification/Change Control of Validated Systems 2/4/97
500-018 Training of Production Department Employees 2/4/98
500-019 Training for Extraordinarily Hazardous Substances 2/4/98
XX0-001 Guidelines for Cleaning of Equipment & Facilities 2/4/98

XX0-002 Sanitization of Equipment 2/4/98
XX0-003 Guidelines for Developing Cleaning 2/4/98
Procedures-Reactors, Filters, Dryers,
Mills, Blenders, Centrifuges, etc.
XX0-004 Approved Cleaning Detergent List 2/4/97
600-001 Honeywell DCS Security 2/4/98

600-002 Honeywell DCS-System & Software Maintenance 2/4/98
Number SOP Title Effective Date

650-001 ISO 9000 Internal Audit Program 2/4/97
650-002 ISO 9000 Inspection by an Outside Auditor 2/4/97
700-001 Receiving & Unloading Tank Trucks 1/4/98

700-002 Sampling Chemicals from Tank Trucks 2/4/98
700-003 Sampling from Storage Tanks 4/4/98
750-001 Calibration of Equipment, In-Process 4/4/98

Control Laboratories
750-002 Laboratory Notebooks 4/4/98
750-002 Validation of In-Process Control Test Methods 8/4/98
750-002 Validation of Analytical Procedures 8/4/98
800-001 Hydrocarbons and Dew Points of Compressed 8/4/98

Gases Using Draeger Tubes
800-002 Determination of Nonviable Particle Counts 2/4/98
in Compressed Gases and Ambient Air
800-003 Environmental Monitoring of Viable Airborne 2/4/98
Particles
800-004 Microbial Count-Pure Packaging Rooms Walls 2/4/98
and Floors
850-001 Handling of Waste Solvent Containers 2/4/98

850-002 Filling of Portable Tanks (Dumpsters) 2/4/98
850-003 Solvent Stripping Using Steam Distillation 2/4/98
900-001 Foot Protection 5/4/99

900-002 Protective Clothing 5/4/99
900-003 Respiratory Protection Program 5/4/99
950-001 Emergency Plant Shutdown 6/4/99

950-002 Emergency Evacuation Procedure 6/4/99
APPENDIX 7.4
Batch Records-A Validation Viewpoint
To implement a successful validation program, the production manager must
eliminate point values from batch records and assign ranges to the key
process parameters and in-process control test values.
Process parameter ranges and in-process control test ranges are an im-
portant issue in all production operations. With existing operations, these
ranges must be established by reviewing the batch records. For newer
processes, these ranges can be adequately addressed during the process devel-
opment phase. In addition, batch records should clearly dictate the basis for
expected yields, and the rationale employed should be well understood and
used by the operating staff.
Batch records must avoid the use of such words as approximately, ca. 80
and lack of key process data or critical process data. Whenever feasible, a
range should be used rather than an approximation (i.e., 75-80, rather than
approximately 78). If, however, "approximately" is used, it implies being near
or close to the number specified (i.e., approximately 15 minutes does not
mean 10 minutes). Care should also be exercised when deciding the number
of significant figures to be used. For example, "Heat at 70-80°C for 10 min-
utes" would mean that a recorded temperature of 80.2°C could be rounded to
80.0 and would not be considered out of range.
If the operator needs more than one attempt to meet a specification,
batch records format should incorporate loops to meet that specification.
All batch records including cleaning records should be formally adopted
by the organization with approval signatures. All batch records at IDEAL
Corp. were reviewed and approved by Quality Assurance.
APPENDIX 7.5A
Miscellaneous Activities-
Prospective Validation
Support Systems:
TypicaiiQsjOQs-New Facilities
Systems IQs OQs

HVAC duct leak test reports pressurization (containment/
safety)
filter certifications air changes
(HEPA)
air balancing reports temperature and humidity
control
fan performance curves classified area-particulate/
bioburden
Plant Steam weld certifications supply pressure-no load
piping pressure test supply pressure-under load
safety valve certification
Clean Steam materials of construction supply pressure-no load
weld certifications supply pressure-under load
piping pressure test steam quality sampling
safety valve certification •location
pipe slope verification • bioburden/endotoxin
pipe cleaning/flushing
methodology
Compressed Air piping pressure test supply pressure-no load
safety valve certification supply pressure-under load
cleaning and flushing moisture and hydrocarbon
methodology content
for breathing air
• oxygen content
• particulate
• bioburden
Bold face data: for existing facilities with satisfactory history

Systems IQs OQs

Compressed materials of construction supply pressure-no load
Gases
(e.g., nitrogen) piping pressure test supply pressure-under load
safety valve certification moisture and hydrocarbon
content
cleaning and flushing particulate level
methodology
bioburden
Heat Exchange weld certifications supply pressure-no load
Systems
piping pressure test supply flow rate-no load
safety valve certification supply temperature-no load
cleaning and flushing specific gravity (brine,
methodology glycol, etc.)
Water Systems materials of construction supply pressure-no
load/load
weld certifications supply flow rate-
no load/load
• sample welds supply temp
• borescope temperature studies
piping pressure test water quality monitoring-
3weeks
piping slope verification
cleaning flushing
methodology
passivation methodology
Clean-in-Place materials of construction supply pressure
pressure tests supply flow rate
recovery volume verification
Steam-in-Place materials of construction supply pressure-load
piping pressure tests temperature study
safety valve certification steam quality, bioburden

Systems IQs OQs

duct leak tests filter alarms and interlocks
Dust HEPA filter certifications air velocities
Collection
air balancing reports air directional flows
fan performance curves
Vapor/Fume duct leak tests air velocities
Extraction
air blanching reports air directional flows
fan performance curves
Vacuum weld certifications vacuum integrity test-unit
Equipment
piping pressure tests vacuum integrity test-
supply piping
vacuum at use points
Boldface data: for existing facilities with satisfactory history
APPENDIX 7.58
Process Equipment:
TypicaiiQs, OQs-New Facilities
Systems IQs OQs

Reactors/ vessel certification/ volume verification
Crystallizers specification
spark tests-if glass lined pressure and vacuum integrity
batch temperature control
Condensers certifications-unit pressure test
piping pressure tests vacuum integrity test
heat/cool fluid temperature study
condenser functionality test
Holding Tanks vessel certification/ volume verification
specification
spark tests-if glass lined pressure and vacuum integrity
batch temperature control
Centrifuges filter bags, type and rpm (revolutions per minute),
porosity speed control-min/max load
safety interlock and alarms
Dryers vessel certification/ pressure test
specification
vacuum integrity test
temperature control studies
• multiple set points
• temperature mapping for
uniformity
functionality test
Transfer piping pressure tests volume verification
Systems
pipe slope verification transfer-gravity, pressure,
pump

Systems IQs OQs

Process Filters vessel certification/ pressure test
specification
filter media check vacuum integrity test
Ultr afil ters vessel certification/ pressure integrity test
specification
filter media check functionality test-reduction
Agitators materials of
construction verify rpm
• seals verify amperages
• lubricants verify speed at set points
variable speed drives
Blender materials of
construction rpm
intensifier bar seals amperage-min load/max load
gaskets interlocks and safety check outs
lubricants functional testing
Sieves material of construction amperage-min load/max load
• screens functional testing
• gaskets
all screen mesh sizes
Mills material of construction rpm
amperage-min load/max load
functional testing
Boldface data: for existing facilities with satisfactory history

APPENDIX 7.5C
Computer System Validation:

Typical IQs, OQs-New Facilities
System IQs OQs

Start effort during specify and design.
DCS specifications and purchase hardware and software
orders completion, verify
P&IDs, loop diagrams, line loop data sheets
wiring diagrams, I/0 layout
maintenance and operational alarms/safety interlocks check
manuals
component list computer security specifications
physical arrangement backup and recovery procedures
check
control system equipment list I/0 check for all operations,
point-to-point
system instrument list, all computer recipe vs. batch
control loops, identify critical records description, "black box
loops, calibration records testing"
Identify all interlocks, interlock loss of power test
descriptions
utilities verification
environmental requirements
Component labeling for instruments and valves, legend
software verification
IQ summary report OQ summary report
Boldface data: for existing facilities with satisfactory history. Audit critical loops for 1/0 check, point-to-
point.
1.98 Validation of Active Pharmaceutical Ingredients
APPENDIX 7.6
Outline of a Typical Retrospective Protocol
Introduction
Purpose
Scope
Summary and Recommendations
Synthesis Flowchart
General Description of the Process
Process Parameters
List of Key Process Parameters with Ranges
Compilation of Results (Including Statistical Review/Control Charts)
Discussion of Out-of-Range Results (Variance Reports)
In-Process Controls (IPCs)
List of IPC Tests (Typically all IPCs Described in the MFPs)
Analytical Methodologies
Compilation of Results
Discussion of IPC Trends and Failures (investigation reports)
Quality Control Testing
List of Quality Control Tests
Analytical Methodologies
Compilation of Results for Batches Under Review
Discussion of Impurities
Discussion of Quality Control Rejections/Reprocessing (investigation
reports)
Yield Data
Process/Equipment Changes
List of Approvals for Process Change (APCs)
Rationale/justification
Description/Location of Production Equipment and Facilities
Size, Material of Construction, Function
List of PFDs and P&IDs
Maintenance/Instrumentation/Calibration/History
Plant Utilities
Equipment Cleaning
Procedures and Analytics
Attachment
Annual Product Review Report from Quality Assurance
APPENDIX 7.7
Outline of a Typical Concurrent
or Prospective Validation Protocol
This protocol describes the qualification requirements and acceptance criteria
for the equipment system, facility, or process to be validated. It includes data
needed for execution. The main elements of a validation protocol are as fol-
lows:
Objective
Description
Responsibilities
Installation Qualification: A list of the check sheets and engineering draw-
ings and specifications that are needed to document that the system(s) is in-
stalled according to design. There should be certified drawings for new
projects and "as-built" engineering drawings for existing projects. Identify all
critical instruments and confirm these are calibrated. Calibration records
should be maintained by the department.
Operational Qualification: An outline of the operational qualification test-
ing procedures and requirements for the system(s). The prospective validation
will include all hydro testing of process equipment and other equipment per-
formance tests for the new train. Heating, cooling, turning, pressure, and vac-
uum limits for the process equipment are reviewed.
Process Performance Qualification: A detailed description of tests and test-
ing procedures and validation approach is discussed.
Acceptance Criteria: All criteria are clearly documented.
Approval: How the document will be approved and reviewed, summary
report format, and approval signatures.
Attachments: As necessary.
APPENDIX 7.8
Key Instruments Used in OQ Activities
The following instruments were used at IDEAL Corp. to execute OQ activities:
1. Air Data Multimeter, Shortbridge Instrument Inc.
This instrument was used for pressure balancing and static pressure
measurement for HVAC systems.
2. Draeger Aeroset Apparatus
This apparatus was used to verify and confirm specifications re-
garding the dew point and hydrocarbon content of compressed
gases at use points in the process (e.g., compressed air, compressed
nitrogen).
3. Met One Laser Particle Counter
This instrument was used to confirm the specified environmental
quality in the product packaging areas (clean rooms) or to check
the quality of compressed gases used in the process.
4. Alnor Balometer
This instrument was used for monitoring velocity measurements
for supply ducts to confirm specified air changes.
5. Pioneer Porta-Strobe
This tachometer was used for measuring rpm.
APPENDIX 7 .9A
Retrospective Example
1.0 Introduction
The purpose of this retrospective validation report is to provide detailed doc-
umentation demonstrating that the production of Supreme hydrochloride
drug substance has performed satisfactorily and consistently during the
1989-1994 campaigns. This assessment determines whether the process has
consistently met predetermined specifications regarding process parameters,
in-process control testing, quality control testing, and expected process
yields. The time period, 1989 through 1994, represents the most recent pro-
duction experience in which a significant number of lots (19) was produced.
Supreme is marketed under the trade name Sure®, a therapeutic agent
used in the treatment of a disease. Supreme manufacturing con-
sists of six steps.
2.0 Summary/Recommendations
The data compiled in this report demonstrate that all six process steps in the
manufacture of Supreme from the purchased material, , have per-
formed consistently and in an overall satisfactory manner from 1989 to the
present.
Nineteen lots of Supreme, Lots 203 thru 221, were produced by convert-
ing 94 crude batches into 60 pure batches. All Supreme lots passed quality
control testing and were subsequently released. No unusual impurities were
detected, and the annual product records contain no bulk product com-
plaints.
Overall, the batches produced were reasonably consistent in batch
weights. Among the 94 batches, only 1 crude and 1 pure had low batch
weights. These deviations were examined satisfactorily.
Among the 60 pure batches, 58 had process yields within the specified
MFP range. One batch exceeded the specification range, and the second batch
had low yield.
Specification ranges of the operating parameters were refined and noted.
No major process equipment revision or process change was observed during
this review period.
A few equipment- and instrument-related failures were reported. These
were minor in nature, and none had any impact on the quality of Supreme
product.
The master plan for the retrospective validation of APls lists four accep-
tance criteria. Based on the data compiled for this report, the Supreme process
would meet three of the four criteria.
All lots passed QC testing. Each key process parameter has been within
specified ranges at least 90 percent of the time for batches reviewed (exclud-
ing variances caused by equipment malfunction or operator error). In a few
instances, where deviations did occur, these were minor in nature, and none
had an adverse effect on product quality. In-process control test results were
within specifications at least 90 percent of the time for batches reviewed (ex-
cluding test failures caused by equipment malfunction or operator error).
Most variances and test failures were satisfactorily investigated and doc-
umented. A few minor variances were not documented and investigated dur-
ing the 1989-1990 period. Therefore, this criterion is not attained. However,
product quality was not adversely affected by any of the variances. This situa-
tion has now been corrected. Batch records and all variance documents are
now being reviewed by Quality Assurance to ensure compliance with IDEAL
policy (SOP-IDEAL-031).
Based on the batch data reviewed, the following recommendations are
made:
• Approved "end-of-campaign cleaning" procedures should be made

part of the current MFPs for the equipment train that comprises a
crude crystallizer, CRC-48, and a crude centrifuge, CEN-132. Ap-
proved cleaning procedures for the remaining trains are already in
the MFPs.
• After evaluating the compiled data, the process manager should
consider modifying the following process parameters (for example,
replace "ca" with appropriate range).
Drying of Crude, Step 3; Drying of Pure, Step 4; Drying of
Pure, Step 5; drying times
Crystallization of Pure, Step 4; pot temperature
3.0 Synthesis Flowchart

Present a structural flowchart.
4.0 General Description of the Process

Describe process steps briefly.
5.0 Critical Process Parameters

The following process parameters for steps 1 through 6 are considered critical.
The critical parameter data for the batches under review are recorded and
compared with the specification listed in the MFP. Where necessary, devia-
tions are discussed.
A few specification ranges were occasionally adjusted. Critical parame-

ters and their specification ranges in each process step are listed below:
Step 1, : Operating Conditions Reaction
Final Reaction Agitation

Batch No. Date Temperature Hold Period Notes
Spec. Range 62 ± 4°C min. one hour
001 09/18/89 60 1:00
002 09/19/89 61 1:03
003 09/20/89 62 1:00
004 09/21/89 61 1:28
005 09/22/89 61 0:45 1
Notes. 1. Agitation hold period is less than one hour. No variance log sheet was
available in the batch records.
6.0 In-Process Controls

All relevant in-process control tests described in the MFPs are included here. A
compilation follows of the actual results of those tests for the batches under
review in this report. These results are compared with the desired test specifi-
cations that appear in the MFPs. Where necessary, variances from the desired
specifications are discussed.
The following in-process control tests were performed on each batch
during production steps 1, 2 ,3, 4, and 5 of the process.
Process In-Process
Step Operation Control Test Method Specification
Step 1 formation unreacted TLC < 1%
Step 2 base unreacted TLC <2%
formation
Following the drying operation, each batch of methanol pure is sub-

jected to the following in-process control testing:
Test Test No. Method Specification

Appearance IL01.0 visual crystalline powder
If a batch fails any of the in-process tests outlined above (except mois-
ture determination), purification steps 4 and 5 must be repeated. Thus, the
failed batch is recrystallized twice: first from solvent and subse-

quently from methanol solvent. If the moisture test fails, the batch is
redried.
Following blending, each batch/finished lot is subjected to the following
in-process control/finished lot tests prior to testing by Quality Control.
Test Test No. Method Specification

Color IL02.0 visual white or practically white
pH of solution IL16.0 pH 3.0 to 4.0
6.11n-Process Control Testing
Step 1, Operation: (unreacted _ _ _ _ , TLC test)
Batch Number Unreacted _ _ __ Notes

Spec. Range < 1%
6.2 In-Process Control/Finished Lot Testing

Prior to the blending operation, each batch is subjected to the following in-
process control tests:
Batch No.
Test 001 002 003 004 005 006 007
5 % Solution in Water c&c c&c c&c c&c c&c c&c c&c
Color ms ms ms ms ms ms ms
Abbreviations: ms = meets specification; c&c = complete and clear
7.0 Quality Control Testing

7.1 Quality Control Tests/Specifications
The following tests are performed on lots by Quality Control. Lots
203 through 214 were tested as per specifications dated 07/07/80. The re-
maining lots were tested as per specification dated 11/27/91.
Test Method Specification

Appearance visual observation crystalline powder
Color visual observation white to pale yellow
7.2 Quality Control Test Results

The following table presents a summary of the quality control test results for
lots 203 through 221. More information regarding the quality control testing
can be found in the attached product review.
All lots illustrated in the tables below met all quality control specifica-
tions. No unusual impurities were detected, and there were no complaints
filed for this review period.
lot Numbers
Test 203 204 205 206 207
Appearance ms ms ms ms ms
Color ms ms ms ms ms
ms =meets specification
8.0 Yield Data

Yield data are calculated and reported in the MFPs only for the methanol
pure, Step 5 and the sifting operation, Step 6. The yields recorded in the vari-
ous batches under review are given in the tables below:
% of Expected Yield _ _ _ _ Pure from Pure, Step 5
Batch Number Batch Weight (kg) % of Expected Yield Notes

Spec. Range 93-106
005 59.09 102.6
006 61.36 106.6 1
Notes: No variance tog sheet was filed.
Moving range control charts were prepared for both steps (see Attach-
ments). Control chart for step 5 highlights a variability in the yield data for
the 1989-1990 batches and signals a consistent improvement trend starting
with batch 037. It also suggests that the current specification limits should be
modified. Ideally, the process specification limits should fall outside the indi-
cated upper and lower control limits.
9.0 Description of Production Equipment/Facilities

9.1 Equipment Descriptions
This building has two production trains. The first production train is dedi-
cated to the manufacture of and . The second produc-
tion train is dedicated to and . In addition, some
processing steps share the same production equipment. To prevent cross-
contamination, a single product production schedule is practiced in the
building.
Process equipment for is dispersed on both floors of the build-
ing. The key production equipment such as /hydrogenation auto-
clave ...
This is a controlled environment facility and each equipment train is
isolated to minimize contamination. The crude dryer DYR-283 is located in a
separate room with an air lock. To control and minimize process emissions,
this facility is serviced with an environmental scrubber ...
Equipment No. Equipment Description Key Instruments
Steps 1,2,3
AUC-7 Autoclave, 150 gal., temperature recorder controller,
600 psigj600°C rating, level alarm, temperature alarm
316L SS
Additional information regarding the production equipment can be

found in the following PFDs and P&IDs.
9.2 Instrumentation Calibration and Equipment Maintenance

Maintenance and instrument calibration histories are compiled by the Main-
tenance Department using the computer database.
Two types of maintenance are performed on process equipment located
in building on a regular basis.
1. Regular Preventive Maintenance Program

2. Special Toxic Control Prevention Agency (TCPA) Maintenance Pro-
gram
The Regular Preventive Maintenance Program includes most standard

process equipment. The frequency of maintenance varies from monthly to
yearly depending on the equipment manufacturer's recommendations and
IDEAL experience.
The TCPA Maintenance Program applies to process equipment that han-
dles toxic chemicals. This detailed maintenance is typically performed on a
yearly basis and includes such items as pressure testing, relief valves, and
spark testing of glass-lined vessels.
All critical instruments are calibrated periodically by the Maintenance
Department and records are maintained. Critical instruments typically are
calibrated on a quarterly basis. A few equipment- and instrument-related fail-
ures were reported during the time frame of this report. These were minor in
nature, and none had any impact on the quality of the final product.
9.3 Plant Utilities

The following is a summary of the plant utilities used for operating the
_ _ _ _ production equipment. There has been no recorded incidence of pro-
duction interruption due to a suspension of a utility service.
10.0 Process/Equipment Changes

No major process or equipment change was reported from 1989 through
1994. Production of at the facility began in building SO. In early
1989, this facility was upgraded, and improvements were made for contain-
ment, safety, cGMPs, and industrial hygiene. After processing a few experi-
mental lots, the first crude batch 001, covered in this report, was produced.
Two minor process changes were implemented. The practice of combin-
ing two base batches prior to conversion to was avoided
by using a larger autoclave, AUC-7 ...
11.0 Cleaning
The process equipment trains are shared on a campaign basis with
_ _ _ _ production. In a few instances, process equipment modules are ei-
ther dedicated or shared among the pure or the methanol pure processing
steps.
Equipment cleaning is routinely performed after campaign completion

and between the various manufacturing steps where process equipment is
shared. The effectiveness of such cleaning is verified by analytical testing of
the rinse sample by a validated TLC method. Detailed cleaning records are
maintained as part of the batch records. These batch records describe cleaning
procedures for each process equipment/train in detail.
Only one process equipment train, which comprises a crude crystallizer,
YZD-48, and a crude centrifuge, CFC-132, has no written cleaning procedure.
Occasionally, preproduction cleaning is performed prior to the start of
the next production campaign. The need for such preproduction cleaning is
based on the following criteria:
• Maintenance has been performed following the previous cleaning.
• An extended period of time has elapsed since the last use of the
equipment.
• The equipment was inadequately covered, sealed, or otherwise pro-
tected, or unusually dusty operations have been carried out in the
area.
Preproduction cleaning is performed first with filtered potable water

rinse and next with a detergent solution rinse such as alconox. After the de-
tergent wash, the equipment is rinsed again with filtered potable water tore-
move any residual detergent.
The following methodology and cleaning solvents (agents) were em-
ployed for "end-of-campaign cleaning":
Steps End-of-Campaign Cleaning Highlights

_ _ _ _ Train
• filtered potable water washes equip. shared
with _ _ __
• alconox solution washes
• filtered potable water wash
• methanol washes
For the precleaning and the postcleaning needs, the following table
summarizes the solvent wash and limits of detection for the various APis un-
der discussion.
Production Train Final Rinse Solvents Limit of Detection

_ _ _ _ API methanol 0.5 mg
_ _ _ _ API methanoljwater 0.01 ppm
12.0 Attachments
Moving Range Control Charts
Percentage of Expected Yield, _ _ _ _ from----
Percentage Yield, Sifting Operation
Product Review: Test Data, Trend Analysis, Variance Reports, and Investi-
gation Reports
APPENDIX 7.98
Prospective Example:
Process Equipment, Train B (IQs, OQs)
I. Objective
Production of drug substance is being moved from building 60 to
train Bin building 125. The objective of this protocol is to assure that the ex-
isting equipment in building 125 can handle the production of the new drug
substance. This protocol will define requirements and acceptance criteria for
the process vessels and equipment that will be utilized for produc-
tion. Successful completion of these qualification requirements will provide
assurance that the vessels and equipment will perform as required. This pro-
tocol has been prepared under the guidelines established under the Validation
Master Plan, Revision 0, dated Feb. 15, 1999.
II. Description
Process equipment covered under this protocol will handle production of
_ _ _ _ from the starting material
Only one process step, with will be carried out in
the former facility in building . This facility was satisfac-
torily validated for the production of in 1998.
All other processing operations will be conducted in train B,
building 125. This four-story facility was built in 1987 and has satisfactory op-
erational history. This facility has state-of-the-art multipurpose reactor sys-
tems and utility support systems.
In addition, the following filtration equipment, which is small and still
available, will be moved from building and installed in building
125: single plate filter ( ) and two 18-inch glass filters. These filters
were previously used in the process in building _ _ __
All process equipment is covered under regular preventive maintenance
programs. Maintenance frequency varies from monthly to yearly and
depends equally on the equipment manufacturer's recommendations and
IDEAL's experience.
Instrumentation calibration is regularly performed by the Maintenance
Department. A record of such calibrations is kept by that department. Critical
instruments are calibrated either semiannually or annually. Weigh scales are
calibrated once every six months. Any new scales moved to 125 from other
buildings will be recalibrated prior to use.
The following key process equipment will be utilized in the various
_ _ _ _ production steps.
Building 125A
Pos. No. Code No. Description

073-T7405 T-7405 methanol storage, 60 gal, S/S
073-07440 DYR-72 tray dryer, 43 ft3 S/S
073-R7410 YZB-72 methanol wash tank, 75 gal, G/L-brine, steam
073-R7400 YZC-2007 reactor, 100 gal, G/L-brine, steam
073-T7416 T-7416 receiver, 30 gal, G/L
073-E7416 CXA-19 condenser, 10/10 tt2, graphite, brine
TWS-333 water scrubber
FTV-3XX. ceramic vacuum filter, 1 tt2
073-R7415 EVP-2004 evaporator, 90 gal, G/L
CXB-39 condenser, 50/50 tt2, graphite, tower water
073-T7415 XTB-276 distillate reciever, 80 gal, SS
Building 125B
Pos. No. Code No. Description

125-R0010 YZA-59 100 L reactor system 1, G/L
125-R0020 R-0020 100 L reactor system 2, s;s
125-R0030 YZB-213 200 L reactor system, G/L
125-R0040 VZC-433 400 L reactor system, G/L
125-R0050 YZA-137 20 gal, addition kettle, jacketed, G/L
125-X0070 DYR-603 tray dryer, 70 tt3 s;s
125-50050 S-0050 centrifuge, 24 in. dia, SS
125-FSB327 FSB-327 G/L, 0. 75 tt2
125-V OOXX V-OOXX extractor, 150 gal, glass/SS
none none 2 18-inch glass filter
none FSB-218 single plate filter
none none 2 in-line polishing filters, 10 Jl.m
Ill. Responsibilities
This protocol has been developed by the validation team. The responsibilities
of the team and various departments are detailed in SOP . This doc-
ument will be a guide in the execution of this protocol.
IV. Installation Qualification

IQ consists of documenting and performing a system quality audit prior to
equipment operation. IQ will document that the system components con-
form to process needs. The installation of the system will be veri-
fied by reviewing the equipment installed and completing the check sheets
provided in this protocol.
Because this equipment has been satisfactorily used for several years, the
IQ will include only a review of P&IDs. The IQ will verify and document the
"as-built" condition of the equipment being used. The IQ requirements for
the system are as follows:
A. Engineering Documentation (Attachment 1)

If available, complete a list of specifications, purchase orders, manuals, and
equipment operating procedures associated with the system. These docu-
ments are compiled for reference only.
B. Engineering Drawings (Attachment 2)

Complete a list and include copies of PFDs and or P&IDs for the as-built sys-
tem. Verify that modifications made to process equipment for the _ _ __
process are included in the P&IDs.
C. Equipment List (Attachment 3)

Describe key process equipment for this system based on information from
purchase orders and equipment specifications. Indicate position number,
equipment code number, manufacturer, and description for each item.
D. Filter List (Attachment 4)

Document all process filters that will be used by the project. Verify
that the process filters and polishing filters have been installed as specified. If
available, include position number, equipment code number, manufacturer,
and description for each item.
E. Instrument List (Attachment 5)

Complete a list of all system instruments. Include tag number, manufacturer,
location, and description for each item. Also indicate instrument designation
as "critical" or "noncritical." Ensure that all instruments have been calibrated
as per the Process Instrument Calibration Procedures SOP- . Com-
pleted calibration records are maintained by the department.
F. Materials in Product Contact List (Attachment 6)

Complete a list of the materials of construction of the system components in
product contact based on information from engineering drawings, purchase
orders, and equipment spedfications. Verify that the materials of construc-
tion conform to process specifications.
G. Lubricant List (Attachment 7)

Document all lubricants used by the process equipment associated with the
_ _ _ _ project from engineering drawings, purchase orders, and/or equip-
ment spedfications. Verify that the lubricants have been employed as spedfied.
H. Weigh Scales List (Attachment 8)

Document all weigh scales that will be used in the project. Ensure that the
scales have been calibrated as per the Process Instrument Calibration Proce-
dures, SOP-_ _ __
I. Installation Qualification Summary (Attachment 9)

Document any discrepancies or variations noted during the performance of
this installation qualification section. Include the resolution of these items
and/or any item outstanding that will require further effort to resolve. When
all the items are satisfactorily completed and documented, the system is ready
for operational qualification.
V. Operational Qualification
OQ is a testing process that evaluates the equipment. Controls are adjusted
during this phase of testing, and performance trials are conducted to verify
that the process equipment operates in accordance with design spedfications.
The OQ serves as a final operational audit prior to conducting performance
qualification of the process. Because of satisfactory operating history, all con-

trols, alarms, and interlocks will be concurrently reviewed as applicable to
each piece of equipment.
During OQ, data are collected concerning critical processing parameters.
The heating, cooling, vacuum, rpm, and mixing performance of the key
process equipment will be verified with water or step solvent. The
OQ requirements and testing procedures for the system are as follows.
Building 125A
This facility was previously qualified and documented under Protocol
----·Recently, the cold brine (0 to -10°C) was routed to R-7400, R-7410,
and E-7416 to meet FUDR process requirements and to control emissions.
Therefore, only heating/cooling operations in R-7400 and R-7410 with either
water or the step solvent and tray dryer operation will be verified
as follows:
A. Heating/Cooling Systems Checkout (Attachment 10)

The heating/cooling systems will be tested. The tests will verify
minimum and maximum operating ranges for the equipment us-
ing the following testing procedure:
1. Fill vessel with enough water to simulate process volumes;
record volume.
2. Close and secure the vessel; record the initial temperature
reading. Set controller at specified temperature setting.
3. Once temperature is attained, record temperature reading. Re-
peat for other settings as required.
Pos. No. Cool To Using Heat To Using

073-R7400 brine
073-R7410 brine
073-R7400 steam
073-R7410 steam
B. Tray Dryer Checkout (Attachment lOA)

Tray dryer, DYR-72, will be tested. These tests will verify/document
that the hot water loop and vacuum system will perform as re-
quired.
1. Close and secure the dryer; record the initial temperature

reading.
2. Turn vacuum on and set hot water temperature controller at
35°C, 50°C, 60°C, and 70°C.
3. Hold vacuum and temperature for a minimum of one hour.
Building 1258
Where applicable, heating, cooling, vacuum, and mixing performance will be
verified with either water or step solvent for the following process
equipment: R-0020, R-0030, R-0040, S-0050, and X-0070.
A. Vacuum Checkout (Attachment 11)

The vacuum tests will verify and document that the equipment in-
volved is operational and will perform as required by the _ _ __
process. The vessels required to hold vacuum will be tested using
the following procedure:
1. Close and secure the vessel, making sure that the unit is
sealed; record the initial reading.
2. Pull vacuum on the vessel as specified; record reading.
3. Maintain vacuum for specified time; record reading.
Pos. No. Pull Vacuum Maintain For

66A-R0030 min 28 in. Hg min 1 hour
66A-R0040 min 28 in. Hg min 1 hour
66A-X0070 min 28 in. Hg min 1 hour
B. Agitator Checkout (Attachment 12)

The tests will verify that the agitators involved are operational and
will perform as required by the process. Satisfactory ro-
tational speed will be confirmed and documented using the follow-
ing procedure:
1. Fill agitator vessel with enough water to simulate process vol-
umes; record volume.
2. Set agitator at specified speed setting for satisfactory mixing,
observe mixing, and measure the rpms.
Report Monitor *Report Mixing

Pos. No. Confirm Rotation Setting rpm Characteristics
66A-R0020 counterclockwise
66A-R-OOOO counterclockwise
* Mild, moderate, vigorous
C. Heating/Cooling Systems Checkout (Attachment 13)

Heating/cooling tests will verify and document that the process
equipment will perform as required by the process. The
process equipment will be tested using the following procedure:
1. Fill vessel with enough water to simulate process volumes;
record volume.
2. Close and secure the vessel; record the initial temperature
reading.
3. Set controller at specified temperature setting.
4. Once temperature is attained, record temperature reading. Re-
peat for other settings as required.
Pos. No. Cool to Using Heat to Using

66A-R0020 5°C-10°C Dowtherm J 90°C-95°C Dowtherm J
66A-R-0010 5°C-10°C Dowtherm J 90°C-95°C Dowtherm J
66A-R0050 90°C-95°C steam
D. Filter Checkout (Attachment 14)

Each filter checkout will be performed during process qualifica-
tions. The filtrate sample will be checked for clarity.
E. Tray Dryer Checkout (Attachment 15)
Tray dryer, -0070, will be tested. These tests will
verify/document that the hot water loop and vacuum system will
perform as required.
1. Close and secure the dryer; record the initial temperature
reading.
2. Turn vacuum on and set hot water temperature controller at

35°C, 50°C, 60°C, and 70°C.
3. Hold vacuum and temperature for minimum one hour.
In addition, during the first batch of the process validation with
_ _ _ _, special samples will be taken from representative trays
on each drying shelf. These will be tested for percentage loss on
drying (o/oLOD) individually to show that drying is uniform
throughout the dryer.
F. Centrifuge Checkout (Attachment 16)
Tolhurst basket centrifuge, S-0050, will be tested. These tests will
verify and document that the centrifuge is operational and will per-
form as required. This is a two-speed centrifuge; basket rpms at
each setting, under no load and load conditions, will be monitored.
G. Operator Training Records (Attachment 17)
Training of chemical operators will be documented. Include copies
of training records to Attachment 17.
H. Validation Test Instruments (Attachment 18)
Complete a list of instruments required to conduct the operational
qualification testing. Verify that the instruments have been cali-
brated in compliance with the Process Instrumentation Calibration
Procedures, SOP- . All calibration documentation will
be maintained by Plant Maintenance and the Chemical Synthesis
Department.
I. Manufacturing/SOP List (Attachment 19)
All the responsible departments will list all MFPs and SOPs that are
applicable to this protocol.
]. Operational Qualification Summary (Attachment 20)
Document any discrepancies or variations noted during the perfor-
mance of this OQ section. Include the resolution of these items
and/or any item outstanding that will require further effort to re-
solve. When all the items are satisfactorily completed, document
that the system is ready for use.
VI. Acceptance Criteria

A. Installation Qualification Acceptance Criteria
All inspections, reviews, and documentation requirements for the system will
be completed and approved. IQ will document that the system has been in-
stalled in accordance with applicable specifications.
B. Operational Qualification Acceptance Criteria

All monitoring and functional testing of the system will be completed and ap-
proved. OQ will document that the system is capable of operating within
specified parameters for the process and is ready for production.
1. All equipment must satisfy---- process requirements.
2. All alarms and instrumentation must function within required
specifications.
3. All vessels must hold pressure/vacuum within required specifica-
tions.
4. All agitator performance must be satisfactory.
5. The heating and cooling systems must maintain operating temper-
atures required by the process.
6. All pump rotation or mechanical stroke must be correct.
7. All operators must be trained and the training properly docu-
mented.
8. All required MFPs and SOPs must be approved.
VII. Documentation
All required documentation (approved protocol, completed data sheets, etc.)
will be filed in the validation project file. Any discrepancies or variations ob-
served during the execution of this protocol must be documented in the sum-
mary report. During execution, documents will be forwarded to the
validation manager in building _ _ __
Upon completion of protocol execution, a summary report will be pre-
pared. The summary report will be reviewed and approved by the validation
team and by the management of the Chemical Operations, Plant Engineering
and Maintenance, and Quality Assurance Departments. Approval will be doc-
umented on the summary report approval page, which is included as Attach-
ment 21 in this protocol.
VIII. Modification/Change Control and Revalidation

Any modification or changes pertaining to the system will be documented in
compliance with SOP- , Modification Change/Control of Validated
Systems. An assessment will be made before any modification or change to
the system to determine if revalidation is required.
Validation of AP/s: A Case Study 21.9
IX. Index of Reference Attachments

A. IQ Attachments
1. Engineering Documentation
2. Engineering Drawings
3. Equipment List
4. Filter List
5. Instrument List
6. Materials in Product Contact List
7. Lubricant List
8. Weigh Scales List
9. Installation Qualification Summary
B. OQ Attachments
Building 125A
10. Heating/Cooling Systems Checkout
lOa. Tray Dryer Checkout
Building 125B
11. Vacuum Checkout
12. Agitator Checkout
13. Heating/Cooling Systems Checkout
14. Filter Checkout
15. Tray Dryer Checkout
16. Centrifuge Checkout
17. Operator Training Records
18. Validation Test Instruments
19. MFP/SOP List
20. Operational Qualification Summary
21. Summary Report Approval Page
APPENDIX 7.9C
Concurrent Example:
Controlled Environment ( IQ, OQ)
I. Objective
The objective of this protocol is to define the qualification requirements and
acceptance criteria for the controlled environments system. Successful com-
pletion of these qualification requirements will provide assurance that the
controlled environments system will perform as required.
II. Description
The controlled environments system has been designed to provide a clean
processing environment. The system services the air lock, the milling/staging
room, and the sifting/packaging room.
Outside air is prefiltered through 30 percent efficiency filters, 95 percent
efficiency cartridge filters, and finally passed through terminal HEPA filters
(99.99 percent removal of particles 0.3 J.Lm and greater) for each room. The
rooms are maintained at a positive pressure; any room pressure differential of
±0.02 in. WC will activate a local alarm. These alarms have a 20 sec delay.
The air-handling unit controls the facility temperature by modulating a
steam preheat coil and a direct expansion cooling coil. A temperature varia-
tion outside of 72°F ± 6°F will activate a local alarm. The air handler is also fit-
ted with a steam grid humidifier, which maintains the relative humidity. A
value outside of 30 to percent range will activate a local alarm.
A dust collection system (DC-10) provides local collection of any prod-
uct dust. There is a central vacuum system for cleaning the rooms. Normally
the exhaust fan, dust collection unit, and air handler operate constantly. A
failure of any of these units will activate a local alarm.
The new floors are constructed using poured concrete with an epoxy
quartz coating. Drains have proper pitch to ensure that no puddling occurs.
New walls have been constructed and are covered with cocooning. The new
ceiling panels are gasketed aluminum. These are suspended and are secured in
place. Windows, lighting fixtures, and utilities are flush mounted to minimize
dust accumulation. All equipment located in the area has external surfaces of
polished stainless steel or appropriately coated carbon steel, to ensure a
smooth rust-free surface that is easy to clean and maintain.
See other examples for text.

IQ will demonstrate that the system has been installed in accordance with de-
sign drawings, purchase orders, and design specifications.
The IQ testing procedures and requirements for the controlled environ-
ments system for the Supreme pure area in building xx are as follows:
A. Engineering Documentation (Attachment 1)

Complete a list of specifications, purchase orders, and manuals associated
with the system. These documents are compiled for reference only.
B. Engineering Drawings (Attachment 2)

Complete a list of drawings/P&IDs intended to reflect the system "as built" in
Attachment 2a and verify the accuracy of these drawings.
C. Equipment List (Attachment 3)

Complete an equipment list for this system based on information from pur-
chase orders and equipment specifications. Verify that the items have been
installed as specified. Indicate position number, equipment code number,
manufacturer, and description for each item.
D. Instrument List (Attachment 4)

Complete a list of all system instruments. Include tag number, manufacturer,
location, and description for each item. Also indicate instrument designation
as "critical" or "noncritical." Ensure that all instruments have been calibrated
as per the Process Instrument Calibration Procedures.
E. Filter List (Attachment 5)

Complete a filter list for this system based on information from engineering
drawings, purchase orders, and equipment specifications. Verify that the
items have been installed as specified. Indicate position number, equipment
code number, manufacturer, and description for each item.
F. Installation Qualification Summary (Attachment 6)

this IQ section. Include the resolution of these items.
OQ is a testing process that evaluates the system. Controls are adjusted during
this phase of testing, and performance trials are conducted to verify that the
equipment operates in accordance with design specifications under static
conditions. During the OQ, data are collected to establish a performance base-
line to provide assurance that the system can operate as intended, and for fu-
ture troubleshooting. Prior to the OQ testing, the controlled areas will be
cleaned and/or sanitized according to approved procedures.
The OQ testing procedures and requirements for the controlled environ-
ments system for the pure area are as follows:
A. System Balancing (Attachment 7)

The system will be balanced by a qualified contractor to determine whether
the system meets the design criteria. The contractor will issue a report docu-
menting the testing and balancing of the system. The report will include ver-
ification of differential room pressures, airflow, and air changes rates. Include
a copy of the balancing report as Attachment 7.
B. Monitoring of Environmental Conditions

Environmental conditions in the facility will be monitored during validation
to demonstrate that the system operates as designed.
1. Temperature/Relative Humidity Monitoring (Attachment 8)
The temperature and relative humidity in the facility will be moni-
tored under static conditions once a day for three consecutive days.
Monitoring locations are indicated on Attachment 8. The system
must be on for a minimum of 24 hours prior to monitoring. Tem-
perature and relative humidity control are in place for operator
comfort. There are no temperature or relative humidity require-
ments for the process.
2. Nonviable Airborne Particulate Monitoring (Attachment 9)
Nonviable airborne particulate counts will be monitored under sta-
tic conditions over a two-week period. Monitoring will be per-
formed using a Met One Laser Particle Counter, model No. 237B.
Each location will be monitored on three different days over two
weeks, and each reading will be an average of ten 1 ft3 samples.
Monitoring locations are indicated on Attachment 9. The system
must be on for a minimum of 24 hours prior to monitoring. Moni-
toring will be performed a minimum of once a year to evaluate the
performance of the system.
C. Alarm Checkout (Attachment 10)

All alarms supporting the system will be checked for proper operation. Verify
alarm functionality by simulating appropriate set points. Record the results
on Attachment 10.
D. Mechanical Completion Form List (Attachment 11)

Complete a list of the mechanical completion forms required for the system.
E. Laboratory/Standard Operating Procedures List (Attachment 12)

Complete a list of all Laboratory Operating Procedures (LOPs) and SOPs that
are applicable to the system.
F. Validation Test Instruments and Calibrations List (Attachment 13)

Complete a list of all instruments required to conduct the operational qualifi-
cation testing.
G. Operational Qualification Summary (Attachment 14)

this section. Include the resolution of these items.

A. Installation Qualification
All inspections, reviews, and documentation requirements for the systems
will be completed and approved, all discrepancies must be resolved and docu-
mented in the summary report. IQ will document that the system has been
installed in accordance with applicable specifications and is ready for OQ.
B. Operational Qualification
All monitoring and functional testing of the systems will be completed and
approved; all discrepancies must be resolved and documented in the sum-
mary report. The OQ will document that the system is capable of operating
within specified parameters.
1. Prior to operational testing, the controlled areas will be cleaned

and/or sanitized according to approved procedures and the opera-
tion documented.
2. The system must maintain the relative humidity between 30 and
_ _ _ _ percent and the temperature at 72°F ± 6°F.
3. The system must maintain a positive pressure differential with re-
spect to ambient pressure areas in the facility and specified pressure
differentials between processing areas.
4. The direction of the airflow will be verified to be consistent with
design drawings, and the air changes per hour in the facility must
meet the minimum design criteria of 20 air changes per hour.
5. HEPA filters must be factory inspected and dioctyl phthalate (DOP)
tested after installation.
6. The pure area must meet design criteria for cleanable finishes, ab-
sence of crevices and ledges, equipment external surfaces, and gen-
eral appearance.
7. Nonviable airborne particulate monitoring results should be less
than 100,000 particles of 0.5 J.Lm or larger per cubic foot of air.
8. Viable particulate monitoring must be performed, documented,
and evaluated by Quality Control.
VII. Documentation

A. Installation Qualification Attachments

3. Equipment List
4. Instrument List
5. Filter List
B. Operational Qualification Attachments

7. Balancing Report (from vendor)
8. Temperature Monitoring
9. Nonviable Airborne Particulate Monitoring
10. Alarm Checkout Sheet
11. Mechanical Completion Forms
12. LOP/SOP List
13. Validation Test Instruments and Calibrations List
Attachment 7 BALANCING REPORT (from vendor) Pg._of_
Protocol: A -ENV-01 Title: Controlled Environments System Rev. 0
Attach a copy of Contractor Balancing Report for the system.

Document any discrepancies on the Operational Qualification Summary.
Reviewed b y : - - - - - - - - - - - - Date: _ _ _ _ _ _ __
Attachment 8 TEMPERATURE/RH MONITORING Pg._of_
Protocol: A -ENV-01 Title: Controlled Environments System Rev. 0

Room Temperature (Design Specification: 72 ± 10°F)
Temperature Temperature
Room in room (°F) outside (°F) Time Performed by
Rm. 110 Date: OF OF
Date: OF OF
Date: OF OF
Relative Humidity (Design Specification: _____ to _ _ _ _% RH)
Room Relative humidity Time Performed by
Attachment 9 NONVIABLE AIRBORNE Pg. _ _ of _ _

PARTICULATE MONITORING
Protocol: A-ENV-01 Title: Controlled Environments System Rev. 0
NOTE: Sampling location should be as close to the center of each room as
possible.
Room Particle Count Readings Performed by/Time

Rm.110 Date: 51-Lm _ _ _ _,count
Date: 5!-Lm _ _ _ _,count
Date: 51-Lm _ _ _ _,count
Attach Met One Laser Particle Counter printouts.+

Attachment 10 ALARM CHECKOUT SHEET Pg. _ _ of _ _
Acceptable Performed ByI

Alarm Indication Setting Observed (Y/N) Time/Date
Attachment 11 MECHANICAL COMPLETION FORMS Pg. _ _ of _ _

Mechanical Completion Form Equipment Description
Roller Conveyor
HEPA Filters
HVAC Automatic Controls
Piping Pressure Test Report
Satisfactorily completed? (Y/N):
APPENDIX 7.90
Concurrent or Prospective Example:
Supreme Process {PQ)
I. Objective
The objective of this protocol is to define the process qualification require-
ments and acceptance criteria for the manufacture of in building
10. Successful completion of these validation requirements will provide assur-
ance that the manufacturing process meets all in-process tests and QC specifi-
cations. This protocol has been prepared under the guidelines established by
the master plan.
II. Description
_ _ _ _, tech grade, is reacted with in acetone in a dedicated
equipment train to produce . About 160 kg of is pro-
duced in a typical batch. The following is a complete listing of all manufac-
turing operations documented in the MFPs:
MFP Operation Description

Operation A
These manufacturing operations are briefly described below:
Operation A: , charcoal, and dry (min 97 percent as-
say) are charged into a nitrogen inerted 2000 gal glass-lined reactor, R-5000. The
mixture is agitated, the batch is maintained at s 30°C ...
This protocol has been developed by the IDEAL validation team. The respon-
sibilities of the validation team and various departments involved with this
project are listed below.
A. Validation Team ... describe

B. Technical Support/Validation ... describe
C. Engineering ... describe
D. Quality Assurance ... describe
E. Manufacturing Operations
1. Providing personnel, when necessary, to assist in the opera-

tion of equipment and equipment systems during the execu-
tion of qualification studies.
2. Review and approval of this protocol and summary report.
3. Storage and maintenance of the validation project file after
validation package is complete.
F. Plant Maintenance
1. Providing personnel, when necessary, to calibrate critical mea-
suring, recording, and/or controlling instrumentation.
2. Calibration of instrumentation incorporated into the system
prior to validation.
3. Maintenance and calibration of validation equipment.
4. Storage and maintenance of the calibration documentation.
G. Quality Control
1. Providing laboratory services for testing samples.
2. Providing a report on testing results.
IV. Prequalification Requirements

The following prequalification requirements will be completed prior to execu-
tion of this protocol:
• Verify on Attachment 1 that the master plan has been completed
and approved.
• Verify on Attachment 1 that all applicable equipment cleaning op-
erations have been completed prior to the start of the current cam-
paign.
• List copies of as-built PFDs on Attachment 1.
V. Performance Qualifications
During the process validation, all in-process tests will be performed as de-
scribed in the MFPs. QC release testing on the final product will be performed
by the QC labs. A minimum of three successive successful production runs
will be monitored during this testing period. If a successive batch should fail
for a reason unrelated to process performance (e.g., power failure or equip-
ment breakdown), that batch will be removed from consideration and an-
other batch will replace it.
The process qualification testing procedures and miscellaneous require-
ments are as follows:
1. MFPsjSOPs
All MFPs and SOPs associated with the process must be listed on Attachment
2. The process will be run using approved MFPs.
2. Raw Materials
The intermediate, must meet all in-process "finished lot" tests. List
all raw materials utilized for each validation batch, their IDEAL lot/batch
numbers and expiration dates, and QC release date, if any, on Attachment 3.
3. Monitoring of Critical Parameters

Among the critical parameters indicated in the batch records, the xx reaction
temperature is identified as critical. Historically, it has been observed as being
critical to the quality of Supreme produced. Subsequent heating and cooling
of the batch is precisely controlled with a Honeywell computer se-
quence (DCS) operation.
The following table presents the current operating range and proposed
set points for each critical parameter in the three validation runs:
Critical Process Parameters
Critical Parameters Operation Current Validation Values*

Op. Range
1 2 3
_ _ _ _ reaction temp.
during hold period,
controller set point* A
*Note: Validation values are controller set points. Actual values may vary about the set point.
The critical operating parameters will be monitored during the production of

the validation batches. In addition, any significant trends and variations must
be analyzed and evaluated. These data will be documented for each validation
run on Attachment 4. Each process parameter value will be considered ac-
ceptable if the in-process test and the final product meets specifications.
4. Sampling/Testing
The in-process sampling/testing will monitor the development of the product
at individual steps. This sampling/testing will be in accordance with the SOP
5. Performance Qualification Summary

Document any discrepancies or variations noted during the execution of the
performance qualification on Attachment 7. Include the resolution of these
items or any item outstanding that will require further effort to resolve.

All monitoring and testing of the key process steps will be completed and ap-
proved. The process qualification is performed on all processing steps to en-
sure and document the consistency and/or effectiveness of the operation.
a. All raw materials must meet "finished lot" or QC specifications.

b. All critical process parameters must be within the ranges specified
in this protocol and batch records.
c. The final yield must be within the ranges specified in the batch
records
d. All in-process tests must meet specifications as per batch records.
e. Final product must meet IDEAL quality control specifications.
VII. Documentation

1. Prequalification Requirements
2. SOPs/MFPs Review
3. Raw Materials
4. Monitoring of Processing Parameters
5. In-Process Tests
6. In-Process Testing, Finished Lot
7. QC Test Summary
8. Performance Qualification Summary
Attachment 1 Prequalification Requirements Pg. _ _ of _ _
Protocol: A-SUP-01 Supreme Process Validation Rev. 0
The following prequalification requirements have been completed:

Master plan acceptance date:
Essential protocols executed:
Last material campaigned in process train:
Cleaning protocol executed:
The following must be added to every attachment:
Compiled b y : - - - - - - - - - - - - - - - Date: _ _ __
Reviewed b y : - - - - - - - - - - - - - - - Date: _ _ __
Attachment 2 SOPs/MFPs REVIEW Pg. _ _ of _ _
SOP/MFP Title SOP/MFP Rev. Date Resp. Entered By

Dept
Attachment 3 RAW MATERIALS Pg. _ _ of _ _

Lot Number &
Critical Raw Material Supplier/Manufacturer Retest Date or Date of
Expiration Date Testing
MONITORING OF
Attachment 4 PROCESS PARAMETERS Pg. _ _ of _ _
Validation Run 1 Batch/Lot No.: _ _ __
Process Parameters/ Acceptable

Step/Data Testing Specified Actual (Y/N)
Attachment 5 IN-PROCESS TESTS Pg. _ _ of _ _

Operation Test No. Test Performed Specifications Test Results
Finished Lot
Attachment 6 IN-PROCESS TESTS Pg. _ _ of _ _
Test No. Test Performed Specifications Test Results
Attachment 7 QC TEST SUMMARY Pg. _ _ of _ _

Quality Control Test Specifications Test Results Acceptable (Y/N)
Attach QC test report.
PERFORMANCE QUALIFICATION
Attachment 8 SUMMARY Pg. _ _ of _ _
Document below all discrepancies in processing:

Reference:
Discrepancy;variation:
Satisfactorily completed: (Y/N) _ _ __

APPENDIX 7 .9E
Concurrent or Prospective Example: Cleaning
I. Objective
Two products, and , are routinely campaigned through
the process train AA. The objective of this protocol is to define the qualifica-
tion requirements and acceptance criteria for the various equipment cleaning
procedures utilized in this operation. This protocol pertains to the end-of-
campaign cleaning performed for this facility.
Successful completion of the qualification requirements will provide as-
surance that execution of these cleaning procedures consistently results in
product contact surfaces at acceptable levels of cleanliness. The equipment
will be considered clean if the next batch to be manufactured will not be con-
taminated with more than 12.5 g of the cleaned product residue. This value
is based on the 25 ppm limit and the smallest final batch size of 500 kg. The
25 ppm criterion is chosen for this dedicated train.
II. Description
This protocol will specifically address all end-of-campaign equipment clean-
ing operations that offer contact surfaces to the acetyl product being pro-
duced.
During end-of-campaign cleaning, all key vessels, reactors, and transfer
pipes are treated with = 2-3 percent sodium hydroxide solution. Where feasi-
ble, difficult to clean equipment components and piping are dismantled and
immersed in a portable cleaning tank containing = 2-3 percent sodium hy-
droxide solution. Equipment is adequately rinsed with potable water, and to
confirm cleanliness, final rinse samples are analyzed using an HPLC test pro-
cedure with 0.2 J,Lg detection limit. If the cleaning specification is met, equip-
ment is considered clean and ready for use in the next production campaign.
Key process equipment is routinely sanitized with either acetone rinse or
sanitized with regular steam and finally rinsed with purified/DI water.
During a long production campaign, once every three months, all end-
of-campaign cleaning operations are scheduled and performed on the entire
equipment train.
Following is a complete listing of the end-of-campaign cleaning opera-
tions documented in the MFPs:
MFP Operation Items Cleaned Description

CLN-01 • Vac-U-Max System Transports xx from drums to reactor
CLN-02 F-2121, G-2120, K-Tron Screw Feeder, Air Jet Pulverizer,
S-2105, S-2120 Nu-Con Sifter, Dust Collector
CLN-05 • R-2105, • C-2105, Acetone Recovery Still, Condenser,
• S-2002, Recovery Centrifuge
• This equipment does not present contact surface to xxx product.
These cleaning operations are briefly described below:
CLN-01, Vac-U-Max System

Vac-U-Max is used for unloading powder from drums into there-
actor, R-2100. At the end of each campaign, the hopper, chute, flex hoses, and
wand are disconnected and washed until clean with hot potable water. The
vacuum system filter is discarded and replaced with a new filter. All clean and
dry components are finally reassembled.
Operation CLN-06, Packaging Clean Rooms

The pulverization and packaging operations are performed in clean rooms
(Class 100,000) on the first floor: The K-Tron hopper/screw feeder and air jet
pulverizer are located in the milling room. The milled product drops from
dust collector into the Nu-Con sifter located in the packaging
room.
Each room is broom cleaned and its floors, walls, and ceiling are hosed
with water to remove dust and product. Cleaning detergent Arrive® is sprayed
onto ceiling and walls three-fourths of the way down. After leaving the deter-
gent for five minutes, ceiling and walls are hosed with purified water (PLEW)
until all detergent is rinsed off. Next, the bottom one-third of the walls and
floor is cleaned. Once water has drained from the floor, a new sanitary mop is
used to dry the floor. The rooms are inspected visually to confirm cleanliness.
Finally, all equipment is reassembled with new filter bags and new gaskets.
IV. Cleaning Validation

The intent of this validation is to provide confidence that the cleaning proce-
dures result in equipment that is acceptably clean for the next production
campaign. PQ will be performed to ensure the consistency and effectiveness
Validation of APfs: A Case Study 235
of the equipment cleaning procedures. Critical operating parameters are listed

in the MFPs and will be monitored during protocol execution. Any variance
in operating data will be fully explained and will be reported in this protocol.
The end-of-campaign cleaning will be performed at least on one occasion to
complete the cleaning validation review as IDEAL plans to suspend _ _ __
production at the facility very shortly. If a cleaning should fail for any reason
unrelated to the performance of the equipment cleaning procedures (e.g., a
power failure or equipment breakdown), that cleaning run will be removed
from consideration and one additional cleaning will be required.
The cleaning procedures will be performed as described in section II of
this protocol and defined in the applicable MFPs and SOPs. The equipment is
considered to be acceptably clean when the summation of total residue (TRi)
values of the various subsections is less than or equal to the established maxi-
mum allowable residue (MAR) value. If the !.TRi value exceeds the MAR value,
or the weighted TRi value exceeds the weighted MARi value, an investigation
will be made and the cleaning procedure will be amended as neccessary. Val-
ues of weighted MARi are given in the table below. A detailed explanation of
the calculations is presented in SOP _ _ __
The cleaning procedures have been developed based on the best infor-
mation available. Sampling for cleanliness will utilize both the rinse and the
swab methods. Equipment cleanliness will be verified by testing a final rinse
and a swab sample when equipment can hold the final rinse. The swab sam-
ple will be taken after the successful completion of the final rinse operation.
Confirming swab results will be recorded. If process equipment cannot hold
the final rinse water, then its cleanliness will be verified by at least two swab
samples.
Where equipment is totally enclosed and swabbing is not feasible, a
minimum of two final rinses will be required to verify its cleanliness. In the
event the residual concentration in the first rinse meets the acceptance crite-
rion, one additional rinse will be tested to demonstrate a residue reduction
trend in the rinse sample.
The rinse and swab samples will be tested by the Plant Support Labora-
tory during execution of this protocol. The concentrations of sulfa residue in
the rinse samples will be determined via HPLC, and these will be reported to
the validation team in 1-Lg/mL. Swab samples will be analyzed via HPLC and
results will be reported to the validation team in 1-Lg. Swabbing procedure is
described in Appendix A.
TRi is calculated as follows:
Via Rinse Method

TRi = [Ci X Vi] X [3.7854 L/1 gal]
Via Swab Method
TRi = [average SRi x Ai x 144(in.2Jft2)]
Where
11 11
MAR= LMARi = LTRi ~ 12.5 g
1 1
MARi = Wi X MAR
MAR = maximum allowable residue on contact surfaces for the acetyl
train
MARi = maximum allowable residue on contact surfaces for operation i
TRi = total residue (mg) on contact surfaces for operation i
Ci = residue concentrations (mg/L or f.Lg/mL)
Vi= volume of rinse (gallons)
i = 1 through n, cleaning suboperations
Wi = weight factor for operation i
SRi = swab residue per inch 2 of contact surface for operation i
Ai = contact surface area (ft2) of equipment for operation i
The weight factors, Wi, for each suboperation, are calculated by dividing
the product contact surface area of the cleaned equipment in the subopera-
tion by the total product contact surface area of the train.
The following table shows the estimated value for Wi and the corre-
sponding maximum allowable product residue on equipment.
Product Cleaned
Contact Weighting Assigned Assigned Swab Final MARi

Cleaning Areas Factors Rinse Sample Rinse Max
Operations {sq. ft.) {Wi) Sample {gal.) Vol. {g)
02 W02
D-2100 1700 2A-S1 7.5

thru S5
F-2120 XX 2B-S1,S2 0.25
Total Estimated Contact Areas = 2,832 ft2
The PQ requirements for the equipment cleaning procedures are as fol-

lows:
A. Results Summary (Attachment 1)

Monitor all visual, pH, and HPLC test results on Attachment 1, 1A,
and 1B for each cleaning operation W.
B. Manufacturing/Standard Operating Procedures List (Attachment 2)

Furnish a list of all MFPs and SOPs that are applicable to the perfor-
mance of the equipment cleaning procedures.
D. Validation Test Instruments and Calibrations List (Attachment 3)
Furnish a list of instruments required to conduct the PQ testing.
Verify that the instruments have been calibrated in compliance
with the process instrumentation calibration procedures.
E. Performance Qualification Discrepancy Review (Attachment 4)
Document any discrepancies or variations noted during the execu-
tion of this protocol. Include the resolution of these items and/or
any item outstanding that will require further effort to resolve on
Attachment 4.
V. Acceptance Criteria
The following acceptance criteria are required for this cleaning validation:
1. All equipment must be inspected and verified as visually clean.
2. The total residue (TRi) found in the final rinse/swab of any subop-
eration must not exceed the maximum allowable residue (MARi).
3. After the rinse sample meets the acceptance criteria, a swab sample
will be tested for verification. If confirming swab test results exceed
105 percent of the rinse sample results, then the cleaning operation
will be repeated.
4. If swabbing is not feasible, a second final rinse sample will be tested
to confirm cleanliness. The second rinse sample must show a
downward trend in TRi residue or confirm a "none detected" result.
5. If process equipment being cleaned cannot retain the rinse water,
then its cleanliness will be verified by two swab samples.
6. The summation of total residue (ITRi) found in the final
rinse/swab of all contact areas in suboperations must not exceed
the MAR (i.e., 12.5 g).
7. The completed cleaning batch records must be approved by the
Quality Assurance Record Release group.
8. After cleaning, the first batch campaigned must meet
Quality Control chemical and microbial testing specifications.
VI. Documentation
See other appendices for text.
VII. Modification/Change Control and Revalidation

Any modification or changes pertaining to xx equipment cleaning procedures
will be documented in compliance with SOP , Modification
Change/Control of Validated Systems. An assessment will be made before any
modification or change to the system to determine if validation is required.
VIII. Index of Reference Attachments
Appendices:
A. Swabbing Procedure
Bl-B7 Diagrams Showing Swabbing Locations
C. Maximum Allowable Residue, Acceptance Limit
Attachments:
1. Monitoring of Cleaning Results
lA. Swab Test Results
lB. Total Residue Values
2. MFP/SOP Review
3. Operator Training Checkout
4. Validation Test Instruments and Calibrations List
5. Performance Qualification Review
Appendix A: Swabbing Procedure

The following swabbing procedure will be utilized:
1. Swab material is SUPER POLIX™ 1200 wipers, a 100 percent knitted

polyester material, cut into 1" squares.
2. The solvent for all swabs will be ethanol. No more than 24 hours
prior to use, the swabs will be placed in a clean, stoppered vial with
approximately 1 mL of ethanol.
3. In use, the swabs will be held in a clamping hemostat or tweezers.
The swab will be applied to the surface using moderate pressure.
4. Label each vial before use. Label two unopened vials (with swabs) as
"negative control." Return these vials, unopened, with the used
vials.
5. On flat surfaces, a 4 in. 2 template will be used for the swabbing
area. The swab is passed vertically over the entire template area, us-
ing as many single strokes as needed to cover the area one time
only. Then the same swab is passed horizontally over the same area,
using as many single strokes as needed to cover the area one time
only. Do not repeat in a horizontal direction. Place the swab back
into its vial and seal.
6. On surfaces that are not flat, or where the use of a template is not
possible, apply the swab to the area, and make a best estimate of
the surface area in contact with the swab. Record the estimated
swabbing area. Place the swab back into its vial and seal.
7. Send all swabs, in their marked vials, to the laboratory for extrac-
tion and analysis. Send one vial with swab/water to test a blank
(once/day).
Each piece of equipment will be swabbed in at least three areas: that is,
one random (4 in.Z) head of tank, one random head gasket area, one random
(4 in. 2 ) side of tank. Average each pair of swabs to get the average quantity of
residue for each piece of equipment. Record individual swab values, swabbing
area used, and the average residue per square inch on Attachments IA and lB.
Appendix C: Maximum Allowable Residue,

Acceptance Limit Per SOP _ __
Twenty-five parts per million criterion applicable-family product (similar
therapuetic and toxicity) in the train. After cleaning the train, this is the max-
imum level of contaminant residue allowed in the first batch processed. Typi-
cal batch sizes of acetyl sulfisoxazole produced is 500 kg.
Therefore,
MAR TOTAL using 25 ppm =
(25 mg/kg) x (500 kg/batch) = 12.5 g
Attachment 1 Monitoring of Cleaning Results Pg. _ _ of _ _
Protocol: A-CLN-02 Cleaning Validation of Rev. 0

Process Equipment
Validation Run 1 Last Batch in Train, Batch No. _ _ __
Product Cleaned: _ _ __
Description
Operation CLN Vac-u-Max System Results
CLN-01, Step 4 wand & hoses, visual Acceptable (Y/N):
check (loop no.)
CLN-01, Step 5 vacuum filter replacement Acceptable (Y /N):
CLN-03, Step 5 R-2101, visual & HPLC pH water rinse _ _ __
check (loop no.)
Residue _ _ _ _ mg
Attachment 2 SOPs/MFPs REVIEW Pg. _ _ of _ _

Process Equipment
MFP/SOP Title SOP/MFP Rev Date Responsi- Reviewed

ble Dept. by
Attachment 3 OPERATOR TRAINING CHECKOUT Pg. _ _ of _ _

Process Equipment
Name of Operator Training Performed by/Date

Attachment 5 PERFORMANCE QUALIFICATION REVIEW Pg. - - of - -

Protocol: A-CLN-02 Cleaning Validation of Ref. 0
Process Equipment
Document below all discrepancies in cleaning operations:
Compiled b y / D a t e - - - - - - - - - - - - - - - - - - - - - -
Reviewed b y / D a t e - - - - - - - - - - - - - - - - - - - - - -
Attachment 18 TOTAL RESIDUE VALUES Pg. _ _ of _ _

Process Equipment
Validation Run 1 Last Batch in Train, Batch No. _ _ __
Product Cleaned: _ _ __
Cleaning Assigned Rinse Assigned Swab MARi Max TRi

Operations Sample Sample g g
02 W02
D-2100 2A-S1 thru S5 7.5
F-2120 2B-S1,S2 0.25
Compiled b y / D a t e : - - - - - - - - - - - - - - - - - - - - - -
Reviewed b y / D a t e : - - - - - - - - - - - - - - - - - - - - - -
APPENDIX 7.9F
Concurrent or Prospective Example:
Micronization
I. Objective
The objective of this protocol is to demonstrate that the micropulverization
equipment in cell , of building , will perform as required
and that the micronized product will meet its predetermined specifications.
II. Description
Supreme is micropulverized in approximately 100 kg batches. The primary
pieces of equipment employed in this service are the Fitzmill and the Micron-
Master Jet Pulverizer. This facility is also used for conducting , pro-
duction campaigns.
Supreme is pulverized in a 10 HP Fitzmill fitted with fixed s/s impact
edge blades and 60 mesh s/s screen. The dry crystalline powder is hand fed
and milling temperature is controlled by circulating a coolant through the
grinding chamber jacket. The mill is operated at -5000 rpm and at lowest
feed screw setting. The pulverized powder pushes through a 60 mesh screen
and collects in the hopper.
Next, the pulverized material is continuously micronized through a 4"
Teflon lined Orbital Micron-Master Jet Pulverizer. This micronizer is operated
with SO CFM of 105 psig filtered nitrogen (.01 f.Lm filter) and the feed rate is
controlled between 8 to 10 kg/hr. This feed rate minimizes blow back and has
historically produced Supreme with 90th percentile below 10 f.Lm particle size.
The entrained particles from the Micron-Master enter a cyclone from
which most of the product exits into a fiberpack. The balance of the product
is carried with nitrogen into a bag collector where fines accumulate. The bag
collector is intermittently pulsed with nitrogen to allow fines to drop into a
second fiberpack. Nitrogen exits through a HEPA filter located on the roof.
The micronization facility exhaust exits through a terminal HEPA filter
located on the roof. The production area is maintained under negative pres-
sure (.04 to .08 inches of water).
The operator walks through an air lock; dons a proctective cap, gown,
gloves, and shoe covers; and then walks through a water shower to enter the
cell area. Once in the cell, the operator wears a protective breathing apparatus
hooked to the fresh air supply port.
111. Responsibilities

IQ is the documentation process that verifies that the physical components of
a system have been installed according to design specifications. The IQ also
serves as a final major component and system quality audit prior to equip-
ment operation (for new facilities).
The installation of the system will be verified by reviewing the equip-
ment installed, using the check sheets provided in this protocol, to document
that the system components conform to design specifications. In addition,
engineering documentation will be reviewed and compared to the installed
system.
The IQ requirements for the system are as follows:
1. Engineering Documentation (Attachment 1)

2. Engineering Drawings (Attachment 2)
3. Equipment/Filter List (Attachment 3)
4. Materials in Product Contact (Attachment 4)
S. Utilities (Attachment S)
6. Spare Parts List (Attachment 6
7. Instrument List (Attachment 7)
8. Lubricant List (Attachment 8)
9. Installation Qualification Summary (Attachment 9)
Document any discrepancies or variations noted during the performance

of this section. Include the resolution of these items and/or any item out-
standing that will require further effort to resolve.
OQ is a testing process that evaluates the control system. Controls are ad-
justed during this phase of testing, and performance trials are conducted to
verify that the system operates in accordance with design specifications.
The OQ also serves as a final major component and systems operational
audit prior to use. During the OQ, data are collected concerning critical pro-
cessing parameters that could affect operation. The operational data collected
during OQ will serve as the baseline for PQ (for new facilities).
The OQ testing procedures and requirements for the existing micropul-
verization system are as follows:
• SOPs/MFPs Review (Attachment 10)

• Operators Training Record (Attachment 11)
• Set Up and Verifications (Attachment 12)
• Alarm and Safety Switch Verification (Attachment 13)
• Operational Qualification Summary (Attachment 14)
V. Performance Qualification
PQ is performed on the process to ensure the consistency and/or effectiveness
of the process. Critical operating parameters are defined and will be moni-
tored. A minimum of three successive batches will be monitored during this
protocol execution. If a batch should fail for a reason unrelated to process per-
formance (e.g., power failure or equipment breakdown), that batch will be re-
moved from consideration and an additional batch will be made.
The PQ requirements for the Supreme micropulverization process are as
follows:
A. Validation Batches
The validation batches must be run using approved manufacturing proce-
dures. Include copies of the batch records for the validation batches as At-
tachment 10.
B. Feed Materials
All feed materials utilized for validation batches must be released by Quality
Control, and these should be identified with lot numbers. Include a copy of
QC test results on Attachment 15.
C. Monitoring of Micropulverization of Supreme

The proper assembly of key components will be critical to process perfor-
mance. Verification of correct insatllation of these components shall be docu-
mented in the batch records and on Attachment 12. The Fitzmill amperage
will be monitored and documented on Attachment 16 to access its operating
condition.
Other critical operating parameters such as feed screw setting, rpm,
coolant temperature, and nitrogen pressure will be monitored. No attempt
will be made to challenge these settings since these have been successful in
meeting powder specification in the past (for existing facilities). These read-
ings will be documented on the batch records and on Attachment 16.
D. Sampling/Testing for Micropulverized Supreme

Sampling and in-process testing will be performed on the validation batches
to evaluate the process performance using the microscopic appearance deter-
mination test. This in-process test determines that the product is uniform. All
samples specified in the batch records must be taken. Test results will be sum-
marized on Attachment 16.
In addition, validation samples will be submitted to Quality Control for
complete particle size analysis. Representative samples will be collected in
sample bottles that have been properly labeled. The following samples will be
submitted to QC:
1. One - 5 g representative sample from each polyethylene-lined
drum during the micropulverization operation. QC will perform
tests for appearance and particle size analysis (Attachment 17).
2. One - 5 g representative sample from each polyethylene-lined drum
to prepare a composite sample. QC will perform tests on a composite
sample for complete Supreme characterization (Attachment 18).
E. Performance Qualification Summary

The PQ summary will document any discrepancy or variation noted during
the execution of this protocol on Attachment 19. This summary will include
resolution of these items or any item outstanding that will require further ef-
fort to resolve.

A. IQ Acceptance Criteria
All inspections, reviews, and documentation requirements for the system will
be completed and approved. IQ will document that the system has been in-
stalled in accordance with applicable specifications.
B. OQ Acceptance Criteria
All monitoring and functional testing of the system will be completed and ap-
proved. OQ will document that the system is capable of operating within
specified parameters and is ready for use.
1. System will conform to general acceptance criteria.

2. System interlocks and safety devices must operate in accordance
with design parameters.
3. The Fitzmill and Micron Master must operate in accordance with
specifications.
C. PQ Acceptance Criteria
All monitoring and testing of the micropulverization step will be completed
and approved. PQ is performed on the processing step to ensure and docu-
ment the consistency and/or effectiveness of the operation.
1. All feed material must meet "finished lot" or QC specifications.
2. All critical process parameters must be within the ranges specified
in this protocol and MFPs.
3. The final yield obtained must be within the ranges specified in the
MFPs.
4. All in-process tests must meet spedfications as per MFPs.
5. Final product must meet IDEAL Quality Control specifications.
VII. Documentation
IX. Index of Attachments
A. IQ Attachments
3. Equipment/Filter List
4. Materials in Product Contact
5. Utilities
6. Spare Parts List
7. Instrument List
8. Lubricant List
B. OQ Attachments
10. SOPs/MFPs Review List
11. Operators Training Record
12. Set Up and Verification
13. Alarm and Safety Switch Verification
Validation of AP/s: A Case Study 24 7
C. PQ Attachments
15. Feed Materials
16. Micronizer Operational Data
17. Particle Size Analysis
18. QC Test Summary-Certificate of Analysis
19. PQSummary Report
Attachment 1 ENGINEERING DOCUMENTATION Pg. _ _ of _ _
Protocol: SUP-MIC-01 Title: Supreme Micronized Rev.: 0

Doc. No.: Rev.jlssue No.: Date:
Title:
Inspected by & Date: Discrepancy (Y/N):
Attachment 2 ENGINEERING DRAWINGS Pg. _ _ of _ _

Dwg. No.: Rev.jlssue No.: Date:
Title:
Attachment 3 EQUIPMENT LIST Pg. _ _ of _ _

Attach Equipment List
Attachment 4 MATERIALS IN PRODUCT CONTACT Pg. _ _ of _ _

Protocol: SUP-MIC-01 Title: Supreme Micronized Rev. : 0
Serial No. Micronization Train 109 Material of

No. Component Name Construction
1 Pulverizer Head
3 Pulverizer Screen
Attachment 5 UTILITIES Pg. _ _ of _ _

Compressed Air (Breathing)
Utility Pressure Check
Day 1 Day 2 Day 3 Day4 Day 5
Monitoring Location _ _ psig _ _ psig _ _ psig _ _ psig _ _ psig
Performed By/Date --1 -1 -1 -1

Nitrogen
Utility Pressure Check
Day 1 Day 2 Day 3 Day4 Day 5
Monitoring Location _ _ psig _ _ psig _ _ psig _ _ psig _ _ psig
Performed By /Date --1 -1 -1 -1 -1

Note: Chilled glycol service and other utilities were validated under utilities
protocol _ _ __
Attachment 6 SPARE PART LIST Pg. _ _ of _ _

Protocol: SUP-MIC-01 Title: Supreme Micronized Rev. : 0
No. Parts Description Manufacturer Ref. No.

Or attach spare part report
Attachment 7 INSTRUMENT LIST Pg. _ _ of _ _

Tag No.: Manufacturer:
Description:
Calibration Date: Recal. Date:
Attachment 8 LUBRICANT LIST Pg. _ _ of _ _
Protocol: Title: Supreme Rev.: 0

045-SUP-MIC-01 Micropulverization
Lubricant:
Description:
Lubricant in direct product contact? (Y /N): Acceptable? (Y /N):
Inspected by & Date: Discrepancy (Y /N):
Attachment 13 ALARM AND SAFETY SWITCH VERIFICATION Pg.1 of 2

Protocol: Title: Supreme Rev. 0
064-SUP-MIC-01 Micronized OQs
Alarm Checkout
Alarm Description/Test Test Result
Expected Actual
Hopper Cover on Rtzmill
Performed by/date:
Attachment 15 FEED MATERIALS Pg. _ _ of _ _
Protocol: SUP-MIC-01 Title: Micronized Supreme Rev. 0

VALIDATION RUN: _ _ __
Identify Drums Used:
Attach QC cerificate of analysis.
MICROPULVERIZATION
Attachment 16 OPERATIONAL DATA Pg. _ _ of _ _

Fitzmill Pulverizer
Glycol Coolant
Feed Screw Setting rpm Temp. (°F) Amperage
Micron-Master Jet Pulverizer

Feed Screw Inlet N2 N2 Supply N2 Supply
Setting (PSIG) "Nozzle A" (PSIG) "Nozzle B" (PSIG)
Microscopic Appearance Test IL01.1
Sample
Location Uniform Nonuniform Performed By Date
Drum1
Drum2
Attachment 17 PARTICLE SIZE ANALYSIS Pg. _ _ of _ _
PARTICLE SIZE ANALYSIS
Particle Size Analyzer Model No. Type

goth Percentile soth Percentile
Specification < 10 ,...m Specification < 5 ,...m
Sample Gross Tare Net Weight Result Result

Location Weight (mg) Weight (mg) (mg) (mg)
(mg)
Drum 1
Drum 2
Fines Drum
Compiled b y - - - - - - - - - Date-------------
Or attach QC certificate of analysis for particle size.
Attachment 18 QC TEST SUMMARY Pg. _ _ of _ _

Protocol: SUP-MIC-Q1 Title: Micronized Supreme Rev. 0
Attach QC cerificate of analysis.

Add the following to all attachments:
Comments: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __
Reviewed b y : - - - - - - - - - - - - - - - - Date: _ _ _ __
APPENDIX 7.9G
Concurrent Example: DCS Summary Report
Table of Contents
I. Summary ..............................................000
II. Objective .............................................. 000
III. Description .............................................000
IV. Results ................................................ 000
V. Conclusions ............................................000
Appendix 1-Copy of Approved Protocol without Attachments ........000
Appendix 2-All Executed Protocol Attachments and Supporting Data ... 000
I. Summary
Protocol 125- -DCS-01, Computerized Process Control System for
_ _ _ _ Production, was approved in May 1999 and was concurrently exe-
cuted during July/August 1999.
The process in building is controlled by the dis-
tributed control system (DCS) that was assembled with selected Honeywell
TDC3000 components. In this fadlity, the DCS controls the and
_ _ _ _ steps and the wastewater stripping.
All monitoring and testing spedfied by the protocol were adequately ad-
dressed, documented, and reviewed, and were acceptable. The satisfactory ex-
ecution of the protocol has confirmed that all modules of the DCS will
continue to perform as expected and, therefore, are qualified. Thus far, the
DCS has an excellent performance record for the process in build-
ing _ _ _ _ ,
Protocol 125-----'-DCS-01 is a part of the validation effort being
undertaken for production at Nutley. The overall validation plan is
presented in the Validation Master Plan, Rev. 1, dated 26 January
1999.
II. Objective
The objective of Protocol 125- -ACS-01, Rev. 0, was to demonstrate
concurrently that the existing DCS servidng the production facil-
ity in building will operate reliably and repeatedly over time.
The validation plan defines the activities, which will be carried out to as-
sess the state of the system against current practices, identify any deficiencies,
and ensure their correction. The results of these activities will provide the
documentation needed to support the validation of the system.
This validation plan has been prepared under the guidelines established
by the Process Validation Master Plan and to comply with the fol-
lowing IDEAL computerized systems validation (CSV) documents: (1) CSV
Policy, (2) CSV Planning and Reporting Guideline, and (3) IDEAL Pharma
Computerized Systems Validation Guidelines, SOP-·_ _ __
Ill. Description
The DCS is associated with the following two key steps of the _ _ __
process in building : (1) , and (2) . This system
controls and monitors (a) slurry transfer, (b) delivery
and addition, (c) generation, (d) reaction, (e) _ _ __
neutralization, (f) step, and (g) wastewater stripping. In the
_ _ _ _ step, the DCS automatically makes the necessary prechecks before
batches are begun and carries out process operations according to the batch
sequence program.
This system was installed in several phases between 1990 and 1994. First,
the two reactors, R100 and R101, were converted from board-
mounted single loop controllers and on/off switches into the DCS. Next, a
third reactor, R102, and the HCL feed unit were added. And finally
the step was converted into the DCS in 1994.
The DCS is assembled with selected Honeywell TDC3000 components. It
provides centralized control and monitoring capabilities utilizing operator
consoles with a touch screen display. The system links to the process through
the Data Hiway, which is a proprietary network that uses a command/
response message-exchange technique. A detailed general description of the
DCS is available in the protocol.
Based on inputs from Production as well as hazard and operability study
(HAZOP) analysis, several improvements have been incorporated successfully
into this system during the last few years. The DCS controls the process in a
reliable and consistent manner. To date, this system commands an excellent
performance history.
IV. Results
The following IQs were executed:
A. Engineering/Honeywell Documentation (Attachments 1 and 2)

Key purchase orders of this project, issued between January and
September , are included in the attachment. In addition, the fol-
lowing technical binders are available from Honeywell for consultation: Sys-
tem Technical Data, History Module Specification, Highway Gateway (HG)
Specification, Universal Station Specification, and Malfunction Controller
Specification. Hard copies of the manuals are available in the control room of
building , and spare copies are placed in the validation record de-
positary in building , room _ _ __
B. Hard Copy of Software for Specific Hardware (Attachment 3)

This attachment lists all the application software for specific control modules
in the DCS. The Bernoulli cartridges that are used for loading the application
software to the universal stations, HG, and application module, are located in
the control room, and spares are located in validation record depositary in
building , room _ _ __
C. Engineering Drawings (Attachment 4)

Several as-built drawings, PFDs, and P&IDs associated with the DCS in build-
ing are identified on nine pages in the attachment. The electronic
copies of these drawings are available in Documentum, which can be accessed
through the central engineering local area network system. Hard copies are lo-
cated in validation record depositary in building , room _ _ __
D. Equipment List (Attachment 5)

The following five components make up the DCS: (1) four universal stations,
(2) two HG, (3) one history module, (4) one application module, and
(S) seven malfunction controllers. It was verified that these have been appro-
priately installed.
E. Instrument List (Attachment 6)

Instruments that monitor or control the operating conditions specified in the
manufacturing procedures are deemed critical. These are included on the SAP
Preventive Maintenance System, and the calibration records are included in
the attachment. These instruments were calibrated on a routine schedule,
which is either quarterly, semiannually, or annually, as per the Process Instru-
mentation Calibration Procedures, SOP- . No discrepancy was ob-
served.
F. MFP/SOP Review (Attachment 7)

A current copy of the continuous manufacturing procedures (CMPs) dealing
with the operation steps performed by the DCS system is included
in the attachment. These procedures have a good performance record.
G. History Module Partitioning (Attachment 8)

The configuration of the history module was completed and verified. The cur-
rent file usage is 66 percent of the hard disk, which is adequate for the sys-
tem's storage needs. Data are grouped every 5 seconds and stored. These
groups are subjected to averaging every 5 minutes (i.e., sixty 5-second groups
are averaged). These 5-minute averages are stored for 168 hours (1 week). Af-
ter 168 hours, the averages are overwritten (i.e., destroyed and replaced with
new data) on a rollover basis. In addition, one month of daily averages and
one year of monthly averages are stored. These too are overwritten by day or
year, respectively. These storage conditions are adequate for the system needs.
H. Batch Sequence Programs (Attachment 9)

A list of the batch sequence programs titled "CL Program List," written in CL
code (control language), is included in the attachment. Each program was
compared with written CMPs to ensure that the DCS process matches the ex-
pected manual performance of the process. No discrepancy was observed.
These programs are frequently tagged with explanations to allow easy under-
standing of what the controls are doing. Hard copies are located in the valida-
tion record depositary in building , room~__ __
I. Environmental Conditions (Attachment 10)

The environmental data were satisfactory and were well within the vendor's
suggested limits. The recorded data are presented in the attachment.
Both temperature and humidity were monitored for one week in the
control room and in the area behind the control panel, where the TDC3000
mainframe is stored. This monitoring was completed in the summer month
as a worst-case challenge. No discrepancy was observed.
J. Emergency Procedures (Attachment 11)

Manual emergency procedures that will be needed in the event of a failure are
listed in this attachment. These cover failures from the following sources:
(1) l/0 card, (2) multifunction controller, (3) power to the DCS, (4) universal
station, and (5) history module.
In the event of the above listed failures, the following titles describe the
appropriate response: (1) Honeywell Emergency Procedures, (2) Interlocks
and Other Safety Features, and (3) Bernoulli Boot-up Procedure for TDC 3000.
These procedures are listed in the attachment.
K. Alarm Indications (Attachment 12)

A computer listing of all process alarms associated with the DCS, along with
alarm priorities (emergency, high, low, no action), is provided in the attach-
ment. No discrepancy was observed.
L. Printer Generated Data (Attachment 13)

The DCS operation is configured among 12 process units. Several graphic dis-
plays and reports are available to the operator from the system menu screen.
The operator can select, monitor, and print the graphic displays. These dis-
plays present an overview of critical operating parameters, alarms status,
process messages, process errors, process changes, system status, trend data,
system maintenance information, and auxilliary equipment status.
A list of the titles of reports and print-out examples are included in the
attachment.
M. Interlock Identification (Attachment 14)

All interlocks in the system are identified in the 10 drawings listed in Attach-
ment 14. A copy of each drawing (interlock descriptions; safety interlock de-
scriptions; logic block diagrams 5, 6, 8, and 11; logic block descriptions 5, 6,
and 8; communication flags) are included in the attachment.
N. Keyboard Overlays (Attachment 15)

The keys are marked to call the necessary graphic displays. Each key was
tested; no discrepancy was observed.
0. Installation Qualification Summary (Attachment 16)

IQ review was satisfactory. Calibration records of all critical instruments were
verified.
The Bernoulli cartridges that are used for loading the application soft-
ware to the universal stations, HG, and application module are located in the
control room, and spares are located in the validation record depositary in
building , room . Also, hard copies of the batch sequence
programs, written in CL language, are located in the validation record deposi-
tary in building , room _ _ __
The following OQ were executed:
A. Access Level Assignments and Restrictions (Attachment 17)

The security system was challenged by attempting to access designated para-
meters as follows: (a) without key (operator level), (b) with supervisor's key,
and (c) with engineer's key. Access worked as expected, and the printout
sheets of this trial are attached.
B. Module Power Failure (Attachment 18)

In case of a power failure to any DCS module, the system is designed to fail-
safe automatically. Steam will close and nitrogen opens. The operator resets
valves manually and proceeds to an appropriate point in the program to re-
sume production and brings the batch to completion.
The universal station and history modules were powered down. In each
case, an alarm alerted the operator to the power failure, and the process con-
tinued to function .as expected. Also, the process continued to function when
the multifunction controllers were disconnected from the Highway Gateway.
C. Process Restart (Attachment 19)

A power failure was simulated part way through the program in six opera-
tions, and the process was started again using the batch sequence program.
This test was completely successful. The procedure allowed the process to be
reinitiated in a controlled manner.
D. Communication Failures (Attachment 20)

The simulated failures of the data highway (DH) and the HG developed error
messages as expected, and the systems assumed their backup positions. This
was achieved by disconnecting the cables. After the cables were connected,
the error messages disappeared, and normal function was restored.
E. Software Interlocks (Attachment 21)

All interlocks identified in Attachment 14 were tested during HAZOP analysis.
Functionality of the interlocks was also tested during the original process
start-up. The results of this analysis are documented in the binders titled
Process Hazard Analysis Report Process, which are located in
building _ _ __
F. Power Source Verification (Attachment 22)

The DCS power panel has five breakers. Each breaker was opened to verify
that the targeted device was powered down. The targeted device was powered
down in each case. Also, each breaker is adequately marked to indicate the de-
vice being served.
G. Keyboard Overlay Functions (Attachment 23)

Keyboard functions were tested. All assigned keys produced the graphical and
system displays as marked.
H. Emergency Procedures (Attachment 24)

As explained earlier, DCS modules are designed to fail-safe automatically in
the event of power failure. Steam will close and nitrogen opens. Then the op-
erator resets process valves manually and proceeds to an appropriate point in
the program to resume production and brings the batch to completion.
Parts of the CMP Interlocks and Other Safety Features describe the steps
to be taken in the event of a power failure. Sample copies are in the attach-
ment.
I. Validation Test Instruments and Calibration (Attachment 25)

A temperature and humidity recorder, Dickson Model THDx, Serial No.
_ _ _ _,was employed for monitoring the control room area. It was cali-
brated on 6/18/99 via _ _ __
J. Training Documentation (Attachment 26)

The training documentation on General Principles of Operational Use of the
TDC3000 Console and Keyboard is in the attachment. Fifteen operators are
listed as adequately trained for the routine use of the DCS and all its modules.
Refresher training is performed following the change control or as determined
by the process manager.
K. Operational Qualification Summary (Attachment 27)

The operational qualification review was satisfactory. Access level assign-
ments and restrictions are adequate, and access to DCS modules worked as ex-
pected. After the planned power failure, the procedures allowed the process to
be reinitiated in a controlled manner.
V. Conclusions
The IQs and OQs of Protocol were satisfactory. All items referenced
in the protocol were adequately addressed. The successful execution has
demonstrated that all modules of the DCS will perform as expected.
Auditing of critical loops was postponed in the current review, because
such an evaluation would have required a complete shutdown of the system.
Such an audit will be scheduled during the intended shutdown in July 2000,
and a separate report will be issued.
8
INGREDIENT VALIDATION:
AN OVERVIEW AND
COMPARATIVE ANALYSIS
Max S. Lazar
Hoffmann-La Roche Inc.
Nutley, New Jersey
Attention to active pharmaceutical ingredients (APis) by both regulators and

manufacturers has continued to increase. During the 1990s, the U.S. Food
and Drug Administration (FDA) began to increase its review of API filings,
manufacturing facilities, and the general current Good Manufacturing Prac-
tices (CGMPs) utilized by manufacturers.
A great deal of this regulatory attention was brought about by the
!-tryptophan incident-an impurity situation believed by some regulators to
have been caused by "minor" deviations in the processing of the compound
by its manufacturer.
In any event, U.S. regulatory authorities have continued to expand the
level of attention and the resources assigned to the review of API manufac-
turers. The public position held by the FDA during the early part of the last
decade was that the FDA had no concerns with what was then referred to as
bulk pharmaceutical chemicals. By the end of the decade, the FDA became
aggressive and began requiring industry to bring its operations into closer
compliance with existing GMP guidelines (FR 1978). In the Preamble to the
1978 revision of the drug product CGMP regulations, the FDA commissioner
261
stated that 21 CFR Part 211 would be considered the guideline for application
to bulk pharmaceutical chemicals.
The FDA began to identify specific areas of focus. Two notable initial fo-
cal points were water systems, including endotoxin monitoring, and valida-
tion of the bulk manufacturing process.
FDA FOCUS
The FDA began to move rather quickly by using industry and FDA meetings
to bring their new message to the forefront. The FDA also increased the fre-
quency and number of overseas inspections of API facilities. It continued to
say that nothing was new in its position; however, this increased level of at-
tention from the FDA sent shock waves through the API industry.
The industry knew the FDA commissioner's position from the 1978
CGMP Preamble. However, the FDA's past public positions, lack of action,
and no public guidelines establishing which sections of the current drug
product GMP regulations applied to this industry all added to the confusion.
Suddenly, the industry was faced with a regulatory position that demanded
validation or shut down! While the industry had recognized the need for the
basic documentation and control requirements of the GMPs, it did not gen-
erally believe that full validation was a formal requirement. Ultimately, the
FDA agreed that if firms had active validation plans in effect, and were actu-
ally implementing them, no major regulatory action would be taken.
INDUSTRY REACTION
While the industry tried to determine what was happening on the regulatory
front, the FDA continued to state that nothing was new. The FDA's stated po-
sition was that they thought that industry was doing validation as part of
normal operations.
Of major concern to API producers was the fact that there existed a per-
ception within the FDA that dosage form and API validation were the same.
The industry decided to develop a validation document that would illustrate
the actual practices (CGMP) and provide the industry position on this matter.
Bulk producers were concerned that, without such information, the regula-
tory authorities would overreact and force the industry into practices that
were inappropriate and not germane.
API Validation: An Overview and Comparative Analysis 263
VALIDATION: A COMPARISON OF DOSAGE VERSUS APis

There is a difference! No one should be confused by the fact that there are
some very real differences between API and dosage form processing. For a
start, we would generally find that dosage form manufacturing involves what
would be considered relatively simple operations when compared with the
complexity of chemical processing. Some comparisons of dosage form and
API production are shown in Table 8.1.
A comparison of the two product forms can provide you with a greater
understanding of the industry's concern with the appropriate application of
regulatory requirements for validation. Given the very large capital invest-
ment costs, facility construction times, and development time for the chem-
istry, demanding that prospective validation of an API be performed in the
same way as a dosage form can be costly and inappropriate. In addition,
chemical reactions, extraction, and purification chemistry can be dynamic
and robust and can allow for greater flexibility than normally achievable in
routine dosage form processing.
The industry was concerned that the very large number of investigators
in the FDA would begin to demand systems and documentation that were
commonly observed at galenic manufacturers.
Fortunately, a number of FDA personnel recognized that significant dif-
ferences did exist between these industries and developed a guide to be used
by its personnel (FDA 1993). While the FDA guide recognized a number of dif-
ferences between the processes, the industry was still concerned that the com-
plexity of bulk chemical manufacturing would not be understood. As a result
of the heightened interest by FDA, in 1994, the then Pharmaceutical Manu-
facturers Association (now known as PhRMA, Pharmaceutical Research and
Manufacturer of America) developed and published a position paper on the
validation of bulk processes (Pharmaceutical Manufacturer's Association
Table 8.1 Dosage Form Manufacturing Versus Active Pharmaceutical Ingredients
Dosage Form Manufacturing Active Pharmaceutical Ingredients
Generally physical processing Complex chemistry

Mixing, drying, filling, packaging Usually involves synthesis, extraction,
crystallization
No purification Purification steps
Usually no by-products By-products likely
Process can be put in place relatively quickly Facility takes years to construct and start-up
Relatively low capital investment High capital costs
Degradation products possible Degradation products possible
1993). The paper identified key elements needed during the validation steps
and focused on important differences between galenics and bulk chemicals
(Table 8.2).
One key difference between galenic and bulk chemical (API) manufac-
turing is the dynamic nature of chemical processing. Due to the complexity of
the chemistry normally involved, it takes years of experience and real-time
development to fine-tune a chemical process.
Flexibility is a basic requirement of bulk chemical processing, so that
yields and subtle variations in chemical by-products can be controlled and ad-
dressed using the defined process. It is much more difficult to lock in a chem-
ical process than a galenic operation. Normal regulatory rigidity could be
disastrous and potentially hindering to modern chemical processing.
Flexibility applied to operating conditions allows chemists to address
chemical variations that may, from time to time, result in the formation or in-
troduction of new impurities or concentrations of known impurities that are
unexpected. A well-designed and well-developed process can adequately cope
with such occurrences. Therefore, the development phase of a chemical syn-
thesis becomes one of the most important phases in the life cycle of an API.
Unlike galenic validation, where prospective protocols form the foundation
of validation, the development report for bulk chemicals is the building block
critical to its validation.
DEVELOPMENT DOCUMENTS
Any new bulk chemical or API process validation should contain the key ele-
ments identified in Table 8.2. Probably the most important element is the de-
velopment document. It is during the development phase that the chemistry
is identified, side reactions described, by-products examined, and critical op-
erating conditions established. The purification steps are established that are
capable of producing a final compound that is of sufficient purity and that
possesses the physical characteristics to generate reliable dosage forms that
are reliable and consistent in their medical benefits.
Table 8.2 Key Validation Elements

Development documents
Technology transfer documents
Change control
Defined critical steps
Well-defined purification
Impurity profiles need to be identified and the chemistry and operating

conditions established so that the material is reproducibly generated. Appro-
priately validated analytical controls need to be developed during this phase
so that impurities can be monitored and detected. Key operating conditions
need to be identified to determine conditions that reduce the chance of im-
purity formation.
The purification phase of the synthesis needs to be robust so that impu-
rity removal down to acceptable levels is assured. While there exist many so-
phisticated analytical techniques for monitoring impurities, methods should
be developed that are easy, relatively fast, and yet capable of detecting the
formation of generally unexpected compounds. Thin layer chromatography
(TLC) is commonly used for such in-process control. One major benefit of
such testing is its ability to detect unexpected compounds. Through the use
of proper detection systems, compounds that could go undetected using high
performance liquid chromatography (HPLC) or gas chromatography (GC)
can be visualized as "origin" spots on a TLC plate. This, at least, provides the
chemist with a clue that something is present.
All of these important factors need to be determined, examined, and
documented in the development report. Although final validation of the ana-
lytical techniques may not take place until the bulk process is fixed in its
chemistry, properly validated procedures need to exist so that decisions about
the process design and engineering are based on reasonably accurate data.
This important document is then available for future use by chemists
and engineers for the scaling up and construction of full-scale bulk chemical
pharmaceutical processes. The development report is the foundation of a
sound bulk chemical validation.
Considerations During Development

It is completely reasonable not to conduct process validation during the de-
velopment phase before the final commercial process is fixed (ICH 2000). It is
unreasonable and unrealistic to expect the validation to be conducted while
process changes are being implemented as part of the developement phase.
This concept has been recognized by the current work being done by the In-
ternational Conference on Harmonisation. This group, which is a six-party
organization from the United States, the European Union, and Japan, is cur-
rently developing a guidance on CGMP covering API.
TECHNOLOGY TRANSFER
The next critical element in the validation process is the technology transfer
program and documentation. This is the step where laboratory-scale or pilot
plant-scale technology is transferred to full-scale operation. Using information
from the development phase:
Identified Parameters ~ Controlled Conditions ~ Monitored Results ~

Crude API ~ Purified API
The technology transfer document acts almost like a concurrent or prospec-

tive validation protocol and report. It is at this phase that all of the identified
parameters are initiated using the controlled conditions. The in-process con-
trols are utilized to monitor expected and unexpected results. Finally, the
crude compound is generated and the purification process tested to assure ex-
pected results at full scale. Any unexpected results are investigated, causes
identified, and process adjustments initiated.
All of these activities are again documented so that any future aberra-
tions can be reviewed based on experiences encountered during development
or technology transfer.
CHANGE CONTROL
Another key element in any validated process is the use of an effective change
control system. Without such as system, any process will go out of control over
time. Although such changes may result in acceptable product, it may be slowly
migrating toward an "out-of-control" state. A disaster is waiting to happen!
Proper change control procedures help assure that minor changes over
time do not add up to an unexpected quality event. A sound change control
system will review and contain some key elements. A number of important
fundamentals are included in Table 8.3.
Table 8.3 Important Change Control Elements

Independent review and approval-impact on validation.
Examine change against development and technology transfer documents.
Examine impact on impurity profiles.
Examine impact on yield.
Examine impact on regulatory filings.
Final step changes should evaluate stability impact.
Determine impact on physical attributes of final substance.
A sound change control system will always monitor the impact of

change on API material stability and regulatory filings. In addition, the review
and approval process should include an independent review by an organiza-
tional element independent from the responsible unit producing the mater-
ial. This independent review should normally take place under the authority
of an independent quality unit. The primary benefit of such a procedure is
that such a unit is capable of being objective in its evaluation of the requested
change and its impact on the current validation status.
Care needs to be exercised to assure that yield improvement changes,
which may result in significant economic benefits, do not contribute an in-
creased risk for new or greater levels of impurities. Such changes need to be
evaluated against the impurity profile of the biobatches evaluated during
drug safety and clinical testing.
Of particular importance is the effect of any change on the physical at-
tributes of the API substance. Simple changes can affect crystal structure, par-
ticle size, bulk density, or even the formation of polymorphs. Since all these
elements could have an important impact on the performance of final dosage
forms, these effects must be carefully examined. For many years, bulk chemi-
cal (API) manufacturers did not recognize the importance of these characteris-
tics. Most physical attributes were considered important from economic or
product handling perspectives only. However, it has become evident that
some of these characteristics play a more significant role in drug product per-
formance and drugbioavailabilty (FDA 1991).
DEFINED CRITICAL STEPS
The work done during the development phase results in the identification
and documentation of steps critical to the successful synthesis and purifica-
tion of the API. However, due to the complexity and dynamic nature of most
chemical syntheses, running experience will add additional important infor-
mation that can further identify critical steps or processing conditions.
A great deal of new information is gained during the start-up and initial
years of full-scale operations. Important information is usually identified dur-
ing the investigation of deviations encountered by the process. When prop-
erly documented, these data form the basis for the identification of additional
or revised critical operating parameters.
WELL-DEFINED PURIFICATION
One of the most significant differences between dosage forms and APis is the
fact that API chemicals have purification as part of their normal processing.
Unlike galenics, the process has the ability to improve the purity of the active
ingredient and reduce impurity levels. This one attribute of API allows
chemists to control variations by improving the purity profile of the final API
substance. This makes bulk or API manufacturing far more robust in its ability
to deal with variation than galenic production.
The purification process established during the development phase must
be monitored and enhanced as experience is gained by manufacturing
chemists running full-scale production. Again, a good change control system
together with an investigation system that carefully reviews deviations will
provide for enhancement of the originally developed purification steps.
TYPES OF VALIDATION
As with dosage form manufacturing, APis can undergo various forms of vali-
dation, such as the following classical types currently in use by industry:
• Retrospective
• Prospective
• Concurrent
Each of these validation approaches has its strengths and weaknesses. It is im-
portant to note that FDA personnel have generally taken a negative position
on the use of retrospective validation.
Retrospective Validation
While the FDA is not receptive to the use of retrospective validation, in the
case of "old," long-running bulk processes, it has had its place. Retrospective
data can be very helpful in identifying processes that are in control and can
be reliable in producing reproducible materials.
Retrospective data should be used to determine if a process needs further
development. The greatest problem in using retrospective data is to determine
whether any significant changes occurred during the life cycle of the process.
While such changes are the primary reason for regulatory resistance to the use
of retrospective validation, this alone should not invalidate its use. A process
that has reliable product history, showing no quality failures over a long period
of time, should be able to be retrospectively validated. The robust nature of
many processes, together with sound change control and investigation sys-
tems, should be able to undergo changes without reducing the assurance that
the process is reliable in consistently producing a quality product. After all,
isn't this what validation is all about? It is important to note that current
changes need to be prospectively or concurrently validated. Using retrospective
validation for such justification is inappropriate under current requirements.
Prospective validation is the process of choice by regulators. Under this ap-
proach, a predefined set of criteria is established, acceptance criteria are set,
and the process is run to assure that at least three consecutive lots will meet
these established limits. When this occurs, the process is said to be validated.
Concurrent Validation
Concurrent validation is essentially the same as prospective validation. How-
ever, as material is produced and each lot's performance against established
protocols is determined, product is not withheld until three consecutive lots
are produced. Validation is ongoing while production and distribution takes
place.
For new APis, the use of concurrent validation makes the greatest sense.
While an initial lot should always be produced under prospective validation
conditions, the rest of validation should be conducted within the scope of
concurrent validation. The primary reason for this position is that, as stated
earlier in this chapter, bulk chemical (API) manufacturing is more dynamic
and robust than most dosage form processes. Its chemistry has purification
that can address variations better than those found in galenic production,
and the actual development process is ongoing for years under full-scale pro-
duction. To expect a full-scale bulk chemical process to be fixed and locked in
is unrealistic and simplistic. The best approach is to apply concurrent valida-
tion techniques to such processes, so that improvements can be made and re-
alized, while improving economic and quality attributes.
Concurrent validation provides the manufacturer with flexibility for im-
provement while giving the regulatory authorities a chance to see that proper
CONTROL and change systems are established. This approach provides the
best of all worlds.
THE FUTURE HORIZON

Validation is a dynamic process. Although everyone wishes that perfect vali-
dation could be routinely achieved, only a fool believes this occurs on a regu-
lar basis. A high degree of assurance is just that, "A HIGH DEGREE OF
ASSURANCE!" It is not a guarantee of perfection. There are always factors that
contribute to an operation that can affect its success. The industry and regu-
lators will continue to learn and modify their processes for validation.
New areas of interest will continue to evolve. Industry and regulators
will continue to work toward relative perfection, never achieving it, but seek-
ing to approach it if economically feasible. Computer validation will grow in
importance as computer control systems become more than data loggers.

Cleaning validation will become a significant subject for the multipurpose
plants of the future.
No matter how hard we try, validation will never prevent deviations.
However, a well-validated facility will reduce variation and result in a more re-
producible product that can be produced within appropriate economic
boundaries-boundaries that are applied on a relatively uniform basis around
the world!
REFERENCES
FDA. 1991. Guide to inspection of bulk phannaceutical chemicals. Rockville, Md., USA:
FDA. 1993. Guide to the inspection of bulk phannaceutical chemicals. Rockville, Md., USA:
FR. 1978. Part 211-Current good manufacturing practice for finished pharmaceuti-
cals. Federal Register 43 (190), Book 2.
ICH. 2000. Draft guidance ICH Q7a Expert Work Group. Geneva, Switzerland. Interna-
tional Conference on Harmonisation.
Pharmaceutical Manufacturer's Association. 1993. Concepts for the process validation
of bulk pharmaceutical chemicals. Phann. Technol. (December): 32-40.
9
IMPURITIES IN DRUG
SUBSTANCES AND
DRUG PRODUCTS
Stephen R. Byrn
Joseph G. Stowell
Purdue University
West Lafayette, Indiana
Impurities in drug substances and drug products are reviewed in this chapter.
Impurities are among the most important quality issues in pharmaceuticals.
Obviously, the presence of impurities or contaminants can be a major safety
issue. It is the dear goal of the industry to minimize impurities whenever
possible.
Impurities are defined and described in a wide range of documents, in-
cluding the United States Pharmacopeia (USP) (USP 1999a), several guidances
and amended regulations from the Food and Drug Administration (FDA)
(Federal Register, january 12, 1999; June 28, 1999; November 23, 1999; De-
cember 3, 1999; FDA 1999a, 1999b), and several draft guidances (Federal Reg-
ister, january 5, 1999; january 21, 1999; June 28, 1999; October 1, 1999; FDA
1999b, 1999d, 1999e). The discussions in these various documents regarding
impurities are reviewed and defined in this chapter. The use and validation of
assays for impurities also are reviewed. Following this, an example of an im-
purity study is presented. This chapter provides an overview of the various is-
sues related to impurities.
As the science of analytical chemistry advances, driven by scientific
curiosity, the concepts of purity change. For example, high performance
liquid chromatography (HPLC) has greatly advanced our ability to detect
271
impurities. Consequently, drug substances previously thought to be pure are

shown to be impure. Even now, as techniques to resolve peaks improve and
detection limits decrease, more and more impurities are detected in drug sub-
stances and drug products previously thought to be pure. Since the concept of
quality is defined in terms of our ability to determine purity and fitness for
use, it is clear that the acceptable levels of impurities will decrease with time.
In addition, with the advance of science, concerns have arisen over compo-
nents not historically considered impurities. There is considerable interest in
controlling the levels of unwanted optical isomers and diastereomers in drug
substances and drug products. In recent years, different solid phases, includ-
ing polymorphs and hydrates, have also become a concern, especially since
these components can have different physical properties and different disso-
lution rates.
QUALITY
Quality is the totality of features and characteristics that bear on the ability of
a drug substance or drug product to satisfy fitness for use, which includes
safety, efficacy, and performance. Quality requires a strong system of controls
and specifications that serve to define in measurable ways the excellence of a
product. Quality cannot be tested into a product, but rather, it is a system that
controls everything that affects the product.
A TYPICAL USP MONOGRAPH
For USP substances, the USP monographs ensure quality. A USP monograph is
a highly abbreviated Drug Master File (DMF) and defines the specifications
and tests needed to list a substance as being USP compliant. In recent years,
the gap between the specifications required by the USP and those required
by the FDA in New Drug Applications (NDAs) has widened considerably.
Thus, the USP specifications should be viewed as a minimum requirement.
The USP monograph for digoxin drug substance active pharmaceutical ingre-
dient (API) involves the following methods and procedures for analysis of im-
purities (USP 1999e):
• USP gitoxin impurity standard
• Dissolve in chloroform:methanol (2:1) at 0.30 mg/mL
• Spot digoxin standard solution, gitoxin standard solution, and
the test solution on a reverse-phase (C18) thin layer chromatogra-
phy plate
• Develop using methanol:water (7:3)
Impurities in Drug Substances and Drug Products 273
• Visualize using chloramine T-trichloroacetic acid reagent spray

• Assay for digoxin concentration using reverse-phase (C18) HPLC
• Assay 95.0 to 101.0% on a dried basis
USP DESCRIPTIONS OF IMPURITIES

The USP describes impurities and foreign substances and also specifies tests
for impurities and foreign substances to limit such material to "unobjection-
able" amounts (USP 1999c, 1999d, 1999f, 1999g, 1999h). This is consistent
with the objectives of the USP to ensure the identity, strength, quality, and
purity of official articles.
Foreign Substances
It is impossible to include in each monograph tests for every possible impu-
rity, contaminant, or adulterant that might be present. Examples of foreign
substances are pesticides in plant-derived products or cyanide adulteration
by malicious intent. Thus, tests for cyanide are not included in every article
even though cyanide adulteration of pharmaceutical products was a major
problem a few years ago. Instead, current Good Manufacturing Practices
(cGMPs) are relied on to ensure that contamination or adulteration does not
occur.
Toxic Impurities
Toxic impurities have significant undesirable biological activity. Such impuri-
ties require individual identification and quantification. All impurities that
are toxic need to be identified.
Ordinary Impurities
Tests for ordinary impurities are defined in each monograph. Ordinary impu-
rities, according to the USP definition, can arise either from the synthetic
process or from degradation. Monographs generally contain a chromato-
graphic purity test coupled with a nonspecific assay for percentage purity, or a
chromatographic purity-indicating assay that serves as an assay for percent-
age purity. HPLC methods are becoming widely used for determining ordi-
nary impurities. Thin layer chromatography is another good method for
detecting ordinary impurities. However, this method does not generally have
the precision, accuracy, or limit of detection of HPLC. In some cases, specific
tests for a given impurity are included. Analytical methods for ordinary im-
purities must be validated as described in the USP.
Ordinary impurities, at the levels allowed, are not considered toxic and
are considered to be qualified based on clinical trials of the drug product.
However, as our knowledge of toxicology advances, it is important to realize
that materials previously considered safe might be redefined as toxic.
Purity of drug products is an important issue since degradation of the
drug substance when mixed with excipients often accelerates, in part because
of processing. If possible, an analytical method that detects impurities while
measuring percentage purity is most desirable. However, two different meth-
ods are used in many cases. These methods are made difficult by the need to
separate excipients from the drug substance. In some cases, the USP contains
specific limit tests for certain impurities.
Other Impurities
USP materials may be manufactured by a variety of routes and thus may con-
tain impurities that were not considered during validation of the monograph
tests or assay for impurities. Excluding organic volatile impurities (OVIs) and
solvents, the amount and identity of the new impurity is stated and labeled
under the heading "Other Impurities" in the certificate of analysis. Of course,
the other impurities must not be toxic. The presence of an unlabeled impurity
at 0.1 percent or greater is a variance from the USP standard. In addition, the
sum of other impurities combined with the monograph-listed impurities can-
not exceed 2.0 percent unless otherwise stated in the monograph.
Signal Impurities
Signal impurities are distinct from ordinary impurities in that they require in-
dividual identification and quantification using specific tests. For example,
diazotizable substances in thiazides are considered signal impurities.
Organic Volatile Impurities

OVIs are organic solvents that are present in the drug substance or drug prod-
uct and are introduced by the manufacturing process in essentially all cases.
OVIs include ethylene oxide, benzene, chloroform, dioxane, methylene chlo-
ride, and trichloroethylene. These OVIs are limited to the parts per million
(microgram per gram) range. Several methods are available for determination
of these impurities but the best method involves gas chromatography.
Concomitant Components
Concomitant components are components such as optical and geometrical
isomers and mixtures (e.g., conjugated estrogens). Concomitant components
are not considered impurities in the ordinary sense. However, the FDA has
raised considerable eoncern about optical isomers. In addition, major con-
cerns have arisen over polymorphs and solvates in the last few years, espe-
cially since these materials have different physical properties and can have
different dissolution rates.
ICH DOCUMENTS ON IMPURITIES

The International Conference on Harmonisation (ICH) guidelines section
Q3A addresses impurities in drug substances (Federal Register 1996; ICH
1996b) and section Q3B addresses impurities in new drug products (Federal
Register 1997a; ICH 1997). Three types of impurities are defined in this docu-
ment: organic impurities, inorganic impurities, and residual solvents. The
ICH document defines impurities as in the following paragraphs (emphasis
added).
Organic impurities may arise during the manufacturing process

and/or storage of the new drug substance. They may be iden-
tified or unidentified, volatile or nonvolatile, and include
• starting materials;
• by-products;
• intermediates;
• degradation products; and
• reagents, ligands, and catalysts.
Inorganic impurities may derive from the manufacturing

process. They are normally known and identified, and include
• reagents, ligands, and catalysts;

• heavy metals;
• inorganic salts; and
• other materials (e.g., filter aids, charcoal, etc.).
Solvents are organic or inorganic liquids used during the

manufacturing process. Since these are generally of known toxi-
city, the selection of appropriate controls is easily accomplished.
Excluded from this document are extraneous contam-
inants that should not occur in new drug substances and are
more appropriately addressed as Good Manufacturing Practice

(GMP) issues; polymorphic form, a solid state property of the
new drug substance; and enantiomeric impurities.
The ICH guidelines direct the submitter of regulatory documents to
summarize actual and potential impurities. The studies conducted to find
impurities should be summarized including intentional degradation stud-
ies and manufacturing batches. The structure of all impurities and degra-
dation products greater than 0.1 percent must be determined. All
analytical methods must be validated. (Approaches to validation will be
discussed later in this chapter.) In addition, differences in methods used
during development must be explained. This will provide the reviewer
with important background on impurities and the quality of the drug sub-
stance (API).
Impurity levels for all batches used for clinical trials should be reported.
This information will also provide the reviewer with background on impuri-
ties and drug substance (API) quality. This information will help to qualify all
impurities present in these batches.
Specifications
If toxic impurities are present, the specifications and the method to detect
them should be below their toxic limit. For organic impurities, the specifica-
tions should include
• each specified identified impurity,
• each specified unidentified impurity at or above 0.1 o/o,
• any unspecific impurity with a limit of not more than 0.1 o/o, and
• total impurities.
Specifications should also include limits for residual solvents (Federal
Register 1997a) and inorganic impurities.
Qualification of Impurities
Qualification is the process of "acquiring and evaluating data which estab-
lishes the biological safety of an individual impurity or a given impurity pro-
file at the level(s) specified" (ICH 1996b). The level of the impurity that has
been tested in safety studies and/or clinical studies is considered qualified. Im-
purities that are metabolites do not need further qualification. Qualification is
particularly important if there is evidence of adverse reactions in patients.
New impurities above the threshold level should be qualified in the same way
as existing impurities.
Figure 9.1 shows a decision tree from the ICH guidelines section Q6A
that guides the establishment of acceptance criteria for a specific impurity in
a new drug substance (Federal Register 1997b). This decision tree directs the de-
termination of the impurity level plus upper confidence level in relevant
batche~. It also directs determination of the upper limit after shelf life has ex-
pired. If either of these levels is greater than the qualified level, then a new
level needs to be set.
Figure 9.2 from the ICH guidelines section Q6A describes a procedure to
establish acceptance criteria for a degradation product (Federal Register 1997b).
As in Q6A Decision Tree 1, if the total level of impurities exceeds the qualified
level, then a new qualification level must be set.
Figure 9.1 Q6A Decision Tree 1 for Establishing Acceptance Criteria for a Specified
Impurity in a New Drug Substance (Federal Register 1997b)
Determine impurity level

in relevant batches 1
Estimate maximum
Determine mean + upper increase in impurity at
confidence limit for the retest using data from
impurity (let this = Al relevant accelerated and
long-term stability studies.
Determine maximum likely

Acceptance criterion = A level as: A + increase in
orB (as appropriate) degradation product at
appropriate storage
Acceptance criterion =
qualified level OR establish
new qualified level2
1 Relevant batches are those from development, pilot, and scale-up studies.
2 Refer to ICH Guidance on Impurities in New Drug Substances.
Definition: uper confidence limit= three times the standard deviation of batch analysis data
Figure 9.2 Q6A Decision Tree 2 for Establishing Acceptance Criteria for a Degrada-
tion Product in a New Drug Product (Federal Register 1997b)
NO Estimate maximum increase in degradate at

shelf life using data from relevant accelerated
and long-term stabilitv studies (let this =D)
Estimate maximum increase in Determine maximum likely level

degradate during manufacture from as drug substance acceptance
relevant batches 1 (let this = Cl criterion ICA or 8)2 + C + D1
Acceptance criterion = NO
maximum likely level
YES
Acceptance criterion = qualified level

OR establish new qualified level3
OR new storage conditions
1 Relevant batches are those from development, pilot, and scale-up studies.
2 Refer to Decision Tree 1
3 Refer to ICH Guidance on Impurities in New Drug Substances
Analytical Procedures for Degradation Products

or Drug-Excipient Reaction Products
Analytical methods should be validated to demonstrate that impurities are
not obscured by any other components present. Impurities should be sepa-
rated from both specified and unspecified degradation products. As part of
the validation, reference standards should be evaluated and characterized ac-
cording to their intended uses. The drug substance may be used to estimate
the levels of degradation products. A correction factor may be applied.
All materials observed during stability studies of the drug product

should be summarized. This summary should be based on degradation
pathways and laboratory studies. If any impurities are excluded because
they are not degradation products, the rationale for this exclusion should
be presented. If identification is not possible, then the reason for this
should be explained. This should be substantiated with extensive labora-
tory studies. Generally, degradation products below the indicated levels do
not need to be identified unless they are suspected of being unusually po-
tent or toxic.
Specification Limits for Degradation Products

or Drug-Excipient Reaction Products
Specifications for these products should be based on a combination of the fol-
lowing factors:
• Stability studies
• Knowledge of degradation pathways
• Product development studies
• Laboratory studies
Limits should be set for specified and unspecified degradation products
as well as total degradation products. Batch-to-batch variation in impurities
should be explained. Any new degradation products above the threshold
should be handled in the same way as any other impurity.
Impurities in Drug Products in Abbreviated

New Drug Applications (ANDAs)
This is a guidance that addresses only degradation products and reaction
products with excipients or reaction products with container/closure systems
(Federal Register 1999a; FDA 1999c).
Degradation products are divided into two classes: (1) specified degrada-
tion products that can be identified or unidentified and occur in all batches,
and (2) unspecified degradation products that do not appear in all batches.
Degradation products observed during stability studies for ANDAs should
be reported. In addition, laboratory studies should be summarized. If any impuri-
ties are excluded, the rationale for this exclusion is required. A validated method
is required for each study. Reference standards must be evaluated and controlled;
the origins of impurities that are not degradation products must be determined.
Acceptance criteria for impurities in ANDAs must be established and
should include specifications for degradation products expected to occur
during storage based on accelerated data and storage conditions. Require-

ments should be set for each specified degradation product, any unspecified
degradation products, and total degradation products. Any degradation
product that exceeds specified levels must be set. Of course, degradation
products suspected of causing adverse reaction in patients must be moni-
tored and identified.
Figure 9.3 shows a flowchart from the draft guidance on impurities in
drug substances (ANDAs) dated July 21, 1998 (Federal Register 1997b).
VALIDATION
The suitability of each validated method for its intended purpose must be
demonstrated (Federal Register 1995, 1997b, 1997d; ICH 1995; 1996a). Valida-
tion applies to the four most common types of analytical procedures:
1. identification tests,
2. quantitative test for content of impurities,
3. limit tests for control of impurities, and
4. quantitative tests of the active moiety in samples of drug sub-
stance or drug product (or other selected components in the drug
product).
Identification tests must ensure the identity of the analyte. These tests
are usually performed by comparison of the sample properties with a refer-
ence standard. The most common method involves infrared spectroscopy, but
chromatographic behavior and chemical reactivity also are used sometimes.
The USP allows dissolution and recrystallization as a means to eliminate
polymorphism from identification. This procedure sometimes produces
amorphous material that contains broad, featureless X-ray diffraction pat-
terns that may not ensure the absence of foreign substances. In addition, the
creation of impurities during this procedure cannot be ruled out. Finally, the
polymorph initially present may be crucial for stability or drug performance.
For all of these reasons, use of this method is discouraged. It is much better to
show identity between the drug substance and the reference standard directly.
Impurity tests can be either quantitative or limit. They must accurately re-
flect the purity of the sample. Of course, more extensive validation is required
for a quantitative test than for a limit test. Assay tests determine the level of the
analyte in a given sample. These tests provide quantitative measurement of the
major component. Assay tests for a drug product, a drug substance, other com-
ponents, and for dissolution tests must be performed in the same manner.
Validation of a method requires specificity, accuracy, precision, repeata-
bility, intermediate precision, reproducibility, limit of detection (LOD), limit
of quantitation (LOQ), linearity, and range where:
Figure 9.3 Decision Tree for the Qualification of Degradation Products (Generic
Products) (Federal Register 1999g; FDA 1999b)
Decrease DP level
below threshold Qualified
Decrease below Is the DP observed NO

I--~ in the RLD and at
threshold
a similar level?2
YES YES
Toxicity documented and

sufficient? 3
NO YES
• Compliance with a USP drug
product specification for an
identified DP?
Or significant metabolite?
Or literature justification?
Decrease below
threshold
~NO Qualified
• Is the DP observed in the
RLD and at a similar level?
~NO
NO
•If at a higher level, or a new
YES
DP is detected ... is it
qualified from the scientific
literature?
YES
Acceptable
Justification•
Qualified
Qualified
but not 505(iJ
1Best effort; not possible; 2 RT, peak heights/area spectral similarity; 3 Genetic Drug Pathway; 4 e.g., qualified by
QSAR
DP = drug product; RLD = reference listed drug; QSAR = quantitative structure activity relationship
• Specificity is the ability to assess the analyte in the presence of com-

ponents that are expected to be present including impurities,
degradants, matrices, and so forth. Specificity needs to be assured
for all identification tests, purity tests, and assays.
• Accuracy is the closeness of agreement between the accepted true
value and the value found. Accuracy requires the availability of a
reference standard or a method to calculate the true value.
• Precision is the degree of scatter between a series of measure-
ments obtained from multiple sampling of the same homoge-
neous sample.
• Repeatability is the precision under the same operating conditions
over a short interval of time.
• Intermediate precision is the variation within the same laboratory on
different days, with different analysts and different equipment.
• Reproducibility is the precision between laboratories.
• Limit of detection (LOD) is the lowest amount of analyte that can be
detected.
• Limit of quantitation (LOQ) is the lowest amount that can be quanti-
tated with suitable precision and accuracy. The quantitation limit is
often taken as three times the limit of detection.
• Linearity is the ability to obtain test results that are directly propor-
tional to concentration.
• Range is the interval between the upper and lower concentration
for which it has been demonstrated that the procedure has a suit-
able level of precision, accuracy, and linearity.
These measurements are made following the ICH guidelines in sections QZA
and QZB (Federal Register 1995, 1997b, 1997d; ICH 1995, 1996a).
Revalidation of the analytical methods is required if there are any
changes in the drug substance. Likewise, the methods must be revalidated if
the composition of the finished product is changed. Finally, any changes in
analytical procedures must be revalidated.
IMPURITY ISSUES RELATED TO MANUFACTURING,

PROCESSING, OR HOLDING DRUG SUBSTANCES (APis)
The guidance for manufacturing, processing, or holding APis was published

in March of 1998 (Federal Register 1998a). This guidance contains a number of
references to stability, which is reviewed in the following paragraphs.
Impurities can accumulate in equipment. For this reason, equipment

must be cleaned often enough to ensure that carryover of contaminants or
degradants does not adversely affect the impurity profile. This can be espe-
cially important for drying equipment in which the higher temperatures can
cause degradation.
Special care must be taken to ensure contamination does not occur. Con-
tamination can involve foreign chemicals or can be of a microbial nature.
Contamination can occur during production, sampling, packaging, repackag-
ing, storage, or transport. A famous case of contamination occurred when
containers for glycerol were contaminated with ethylene glycol and caused
the adulteration of a pediatric acetaminophen formulation. The deaths of a
large number of children in Haiti resulted.
Water purity is critical to the proper manufacture of some drugs. If im-
purities in the water affect the final API purity, they must then be monitored.
For example, if impurities from water used in the final wash or final crystal-
lization are present, then they must be controlled. Water can be treated con-
veniently by reverse osmosis, ultrafiltration, deionization, distillation, or a
combination of these techniques.
Process validation is a critical component of any cGMP procedure. Valida-
tion should embrace steps in the processing that are critical to purity and
quality. Thus, validation should monitor chemical purity and the impurity
profiles of the drug substances as well as its solvent content. Successful
process validations will confirm that the impurity profile is comparable with
that in the pivotal clinical trials and the pivotal toxicology studies.
Figure 9.4 shows the components of process validation as outlined by
Scott Reynolds, Merck and Co., at the FDA Site Specific Stability Meeting in
Figure 9.4 Elements of a Successful Process Validation (Reynolds 1999)

1999 (Reynolds 1999). Impurity measurements are critical for release tests,
raw materials, and possible in-process tests. It is very important to show that
the validated process is robust and unlikely to result in excessive impurities.
Development research is a critical component in process validation. De-
velopment research will identify the mechanism and rate of degradation and
predict degradation levels at expiration. Ultimately, development research
will allow the establishment of specifications. Stability of the drug substance
is evaluated during validation. Of course, understanding stability is critical to
the development of a validated process. Figure 9.5 summarizes the compo-
nents of stability testing during validation (Reynolds 1999).
The control of impurities during changes is critical to maintaining qual-
ity. Changes to improve yields should be evaluated carefully to determine
whether these result in increased impurity levels. The resulting impurity pro-
file should be comparable with the impurity profile of the API batches used in
drug safety and for clinical trials. Process changes should also be evaluated to
ensure they do not have an adverse impact on analytical methods because of
increased interference caused by new or higher levels of impurities or by-
products. If these methods are affected, then they should be modified as nec-
essary. Dosage-form manufacturers should be notified of any changes in the
manufacturing process.
Drug substance batches that have excessive impurities must be re-
processed or discarded. Any reprocessing must follow established methods and
procedures. Appropriate tests should be conducted to make sure the reprocess-
ing does not affect other critical quality attributes of the drug substance.
Figure 9.5 Components of Stability Evaluation During Process Validation (Reynolds

1999)
ENANTIOMERS AS IMPURITIES
Enantiomers, or optical isomers of the drug substance (API), have the same el-
emental analysis as the drug substance. However, the ICH guidelines section
Q6A point out that for chiral drug substance developed as a single enan-
tiomer, the other enantiomer "should be considered in the same manner as
for other impurities" (Federal Register 1997b). Furthermore, the ICH guidelines
section Q6A also points out that technical limitations may prevent the appli-
cation of the 0.1 percent limit. Nevertheless, the ICH guidelines section Q6A
requires assurance of control and appropriate testing with suitable justifica-
tion. A chiral HPLC assay is preferred to an achiral assay and methods such as
optical rotation.
POLYMORPHS AS UNWANTED COMPONENTS
Polymorphs, like enantiomers, have the same elemental analysis as the drug
substance. Solvates and hydrates have different elemental analyses because of
the incorporation of solvent or water. The solvent will be detected as an or-
ganic volatile impurity. Water will be detected as part of the water test. How-
ever, polymorph solvates and hydrates are sometimes unwanted components
of the drug substance. In particular, these alternative solid forms can have dif-
ferent dissolution rates and stability from the parent drug substance. In such
cases, these solid forms need to be controlled.
The need for control is most clearly outlined in the ICH Q6A docu-
ment, which describes methods to set specifications for new drug substances.
Figures 9.6 and 9.7 show the decision trees in ICH Q6A related to setting
specifications for polymorphs. It requires acceptance criteria if the poly-
morph affects safety, efficacy, or performance. In fact, many major compa-
nies are setting acceptance criteria for polymorphs because of the difficulty
of proving that the solid form does not affect safety, efficacy, or perfor-
mance. In many cases, it is easier and faster to set criteria than it is to prove
a lack of effect.
Although the USP contains a procedure to negate the influence of poly-
morphs or solvates on an identity test, some monographs contain controls on
polymorphs. In particular, the carbamazepine USP monograph contains the
following tests for drug substance (USP 1999b):
• Packaging and storage
• USP reference standards <11>
• Identification, Infrared Absorption <197M>
• X-ray diffraction <941>
• Acidity
• Alkalinity
• Loss on drying <731>
• Residue on ignition <281>
• Chloride <221>
• Heavy metals, Method II <231>
Figure 9.6 Q6A Decision Tree 4 for Investigating the Need to Set Acceptance Crite-
ria for Polymorphism in Drug Substances and Drug Products (Federal Register
1997b)
Drug Substance
r-:l
U Conduct polyroorphism screen
on drug substance NO FURTHER ACTION
YES
Characterize the fonn:

e.g.. X-ray powder diffraction
DSCfTherrooanalysis GOT00
Microscopy
Spectroscopy
NO
NO FURTHER TEST OR
ACCEPTANCE CRITERION
FOR DRUG SUBSTANCE
NO
SET ACCEPTANCE CRITERION

FOR POLYMORPH CONTENT 1-----+ GOT00
IN DRUG SUBSTANCE Figure 9.6 continued as
~--------------~ Figure 9. 7 on next page.
Figure 9. 7 Q6A Decision Tree 4 for Investigating the Need to Set Acceptance Cri-
teria for Polymorphism in Drug Substances and Drug Products (Federal Register
1997b)
Continued from Figure 9.6 Drug Product - Solid Dosage Form or Liquid Containing
on previous page. Undissolved Drug Substance
N.B.: Undertake the following process only if technically possible
to measure polymorph content in the drug product.
YES Establish acceptance criteria

for the relevant performance
test(s).
No need to set acceptance

cnteria for polymorph content
in drug product.
Establ1sh acceptance cnteria

that are cons1stent with
safety and efficacy.
• Chromatographic purity
• Organic volatile impurities, Method V <467>
• Assay
The X-ray diffraction test ensures the polymorph purity of the carbamazepine
drug substance.
BACPAC
BACPAC (Bulk Active Chemical Postapproval Changes) is an initiative aimed
at developing guidances that allow postapproval changes in drug substance
synthesis for site, scale, and equipment changes. BACPAC is divided into two
parts. BACPAC I deals with changes in the final intermediate and steps lead-
ing up to the final intermediate, whereas BACPAC II (not yet finalized) will
deal with changes in the API. The final intermediate is defined as the last
compound synthesized before the reaction that produces the drug substance
(Federal Register 1998b; FDJ\_1998). The final step forming the new drug sub-
stance must involve covalent bond formation; ionic bond formation (i.e.,
making the salt of a compound) does not qualify. Consequently, when the
drug substance is a salt, the precursors of the organic moiety used to make the
salt should be considered the final intermediate rather than the organic moi-
ety itself. A central tenet for the guidance is that any change can be assessed
by comparing pre- and postchange material. The prechange material is de-
fined by 10 historical lots (the average plus 3 times the standard deviation);
the postchange material is defined by 3 lots (the average plus 3 times the stan-
dard deviation). Three criteria determine equivalence of the impurity profiles
of the pre- and postchange material:
1. If the postchange material shows no new impurity at or above
0.1 percent
2. If the existing impurities and residual solvents are at or below the
upper statistical limit of the historical data
3. If the total impurities are at or below the upper statistical limit
If all three of these criteria are met, the postchange material is equivalent to
the prechange material and the appropriate relaxed reporting requirements
apply. The physical properties of the API are generally unaffected by the phys-
ical properties of the final intermediate. The particle-size distribution profile
and the solid form of the API are considered critical and other physical prop-
erties may also be important in some cases. However, physical properties of
the API need not be evaluated if equivalency in the impurity profile can be
demonstrated for the final intermediate.
For a BACPAC I example, consider a case involving the simultaneous im-
plementation of a site change, a scale change, and a process change of an in-
termediate produced in a four-step process (Moss 1999). The site change was
from one building to another on the same campus. The scale change was an
increase from 300 to 500 gal. The process change involved eliminating water
washes in the Stage 3 intermediate. In this example, the most stringent re-
quirements apply, which is the filing of a Changes Being Effected (CBE) sup-
plement. The combined data package needs to contain a description of the
changes (i.e., the site, scale, and process changes) along with a comparison of
impurity profiles before and after the changes for the final intermediate that
is produced in Stage 4 of the process (see Tables 9.1 and 9.2).
Table 9.1 describes the impurity profile comparisons for the Stage 3 ma-
terial. It is clear that the postchange material contains more impurities than
prechange material. For this reason the purity of the intermediate at Stage 4,
the final step, was assessed to determine whether these impurities were carried
Table 9.1 Comparison of Impurities at Stage 3 of the Process for Prechange and
Postchange Materials
Impurity Specification Upper Statistical Limit Maximum Result
in an Existing Building in a New Building
1 Report result 0.14 1.8

3 0.14 0.27
Solvent A 0.5%wjw 0.11 0.17
Source: Moss 1999
Table 9.2 Comparison of Impurities at Stage 4 of the Process for Prechange and
Postchange Materials
Impurity Specification Upper Statistical Limit Maximum Result
in an Existing Building in a New Building

7 0.2% 0.1 0.0
Total Impurities Report result 1.5 0.7
Source: Moss 1999
through. Table 9.2 shows the results of this comparison. It is clear that at
Stage 4 the materials of the two processes are equivalent. Thus, the change
was filed using the CBE filing mechanism. The physical properties of the drug
substance pre- and postchange were also compared and shown to be equiva-
lent, although the analysis was not necessary since the impurity profiles of the
pre- and postchange Stage 4 material (the final intermediate) are equivalent.
SUMMARY AND CONCLUSION
This chapter has reviewed impurities in a broad range of pharmaceutical situ-

ations. Impurities are extensively addressed in the USP, in which numerous
terms are defined. In FDA documents, impurities are defined as organic impu-
rities, inorganic impurities, and solvents. This review also addresses specifica-
tions for impurities and qualification of impurities as well as listing the
definition of key terms. Validation is briefly reviewed since all impurity assays
must be validated. The role of impurities in cGMP and process validation is
also summarized. The concept that enantiomers and polymorphs can be
viewed as impurities is addressed. This review concludes with a discussion of

how impurities are viewed in the BACPAC document. Overall, the broad ap-
plication of concepts related to impurities is summarized and addressed.
REFERENCES
FDA. 1998. Guidance for industry. BACPAC I: Intermediates in drug substance synthesis.
Bulk active postapproval changes: Chemistry, manufacturing, and controls documenta-
tion. Draft guidance. Rockville, Md., USA: Center for Veterinary Medidne.
FDA. 1999a. Guidance for industry. Changes to an approved NDA or ANDA. Rockville, Md.,
USA: Center for Drug Evaluation and Research.
FDA. 1999b. Guidance for industry. ANDAs: Impurities in drug substances. Rockville, Md.,
FDA. 1999c. Guidance for industry. ANDAs: Impurities in drug products. Draft guidance.
Rockville, Md., USA: Center for Drug Evaluation and Research.
FDA. 1999d. Guidance for industry. NDAs: Impurities in drug substances. Draft guidance.
FDA. 1999e. Guidance for industry. Chemistry, manufacturing and controls changes to an
approved NADA or ANADA. Draft guidance. Rockville, Md., USA: Center for Veteri-
nary Medicine.
Federal Register. 1995. Guideline on validation of analytical procedures: definitions and ter-
minology. Federal Register 60 (40, 1 March 1995):11259-11262.
Federal Register. 1996. Guidelines on impurities in new drug substances. Federal Register 61
(3, 4 January 1996):371-376.
Federal Register. 1997a. Draft guideline on impurities: Residual solvents. Federal Register 62
(85, 2 May 1997):24301-24309.
Federal Register. 1997b. Draft guidance on specifications: Test procedures and acceptance cri-
teria for new drug substances and new drug products: Chemical substances. Federal Reg-
ister 62 (227, 25 November 1997):62889-62910.
Federal Register. 1997c. Guidelines on impurities in new drug products. Federal Register 62
(96, 19 May 1997):27453-27461.
Federal Register. 1997d. Guideline on the validation of analytical procedures: Methodology.
Federal Register 62 (96, 19 May 1997):27463-27467.
Federal Register. 1998a. Draft guidance for industry on manufacturing, processing, or
holding active pharmaceutical ingredients. Federal Register 63 (74, 17 April 1998):
19267-19268.
Federal Register. 1998b. Draft guidance for industry on PACPAC I: Intermediates in drug syn-
thesis; bulk actives postapproval changes: Chemistry, manufacturing, and controls docu-
mentation. Federal Register 63 (229, 30 November 1998):65793-65794.
Federal Register. 1999a. Draft guidance for industry on ANDAs: Impurities in drug products.
Federal Register 64 (2, 5 january 1999):516.
Federal Register. 1999b. 21 CFR Parts 172, 173, and 184: Foods and drugs, technical
amendments. Federal Register 64 (7, 12 january 1999):1758-1761.
Federal Register. 1999c. Draft guidance for industry on NDAs: Impurities in drug substances.
Federal Register 64 (13, 21 january 1999):3303.
Federal Register. 1999d. 21 CFR Parts 5, 206, 250, 314, 600, and 601: Supplements and
other changes to an approved application. Federal Register 64 (123, 28 june
1999):34608-34625.
Federal Register. 1999e. Draft guidance for industry on changes in an approved NDA or
ANDA. Federal Register 64 (123, 28 june 1999):34660-34661.
Federal Register. 1999f. Guidance for industry on changes to an approved NDA or ANDA.
Federal Register 64 (225, 23 November 1999):65716-65717.
Federal Register. 1999g. Guidance for industry on ANDAs: Impurities in drug substances.
Federal Register 64 (232, 3 December 1999):67917-67918.
ICH 1995. Guideline for industry. Q2A: Text of validation of analytical procedures.
ICH 1996a. Guideline for industry. Q2B: Validation of analytical procedures: Methodology.
ICH 1996b. Guideline for industry. Q3A: Impurities in new drug substances. Rockville, Md.,
ICH 1997. Guideline for industry. Q3B: Impurities in new drug products. Rockville, Md.,
Moss, A. 1999. Unpublished results. Research Triangle Park, N.C., USA: Glaxo Wellcome.
Reynolds, S. 1999. Presented at the Advisory Committee for Pharmaceutical Science
Site-Specific Stability Subcommittee. Rockville, Md., USA: Center for Drug Evalua-
tion and Research.
United States Pharmacopeia, 24th ed. 1999a. Rockville, Md., USA: U.S. Pharmacopeial
Convention.
USP. 1999b. Carbamezapine. In United States Pharmacopeia, 24th ed. Rockville, Md.,
USA: U.S. Pharmacopeial Convention.
USP. 1999c. Chemical tests <466>. In United States Pharmacopeia, 24th ed. Rockville,
Md., USA: U.S. Pharmacopeial Convention.
USP. 1999d. Chemical tests <467> Organic volatile impurities. In United States Phar-
macopeia, 24th ed. Rockville, Md., USA: U.S. Pharmacopeial Convention.
USP. 1999e. Digoxin. In United States Pharmacopeia, 24th ed. Rockville, Md., USA: U.S.
Pharmacopeial Convention.
USP. 1999f. General information <1086> Impurities in official articles. In United States
Pharmacopeia, 24th ed. Rockville, Md., USA: U.S. Pharmacopeial Convention.
USP. 1999g. General notices: Foreign substances and impurities. In United States Phar-
macopeia, 24th ed. Rockville, Md., USA: U.S. Pharmacopeia! Convention.
USP. 1999h. Preface: Impurities. In United States Pharmacopeia, 24th ed. Rockville, Md.,
USA: U.S. Pharmacopeia! Convention.
10
INVESTIGATING
PROCESS DEVIATIONS
Frank J. Golden
Glaxo Wellcome, Inc.
Zebulon, North Carolina
Active pharmaceutical ingredients (APis) are drugs as defined by the Food,

Drug, and Cosmetic (FD&C) Act. As such the United States Food and Drug Ad-
ministration (FDA) requires that they be manufactured within current Good
Manufacturing Practices (cGMPs). Section 501(a)(2)(b) of the FD&C Act states
"A drug shall be deemed to be adulterated if ... the methods used in, or the
controls used for its manufacture, processing, packing or holding do not con-
form to or are not operated or administered in conformity with current good
manufacturing practice to assure that such drug meets the requirements of
this Act."
The investigation of process deviations is one of the requirements of
cGMPs. Section 211.192 of the cGMP for finished pharmaceuticals requires
that any unexplained discrepancy be investigated. A compliance controversy.
has existed for some time as to what part of these cGMPs in Code of Federal
Regulations (CFR) Title 21 Parts 210 and 211 applies to APis. The FDA issued
the Bulk Pharmaceutical Chemical Guide in 1984 to clarify its position and de-
fine the steps in which full cGMP compliance applies. Most recently (March
1998) a draft guidance, Manufacturing, Processing, or Holding Active Pharmaceu-
tical Ingredients, was issued. This document states that full cGMP compliance
is needed from the use of starting materials. Additional government and in-
dustry guidances have been published dealing with the same subject.
This chapter examines the current regulatory gui9ances relative to API
manufacture, including a review of recent FDA warning letters, to determine
293
the extent to which the FDA considers the cGMPs to apply to APis. It also
includes an explanation of various methods for conducting investigations
into process deviations. At the conclusion of the chapter, examples of process
deviation investigations are provided.
PROCESS DEVIATIONS
Process deviations are defined as any operational nonconformity. This differs
from out-of-specification (OOS) situations, in which a nonconformance
event is noted by the result of a physical, chemical, or biological test in
which the sample did not meet the expected results. OOS situations (dis-
cussed in another chapter) already provide the focus when analytical results
do not meet predetermined limits or expectations. The FDA has made its
opinion known relative to OOS situations by court cases (U.S. v. Barr), pro-
posed GMP revision, and guidance documents. Many of the concepts ex-
pressed in these publications can be used when investigating process
deviations.
Process deviations, also called departures or excursions from approved
conditions or procedures, include product contamination when someone no-
tices the contamination in the course of an operation (e.g., leaking pipe) or
any operational issues in which a measured parameter such as temperature,
time, pressure, vacuum, pH, etc. does not meet its previously approved limits.
A process deviation is any excursion from the previously approved manufac-
turing step. Therefore, if a temperature is exceeded, a mixing time is abbrevi-
ated, an ingredient is added in the wrong manner, or a yield limit is exceeded,
then a process deviation exists.
Process deviations can occur during any step in the manufacture of APis.
Following the FDA's guidance, any process deviations, regardless of whether
they occur in a validated step, need to be investigated. This is in contrast to
the guidance provided in the FDA's Manufacture, Processing or Holding of Active
Phannaceutical Ingredients which states that only "critical" steps need be vali-
dated (FDA March 1998). However, this qualification does not apply to
process deviations, and as such all process deviations require investigation.
The depth of the investigation may be impacted by the level of the step in the
API process.
The challenge for process deviations is to determine the cause, extent,
and impact of the deviation. The way one detects a deviation is by comparing
the preapproved methods or steps with what was actually done. Unlike OOS
cases, there may not be a test result that indicates the deviation.
Investigating Process Deviations 295
REGULATORY CONSIDERATIONS
To further illustrate the point that the FDA considers APis to be drugs and that
APis need to be manufactured under GMPs, a number of excerpted FDA warning
letters are listed below. A warning letter is correspondence from the FDA advis-
ing a company that its actions are in violation of the FD&C Act. The following
citations were found through a search of the FDA warning letter Web page.
• No distinction is made between bulk drug substances and fin-
ished pharmaceuticals, and failure of either to comply with
cGMP constitutes a failure to comply with the requirements of
the Act
• Although the GMP regulations under Title 21 ... , Parts 210 and
211, are used as guidelines in the API industry, Section 501(a)(2)(B)
of the Act requires that all drugs be manufactured ... in accordance
with cGMPs. Failure to comply with cGMPs constitutes failure to
comply with ... the Act.
• No formal system existed to assure that changes in manufacturing
processes were drafted, reviewed and approved by appropriate orga-
nizational units and reviewed and approved by the Quality unit.
• The Quality Control Unit failed to:
~ Properly exercise the authority and responsibility for rejecting

non-conformance ... batches
~ Conduct an investigation as to the cause of the failing batch
~ Review and approve the use of reprocessing procedure for a
finished active pharmaceutical ingredient
~ Assure that a reprocessing step is validated and will produce
the same quality product conforming with all established
standards, specification, and characteristics.
• This investigation should, at a minimum, evaluate the impact of

the failure on the lot itself and on other lots of the same product or
similar product. The investigation should also address procedures
to prevent future failures
• XX batches are reworked without data to demonstrate the procedures
used will consistently yield product that conforms to specifications.
For example, XX, failed to meet solubility and sulphate ash specifica-
tion, due to excessive inorganic salt levels. The lot was reworked XX
times but failed solubility and sulphate ash specifications.
• FDA expects to see conclusive results of detailed investigations to
justify reworking or corrective actions to demonstrate that you
understand and control the various variable involved to assure that

all specifications are consistently met.
• Failure of the quality control unit ... to assure ... that all discrep-
ancies have been fully investigated
The Bulk Pharmaceutical Chemical [BPC] Guide was published in 1984 and
is still the current approved guide, covering both active and inactive ingredi-
ents. The guide defines the step in the process at which the active drug moi-
ety is separable from the rest of the process as the point where cGMPs apply.
When BPCs are reprocessed, written documentation is required covering the
reason for failure, procedures involved in reprocessing, and changes made to
eliminate recurrence of the problem. Final testing of the reprocessed BPC is
not enough. Reworked BPCs need to be equivalent to acceptable BPCs. Little
difference is made between reprocessing and reworking in this guidance.
The latest version of the draft guidance for industry-Manufacturing, Pro-
cessing, or Holding Active Pharmaceutical Ingredients-was issued in March 1998.
Significant changes were made in defining reprocessing and reworking. Repro-
cessing is defined as a repeat of a previous step. Reworking is defined as using a
different step. The importance of this is that reprocessing may occur without
a regulatory filing, whereas a rework of an API may require such a filing.
This API guidance requires investigations for out-of-limit yields, failure
of a batch to meet specifications, or any OOS test results. The investigation
record needs to include the reason for investigation; a summary of the inves-
tigation conducted, including all laboratory tests and results; the conclusion
and corrective action taken regarding batches associated with the failure; and
the signatures of the persons responsible for approving the record of the in-
vestigation and dates of signatures.
The Bulk Actives Postapproval Changes: Chemistry, Manufacturing, and Con-
trols documentation draft guidance was last issued in November 1998. This
document discusses, in part, the way in which industry can evaluate the
equivalency of changes to processes.
The Federal Register dated May 3, 1996, contained proposed amendments
to 21 CFR 211.192 relative to investigations of process deviations. These
changes specified that a thorough investigation be conducted of any unex-
plained discrepancy including a lot's failure to meet specifications and ex-
tending the investigation to associated batches.
The investigation must attempt to identify the cause of the failure, in-
clude criteria for extending (or not) the investigation to other batches, andre-
view and evaluation by quality assurance (QA) with criteria for approval or
rejection. Other items required include the reason for, description of, and re-
sults of the investigation; justification for excluding any data; retest data to
show conformance to specifications; conclusion and actions for all associated
batches and products; signatures of persons approving and dispositioning
batches; and dates of signatures.
PROCESS DEVIATION PRINCIPLES
The reason for performing process deviation investigation is twofold. The

first part of the reason is to substantiate that the lot or lots in question are ac-
ceptable. The second is to improve the process to prevent recurrence of the
deviation.
The cGMPs require procedures and manufacturing master records of suf-
ficient detail. In the FDA's view, API manufacturers should have established
procedures that, if followed, would produce a drug that meets all specifica-
tions. After-the-fact testing to determine acceptance is not enough. Therefore,
if any of the procedures or master formulas are violated then a process devia-
tion has occurred. This can be determined by the operator performing the
step, the person checking the step, an internal audit of the process, or in the
batch record review. GMPs require that there should be sufficient checking
points that allow for determination of compliance.
Once a deviation is detected the essential action is to identify the cause
of the procedural departure. If the assignable cause cannot be determined
then the process adequacy and validation can be questioned. If a manufac-
turer has determined the adequacy of its API process then it will know what
causes the problems. Without that cause the entire process is suspect. Causa-
tion can come from many areas such as human error involving employee
training or discipline, and equipment or facility malfunction.
The following sections present areas to cover during process deviation
investigation.
Problem Description
There must be a clearly stated problem so the investigation can be organized.
For example, if a temperature in a particular step was exceeded then the sub-
sequent investigation can concentrate on the effects of that excursion. If the
problem is not clearly stated then resources might be expended on issues that
do not impact the problem.
Classification of Deviation
At this point it is worthwhile to classify the deviation. Only a few general
categories would be used, such as process, equipment, component, or em-
ployee. These classifications will be useful for trend analysis to determine if
there is a need for a more serious fix. Keeping the classification types to a
small number will allow an easier review in a later trend analysis. Remember
that any computer system used for a cGMP compliance purpose requires
validation.
Examination of Data Available

In any problem investigation it is important to determine what is known and
what is not. Therefore, a timely review of the deviation should include ana-
lytical data, batch records, equipment logs, training records, development
data, and regulatory requirements. From the information learned at this step
one can determine what other information may be helpful before potential
information is lost; e.g., campaign changes, equipment dismantling, or em-
ployee severance. At this point an evaluation of the deviation is needed to de-
termine if any further work can exonerate the batch. For example, if nonfood
grade oil has spilled into a batch there is probably no way to remove the ma-
terial and demonstrate that removal. That batch will need to be rejected and
the investigation will focus on the cause and how to prevent it from happen-
ing again.
Review Procedures Utilized

What procedures were being followed when the deviation occurred? Even
though there may be a batch record for the employee to follow, the question is
whether the employee followed it or whether an unofficial method was used.
This can be determined through interviews with the employees involved, a re-
view of training records, or an examination of the work area to determine the
extent to which modified instructions are used, such as "sticky" notes or hand-
written modifications to procedures. Obviously, it is essential to determine the
exact deviation or the investigation will be skewed in the wrong direction.
Materials Used
Are the materials used the ones designed for this stage of the process? Different
materials might yield different results. Most companies require raw materials
to go through an acceptance by QA, but what about other production materi-
als like filters or filter aids (e.g., charcoal)? Is there an opportunity for an em-
ployee to choose what is needed? What kind of documentation or traceability
system is there to show exactly what material was used? If reused materials
such as solvents are used, is there a way to ensure that they are of a particular
quality, or a way to determine how long they have been used? If a material re-
quires some preparation before its use, are there records that document this?
Suitability of Facilities
Some API manufacturing processes can be done outside, in open nonwalled
buildings, or in very controlled environments. The nature of the facilities
needed depends on the step involved in the process and what contaminants
need to be excluded from a product. If a facility has been subjected to corro-

sive agents and rust is found during the operation, it is not hard to find the
cause of this problem. An examination of the area where the deviation oc-
curred should be done to determine if the controls needed were in place dur-
ing the manufacture of the product.
Suitability of Equipment
What is the calibration and/or preventive maintenance (PM) history for a par-
ticular piece of equipment involved in an investigation? The equipment log-
books required by the cGMPs can serve as fast methods of determining that
history. Missed calibration schedules or out-of-calibration reports associated
with a piece of equipment could cause performance issues. Is the PM adequate
for the equipment?
Compare the PM with the equipment manufacturer's manual and de-
termine if they are equivalent. If not, the API manufacturer should have a
way to ensure that the equipment is being maintained adequately. Some-
times equipment is old or was bought through other agents and may no
longer have an operations manual. Then one can compare the equipment
used with similar equipment for which a manual is available or contact the
equipment manufacturer for guidance. Is the equipment in suitable condi-
tion? Look for evidence of tape or wire or any other informal mechanism of
keeping equipment running. If such evidence is present, the manner in
which the equipment operates could be affected. The cGMPs require equip-
ment to be suitable for intended use. Ensure that the correct equipment is
used both in size and makeup. A larger reactor may have an effect on a
process designed for a smaller vessel. Some processes require glass-lined reac-
tors and can be affected if not processed that way. The batch record should
document the equipment used in the process, so this determination should
be fairly simple.
Employee Training
When a deviation occurs in which an operator failed to follow the prescribed
parameters, it is necessary to determine if that employee's training was ade-
quate. Many companies use these deviations and do trend analysis to deter-
mine where they need to focus the training. The manufacture of APis takes
some very unique skills, which can involve the handling of very toxic materi-
als and require significant controls of the operation. Employees may need
more than just Standard Operating Procedures (SOPs) or cGMP training to do
their jobs. Adequacy of training is somewhat subjective in an environment
where there are few constants and employees must improvise to do their jobs.
Therefore, the adequacy of training does not focus just on the employee but
on the training system as a whole. Even in the best situation there can be em-
ployees who are either unwilling or unable to do the job correctly. This situa-
tion could require the API manufacturer to take some disciplinary action.
Extent of Deviation
The event that is being investigated was probably found during the manufac-
turing of one batch. However, most APis are made in groups of batches (cam-
paigns}, and companies use similar equipment. So how does this deviation
affect other batches? Expand your review to other products or manufacturing
trains. You may also want to know how often a particular deviation has oc-
curred. This may affect your judgment regarding what action to take. A devi-
ation database is helpful here so you can search for similar problems.
Validation Impact
According to the current API draft guidance all critical steps in the manufac-
ture of an API need to be validated. Therefore, the API manufacturer has pre-
viously determined that the process employed will yield a product of
consistent quality. However, the deviation has changed the process. An evalu-
ation needs to be performed to determine if the deviant process is equivalent
to the validated process. For noncritical processes and other nonvalidated
processes the deviant batch can be compared with historical production.
Equivalency
The tool best suited to determine variation in different populations is statis-
tics. The deviation lot is different from the validation lot in that something
was changed in the deviation lot. This difference could lead to variability in
the product, which may not be of the same quality as the validation or his-
torical batches. Techniques such as process capability and relative standard
deviation are available for determining the equivalency.
Testing Required
Depending on the deviation encountered, the testing to show adequacy will
vary. Safety testing may be needed if low levels of a particulate are found. In
most cases full assay tests will be required to determine that the deviation
batch meets the specifications. These tests are basically experiments designed
to prove the hypothesis that the deviation had no impact on the product.
Therefore, appropriate acceptance criteria need to be established and the null
hypothesis accepted, which could have significant consequences for the

batch and associated batches. If there is a controversial test, it may be worth-
while to perform it early in the investigation to determine whether to pro-
ceed. There also could be a deviation so significant, such as contamination of
the API with nonfood grade grease, that it can't be tested to a sufficient level,
which probably will lead to rejection of the batch.
Regulatory Impact
Since most APis are involved with some regulatory submission, the process
deviation must be evaluated before any action is taken. Reprocessing is gener-
ally permissible, but reworking a product may require a regulatory filing. As
regulatory agencies harmonize it is important that all submissions are
checked to ensure compliance in the various markets. However, even an ap-
proved rework procedure can pose questions for a validated process if used
too often.
Results of Investigation
After the investigation is concluded, the results need to be documented in an
objective format. Reference needs to be given to information sources. Some-
times the sources can be included with the results; however, for large amounts
of information it may be easier just to reference it, as long as the information
can be found at a later date. Report what is known and what the impact of the
results mean. Summarize results for easy review.
Corrective Action
The action taken to correct the deviation needs to be listed. Corrective action
corrects the deviation and is focused on the deviant batch. When followed,
the action will cause the batch to be acceptable.
Preventive Actions
Preventive action is taken to prevent the deviation from recurring. This often
requires some future activity such as training, new equipment purchase, or
change to operations. A follow-up system needs to be established to ensure
that future actions are completed. The use of a tracking database can help to
ensure actions are taken.
Conclusions
The conclusion is generally a short statement indicating what the deviation
was, a summary of the results of the investigation, the impact on other lots,
and whether the deviant batch can be accepted or rejected.
Documentation
In a regulated environment such as API manufacture, the documentation is
very important. Its purpose is to collect all the available information that
shows the deviant lot is acceptable. It also allows for a later review to deter-
mine if there are adverse trends. Documentation needs to be properly filed so
that it can be found quickly in the event of a regulatory inspection.
Signatures and Approvals

A variety of disciplines are usually involved in a deviation investigation. Re-
sponsible persons from these areas should sign the deviation documentation.
These can include development, production, validation, and regulatory. Ap-
proval of the final disposition is the responsibility of the quality unit, and
there should be a signature from a person designated with that responsibility.
Periodic Review
Documentation on deviant lots needs to be reviewed periodically to identify
adverse trends. Pareto-type analysis can be performed to determine if particular
problems, products, or systems have recurring issues. Changes made to a
process need to be documented and reviewed for cumulative validation impact.
The following steps can be used as a checklist to aid in performing devi-
ation inventions: define problem, identify probable cause, prioritize and in-
vestigate causes, analyze information obtained, determine extent, verify
solutions, document investigation, complete investigation in a timely fashion
(circa 30 days), get approval signatures, track for future reference, and follow-
up on commitments.
INVESTIGATING QUALITY PROBLEMS

In support of the concepts I have related in this chapter, I utilized the infor-
mation presented in Quality Planning and Analysis by Juran and Gryna (1980).
The following is a brief overview of some of the ideas discussed there and how
they relate to the investigation of process deviations for APis.
Quality problems are defined as sporadic problems, which are sudden

adverse changes in the status quo, and as chronic problems, which are a long-
standing adverse situations. API process deviations generally fall into the spo-
radic problem category as events that occur as sudden departures from the
historic level of operation. These sporadic problems, however, may mask a
more fundamental chronic problem. Proper investigation should reveal
which problem type is causing the adverse event. The goal of solving sporadic
problems is to restore the status quo of the process, whereas the remedy for
the chronic problem is changing the status quo.
To investigate deviations or adverse events properly, there must be an es-
tablished system of controls. The concept of control requires using a feedback
loop and a sequence of steps as follows:
1. Choosing the control subject: We choose APis because that is our busi-
ness and the FDA has chosen to regulate APis in this manner.
2. Choosing the unit of measure: The unit of measure is the actual API
manufacturing process as demonstrated by records and observations.
3. Setting the standard: The standard for API processes in the context of
this chapter is preset operational instructions and parameters.
4. Choosing a sensing device: The sensor for measurement is generally a
person who has observed that nonconformance has occurred.
These observations can come from instruments and equipment.
S. Measuring the actual performance: Performance of API processes takes
place during manufacturing and during document review. At these
times one can observe whether the process has been followed in
conformance with the operational requirements.
6. Interpreting the difference between the actual and the standard: The dif-
ference between the observed performance of a deviant batch and
the performance of a nondeviant batch requires interpreting.
7. Taking action (if any) on the difference: As differences occur, actions
are needed to determine whether the differences are significant.
Significant differences will require a remedy.
Juran and Gryna (1980) also discuss the following techniques for per-
forming problem analysis and improving the level of quality:
• Determining that a quality problem exists and defining the problem

• Collecting factual information on the problem
• Classifying the defect
• Studying the symptoms surrounding the defect
• Theorizing on the cause of these symptoms
• Analyzing and experimenting to determine the true causes

• Developing experiments to "prove" the source of the problem
• Deciding on the best remedy
• Instituting the change
• Checking the fix to ensure it remedied the problem
All of these are necessary to investigate process deviation adequately in
the manufacture of APis.
PROCESS DEVIATION EXAMPLES
Example 1
Description of the Deviation
During the manufacture of API lot 45 the temperature in the reaction vessel
exceeded the limits of the process by 10°F. The master formula requires a tem-
perature between 120 to l40°F. An automatic vent on the vessel failed to open
during the process.
Classification of the Deviation

The deviation is associated with an equipment failure.
Extent of the Deviation

A review of the deviation database showed this was the only exception for
this API. However, a review of equipment deviations showed two other APis
manufactured in the same vessel had problems with excessive heat.
Impact of the Deviation

The temperature excursion in the process of this API represents a deviation
from the API master formula. Since this lot was manufactured out of validated
conditions, a comparison of this deviant lot with previous lots is necessary to
determine if they are equivalent. Also, the suitability and maintenance of the
suspect valve needs to be addressed because it is implicated in the deviation.
Results of the Investigation

The API master formula step 10 requires that the reaction be heated between
120 to 140°F for 30 minutes. Due to a valve failure the reactor was overheated
by 10°F for 10 minutes. The operator was able to open the exhaust valve
manually to relieve the pressure. It was determined that the plant compressed
air system had gone down for about 1 hour, which prevented the automatic
valve from working. The other instances of temperature excursion noted dur-
ing the database review were attributed to operator error and therefore are ir-
relevant to this deviation.
The API was sampled in triplicate and the assay results were 95.6, 96.3,
and 96.2 percent. The relative standard deviation of the values was within the
RSD found during the validation of the API. An impurity profile was also per-
formed and the results were consistent with the validation batches. Reference
QC notebook 1122, page 30.
Follow-up Action
Production needs to investigate a system of notifying the operator when plant
utilities such as compressed air go down. Responsible person: Fred Lee. Target
date: March 1, 2000.
Conclusion
The API exceeded the temperature for 10 minutes during the process. The fail-
ure of the plant compressed air system caused an automatic valve not to
open. Tests of the deviant lot showed there was no adverse impact on the
API's quality attributes or the validated process. API lot 45 is acceptable and
can be approved and released.
Example 2
During the manufacture of API lot 100 an operator used an unapproved raw
material. The raw material used was the correct type but had been supplied by
an unapproved supplier.

The deviation is the result of a human error.

A search of the deviation database showed no other instances in which unap-
proved material was used. However, all the API lots manufactured in the cam-
paign with lot 100 may contain the same material from the unapproved
supplier.

The master formula requires that raw material R223 be added at step 2 in the
manufacture of this API. The operator selected the correct raw material from
the warehouse and added it properly to the vessel during processing. Later,
during the batch record review, it was discovered that the raw material was
sourced from an unapproved supplier. Only approved supplier raw materials
are allowed for use in the manufacture of APis.
Receipt records showed the raw material in question was received two
days prior to the manufacture of lot 100. A reconciliation of the inventory
showed that the amount used from the lot could only have been used in
one batch of API. Thus, no other batches in the campaign used this raw
material.
Incoming QA did not detect that the supplier of the raw material was
not listed on the approved supplier list.
Samples of lot 100 were analyzed in triplicate and the results were equal
to or exceeded the results obtained from the validation lots. Also, the analyti-
cal variation was consistent with that noted in the validation lots. Reference
QC notebook 45, pages 100-120.
A review of the regulatory filing for this API showed that the specific
supplier of this raw material is not listed.

Raw material R223 used in the manufacture of API lot 100 was sourced from
an unapproved supplier. Incoming QA failed to detect this and released the
material to be used in production. Inventory and batch records show that this
unacceptable raw material was used only in batch 100. There are no regula-
tory implications of this misuse.
Follow-up Action
QA needs to counsel the staff to ensure that all material received are from ap-
proved sources. Responsible person: Joe Smith. Target Date: Completed. QA
needs to perform an audit of this supplier to determine if they can be added to
the approved supplier list. Responsible person Frank Gordon. Target date: Jan-
uary 2000.
Conclusion
API lot 100 will remain on hold until QA has audited the supplier and deter-
mined if they are acceptable.
Postscript
It has been determined that the cost of auditing this supplier is greater than
the cost of losing this one batch. Therefore, API lot 100 will be rejected and
destroyed.
Example 3
After the manufacture of API batch BB it was discovered that the cleaning
documentation from the previous lot (batch AA) was lost. Batch AA was a dif-
ferent API and a complete cleaning was required before the equipment could
be used to manufacture lot BB. The cleaning documentation is held in a sepa-
rate system from the batch records.

The deviation is classified as a process error because the process for retaining
cleaning records was not adequate to retrieve the pertinent record.

A search of the database showed no other instance in which records had been
lost. This deviation is limited to batch BB.

Since lot AA was a different API from lot BB the documentation of cleaning is
necessary to show that the equipment was clean prior to the manufacture of
lot BB. If residue from batch AA remains in the equipment, then batch BB
may be contaminated.

API lot BB was manufactured in the same equipment used to manufacture a
different API (batch AA) two days previously. After the manufacture of a
batch, operators complete cleaning records and file them in the production
office. QA reviews these records during the normal course of batch record re-
view. During the batch record review for lot BB the cleaning record for lot AA
could not be found.
The two operators who reportedly did the cleaning were interviewed and
said that they had done the cleaning as required. A record that the equipment
had been cleaned is in the equipment logbook. Also, this cleaning requires a
laboratory verification by infrared (IR) scan; the production lab's record

demonstrates that this test was done, and the results were acceptable (refer-
ence production lab note 77, page 12).
Additional testing was performed on lot BB to determine if any residue
from lot AA could be found. The results showed no residue. Reference QC
notebook 99, page 32.
Follow-up Action
Production will now file the cleaning records with the batch documentation
so QA can review them at batch release. Responsible person: Judy Jones. Tar-
get date: Completed.
Conclusion
The documentation for the cleaning of equipment after the manufacture of
API lot AA was lost. Lot BB was manufactured after lot AA. Interviews with op-
erators confirmed the cleaning was done. The cleaning is documented in the
equipment log book. An in-process lab test shows that samples for the clean-
ing solvent passed the IR test. Additional tests of lot BB showed no residue
from lot AA. This lot can be approved and released.
REFERENCES
Code of Federal Regulation, Title 21, Parts 210 and 211: Current good manufacturing
practices for finished pharmaceuticals.
FDA. November 1998. Bulk active postapproval Changes: Chemistry, manufacturing, and
controls (Draft guidance). Rockville, Md., USA: Food and Drug Administration.
FDA. 1984. Bulk pharmaceutical chemical guide. Rockville, Md., USA: Food and Drug
Administration.
FDA. 1996. 211.192 Proposed amendments. Federal Register (3 May 1996).
FDA. 1998. Good manufacturing practices for finished pharmaceutical. Code of Federal
Regulations, Title 21, Part 211.
FDA. March 1998. Manufacturing, processing, or holding active pharmaceutical ingredients
(Draft guidance). Rockville, Md., USA: Food and Drug Administration.
Food Drug and Cosmetic Act as amended, 1985.
ICH. 1999. Good manufacturing practice guides for active pharmaceutical ingredients (Draft
No. 4), Geneva, Switzerland: International Conference on Harmonisation.
Juran, and Gryna. 1980. Quality planning and analysis, 2nd ed. New York: McGraw Hill.
www.fda.gov/cder/drug.htm.
11
TECHNOLOGY TRANSFER:
INGREDIENTS
B. J. Evanoff and K. L. Hofmann, Jr.

Bristol-Myers Squibb Co.
Syracuse, New York
Although widely used in the pharmaceutical industry, the term technology

transfer has not been formally defined. At the heart of the concept, of course,
is CHANGE. Expressed simply, it means a defined process will be performed in
a new venue. In a very broad interpretation, almost any change, (e.g., a new
manufacturing location, different process equipment, new laboratory instru-
mentation, etc.) is a technology transfer. In a more restrictive sense, and the
one discussed in this chapter, technology transfer is the sum total of the var-
ious steps and manipulations required to take a clinical drug candidate from
the research chemist's laboratory into a commercial scale manufacturing fa-
cility or from one facility to another. The discussion will be restricted to drug
substances derived from chemical synthesis; however, the principles and con-
cepts could apply equally to products of biological origin. Since drug research
is extremely expensive and time-consuming (Neiss and Boyd 1984, pp 4, 5),
the sponsor firm must call on all available resources to ensure a successful
candidate reaches the marketplace expeditiously. Additionally, this work
must be accomplished with a consideration to minimizing costs in the man-
ufacturing environment. A key milestone is completion of the technology
transfer project.
Another consideration in the execution of technology transfer is the
regulatory environment. The U.S. Food and Drug Administration (FDA) is
309
aware of the evolving environment in which the pharmaceutical companies

operate.
The FDA understands that changes, driven by the need to optimize
processes and control costs, improve Good Manufacturing Practice (GMP)
compliance, and meet environmental and safety requirements, will continue
to occur. The FDA, of course, is concerned that changes be properly con-
trolled, documented, and above all, are determined to have no detrimental
impact on the product quality.
To focus the scope, this chapter addresses only changes that occur to
active pharmaceutical ingredient (API) manufacturing from its inception in
the research laboratory, through changes in well-established or validated
processes. Later the chapter identifies the disciplines necessary for the
technology transfer team and provides a generic description of the mem-
bers' roles. It discusses elements of a typical process development report
and presents examples of problems encountered in technology transfer
projects, which could have been avoided by more rigorous planning and
control.
PRELIMINARY CONSIDERATIONS
The Role of Marketing

Once the drug candidate is identified, Marketing will prepare a forecast of the
drug substance requirements to support the launch and initial sales projec-
tions. This estimate is based on the clinical profile of the product, the unique-
ness of the drug to the marketplace, the "blockbuster potential" of the drug,
and the ability of the sales unit to find a niche for the drug and promote it to
the proper market. The quantity of drug substance required will determine
(1) if facilities within the company have the capability to supply the market
demands or (2) if an external vendor is required. Significant overestimation of
the drug candidates sales potential will result in underutilized plant capacity
and higher than necessary manufacturing costs. Conversely, underestimating
the market potential could likely result in the inability of the manufacturing
operation to supply the required quantity of drug substance, resulting in back
orders that will erode the market for the drug, particularly if there is competi-
tion in the particular therapeutic area.
Marketing must also be able to provide a reasonable estimate to establish
pricing. For instance, a small niche for a very expensive product will likely
cause marketing to abandon the candidate (unless it can gain orphan drug
status) in favor of a lower cost drug with a wider clinical profile. Throughout
the development of a drug, the marketing projections will change many
times. It is important for marketing personnel to communicate these changes
to the development team.
Technology Transfer: Active Pharmaceutical Ingredients 311
Example: Lack of Effective Communication

In a classic case of communication failure, a major pharmaceutical firm's
marketing division selected a promising drug candidate for "fast track" devel-
opment and launch. The development team was afforded a very narrow win-
dow of opportunity to develop an effective manufacturing process. At the
height of this activity, a competitor company launched a drug, for the same
indication, with a similar clinical profile. With the market potential severely
diminished, marketing decided to cancel the project entirely. However, this
decision was not communicated to the development team, which continued
to proceed with process optimization, securing raw materials, and conducting
large-scale pilot plant trials. Timely communication could have avoided the
significant waste of time and money.
Defining the Process

Before consideration of a drug substance as a candidate for a technology
transfer, it should be well characterized (physicochemically) and demonstrate
a degree of biological efficacy in the expected therapeutic area. Typically,
while within the research arm of the organization, the drug substance is pro-
duced by an evolving and changing synthetic scheme, with minimal or no
consideration given to a cost-effective, final, scalable pathway. This is one rea-
son to promote the intervention of a multidiscipline team, including chemi-
cal development and engineering representation, once the clinical candidate
is deemed safe and identified as a potentially marketable item. If the team is
well chosen, it can evaluate the synthetic schemes performed to date and
identify alternate schemes to increase process efficiency and reduce process-
ing costs.
Usually, once human clinical trials have begun on the research drug can-
didate, the molecule is structurally and physically characterized. Therefore,
any processing changes implemented for process optimization, or any other
reason, must not adversely affect any of the physicochemical or stability
characteristics.
Prior to initiation of any technology transfer project, and near the end of
the research cycle, it is beneficial for the medicinal chemist to prepare a full
Process Development Report on the candidate drug substance. This document
will be useful for providing background information for a New Drug Applica-
tion (NDA) filing, in which the FDA requires a process justification, and a his-
torical perspective of the synthesis. If the development report is complete and
well written, most information required for the regulatory filings should be
available therein.
CATEGORIES OF TECHNOLOGY TRANSFER

For the balance of this discussion, it is useful to classify types of technology
transfer projects in terms of their respective complexities. Two different types
of projects will be considered here.
Although the mechanisms for each type of tech transfer project are sim-
ilar, there are significant differences that warrant separate discussion. There
are two critical milestones in the transfer of a drug substance from the clinic
to commercial manufacturing when technology transfer is key to the success
of the project:
1. The point where the clinical candidate is transferred from the

medicinal chemist to the process development chemist for process
optimization
2. When the optimized process is transferred from the laboratory de-
velopment chemist to the Process Engineering Department for
scale-up.
Often, due to project timing, these two events may actually occur simultane-
ously.
New Chemical Entities

For the introduction of new drug candidates, the API manufacturing tech-
nology transfer is often accomplished on unvalidated, untested processes
during manufacture of the initial pilot batches. The development engineers
can exercise a degree of latitude, within defined constraints, to tailor the
process to "fit" the existing equipment and perform in a manner designed
for commercial scale manufacture. Many pitfalls that cannot be predicted
from the laboratory scale experience are very evident during the first at-
tempts to manufacture at pilot scale or commercial scale. Close working
synergy between the research chemist and the development and engineer-
ing disciplines, at this stage, can avoid costly and time-consuming project
delays.
Changes to Established Processes

After the initial successful scale-up of API manufacturing processes, occasions
arise when changes to the manufacturing processes need to be made. This sec-
ond type of technology transfer can range from a simple change (e.g., a
change in reactor) to a complex change (e.g., a major processing change or
the transfer of a process from one facility to another).
Although every attempt may be made to duplicate the process to be

transferred to the maximum extent possible, in reality this is often impossi-
ble. The receiving site or location is obviously different from the originating
location. The operating personnel are different, and the equipment and phys-
ical layout are very likely different, even if the equipment is of similar capac-
ity and operating principle. Starting materials may be from different sources
and varying grades of quality. And clearly the process expertise lies (hope-
fully) with the originating site. Every effort should be made to minimize the
impact of these known, inherent sources of variation, since unforeseen addi-
tional variation will occur in proportion to the complexity of the project.
PROCESS DEVELOPMENT REPORT

The Process Development Report should include a full history of the evolution
of the synthesis up to the current synthesis in use, information describing the
evolution of the analytical methods in use to monitor the drug substance, and a
list of proposed specifications for the drug substance. Some of this information
should be available in the Investigational New Drug Application (IND) or other
regulatory document previously filed for the product. Any established solubility
characteristics and all other established physical properties should be defined.
Pertinent information regarding the hazards of the drug substance (toxicity, car-
cinogenicity, or explosivity) and the packaging and handling of the drug sub-
stance should be addressed. Ideally, a copy of the Material Safety Data Sheet
(MSDS) or similar document detailing safety information for the drug substance
and intermediates should be incorporated. Stability data generated on the drug
substance should be included, noting in particular the packaging used in the
performance of the studies, the temperature, humidity, light, and any other per-
tinent factors. An often overlooked part of this report is the list of key observa-
tions about the manufacturing process, including any in-process controls that
may have been developed, and recommendations about the synthesis for the
process development chemist. Known by different names including "develop-
ment summary report" or "process transfer report," this document is the com-
plete record of the laboratory scale work done on the compound and represents
the chemist's knowledge of this process. It is here the range of parameters is ex-
plored and defined. This document sets the stage for commercial manufacture
and forms the basis for process validation. (Repic 1998, pp. 179-194)
A typical process transfer document might be organized as shown in
Table 11.1.
The process flow section creates a pictorial scheme for the reviewer to as-
certain an overview of the steps and obtain valuable perspective on the
process. A hypothetical schematic is depicted in Figure 11.1. Note the signifi-
cant amount of information that can be obtained from inspection of this dia-
gram. For example,
Table 11.1 Table of Contents for Typical Process Transfer Document

I. Introduction
II. Abbreviated Process Description
Ill. Chemistry Schematic
IV. Process Row Diagram
V. Mass Balance, Yields
VI. Analytical Results and Specifications
VII. Equipment list and Description
VIII. Process Detail
IX. Drug Substance Stability
X. Hazard Evaluation and Safety Considerations
XI. Waste Stream Processing
XII. Process History
XIII. Discussion and Recommendations for Further Evaluation
XIV. References and Appendices
• The step numbers directly linked to the process manufacturing

records are depicted.
• Vessel design and construction are readily apparent (e.g., HST 39 is
a Hastelloy reactor).
• Significant steps can be emphasized (e.g., the coupling reaction in
HST 39).
• Identification of starting materials, intermediates, and reagents is
facilitated in this type of diagram (e.g., SM 1212 and INTM 3456).
• Process utilities and point at which they are required are identified
(e.g., liquid nitrogen).
• Finally, any steps of the process requiring special precautions for
safety or environmental reasons are readily apparent (e.g., step 9,
Hazardous Waste).
Another very useful section in the process transfer document is the process
status table usually found in the process detail section. An example is seen in
Table 11.2.
Knowledge of the identity, quality, and quantity of starting materials, in-
termediates, solvents, and reactants is critical to a thorough understanding of
the process and the ability to carry out a successful scale-up. An example of a
typical report format is shown in Table 11.3.
Figure 11.1 Typical Manufacturing Process Flow Diagram
RXN-4414414 - - - - - - - - ,
.----2____ SM 1212
RCOOH
50%Me0H:50%/IPA
4
TN 31
Coupling Reaction
Aqueous
' - - - - - - - - - - - • Hazardous Waste
Toluene
Table 11.2 Process Status Table

Step No. 3 6 10
Reactor RCT 34 HST 21 GLR 22
Batch wt or volume 150 L 75 L 300L
Temperature oc 4 -42:2 20-22
PH 3.5 4.2-4.5 6.0-6.6
Pressure: Bar or mm Hg 1 1 1
Agitation rate: rpm 25 25 75-80
Nitrogen flow: 0 1-2 0
L/min
Step No. 11 17 22
Reactor GLR22 GLR 22 CFG 9
Batch wt or volume 300 L 175 L 65 kg.
Temperature oc 20-25 2-25 N/A
PH 7.2-8 7.5-7.8 N/A
Pressure: Bar 20-25 mm Hg 1 1
Agitation rate: rpm 75-80 >10 N/A
Nitrogen flow: 0 0 0
L/min
Table 11.3 Raw Materials

RM Code Item CAS#* Moi.Wt. Sp. Gr. Amount Assay% Moi-Eq.
51111 RXN-4414414 N/a 635.22 N/A 22.50 kg. 98.5 1.00

11121 SM 1212 N/a 257.98 N/A 9.87 kg. 97.6 1.37
R4345 INTM 3456 N/a 333.95 N/A 18.66 kg. 92.5 1.44
RE222 RCHOOH N/a 237.45 N/A 27.85 kg. 95.6 1.06
34201 Acetic acid 111-11-1 60.05 1.0492 17.886 L 99.8 15.5
87655 Methanol 108-88-3 32.04 .8127 84.66 L 99.6 22.6
67675 Isopropanol 108-24-8 60.10 .7885 84.66 L 99.1 11.4
99878 Toluene 132-34-9 92.14 .8669 114.55 L 97.8 37.5
*Chemical Abstracts Service numbers not accurate (for example only).

ORGANIZATION FOR TECHNOLOGY TRANSFER
Technology Transfer Team

Since a team concept is always the best approach to accomplishing a success-
ful technology transfer project, the core technology transfer team should be
commissioned immediately following the decision of executive management
to pursue the drug candidate to commercialization. The core team should
consist of qualified representatives from the major segments of the organiza-
tion whose participation is essential for successful completion. These individ-
uals should be assigned as permanent members to carry out the project to
completion. The team leader or project manager should be an excellent com-
municator, well versed (but not necessarily the expert) in the technology, a
good motivator, and extremely well organized. He or she should have suffi-
cient, well-rounded knowledge of the business to appreciate the impact of the
project on each involved business segment. The team leader should be vested
with the authority, as well as the responsibility, to ensure that all established
timelines and assigned tasks within the scope of the technology transfer are
completed on time and within budget. Additional team members from other
parts of the organization may participate on an ad hoc basis to address spe-
cific tasks. Membership should include all relevant disciplines but still be
limited to facilitate communication and decision making. To ensure conti-
nuity and a successful process, the core team membership should be main-
tained until project completion (Allen 1985, pp. 152-181; Feigenbaum 1991,
pp. 149-199).
A typical technology transfer core team will likely be comprised of indi-
viduals representing different segments of the business. Typical team mem-
bers' assignments are as follows:
• Project Manager-for overall responsibility, coordination, and
progress communication to management. His or her role may be
enhanced as necessary by additional staff and responsibility and
authority delegated as appropriate.
• Regulatory Affairs-for coordination of the appropriate regulatory
filings, advice on approval timing, content of the filing documen-
tation, and response to regulatory inquiries.
• Engineering-to coordinate associated capital projects and direct
and control construction, equipment acquisition, installation, and
qualification.
• Materials Management-to include those units responsible for pur-
chasing, strategic planning, resource allocation, and supply chain
activities. This member (or members) will analyze and recommend
the most favorable manufacturing strategy, in consideration of
internal capability, business partnerships, and tax advantages for

the corporation.
• Manufacturing Operations-to represent the originating site and
receiving location production activities. These representatives
should have sufficient authority to commit the necessary personnel
and plant resources to accomplish the project within the defined
cost and time limitations.
• Research and Development-to support the technical issues andre-
solve problems. This group provides the process expertise and
would be expected to train and direct the production trials at the
receiving site.
• Quality Control/Quality Assurance-to provide necessary GMP
oversight. This would include initiating the necessary stability test-
ing, compiling and reporting the results, and completing any re-
quired discrepancy investigations. These members would complete
preparations for any required regulatory inspection (e.g., FDA
preapproval inspection).
• Environmental Safety and Industrial Hygiene-to address environ-
mental health and safety concerns, including (in conjunction with
engineering) securing required permits and filing environmental
impact statements.
• Business units-to represent taxation, finance, sales, and marketing
Intracompany Project
Nearing the end of the research involvement, when the need for additional
quantities of drug substance for expanded clinical trials is established (i.e., the
company makes a "go" decision about the continuation of the clinical candi-
date), technology transfer becomes important. In anticipation of this deci-
sion, preliminary meetings of interdivisional teams may be held to plan for
the project, well in advance of any actual technology transfer activity. It is im-
portant to begin information exchange early to facilitate the planning
process.
When technology transfer from pilot scale to full commercial scale be-
gins, the process should be well defined and sufficiently rugged. The manu-
facturing facility selected for the API manufacture should have been evaluated
and deemed adequate to perform the intended operations. In addition to con-
sidering the business issues, such as tax advantages, this evaluation should
obviously include equipment size and design, facility layout, availability of
waste handling systems, and utilities. Additionally, the GMP support systems,
including adequate laboratory facilities, documentation systems, training,
and validation programs should be in place. Again, information exchanges

very early in the process are key to a successful scale-up or site transfer.
External Technology Transfer Project

For a variety of reasons, it often occurs that an external source for the drug
substance, key intermediates, or starting materials may be required. For exam-
ple, following detailed process analysis the engineering member(s) of the
team may determine there are equipment, capacity, safety, cost, or other rea-
sons why a particular step or steps in the manufacturing synthesis cannot be
performed at any of the company's manufacturing facilities. The team must
then define the operations to be performed by an external business partner
and conduct a survey of suitable vendors.
This business arrangement is much more complicated than internal
manufacturing, as it requires secrecy agreements and contracts. In many cases
the API manufacturer is located outside the United States, which adds the ad-
ditional burden of cultural and language issues.
Following identification of a candidate business partner, a small team
representing the business unit, development, operations, engineering, and
quality control/quality assurance should visit the vendor's manufacturing fa-
cility to determine if the vendor will be a reliable business partner. This visit
should take place prior to the initiation of any technology transfer activities.
Selection of the vendor is normally based on evaluation of product quality,
capacity, pricing, delivery, and compliance with applicable current GMP and
Environmental Health and Safety (EHS) regulations. The team must deter-
mine if the external vendor will be an exclusive source of the drug substance
or will supplement to internal capacity.
Once the final selection is made, a functional team should be commis-
sioned to facilitate the technology transfer activities at the business partner's
manufacturing facility. These specialists will provide support in the form of
engineering recommendations, preparation and review of process documents,
and on-site assistance during the initial manufacturing trials and inspections
from regulatory agencies.
CONSIDERATIONS FOR PLANT SCALE-UP

One of the most important phases of the technology transfer project for APis
is process scale-up. Rarely, if ever, will the process perform at full commercial
scale in the same manner exhibited at laboratory scale. Much information
can be gleaned about process anomalies by conducting a well-planned scale-
up. This work is often done in a pilot plant. Ideally, the equipment and sup-
port systems at the pilot plant should be similar in operating principle and of
the same material of construction as those in the commerctal facility, with the
exception of size. Although all processes are different and have different re-
quirements, as a guideline the pilot scale equipment should be nominally at
least 10 percent of the capacity of that found in the commercial plant.
Another reason for pilot plant scale-up is to ensure the API impurity pro-
file is well characterized. Since the reactions in large-scale equipment often
are subject to variations caused by interphase reactions, localized reactions,
and so forth, it is not unusual to encounter reaction by-products not foreseen
from the laboratory-scale experience. These can be dimers of the desired com-
pound, sterioisomers, different polymorphs, enantiomorphs, or a variety of
by-products from the reaction mixture. Often the scale-up experience reveals
the need for additional downstream purification steps to purge the unwanted
moieties to acceptable levels.
Raw Materials
Starting materials for the synthesis should be evaluated. Typically, the prelim-
inary quality specifications were established from the early research synthesis,
and further refined based on manufacturing experience. It is likely that com-
pendia grade materials were utilized in the prescale-up batches. Potential
commercial suppliers of all materials need to be investigated. If a business
partner is the source for any intermediates, the product specifications should
be set forth in the contractual documents prior to the initiation of any work.
These specifications are intended primarily to provide assurance that the in-
termediate will be of the requisite quality to perform consistently in the sub-
sequent synthetic steps. The impact on product quality of using grades of raw
materials and/or solvents that are different from those identified in the devel-
opment work must be evaluated and justified.
Plant Equipment and Utilities

It seems obvious, but nevertheless worth mention, that process equipment
and systems in the receiving site should be properly qualified and maintained
in good repair and operating condition.
Example: Equipment Failure

In one example, a series of process failures encountered during the scale-up of
a process intermediate at a new site was traced to equipment failure. A process
that is easily managed at one site, under ideal conditions, may prove not suf-
ficiently robust to perform well at another site where conditions are not as
tightly controlled. In this particular case, power failures, an undirected shut-
down of an emission control system, and leaks around a dryer seal were cited
as the causes of process excursions. These problems led to excessive tempera-

tures in the drying chamber and extended exposure of the product to mois-
ture. Development data indicated these conditions could lead to formation of
a dimerized form of a known impurity, which in fact was the case. It then be-
came necessary to undertake an expensive and time-consuming study to
demonstrate that the presence of this dimerized impurity in the intermediate
was not of adverse consequence to the quality of the final API when the syn-
thesis was complete.
Process Control Parameters

In early development work at laboratory and small pilot scale, the signifi-
cance of a particular process control parameter may be underestimated due to
the relative ease of control at such scale. At commercial scale, this same para-
meter may be difficult to control or even measure.
Example: Undefined Critical Process Parameter

An example of this point occurred during a plant trial to manufacture an early
step intermediate, which involved a coupling reaction in a solvent system of
tetrahydrofuran in the presence of triethylamine. Following addition of an al-
coholic solution of base, an aqueous ammonium chloride solution was added
to the reaction mixture. Solvent is removed by vacuum distillation, followed
by addition of toluene and mixing to extract the desired compound into the
organic phase. Finally, a phase separation step completed the isolation of the
product.
Due to incomplete phase separation because of equipment design, por-
tions of the base and ammonium chloride solution were retained in the or-
ganic solution containing the desired compound. Later, following distillation
of the organic solvent, the compound was crystallized by dissolution in ace-
tone and reaction with HCl to form the HCl salt of the intermediate.
Due to the presence of the inorganic base, however, the mineral acid re-
acted with the base to form a salt, while traces of the ammonium chloride re-
mained present.
Although the presence of small amounts of inorganic salt at this stage
did not present operational difficulties (there was ample opportunity to re-
move them since many of the downstream processing steps involved aqueous
streams), the assay method for the intermediate purity in this case was a titra-
tion. Presence of the inorganic salt biased the result and led to an incorrect
charge of starting materials for the subsequent step, resulting in incomplete
reaction and yield loss.
Had the significance of complete phase separation been emphasized,
and the equipment selection been carefully considered, these difficulties
could have been avoided. The importance of careful and accurate definition
of critical process parameters is probably the most important consideration in
the success of a technology transfer.
Process Equipment
As stated earlier, the goal of the technology transfer project is to duplicate the
existing validated process at another location. For this reason, any variation
from the specified process equipment must be carefully controlled to mini-
mize adverse impact on the process.
Analysis of the existing equipment, considering the requirements of the
particular chemistry, is essential to predict and eliminate problems prior to
initiating scale-up runs. An example of a typical process analysis listing po-
tential problems and recommendations for resolution is given in Table 11.4.
Example: Uncontrolled Equipment Change

In another example, a seemingly minor change from a pump-controlled vac-
uum system -to a steam jet-controlled vacuum system set the stage for a
slightly higher distillation time and temperature for the penultimate step in
the manufacture of an API. This change in operating conditions led to the for-
mation of an analogue of an open-ring compound that was a known impurity
in the API.
Table 11.4 Process Analysis

Equipment Layout Potential Process Problems Required Modifications
Reactor A-Glass Reactor A-Preparation of

dissolution solution.
1. HCI gas required is a severely 1. Provide covered enclosure
corrosive and volatile with ventilation pickups.
substance. Necessary to attach Handle cylinders in are
CH,OH
and disconnect cylinders. remote location. Vent
Vapors will settle. exhaust air to alkaline
scrubber with pH control.
2. Reaction is exothermic. 2. Provide glycol to jacket of
dissolution vessel.
3. Due to corrosive nature of 3. Provide a nitrogen purge to
HCI, the transfer piping and remove HCI from the
control devices should not piping and control devices.
Vessel B
retain gas for extended Vent to an alkaline
periods. scrubber.
HCI
The open-ring analogue had not been detected previously, although this
was a well-characterized synthesis and hundreds of batches had been manufac-
tured, albeit at the originating site. Fortunately, in this particular case, the down-
stream processing was demonstrated to purge the impurity to below acceptable
levels. Had this not been the case, however, it might have been necessary to de-
velop and validate (and possibly file a regulatory petition) to recover this batch.
Cleaning Validation
Unless-and even if-the technology transfer is done in a new facility, the issue
of equipment cleaning must be addressed. A treatise on cleaning validation is
not in the scope of this chapter, but cleaning validation is an important re-
quirement for successful completion of the project. For most chemical opera-
tions, the cleaning agent is typically a solvent. For aqueous process streams
where the reagents are water soluble, the task may be straightforward. When
reactions are carried out in organic solvents, the task becomes more formidable
and may prompt safety and environmental concerns. In any case, a formal pro-
tocol such as those outlined in various papers on the topic (see, e.g., Mc-
Cormick and Cullen 1993, pp. 329, 330) and study to verify the equipment is
suitable for use in carrying out the process is a GMP requirement. Although the
goal of any cleaning process is complete removal of the previous product, the
capabilities of modern analytical techniques, detecting residual compounds at
the parts-per-billion level, reveal the need to establish acceptable residual levels
following the cleaning procedure. Such levels are determined after considering
a number of factors including toxicity of the original compound, minimum
therapeutic effect levels, equipment surface area, and minimum batch size for
the subsequent manufacturing. Once the levels are established, a plan is set
forth in a protocol to study the effectiveness of the selected cleaning procedure.
Prior to initiating the formal study, it is appropriate to determine the rel-
ative effectiveness of the cleaning process at small scale using coupons or
swab/ rinses. This also requires validation of the swab recovery technique
(e.g., percentage recovery of a known charge), rinse technique if used, and, of
course, the analytical method.
Note: Many in the field would claim only an automated cleaning process
(i.e., clean-in-place) can be validated, hinting that human intervention can-
not be deemed reliably consistent. In any case, cleaning effectiveness must be
demonstrated.
Process Validation
No discussion of technology transfer would be complete without the mention
of process validation. In a pure sense, the project may not be considered com-
plete until the process validation at commercial scale has been successfully
completed. It is not the purpose of this chapter to delve into the detail of
process validation for APis; however, this part of the project is critical because
it demonstrates the link between the process development activity and the
commercial scale production and verifies the critical parameters identified in
the earlier work. In the course of the study, the critical process parameters will
be controlled to ensure the process remains within established ranges.
The study report should provide a comparison between the ranges or
limits established at development scale and those demonstrated by the three
successive validation lots or batches. Verification that these parameters are
indeed within limits and reproducible is one of the acceptance criteria for
the study. A summary table of typical in-process parameters is provided in
Table 11.5.
Analytical Methods
Simultaneous with the evolution of the chemical process are the development
and refinement of the analytical procedures necessary to properly character-
ize the drug substance and any necessary intermediates and starting materials.
Table 11.5 Critical Parameter Control

In-Process Parameters Validation Batch Data
Step No. Description Rangejlimit FSL99023 FSL99024 FSL99025

3.d Max. temperature :S25°C 24°C 23°C 24°C
during TEA
addition
6.a Completion of :s:0.5% DL4554 0.35% 0.28% 0.41%
coupling reaction remaining
(HPLC)
9.c pH of buffer 10.3-10.8 10.3 10.5 10.5
solution
10.a Batch concentration :s:38°C 36°C 36°C 39°C*
temperature
14.c Residual DL6262 :S2.0% 1.7% 1.6% 1.1%
by HPLC
17.a Holding 35-40°C 36-37"C 36°C 38°C
temperature of
crystallization
slurry
21.c Maximum drying :s:45°C 43°C 43°C 44°C
temperature
* Note: Temperature excursion less than one minute. See deviation investigation sec. VII. B.
The medicinal chemist in the research organization is not concerned with an-
alytical methods development that will be used to ultimately monitor the
quality of the drug substance. Although monitoring methods are developed
in the research organization while the drug is in the clinic, it is unlikely that
these are the final methods that will be used for monitoring the quality of the
drug substance once it is in production.
For drug substance purity determination, usually a specific analytical
method such as high performance liquid chromatography (HPLC) or gas
chromatography will be used for purity determination in small molecules.
Since the impurities that are discovered will probably change as the synthetic
pathway changes, there will be a continuing need for support and interaction
with the analytical methods development members of the team. In develop-
ing the methods, the identity and structure of impurities likely to result form
the proposed synthesis should be determined, and "pure" samples of each
should be synthesized to use as markers to determine at which point in the
chromatogram each will elute. When the retention time for each impurity in
a particular system is established, this information can be used to identify the
presence of a particular impurity in a batch sample. An example of an in-
process isocratic HPLC system with retention times established for the known
reaction impurities is given in Table 11.6.
Additionally, the methods development members of the team may be
called on to provide support for developing in-process methods that may be
used to monitor critical process parameters once the synthetic process is set
and is ready to be performed in a pilot or production facility. A key objective
for the process development chemist is early identification of the key process
parameters, which are amenable to either on-line monitoring or to monitor-
ing by obtaining a sample and waiting for an analysis to be performed.
In addition to chemical characterization, physical characterization of
the molecule must also be performed. Once the API is synthesized in the new
Table 11.6 HPLC Conditions

Column: Waters C-18 m-bondapak, 3.9 x 275 mm
Mobile phase: 75% acetonitrile/25% deionized water
Chart speed: 4.5 cmjmin
Flow rate: 1.1 ml/min
Detection: UV@225 NM
Temperature 25°C
Sample size: 8 ml
Total run time: 45 min
facility either by scale-up, site change, or new equipment/process a thorough

evaluation of the physical characteristics should be done. This is important to
assure the material from the new process will perform identically to the origi-
nal process in the formulation of the drug product.
Examples of the methods used might include the following:
• Infrared or ultraviolet spectrum: of course, this test will also serve to

confirm identity and would be compared with spectra master from
the original process. This test should be performed under identical
conditions to alleviate the effect of pH change.
• Refractive index.
• Polymorphic Forms: Many compounds exist in multiple crystal
forms, and the thermodynamic properties must be fully under-
stood and described. For example, a typical compound exhibited
two onset melting points by differential scanning calorimetry
(DSC) at 175°C. and 188°C. This characterization allowed selection
of the most stable polymorph. X-ray diffraction analysis also will
show polymorphs and crystalline forms.
ANCILLARY ISSUES
API Container/Closure
Along with the properties of the drug substance, characteristics regarding the
stability of the drug substance will have been generated throughout the clinical
development. The manner in which the drug substance and any synthesis in-
termediates have been stored is known and should be communicated in the de-
velopment report. A stability study will have been performed that shows the
drug substance stability to heat, light, acid, base, and humidity in a given con-
tainer system-for a drug substance, generally a polyethylene bag of some type,
or for a sterile drug substance, an aluminum can, glass bottle, or sterile plastic
bag. Ideally, a package should be chosen for the API that has no chemical inter-
actions with the molecule and minimizes the chances for any external chemi-
cal interactions by outside ingress. The storage conditions should be
communicated so that commercial shipping containers that contact the prod-
uct will be of the same chemical composition so that the stability testing for in-
tegrity and compatibility do not have to be repeated. Also, the need for the use
of desiccant of some type for controlled temperature storage, or for sensitivity
to light, should be established and communicated so that any unusual storage
requirements may be accommodated. This can be a problem in the event that
refrigerated storage is required for a large quantity of raw material, and the pro-
posed manufacturing facility has no refrigerated warehousing capability.
Stability
An important part of the medicinal chemist's early work is elucidation of the
drug candidate's chemical stability. The tendency of a drug substance to form
degradation products under normal storage and handling conditions is an in-
dication of difficulties for the formulation chemist and may ultimately
threaten the commercial viability of the drug candidate.
The medicinal chemist will perform acid, base, temperature, light, and
humidity stressed studies on the drug substance to elucidate its decomposi-
tion profile. This information should be communicated in the development
report, which may facilitate the process development chemist's efforts to
identify the optimum synthetic process.
Any changes made to the process after the original scale-up must
demonstrate a drug substance with the same stability characteristics as de-
fined in the original regulatory submissions for the molecule. This evaluation
can be made either under "accelerated" conditions or by direct comparison of
the long-term stability profiles of the molecule. Tests must be chosen that can
adequately indicate the true stability of the molecule, and when the testing is
performed at the appropriate testing intervals, a retest period can be estab-
lished for the API. This combination of tests, storage time, and temperature
results in the generation of a stability protocol that will be followed fairly
closely throughout the API life to evaluate any changes made.
Regulatory Issues
This chapter is not intended to describe the strategies associated with regula-
tory filings (e.g., NDA), but it often makes good sense to conduct manufactur-
ing trials for the process at or close to commercial scale prior to submission of
the final technical process description to the regulatory agency. As stated
above, the commercial scale process rarely, if ever, performs identically to the
laboratory scale. For this reason, subtle or substantial changes to process para-
meters may be necessary to achieve the desired product quality, yield, or op-
erating efficiencies required at commercial scale. If the parameters are too
closely defined in the regulatory documents, based only on laboratory-scale
experience, significant project delays will result from the need to modify the
regulatory filings and await approval.
SUMMARY
Successful technology transfer of drug substance manufacturing requires care-
ful planning, effective communication, and flawless execution. If any of these
elements is missing, the probability of an efficient, timely, and cost-effective
process scale-up, leading to commercial success of the drug product, is dimin-

ished. Effective technology transfer allows quality to be engineered into the
manufacturing operation and creates the basis for process optimization. Com-
plete and accurate documentation of all key activities provides the necessary
link between the early research and development work and the full-scale
manufacturing operations, leading to a successful product launch.
REFERENCES
Allen, T. ]. 1985. Managing the flow of technology. Cambridge, Mass., USA: MIT Press.
Feigenbaum, A. V. 1991. Management strategies for quality. In Total quality control, 3rd
ed. New York: McGraw Hill.
McCormick, P. Y. and L. F. Cullen. 1993. Cleaning validation. In Pharmaceutical process
validation, 2d ed., vol. 57, ed. by I. R. Berry and R. A. Nash, New York: Marcel
Dekker, Inc.
Neiss, E. S. and T. A. Boyd. 1984. Pharmogenology: The industrial new drug develop-
ment process. In The clinical research process in the pharmaceutical industry, vol. 19,
ed. by G. M. Matoren. New York: Marcel Dekker, Inc.
Repic, 0. 1998. Principles of process research and chemical development in the pharmaceuti-
cal industry. New York: John Wiley & Sons.
12
POSTAPPROVAL CHANGES TO
BULK DRUG SUBSTANCES
Eric Sheinin
United States Pharmacopeia
Rockville, Maryland
Kasturi Srinivasachar
Eric Duffy John Smith
Food and Drug Administration,
Center for Drug Evaluation and Research
Rockville, Maryland
In recent years, the Food and Drug Administration (FDA) has undertaken an
initiative to develop guidance for postapproval drug manufacturing changes.
Several guidances for drug product manufacturing changes, the Scale-Up and
Postapproval Changes (SUPAC) guidances, have provided recommendations
for demonstrating equivalence of products following manufacturing changes.
Analytical testing and in vivo testing recommendations were provided for the
following classes of drug products: immediate release and modified release
solid oral drug products and nonsterile semisolid drug products. Guidance is
now being developed for drug substance manufacturing changes under the
Bulk Actives Postapproval Changes (BACPAC) initiative. This brief chapter de-
scribes this initiative from its inception and development to its present form.
The objective of this initiative is to develop recommendations for sound
scientific approaches to assess the potential for drug substance manufacturing
changes to adversely affect the identity, strength, quality, purity, and potency
of drug substances as they may relate to the safety and effectiveness of drug
329
products manufactured from these drug substances. Another objective is to

provide FDA reporting recommendations and, where possible, reduce regula-
tory reporting burden in line with the mandate of the FDA Modernization Act
(FDAMA) of 1997. It was recognized at the outset that this was a difficult
challenge in view of the wide diversity of types of drug substances and manu-
facturing methods and the array of types of changes that might be made.
To begin the development process, a working group was formed in 1996
to plan and organize a public workshop to discuss approaches to this complex
issue. The FDA and the American Association of Pharmaceutical Scientists
(AAPS) cosponsored this workshop; however, a broad spectrum of pharmaceu-
tical trade associations participated in the workshop planning. Representatives
from the FDA's Center for Drug Evaluation and Research (CDER) and Center for
Veterinary Medicine, AAPS, the Animal Health Institute, the Biotechnology In-
dustries Organization, the Generic Pharmaceutical Industry Association (now
part of the Generic Pharmaceutical Association), the Generic Pharmaceutical
Association, the National Drug Manufacturers Association (now known as the
Consumer Healthcare Products Association), the National Association of Phar-
maceutical Manufacturers, the National Pharmaceutical Alliance (now part of
the Generic Pharmaceutical Association), the Parenteral Drug Association, and
the Pharmaceutical Research and Manufacturers of America met on several oc-
casions to design a program to provide a critical analysis of this issue and pro-
vide the FDA with industry's and academia's perspectives.
The objectives of the workshop were the following:
• Discuss the science that might support the assessment of change in
drug substance and drug product attributes and consider how
"equivalence" might be determined.
• Identify types of manufacturing changes with potential high risk
and those with low risk of adverse impact on product quality or
performance.
• Gain an understanding of the complexity of implementing manu-
facturing changes both for drug substance suppliers and drug prod-
uct manufacturers.
• Discuss alternative regulatory approaches for drug substance manu-
facturing changes.
The workshop, which was held in March 1997, had speakers and participants
from a broad range of industry, as well as academia and the FDA. The atten-
dance of approximately 600 participants highlighted the importance of, and
interest in, this issue. Industry representatives from firms that are solely bulk
drug manufacturers, to those that are solely drug product manufacturers, and
those that do both, as well as the FDA, presented their views. Non-U.S. manu-
facturers also participated. Attendees provided considerable input during the
topic breakout sessions.
Postapproval Changes to Bulk Drug Substances 331
The discussions provided the FDA with invaluable input for the develop-
ment of guidance for drug substance manufacturing change, and many of the
concepts considered at the workshop are to be found in the guidances that
were crafted. Since it was made clear that industry would find the greatest
value in guidance on the manufacture of intermediates, this is where the
initial efforts were focused. It was decided that two guidances would be cre-
ated-one for intermediates, BACPAC I, and one for drug substances, BACPAC
II. It was also decided to limit the guidances to chemical synthetic processes
only.
This chapter should not be used in lieu of these guidances, since neither
BACPAC I nor BACPAC II has been finalized.
BACPAC I
A draft BACPAC I guidance was released for public comments, and the com-
ments have been evaluated. When this chapter was written, the draft guid-
ance was being revised based on the comments received.
Scope
BACPAC I is a guidance for industry concerning postapproval changes to in-
termediates in the synthesis of drug substances used in both human and vet-
erinary drug products. It defines the FDA's recommendations regarding the
filing mechanism and data that should be submitted in support of these
changes. Since most of the modifications to intermediates involve an evalua-
tion of the impurity profile, it was considered appropriate to use the threshold
levels for identification and qualification of impurities in the International
Conference on Harmonisation of Technical Requirements for the Registration
of Pharmaceuticals for Human Use (ICH) guideline Impurities in New Drug Sub-
stances, Q3A. Consequently, BACPAC I does not apply to the categories of drug
substance excluded by ICH Q3A, namely, natural products, biotechnology-de-
rived drug substances, synthetic oligonucleotides and peptides, and radio-
pharmaceuticals. These classes of drug substances have been excluded from
consideration primarily because many of them are structurally complex mate-
rials for which monitoring of impurities at low levels may not be feasible. It
can be argued that short synthetic peptides and oligonucleotides are well-char-
acterized small molecules and should be covered by BACPAC I, but in practice
it is difficult to determine at what point these would be better classified as
complex molecules. Furthermore, because each coupling of an amino acid/nu-
cleotide is equally important, dividing BACPAC recommendations between fi-
nal intermediate and final bulk (BACPAC I vs. BACPAC II) is not as logical for
these complex materials as it is for conventional organic molecules. In solid
phase synthesis of such materials, hardly any intermediate is isolated at all. For
these reasons, it was decided to exclude the entire category. Additional guid-
ances will be developed that will address postapproval changes to these sub-
stances. The synthetic steps involved in the preparation of semisynthetic
conventional molecule drug substances do, however, fall within the scope of
this document even though such drug substances are excluded by Q3A.
BACPAC I covers changes up to and including the final intermediate
with some restrictions as noted below. These early modifications should, in
general, have a low probability of having an adverse impact on the identity,
strength, quality, purity, or potency of the drug substance. Additionally, these
modifications would not be expected to affect the physical properties of the
drug substance. Changes in manufacturing site, manufacturing scale, equip-
ment, specification, and process are addressed for all intermediates; however,
changes that result in a structurally different final intermediate or changes to
the specification for the final intermediate are beyond the scope of BACPAC I.
Changes to bona fide starting materials, except for specification changes, are
also excluded. Such changes are not usually reported to the FDA, except for
those starting materials derived from natural sources.
Filing Mechanism
The regulations at 21 CFR 314.70(a) requires that all changes to an approved
application be reported to the FDA. Changes can be documented in a supple-
ment to the application or in an annual report. BACPAC I provides guidance
on the appropriate filing mechanism for a given change to intermediates in a
drug substance synthesis. There are three categories of supplements-prior
approval, when the change may not be implemented before approval by the
FDA; Changes Being Effected in 30 days, which should be submitted at least
30 days prior to distribution of product made using the change; and Changes
Being Effected when the change can be implemented at the time of submis-
sion. It is important to note that Changes Being Effected supplements still re-
quire FDA approval even though material manufactured using the change
may be distributed and used prior to formal approval. As allowed by regula-
tion 314.70(a), BACPAC I provides for less burdensome filing of some postap-
proval changes. It should be emphasized that the only implication of this is
that some changes may be implemented without waiting for FDA approval;
that is, there is no reduction in the type or amount of data needed to support
the change. BACPAC I also suggests that certain minor changes need not be
formally filed with the FDA, and data generated to qualify these changes can
be kept on-site and made available to FDA investigators.
The supplemental New Drug Application/Abbreviated New Drug Appli-
cation (NDA/ANDA) filings referred to in the preceding paragraph are the re-
sponsibility of the holders of the applications. When information on drug
substance synthesis is provided in Drug or Veterinary Master Files, a BACPAC
I change made by the master file holder should be documented in an amend-

ment, and all persons authorized to reference the master file should be
notified of the change. Based on the information provided by the master file
holders to their customers, the change is then filed either in a supplement or
in an annual report by the holders of the applications.
Assessment of Change
BACPAC I advocates a data-driven strategy for the assessment of change that
is considered to be scientifically superior to an arbitrary classification of
changes as major or minor. The diversity of drug substance structures and the
plethora of synthetic routes that can be employed to arrive at a given struc-
ture make it difficult, if not impossible, to make a priori generalizations about
the risk associated with a particular modification. In the BACPAC I approach,
change is assessed by comparing pre- and postmodification material and es-
tablishing equivalence between the two. If equivalence cannot be demon-
strated, the provisions of BACPAC I do not apply and the effects of the
change on the dosage form may need to be evaluated. Under these circum-
stances, it is recommended that the appropriate chemistry review team be
contacted.
Two major factors for determining equivalence in the drug substance are
the impurity profile and physical properties. Equivalence of the impurity pro-
file can be established at an intermediate downstream from the change or on
the drug substance itself. NDA and ANDA holders that follow the former
route will derive the maximum benefit from BACPAC, since the physical
properties of the drug substance are not likely to be impacted. No further an-
alytical testing is needed for these materials. However, this approach repre-
sents a radical change in the way intermediates are characterized and
analyzed. Assessment of change is best carried out at the intermediate imme-
diately following the change, as this provides the most useful information
concerning on potential impurities based on the reactants and reagents used,
the reaction conditions, and the reaction mechanism. Analysis of later inter-
mediates or the drug substance is complicated by the fact that any impurities
initially present can undergo secondary transformations in subsequent steps.
Demonstrating equivalence early in a synthetic process provides greater assur-
ance that a manufacturing modification will not affect the identity, strength,
quality, or purity of the drug substance. For this reason, the guidance some-
times recommends less burdensome filing than the regulation when the im-
purity profile is shown to be equivalent for an intermediate prior to the final
intermediate.
BACPAC I recognizes that establishing equivalence at downstream inter-
mediates may not always be feasible. Intermediates may not have been well
characterized for a number of older synthetic drug substances, and it may not
be economically viable to develop suitable analytical methodologies for these.
In such instances, the more traditional approach of examining the drug

substance itself after a change is acceptable, provided that equivalence criteria
for both physical properties, where relevant to finished dosage form perfor-
mance and the impurity profile, are met.
Since equivalence is the crux of the BACPAC approach, a key aspect of
this document is a list of the criteria that should be met for establishing equiv-
alence of the impurity profile and physical properties and the number of
batches of pre- and postchange material that should be utilized for this evalu-
ation. After considerable discussion, it was decided that assessment of change
was best accomplished by comparing three postmodification batches, which
could be pilot or commercial scale, to the range of historical data from three or
more premodification commercial batches. Historical data should be gener-
ated from representative batches that have been successfully used in subse-
quent processing; demonstration batches are not considered appropriate for
this purpose, even if they are within the approved specification. For the impu-
rity profile, the equivalence criteria address new impurities that can poten-
tially arise from a change as well as higher levels of existing impurities. For
new impurities, ICH Q3A provides qualification and identification thresholds
that have been widely accepted by the pharmaceutical industry and regula-
tory agencies within the ICH regions as well as other regions of the world.
These limits are considered appropriate for evaluating impurity profiles for
BACPAC !-the identification threshold of 0.1 percent when equivalence test-
ing is performed on an intermediate and the qualification threshold when this
testing is carried out on the drug substance. The distinction between high-
and low-dose drugs, which is used in ICH Q3A to determine qualification
thresholds for drug substances, is unnecessary when considering intermedi-
ates, because downstream processing is expected to lead to a decrease in im-
purities levels.
In general, when acceptance criteria exist for individual impurities in the
intermediates or in the drug substance, meeting these specifications for these
materials postchange will be adequate to establish equivalence. However, the
more common situation encountered for intermediates is either a complete
lack of acceptance criteria for impurities or merely a total limit for all impuri-
ties. In these cases, equivalence can be established by a statistical analysis of
historical data. The same rationale applies if equivalence is determined in the
drug substance, although the latter is generally better defined with regard to
impurity profile.
When a change is qualified by testing the drug substance, equivalence of
physical properties should also be established, especially when these are rele-
vant to drug product performance. The final solution step, from which the
drug substance is isolated in pure form by crystallization or precipitation, usu-
ally determines the physical properties of the drug substance. Consequently,
it is unlikely that a BACPAC I change that is at or prior to the final intermedi-
ate will affect the physical properties of the drug substance. However, where
equivalence has not been established at an intermediate, there is a finite
probability of carryover of new or higher levels of existing impurities into the

final solution step, which in turn may lead to a different particle size or
morphic form of the drug substance. It is for this reason that holders of appli-
cations electing to test equivalence at the drug substance stage should evalu-
ate physical properties in addition to the impurity profile. BACPAC I provides
criteria for equivalence of morphic form and particle size, two physical prop-
erties that have an important bearing on drug product performance. For mor-
phic form, conformance to established acceptance criteria will generally
suffice; when these do not exist, then isolation of the same form or mixture of
forms within the range of historical data will demonstrate equivalence. How-
ever, adherence to particle size specifications for the drug substance may not
always be sufficient to ensure that product performance will be unaltered af-
ter a BACPAC I change, and a comparison of the particle size distribution pro-
file is preferred. Different methods for determining particle size are not
completely equivalent since they often yield different results. Research in this
area has been proposed under the Product Quality Research Institute, Inc.
(PQRI), which will hopefully lead to a better definition of the criterion for
equivalence of this attribute.
Manufacturing Site, Manufacturing Scale,

and Equipment Changes
Although BACPAC I does not categorize changes as major or minor, it is intu-
itively obvious that some changes will be less likely to have an adverse impact
on the drug substance than others. Site, scale, and equipment changes fall
into this category, provided the identical synthetic pathway is followed, and
temperature and humidity controls are not altered. Given these constraints
and adherence to current Good Manufacturing Practice (cGMP) regulations,
these changes generally should not adversely affect the impurity profile of the
intermediate involved in the change, and a less restrictive filing mechanism
(annual report or data kept on-site) may be warranted in many instances.
Since a fundamental premise of BACPAC is that the further away a change is
from the final drug substance, the less the likelihood of an adverse effect on
the latter, it is reasonable to treat site changes in the step that produces the fi-
nal intermediate differently with regard to filing mechanism.
New manufacturing facilities for intermediates should operate in accor-
dance with the principles of cGMP-outsourcing an intermediate should not
be interpreted to mean that it may now be synthesized under non-cGMP con-
ditions.
Scale and equipment changes for intermediates are examples of postap-
proval changes that need not be reported to the FDA. Nevertheless, such
changes should be evaluated and documentation kept on-site and be made
available to FDA investigators. Equivalence testing may not be necessary for
all scale and equipment changes but should be considered whenever major
changes are contemplated. NDA and ANDA holders should use their judg-
ment and previous experience to determine which changes are "major"; for
example, if it is known from scale-up studies of pilot scale batches that a cer-
tain step is scale sensitive, then increasing the scale of commercial batches
should be justified by equivalence testing.
Specification Changes
Tightening of acceptance criteria and certain changes to comply with com-
pendia! requirements are of no major concern. However, relaxing acceptance
criteria, replacing an analytical method with one that does not qualify as an
improvement, deleting tests, or revising specifications because of a change in
grade/supplier of a solvent, reagent, or starting material may have the poten-
tial for an adverse effect on the identity, strength, quality, or purity of the drug
substance. In many of these cases, the effect of the change on the impurity
profile of a subsequent intermediate or the drug substance needs to be evalu-
ated and the data submitted in a supplement. There are some exceptions
when the quality of downstream intermediates or the drug substance would
clearly not be affected by the change, such as, elimination of redundant test-
ing; equivalence testing is not called for in these instances, and the change
may be filed in an annual report.
Process Changes
Changes to the manufacturing process account for more supplements than
any of the other types of changes covered by BACPAC I, although there often
is overlap with these and other types of changes. For example, it is likely that
a change in the route of synthesis will involve the use of different equipment
and perhaps different starting materials, and different intermediates may be
formed. These new starting materials and intermediates will have specifica-
tions different from the previous starting materials and intermediates. It is
convenient to divide process changes into three basic categories:
1. Same starting materials and intermediates.
2. Synthesis route changes involving different starting materials
and/or intermediates, excluding the final intermediate.
3. Redefinition of an intermediate as a starting material.
The first section covers changes within a step or steps of the synthetic
scheme and includes, among others, process parameter or solvent changes.
Such changes generally should be supported by equivalence testing. It is de-
sirable to establish equivalence as close to the change as possible and a less
restrictive filing mechanism is suggested if equivalence is demonstrated prior
to the final intermediate.
Intuitively, changes that involve a different route of synthesis have the

greatest potential for adverse effect on the identity, strength, quality, and pu-
rity of the drug substance. Since new impurities and/or different levels of ex-
isting impurities will almost invariably result as a consequence of these
changes, a two-tier approach for the filing mechanism is again logical. A less
restrictive filing mechanism may be applied in which equivalence is estab-
lished soon after the change, whereas a more restrictive mechanism is appro-
priate if equivalence is demonstrated at the final intermediate or the drug
substance itself. Regardless, it is recommended that the identity of the drug
substance be reestablished.
Sometimes, a compound that was an intermediate in the synthesis
scheme of the original application becomes well established in the chemical
literature with increased commercial availability. Redefinition of this interme-
diate as a starting material is the subject of the third section of process
changes. This is a major change and should be proposed only if well justified,
since there are important regulatory implications (e.g., a starting material
need not be produced under cGMPs). Thus, there is no requirement to disclose
the methods used in their preparation. Testing should be carried out on either
a downstream intermediate or the drug substance to demonstrate that the
proposed starting material from the new source leads to equivalent post-
change material. Since such changes in effect shorten the number of steps in
the synthesis scheme that are under the FDA's purview, NDA and ANDA hold-
ers should generally set a more comprehensive specification for the proposed
starting material than the existing specification for the intermediate. Some as-
surance that adequate change control procedures are in place to qualify new
vendors of the starting material is also recommended. However, even if all
these criteria are met, holders of approved applications are advised to contact
the pertinent review division prior to submitting these changes, especially if
the intermediate that will be redefined is close to the final intermediate. Rede-
finition of the final intermediate as a starting material is outside the scope of
BACPAC I.
BACPAC II
The BACPAC II guidance was at a much more preliminary stage in the draft-
ing process than the BACPAC I guidance at the time of this writing; thus,
there was some uncertainty concerning what information the guidance
would convey and what topics it would cover. Nevertheless, some remarks
can be made with a reasonable expectation that they will bear some resem-
blance to the details contained in the final guidance.
Scope
The classes of compounds covered by BACPAC II will almost certainly be the
same as those covered by BACPAC I, since equivalence in the impurity profile
of pre- and postchange materials will probably be a key factor in determining
filing mechanisms in BACPAC II, as it is in BACPAC I. Therefore, BACPAC II
also will likely be limited to conventional, synthetic drug substances for
which impurities can be quantitated at levels comparable to the ICH Q3A
threshold levels. The excluded categories of compounds are the same as those
listed in the BACPAC I guidance.
BACPAC II, by definition, will cover changes in the manufacturing
processes for drug substances that take place after the final intermediate. The
covered changes also will include changes in specifications for final interme-
diates, which were not covered in BACPAC I. Whereas BACPAC I covered site
changes for intermediates only (including changes in the manufacturers of
intermediates), BACPAC II will cover site changes that involve or include
changes in location of the manufacturing operations after the final interme-
diate. BACPAC II may also cover changes in the source of a drug substance.
Principles of Equivalence
It is expected that BACPAC II will embrace the general principles of equiva-
lence described in BACPAC I. Given that BACPAC II covers changes made after
the final intermediate, a few modifications may be needed to the practical ap-
plication of these principles. For example, equivalence testing on intermedi-
ates likely will be eliminated, since by definition few intermediates can exist
after the final intermediate. On the other hand, BACPAC II may need to take
into account the fact that some drug substances can exist in a variety of forms,
for example, the racemate of a single-enantiomer drug substance, or crude ma-
terials that require further purification to attain the purity required by the
drug substance specification, or the premilled or premicronized forms of a
drug substance. There may also be a different emphasis on changes to sol-
vents. Whereas a new solvent introduced early in a synthetic process is un-
likely to remain in the drug substance, a new solvent used in the final
synthetic step, or later, is much more likely to be present.
The principles of equivalence of physical properties likely will receive
greater emphasis in BACPAC II. In BACPAC I, demonstration that physical
properties were equivalent was appropriate only in a few circumstances. In
BACPAC II, there will be a larger number of changes for which equivalence of
physical properties should be demonstrated. Preliminary drafts of BACPAC II
have considered more closely the question of what conditions should prompt
a comparison of pre- and postchange physical properties.
Filing Mechanisms
As in BACPAC I, different types of changes likely will be described in terms of
what information or documentation should be provided to support a pro-
posed change, and what kind of submission(s) should be made to the FDA to
report the change and to provide the supporting documentation. For drug ap-
plications, the choice of submissions will be annual reports, Changes Being
Effected supplements (changes effected immediately or in 30 days), or prior
approval supplements. Although preliminary discussions of BACPAC II have
indicated that there will still be many changes for which an annual report
submission will be sufficient, it is anticipated that a greater proportion of
changes will recommend supplements than was the case for BACPAC I. This is
because changes made late in the manufacturing process (i.e., those covered
by BACPAC II) are usually expected to have a greater potential to adversely af-
fect the identity, strength, quality, or purity of drug substances than those
changes made earlier (i.e., BACPAC I changes).
Types of Changes
In the BACPAC I guidance, the section on types of changes contains the most
specific guidance on the kind of information that should be provided to
support a BACPAC I change and the manner (type of submission) in which it
should be reported to the FDA. There will be a similar section in BACPAC II to
serve the same purpose. Since this part of BACPAC II is the one most likelyto
undergo revision and editing as the draft is developed, it is very difficult
to make accurate predictions about its content. However, it is very likely that
the section will be subdivided, as was this section in BACPAC I, into discus-
sions of (1) manufacturing site, manufacturing scale, and equipment changes;
(2) specification changes; and (3) manufacturing process changes.
Summary
It is expected that BACPAC II will follow the same general form and principles
of equivalence as found in BACPAC I. The primary differences will most likely
be due to the fact that BACPAC II will deal with changes made toward the end
of the manufacturing process of a drug substance, when the potential for ad-
verse effect on the identity, strength, quality, or purity of the drug substance
is significant. It is also likely that there will be a greater emphasis on changes
to the physical properties of the drug substance, and consideration of how
such changes may affect drug products made from those drug substances.
BACPAC II will likely cover the same classes of drug substances as BACPAC I,
and many of the same types of changes.
CONCLUSION
The BACPAC concept follows naturally from the development of the SUPAC
guidances by the Center for Drug Evaluation and Research (COER). The
SUPACs provided a reduction in the regulatory burden faced by the pharma-
ceutical industry when making certain types of changes to certain types of
dosage forms. In a similar manner, these documents provide a faster mecha-
nism for the introduction of a change that can lead to the realization of im-
proved quality of the drug substance and economic benefits for the drug
substance manufacturers as well as for the drug product manufacturers. In
general, the amount of testing that is necessary to support the change will be
the same as it is today, but the filing mechanisms will be less burdensome. For
example, a change that currently requires a prior approval supplement under
the regulations may possibly be reported in a Changes Being Effected supple-
ment or even in an annual report, depending on the change and the intended
use of the drug substance. In some situations, the amount of recommended
testing may actually represent an increase over that expected today but would
be compensated for by the more rapid introduction of the change as the result
of the reduction in the filing burden. The amount of information that should
accompany the submission, whether a supplement or an annual report,
should be the same regardless of how the change is reported.
BACPAC I will lead to regulatory relief for certain types of changes made
prior to the final intermediate. However, although the SUPACs were based on
scientific data gathered at several universities during research sponsored by
CDER, the philosophy of the BACPACs is based more on concepts developed
at the March 1997 workshop as well as on concepts developed by COER's
Drug Substance Technical Committee and the BACPAC I and II working
groups. A further reduction in the regulatory burden, both in terms of recom-
mended filing mechanisms and the amount and type of data that should be
included with any BACPAC submission, may be possible in the future based
on the results of research sponsored by the PQRI. The PQRI Drug Substance
Technical Committee has proposed two projects that will test the hypothesis
that a specification (tests, procedures, and acceptance criteria) can be devel-
oped that will allow certain changes to be made during the synthesis or man-
ufacture of the drug substance with a reduced filing mechanism over those
recommended in BACPAC I and II. The underlying principle in both BACPAC
I and BACPAC II is the assumption that it should be possible to make certain
changes that will not have an adverse impact on the identity, strength, qual-
ity, or purity of the drug substance or the quality of the drug product. This
principle involves the demonstration of the "sameness" of the pre- and
postchange material. The BACPAC I guidance presents a detailed discussion of
how and when the sameness of the impurity profile should be demonstrated.
Ideally, this should be shown at the earliest opportunity in the manufacturing
process. The second critical criterion is the demonstration that the physical
properties of the drug substance have not changed as a result of the change.
Again, the guidance provides a detailed discussion of how and when the
sameness of the physical properties should be demonstrated. It is possible that
the chemical structure should be recharacterized for certain process changes.
The BACPAC working groups accepted the recommendation of the
March 1997 workshop that the reduction of regulatory burden for early steps
in the synthesis would be the most beneficial to the drug substance manufac-
turers. This is why BACPAC I covers changes up to and including the final in-
termediate. Based on the comments received to the draft BACPAC I guidance,
the working groups decided to finalize BACPAC I before announcing the avail-
ability of BACPAC II for public comment. A draft BACPAC II had been pre-
pared and was in the initial stages of the clearance process within COER when
it became obvious that many of the comments received on BACPAC I were
germane to BACPAC II, as well. Further, based on the workshop conclusions, it
seemed appropriate to finalize the first BACPAC before expending additional
resources on the second one.
Once BACPAC I is finalized, work on BACPAC II will proceed. It is ex-
pected that the same concepts that are included in the first guidance will be
part of this latter guidance. At some point in the future, these guidances may
be combined into a single document covering all changes to drug substance
manufacturing.
13
VENDOR QUALIFICATION
AND CERTIFICATION
Ira R. Berry
Wockhardt Americas Inc.
East Hanover, New Jersey
The concepts and practice of "validation" have been applied in the pharma-
ceutical industry for many years. Validation has been discussed by the regu-
latory authorities and has been promulgated in Good Manufacturing Practice
(GMP) regulations since the mid-1970s (Berry 1981, 1988, 1993; Madan and
Komotar 1979; 21 CFR; FDA 1987; Berry and Nash 1993). These practices and
regulations have focused on finished dosage forms, traditionally tablets, cap-
sules, softgels, solutions, suppositories, creams, and other such pharmaceuti-
cal products. Little attention has been given to the validation of active
pharmaceutical ingredients (APis). This particular chapter will focus on the
activities performed by the manufacturer of a finished dosage form, in quali-
fying and certifying a vendor (manufacturer) of an API used to produce a fin-
ished pharmaceutical product. These APis can also be referred to as the drug
substances used in the manufacture of a drug product.
Considerable effort-in the allocation of resources, time, and expense-
is devoted to process validation by a manufacturer of pharmaceutical finished
dosage forms. Plant facilities, equipment, personnel, materials, and manufac-
turing and control procedures are factors that are included in a validation pro-
tocol and study. Requirements have been developing in recent years to extend
the validation process to include the manufacture of APis (Martinez 1994;
IQA 1992; PMA 1994; ISPE/FDA 1995; FDA 1998b; ICH 1998). This program
certainly makes good sense, as we can consider that process validation of a
pharmaceutical product would be invalid if the manufacture included the use
343
344 Validation of Active Pharmaceuticals Ingredients
of an API that may not have been produced following the intent of GMP or
that may have been produced by a manufacturing process that was out of
control.
DEFINITION OF TERMS
There are publications that describe process validation of pharmaceutical fin-
ished dosage forms, which enumerate and define the many terms used in de-
scribing that program (FDA 1987; Berry and Nash 1993). It is important here
to note and define some terms that are specific to APis. These terms already
have taken on different meanings to different people and must be standard-
ized for a discussion of their application to provide clarity and uniformity.
Vendor, supplier, distributor, and manufacturer are not terms that can be in-
terchanged in all cases. In simplistic terms, the "vendor" or "supplier" of an
API is the seller to a manufacturer of finished dosage forms. The "manufac-
turer" of an API may sell its product directly to finished dosage form manu-
facturers, in which case there would be direct contact between both
organizations, and the "manufacturer" would also be the "vendor" or "sup-
plier" as specified in the terms indicated above. Alternatively, the "manufac-
turer" of an API may sell its product to another company that sells to the
manufacturers of finished dosage forms. In fact, that API "manufacturer" may
sell its product to many "distributors" who supply finished dosage form man-
ufacturers. Also, each "distributor" may conceivably purchase the same API
from several"manufacturers." These scenarios have described the "manufac-
turer" of the API as a "vendor" to another company ("distributor") who is a
"vendor" to finished dosage form manufacturers. The term vendor is synony-
mous with the terms supplier and distributor. Thus, it is very possible that a
"manufacturer" of an API may not be the "vendor" or "supplier" to a finished
dosage form manufacturer.
Furthermore, it should also be kept in mind that a "manufacturer" of
APis purchases raw materials from organizations that can also be "manufac-
turers" or "distributors." In either case, again, the "supplier" is the firm from
whom the API manufacturer purchases raw materials. In this regard, it is
very important-when considering validation of an API-to establish the API
manufacturer-vendor relationship. It would be wasteful to qualify and certify a
vendor who may not be the manufacturer of an API and who may sell the
"same" API manufactured by several sources and when some of the API lots
may not meet all the established specifications. When certifying and qualifying
a "vendor," the process must be for a specific "manufacturer" of a specific API.
Agent is a term that is usually used to define a representative of a foreign
API manufacturer and who sells the API in the United States.
Qualification of an API vendor is the process whereby the vendor is ap-
proved by the finished dosage form manufacturer for a given API that will be
Vendor Qualification and Certification 345
used in a specific product. This is accomplished by demonstrating that the

API meets all of the established specifications consistently, with test results
that show comparability between the API and dosage form laboratories and
with established GMP compliance of the API plant. In this qualification
process, the vendor will be determined to be acceptable to supply the API that
meets the established specifications. Usually, qualification of an API vendor
will enable the dosage form manufacturer to perform reduced testing on each
lot of API received; however, the degree of testing (i.e., which tests will be per-
formed), and monitoring (i.e., how often these tests and complete testing will
be performed), must be established in a written program as the next step.
Certification of an API vendor occurs after qualification and is the process
by which the vendor is classified by the finished dosage form manufacturer
relative to its credibility and the degree of testing required to be performed by
the finished dosage form manufacturer for the receipt of each lot of the API.
A vendor will not be certified until it is first qualified.
The terms qualification and certification are sometimes defined differently
by different people. The important point is that the terms should be defined
and correlated with each other in a procedure that explains their use and
requirements.
The last term to be defined is active phannaceutical ingredient, or API,
which currently is used instead of the older term bulk phannaceutical chemical
(or BPC). The term API is defined differently in different documents (FDA
1998b; ICH 1998); however, the intent of each definition is the same. APiis
used to mean the drug substance or active ingredient in a finished pharma-
ceutical product.
For the purposes of vendor qualification and certification, we will con-
sider and relate specifically to APis and not necessarily all ingredients used in
a drug product. Although this chapter will focus on "actives," the same prin-
ciples can be applied to other ingredients such as excipients and processing
aids, especially critical ingredients.
PURPOSE OF VENDOR QUALIFICATION

AND CERTIFICATION
There are two major aspects in explaining the purpose of the vendor quali-
fication and certification program: these are the regulatory and business as-
pects. First, in order to comply with the GMP regulations for finished
pharmaceutical products, a manufacturing operation for those products
must undergo a process validation program. Regulatory authorities world-
wide, including the U.S. Food and Drug Administration (FDA), are extend-
ing the validation and GMP requirements from finished pharmaceuticals to
include APis. This is evident in the United States in the FDA's compliance
guides (FDA 1990, 1993, 1994, 1998b) and foreign inspection guide
(FDA 1992) and internationally in the guideline on GMP for pharmaceuti-

cal excipients (ICH 1998) (IPEC 1995) and the BPC monograph (IQA 1992).
Second, from a business perspective, the API validation requirement is
consistent with the finished pharmaceutical validation requirement in that
proper validation of a finished dosage form cannot be effected without con-
sideration being given to the APis used in the manufacture of that product.
The validation process must be totally inclusive of the manufacture of the fin-
ished dosage form and includes critical parameters that may affect that vali-
dation. This certainly includes the APis for the product being validated.
The finished dosage form manufacturer, in performing its validation
studies, must achieve a reasonable degree of assurance that the APis they
use are in compliance with regulatory requirements. This is accomplished
by a vendor qualification program that is designed to evaluate suppliers
and manufacturers, with an implementation scheme to assure regulatory
compliance.
QUALIFICATION/CERTIFICATION
PROCEDURE OVERVIEW
Every finished pharmaceutical manufacturer should have a written proce-
dure by which to qualify and certify an API vendor. If the vendor is not a
manufacturer, then the vendor should be qualified and certified for each
specific manufacturer. It is imperative that this procedure include all aspects
of the current regulatory requirements. It is not sufficient to simply pur-
chase an API for the first time and use it in a product lot for commercial dis-
tribution without a qualification/certification program, even though that
API may meet all of the raw material specifications and even though the API
may be compendia!.
Written specifications and test methods should be established for every
API that is used to manufacture a product. These specifications must be based
on the testing of material from a specific manufacturer(s) and not necessarily
a vendor-who may be a supplier and distributor for several manufacturers.
An example of a prototype API (raw material) specification document is
shown in Figure 13.1, to be used as a guide.
Qualification of the vendor from whom a finished pharmaceutical man-
ufacturer will purchase an API should be performed following a written pro-
cedure for that manufacturer. This Standard Operating Procedure (SOP)
should describe the various steps to be performed in qualifying vendors. The
procedure also should include a provision to certify a vendor, after it is qual-
ified, by categorizing each vendor based on credibility and history and by ex-
plaining the level of testing required by the finished pharmaceutical
manufacturer on an API lot sampling plan or time schedule basis.
Vendor Qualification and Certification 34 7
Figure 13.1 API Specifications for Raw Material, Gemfibrozil, USP

ACCEPTABLE PHARMACEUTICAL COMPANY, INC.
Raw Material Specifications Date Approved: 7-15-00
Gemfibrozil, USP Date Implemented: 8-15-00
Page 1 of 1
Test Specification Test Method
Identification Infrared absorption spectrum matches USP

Gemfibrozil RS. USP 24
Melting Range 58° to 61° USP 24
Water (Method I) NMT 0.25% USP 24
Heavy Metals
(Method II) 0.002% USP 24
Chromatographic The response of any one peak at a retention time
Purity of 0.25 times that of Gemfibrozil is NMT 0.2%; the
response of any other impurity peak is NMT 0.3%;
and the total of all peak responses other than
Gemfibrozil is NMT 2.0%. USP 24
Organic Volatile
Impurities (Method V) Meets the requirements USP 24
Assay (anhydrous basis) 98.0 to 102.0% USP 24
Acceptable Containers: Fiber drums lined with polyethylene bags.
Approval Shelf Life: One year
Approved Vendors: Fine Chemical Company, ABCD Corporation.
References: USP 24, p. 763
Issued By: Approved By:
xxxx yyyy
HOW TO QUALIFY A VENDOR
In proceeding to qualify a vendor, background information is needed in or-

der to establish a program and then move through the several steps of the
process systematically (Berry 1993). This operation should be performed in an
organized manner following a written protocol that is derived from the Ven-
dor Qualification and Certification SOP. A summary checklist of some recom-
mended steps is provided in Figure 13.2, to serve as an example and some
food for thought.
1. Consider whether the vendor is new to the company or has a history of

supplying other APis to the company. This is the first movement
toward establishing the reliability and credibility of the vendor.
Figure 13.2 Some Recommended Steps in Vendor Qualification

New Vendor Checklist
1. Is the vendor new to the company?
2. Is the API new or second source?
3. Vendor reputation (i.e., regulatory status)?
4. Vendor-manufacturer relationship?
5. Capacity of the vendor?
6. Location of the vendor-domestic or foreign?
7. Price?
8. Obtain samples and certificates of analysis
9. Obtain technical dossier
10. Test the samples
11. Conduct a vendor audit
12. Produce qualification lot(s) of finished product
13. Company committee makes decision
14. Change control (relating to change in the API manufacturing and control process)
Company experience with the vendor will certainly illustrate

whether or not the relationship is a good one.
2. Determine whether or not there already exists a vendor qualified to sup-
ply the API, perhaps for a different product that uses the same API
in the company. Also, if a qualified vendor exists for another raw
material and that vendor has the ability to supply the new API,
then there will be an established history of satisfactory or unsatis-
factory supply with that vendor. In addition, for each case a data-
base will have been established to a certain extent. If a new
(improved) vendor is needed, or if there is a program to qualify a
second source, then the qualification will be based on adding to the
established history.
3. Evaluate the vendor's reputation. This can be accomplished to some
degree by word of mouth through business relationships with other
people and also through the trade press and freedom of informa-
tion. The vendor's regulatory and compliance status is certainly
germane in establishing a reputable and reliable source. This infor-
mation can be found in FDA compliance profiles and Establish-
ment Inspection Reports (EIRs), which will certainly indicate the
regulatory evaluation of the vendor's operation and compliance, or
deficiency, with an indication of Current Good Manufacturing

Practice (cGMP) philosophy and mission that are required. The
vendor's recall and lot failure history will also be helpful in evalu-
ating the vendor.
4. Define the vendor's operation, as discussed previously (i.e., manufac-
turer or distributor). In order to qualify a vendor properly, it is im-
perative to know if the vendor is a manufacturer and, in this
proposed program, we must "qualify each manufacturing source."
5. Consider the capacity of the vendor. It is important to determine the
ability of the vendor to supply the API in terms of quantity and
lead time. The qualification process is time-consuming and costly,
and it would be wasteful to qualify a vendor that cannot fulfill fin-
ished dosage form production needs in a timely manner and that
does not have the capacity and ability to respond to an increase in
demand to a reasonable degree.
6. Consider the location of the vendor. This is an important considera-
tion to determine the lead time needed in supplying the API under
a regular production schedule and, especially, in providing in-
creased quantities of the API in the situation of a sudden increase
in demand. A domestic vendor can usually respond faster than a
foreign vendor; however, a foreign manufacturer may maintain an
inventory in a local warehouse, and this should be considered.
Also, freight costs should be given consideration.
7. Determine the selling price of the API from the vendor (i.e., the cost to
the finished dosage form manufacturer). This information is
needed for a profitability evaluation of the finished pharmaceutical
product. It certainly is not advisable to undergo the process of qual-
ifying a vendor, with all the associated expense and commitment
of resources, and then find that the vendor's price does not allow
for a reasonably profitable product.
8. Begin the actual process of vendor qualification, based on the back-
ground information generated. This is the beginning of the techni-
cal evaluation. Samples of the API, preferably from three
production lots, are requested from the API manufacturer-with
their certificates of analysis (CofAs)-and are taken for laboratory
testing.
9. Request a technical dossier from the API manufacturer. This data should
include the API manufacturer's specifications, validated test meth-
ods, impurities data, standards for testing, chromatograms where
appropriate, stability data on the marketed container/closure sys-
tem, and method of synthesis. This information can then be uti-
lized by the finished dosage form manufacturer to establish
specifications, testing standards, and test methods and will be nec-

essary to establish vendor certification and proper change control
procedures. Test methods must be stability indicating and show,
where appropriate, degradants, process impurities, and residual
solvents.
10. Test the production samples received in the laboratory. Test data must
certainly demonstrate that the laboratory samples (of the API pro-
duction lots) meet the API manufacturer's specifications. Also,
these samples should meet the (tentative) requirements of the fin-
ished dosage form manufacturer; otherwise, consideration should
be given to changing the specifications, provided that this will not
have a negative impact on the finished dosage form.
11. The finished dosage form manufacturer should conduct a vendor audit.
In this case, the audit should include all operations in the vendor
tree (i.e., supplier and manufacturer [if different from the supplier]).
Vendor audits will be discussed in detail later in this chapter.
12. Produce a qualification lot(s) of the finished dosage form product using
the source of API from the vendor being qualified. This step should be
performed following an approved protocol, derived from an SOP,
that describes the requirements for compliance, such as API speci-
fications, manufacturing formula and procedure, product specifi-
cations, and stability studies. The resultant data should be
incorporated into a report for review and decision making, to de-
termimi if the vendor is qualified for the subject API. If the vendor
is being considered as a second source, then the qualification lot(s)
will be compared to a regular production lot.
13. Bring the information and data collected on the vendor to the finished
dosage form manufacturer committee. The decision to approve a new
vendor is one that can be accomplished by presenting the vendor's
background information, audit, and laboratory findings in a report
to a standing committee of representatives from Purchasing, Oper-
ations, Quality Control, Quality Assurance, and Regulatory Affairs.
A procedure such as this can be described in an SOP, whereby the
standing committee is established to rule on this aspect of change
control-the establishment of a new API vendor. The committee
is able to provide judgment, and approval or rejection, based on
the report and the interests of the company and all departments
concerned.
14. Emphasize change control. Subsequent to vendor qualification, there
should be a system and SOP in place to describe the manner
in which changes can be put into effect so as to protect a process
that has been validated and not permit a change in the case of a
qualified vendor, which change may potentially invalidate a vali-

dated process. Change control relates to a procedure by which to al-
low properly for and document a change in the API manufacturing
and control process and provide for revalidation as needed. Change
control can certainly tie into the process by which a new vendor is
approved. It is important to restrict the manner in which changes
can be effected; however, there should be a system to allow for
change, with proper controls, in order to maintain some degree of
flexibility and provide room for improvement in a manufacturing
process.
Also, there are circumstances when a change is required-such
as manufacturing equipment breakdown, for example-and there
must be a procedure to allow for this change. In all cases of change,
we must always maintain regulatory compliance.
One FDA guidance that is useful in providing for postapproval
changes with regulatory compliance is the draft guidance for Bulk Ac-
tive Chemical PostApproval Changes (BACPAC 1) (FDA 1998c). An-
other more recent guidance to bring compliance with the Food and
Drug Modernization Act (FDAMA) provides for changes in approved
NDAs and ANDAs, drug substances, and drug products (FDA 1999).
A vendor will be considered to be qualified as a supplier of an API if the
program described above is completed satisfactorily. Again, it is worthwhile to
reemphasize the importance of change control to, in this case, protect the
qualification of the vendor in a process validation program and provide for
revalidation when it is needed. Once this vendor qualification is completed,
a vendor should be certified and a monitoring program should be established
and implemented.
CERTIFYING A VENDOR
There are several reasons to qualify a vendor (i.e., manufacturer of API), and
these have been discussed in detail above. One of the benefits of this process
is that subsequent to vendor qualification, it may not be necessary to perform
full specification testing on every lot of a raw material on receipt; the process
then creates the need to certify a vendor.
A pharmaceutical manufacturer of finished dosage forms should have a
written procedure to certify and classify vendors, which can be used to de-
scribe abbreviated testing for APis that are vendor qualified. Attention should
certainly be given to the need for differences between actives and excipients,
and compendia! and noncompendial ingredients. The bases for abbreviated
testing are the level of agreement on test results between the vendor and
dosage form quality control laboratories and the degree of process control and
GMP compliance exercised by the API manufacturer and documented in a

vendor audit by the dosage form manufacturer. A sample certification system
follows.
A Category A Vendor is one in which all tests listed in the dosage form
manufacturer's material specifications for the ingredient are performed by the
vendor laboratory. Laboratory results on all samples of the qualification lots
show complete agreement between the dosage form manufacturer's labora-
tory and the vendor's CofAs. Also, an audit has shown the vendor to be
satisfactory.
A Category B Vendor is one in which some tests listed in the dosage form
manufacturer's material specifications for the ingredient are not performed by
the vendor laboratory, or all tests are performed but there is not complete
agreement on all tests between the dosage form manufacturer's laboratory
and the vendor's CofAs. In either case, some tests will be performed on all lots
(i.e., with limited abbreviated testing) by the dosage form manufacturer. An
audit has shown the vendor to be satisfactory or haVing minor unacceptable
features.
A Category C Vendor is one that is undergoing qualification or requalifi-
cation and for which complete testing of all raw material lots is required to be
performed by the dosage form manufacturer. An audit either is in-process or
has shown major deViations.
It is worthwhile to repeat again that a vendor cannot be certified and
classified, such as for abbreviated testing, unless it has been qualified. Also,
the vendor must always have been at a satisfactory level of GMP compliance
to be Category A or B.
Different methods can be used to classify a qualified vendor-the im-
portant point is to adhere to basic quality assurance principles in creating
such a system. By whichever means this is accomplished, it is imperative to
monitor a vendor that is qualified in order to keep the system in control. This
can be accomplished by the dosage form manufacturer performing complete
testing for all specifications periodically, on a time period or lot frequency
basis.
MONITORING A VENDOR
At this point, vendor qualification has been completed and the vendor has
been certified and classified-in conformance to written SOPs. The next step
is to establish a documented program to monitor subsequent deliveries of the
subject material from the vendor. This operation should also be described in
a written SOP.
In monitoring a vendor, a program and schedule should be established
regarding abbreviated testing of the material. If every lot is fully tested against
the material specifications by the dosage form manufacturer, then there is no
issue; however, there may be some tests that will not be performed on every
lot and that will be reported in the vendor's CofA. It is the decision of the
manufacturer to perform full testing "periodically," and this schedule should
be established in a written program. Special attention is focused on APis, non-
compendia! excipients, and excipients that are especially sensitive or critical
to the success of the manufacturing process to establish sound databases be-
fore abbreviating the testing requirements.
In the monitoring program, as well as in a routine testing program, it is
expected that all the dosage form manufacturer's material specifications will
be satisfied in the vendor's CofAs and by the manufacturer's quality control
laboratory. If any out-of-specification or failing result should be reported,
then an investigation should be conducted and a report written. If the out-of-
specification/failure result is confirmed, then consideration should be given
to requalifying the vendor. All of these procedures should be described in
written SOPs. It should be noted also that a written SOP for change control
should be in place so that written documentation, such as laboratory meth-
ods and specifications, cannot be changed without following a defined ap-
proval procedure. Furthermore, if initial material draft or tentative
specifications require change, and such change is supported by scientific data,
then consideration should be given to implementing the change through an
appropriate program.
VENDOR AUDITS
One critical step in vendor qualification is verification that the vendor should
be in compliance with the intent of GMP. This has been indicated above. One
of the problems faced by industry and the FDA is that currently there is no
cGMP regulation for drug substances or excipients. There are several move-
ments underway to develop guidelines; however, there is no official regula-
tory document at this time by which to measure cGMP compliance for a
manufacturer or a "vendor" as described.
There are many elements in an audit that is conducted by a dosage form
manufacturer (or regulatory agency) of the facility that manufactures an API
(i.e., elements that the API manufacturer should have in place in that opera-
tion). The person conducting the audit may want to use a checklist developed
for this purpose for two main reasons. (1) The checklist will include all areas
of the audit to be covered so that nothing will be forgotten. (2) Boxes on the
checklist can be marked, with brief comments that can be added by the audi-
tor, obviating the need for much time spent writing, and allowing for more
time to be spent observing the facility and asking plant personnel questions
in a dialogue. An example of the framework for such a checklist is shown in
Figure 13.3. Remember that this is only a recommendation of a few criteria
that are provided as food for thought.
Figure 13.3 Form for API Vendor Quality Audit Checklist

Page_of_
API Vendor Quality Audit Checklist
cGMP Observation NON D N/A Comments
Documentation
QC/QA program
SOP manual
Change control procedure
Personnel training
Out of spec/failure investigation
Master records
Rework procedure
Process validation program

NDN = no deficiency noted, D =deficiency, N/A = not applicable
The following are some of the major points to be considered in an audit.

This list is just a beginning to the audit program.
Philosophy of Pharmaceutical GMP Compliance

An API manufacturer should have and follow a mission statement that iden-
tifies the firm as being a manufacturer of quality products that satisfies cus-
tomer needs and follows government regulations-including GMP rules-so
as to operate in full regulatory compliance.
There must be a commitment from the firm's top management and all
employees to form a system that will provide quality assurance through team-
work. The philosophy and system must be firm and explicit so that all em-
ployees of the company understand the commitment and participate toward
that objective. It is not sufficient to assign that responsibility only to the
Quality Department; there must be complete involvement by all employees.
Documentation
An organization that follows quality principles must rely on its systems of
documentation in order to maintain regulatory compliance. An API manu-
facturing operation must utilize written procedures that are followed to de-
scribe the manufacturing and control operation.
These SOPs should be assembled into a manual that is available

for personnel in performing their assigned functions. SOPs provide a de-
gree of assurance that an operation will be performed consistently by dif-
ferent people and also consistently by the same person at different times.
Other documentation includes raw material and packaging component
specifications, in-process and finished product specifications, process con-
trols, laboratory test methods, master manufacturing formulas and batch
records, stability records, validation records, and so on-to cover the areas
of GMP. In essence, all operations involved in the API manufacturing
and control operation must be documented in order to assure regulatory
compliance.
Quality Assurance Program

An API manufacturer must have an ongoing quality assurance program in or-
der to comply with the basic concept of GMP. Production personnel should
build quality into the manufacturing operation and the products they manu-
facture; they cannot inspect quality into the operation or its products. The
manufacturing process for a product should include process controls and in-
process tests, in addition to finished product testing, in order to assure that
the manufacturing process is in control and to provide a higher level of as-
surance that the finished product will meet its established specifications. Fur-
thermore, a manufacturer must have a quality unit. Following GMP
principles, this unit has the basic responsibility and authority to approve or
reject all manufacturing components, products, and procedures. The quality
assurance program can be documented as a charter in principle, but should
be described in sufficient detail so that all manufacturing and control per-
sonnel understand clearly that the function of the quality unit is to test
and issue disposition; the function of production personnel is to manufac-
ture products that utilize written procedures and that incorporate quality
principles.
Standard Operating Procedures Manual

A manual of SOPs is necessary for GMP compliance. An API manufacturer
should have SOPs for all basic plant manufacturing and control operations,
including those specific requirements indicated in the cGMP regulations for
finished pharmaceutical products. Basic categories of SOPs include calibra-
tion, cleaning, control, purchasing, maintenance, warehousing, distribution,
production lines, personnel, safety, regulatory, and validation. Some of the
more pertinent requirements that should be included in SOPs are included
in the detail below.
Change Control Procedure

Dosage form manufacturers devote considerable resources to validation and
stability programs in order to comply with GMP. Change control should be
documented in a procedure so as to provide consideration for revalidation
and additional stability studies when changes are being considered in the
manufacturing and control operation. This is true for a dosage form manu-
facturer and an API manufacturer. Furthermore, a change in an API operation
can affect a dosage form in that specifications and stability may be compro-
mised. For these reasons, the API change control procedure should include
communication with their customers. The objective, in this case, is to prevent
a change to an API process that can have a deleterious effect on a dosage form.
Validation of a dosage form can certainly fall short if the API process is not
validated to show that the manufacturing process is in control. In other
words, a dosage form cannot be validated unless an API is manufactured in a
process that is demonstrated to be in control and validated. This means that
consideration should be given to revalidation if an API manufacturing and/or
control process is changed. The more difficult issue is that the dosage form
manufacturer may not be aware of this potential problem (i.e., an API process
being changed), so that they can evaluate any effect of the API change on
their product.
Personnel Training
"People" are one of the major elements in a manufacturing operation. It is
very important that personnel be trained in the duties and responsibilities
that they are expected to perform. If personnel training is not conducted, fol-
lowing an explicit procedure, then there will not be assurance that a manu-
facturing and control process will be performed properly and consistently.
Detailed and complete process validation will not substitute for poorly
trained people who cannot perform a given operation in the same manner,
consistently, and who are not familiar with the procedures that they are
expected to follow. In fact, people may not even be aware that procedures ex-
ist for the functions that they are responsible to perform. Further, these pro-
cedures may not be clear or in sufficient detail and this may not be discovered
unless people are trained properly.
Out-of-specification Data Handling/Failure Investigation

A procedure is needed to provide instructions in the event of laboratory find-
ings showing API material to be out of specifications. This applies to raw ma-
terials, packaging components, and in-process and finished API. The
procedure should describe how to handle such data toward disposition of the
material and consider issues such as retesting and resampling. Also, there is a
need to investigate a failure and provide a written report to explain the devi-
ation-how it occurred and how to prevent it from recurring-and also jus-
tify the disposition of the batch in question. The FDA has issued a draft
guidance (FDA 1998a) to deal with this issue.
Written Master Production and Control Records

with In-Process Controls
Each API product should have an approved master batch record that is used
to manufacture each lot of that product. Deviations should not be permitted
unless they follow the approved change control procedure. Concomitantly,
there should be approved master control records (i.e., raw material specifica-
tions), packaging component specifications, in-process and finished API spec-
ifications, and test methods. All such records should be in sufficient detail,
and in language that is clear and understandable, to provide consistency in
the operation.
Reprocessing and Rework

The master production batch records for an API should provide for reprocess-
ing, or the repetition of any expected purification steps, such as crystalliza-
tion and distillation, that may normally be required to be performed more
than one time, depending on laboratory test results. Steps that are not in-
cluded in the master batch record are considered to be rework and can pre-
sent the need for an API to be revalidated and require additional stability
studies. Further, rework can present serious regulatory implications in that
such steps may not be allowable for use in a commercial product without
proper scientific study and regulatory approval. This area should be given se-
rious thought in the product development stage of an API.
Process Validation Program

This book is devoted to the need and requirements for the process validation
of APis. Suffice it to note here that an API manufacturer should include its
methods and requirements for validation in the SOP system, as a documented
program with the requirement for development and validation reports. These
reports can support the scientific basis for the manufacture of an API and can
be structured as introduction, objective, protocol, data, and conclusion. Fur-
ther, the SOP should describe the use of retrospective, concurrent, and
prospective validation.
Cleaning Validation
One of the important elements of a validation program is cleaning validation.
The objective is to provide cleaning procedures (and agents) for equipment
and facilities to prevent cross-contamination of API products and the intro-
duction of foreign materials. This program is especially important for a man-
ufacturing operation that does not utilize dedicated equipment.
Analytical Methods Validation

Another important element in the validation process is the validation of all
analytical methods used in the testing of an API. This includes verification of
the assay method as stability indicating to indicate the purity of the API and
to identify and quantitate impurities as appropriate. Guides have been issued
by ICH and FDA to address this issue (ICH 1995; FDA 1996).
Stability Program
An API manufacturer should have an ongoing stability program in place by
which to establish expiration dating/retest date for bulk products. There
should be an SOP that describes this program. The program itself should be
based on the use of stability-indicating assay methods that are validated
and that consider degradants, process impurities, and residual solvents (FR
1996). The bulk product samples that are placed into stability testing must
be in the same design bulk container/closure system with the same mate-
rials of construction as those used for production quantities, but may be
of smaller size. Guides are available on this subject (FDA 1998d, 1998e,
1998f).
Control of Suppliers
Attention should be given to those critical raw materials used in the manu-
facture of APis and especially to any intermediates that are purchased. Just
as a dosage form manufacturer must pay attention to their suppliers of APis,
as part of their quality assurance (and validation) programs, so the API man-
ufacturer must turn to their suppliers of critical materials. Validation and sta-
bility efforts are expensive and time-consuming projects, and must indicate
control throughout the entire manufacturing cycle, from the production of
basic raw materials through the production of APis through production of
the dosage form.
Distribution Records
An API manufacturer's documentation system must extend to distribution
records so that each shipment of each lot of each API product can be traced
to every customer shipped that lot. This documentation is especially impor-
tant in the event that a lot of API product is identified as being defective af-
ter it is quality control approved and shipped to a customer so that the lot can
be retrieved by the API manufacturer. An API lot can be found to be defective
if it should fail to meet its predetermined specifications or if any component
used to manufacture the lot is found to be defective to the extent that it im-
pacts on the quality of the API.
Recall Procedure and Capability

An API manufacturer should have an SOP in place to describe the procedure
to be followed in the event of a recall. This SOP should be based on the doc-
umentation system and distribution records that are required. Also, the SOP
should be based on the regulatory requirements and describe any need for a
medical opinion in the event of a safety concern.
Product Complaint Handling Procedure

There should be a written procedure in SOP format to receive, process, andre-
spond to product complaints. This procedure should define complaints and
differentiate them from inquiries. Also, it should define the responsibility of
the person receiving the complaint, which should be integrated into a system
of using a log and form with which the complaint can be tracked and re-
sponded to so that it can be closed out in a timely manner.
Returned Goods Procedure

An API manufacturer should have an SOP that describes the procedure for
handling returned goods. Attention should be given to the handling of ma-
terials that are returned from a customer, for whatever reason. It is not wise
to receive a return from one customer and immediately ship that material to
another customer without an evaluation of the returned material. The extent
of depth in this evaluation should be a function of the reason for the return.
Some common reasons are as follows:
• Customer did not order or want the material.

• Material does not meet the customer's specifications.
• Containers were damaged .

• Material appears contaminated with a foreign substance .
The SOP should be explicit as to the necessary steps to be taken in reevaluat-

ing the returned merchandise and then determining the proper disposition.
Safety Program
Just as for any manufacturing operation, an API manufacturer has invested a
good amount of capital in a facility, equipment, and personnel and has a need
to protect that investment. In addition, a manufacturer has a moral need
to protect its workforce. One important means to provide this protection is
that the API manufacturer should establish, implement, and monitor an in-
tensive safety program. This program should consist of SOPs, personnel train-
ing, and a committee to monitor the program. Sometimes overlooked as
being secondary to the operation of a plant to manufacture and sell product,
the prevention of workplace safety hazards that can result in disasters, such
as fire and flood, certainly demands as much attention. Also, the prevention
of absenteeism by providing personnel with safety equipment, a safe working
environment, and detailed training is a meaningful objective.
Current Drug Master File

A Drug Master File (DMF) must always be current. The DMF is a commitment
that is made by an API manufacturer relative to certain procedures. It is this
commitment that a regulatory agency, such as the FDA, uses when conduct-
ing an audit of a manufacturing facility. The audit findings, when compared
to the DMF, is a measure of the firm's philosophy toward GMP and quality as-
surance. The ideal situation is that a firm's DMF is always current and reflects
the actual practices being followed in the operation. Inconsistencies and dif-
ferences between a DMF and actual practice are an indication of a systems
failure.
Internal/External Audit Program

One safeguard, as a measure of assurance that a manufacturing operation is in
compliance with company standards and GMP, is to establish a program of
self-monitoring. This program should be described by an SOP and consists of
facility and system self-inspection, either by an internal department or by an
external source such as a consulting firm. Whatever the mechanism, the self-
inspection should be conducted on an established schedule and by people
who do not have direct responsibility for manufacturing and testing products.
These programs are performed regularly by dosage form manufacturers-their

customers as well as regulatory authorities-and should also be included in an
API manufacturing operation. The best authorities in a manufacturing opera-
tion, and the people who are aware of and can identify the most weaknesses,
are those people who work in the facility. These are the people who are best
equipped to correct specific problems and their systems and who can accom-
plish this objective in a cost-effective manner-before there are product re-
jects and recalls that are costly events. Also, a facility can certainly be
presented in the best light and the best impression made by showing that per-
sonnel monitor themselves to correct their own problems and even strive to
prevent problems.
Calibration Program
It is very important for an API manufacturer to have a calibration program for
measuring devices used in production and laboratory instruments. This is yet
another example of a program that should be defined in the SOP system. A
manufacturing operation cannot be considered to be in control if the devices
used in production are not calibrated. For example, balances and scales, pres-
sure and vacuum gauges, thermometers, recorders, conveyors, refrigeration
systems, and water meters cannot be used in a manufacturing process, and es-
pecially in a validated manufacturing process, unless they are demonstrated
to be accurate in a program for routine calibration. Furthermore, we cannot
support the accuracy of laboratory test results unless the laboratory instru-
ments are shown to provide accurate results; an ongoing calibration program
is necessary in this case also.
Facilities and Equipment Preventive Maintenance Program

A manufacturing operation relies heavily on the performance of its employ-
ees, equipment, and facilities. Employees get sick, equipment breaks down,
and facilities wear out. Just as we can minimize employee sickness by provid-
ing reasonable working conditions, we can prevent equipment from breaking
down and facilities from wearing out by preventive maintenance. An SOP
program to maintain equipment performance at its optimum by routine ex-
amination and replacement of parts is cost effective, as opposed to employees
having no work to do if there is down time in order to repair a piece of equip-
ment, which may have further complication by having produced defective or
substandard product before it went down. Similarly, maintaining a facility
in a good state of repair in a preventive maintenance program is also cost-
effective. For example, it makes more sense to repair a hole in a wall or
ceiling quickly after it occurs rather than prolonging the repair and finding
plaster or dirt from the hole in a product.
Materials and Labeling Control

An API manufacturer should have systems to assure that materials and label-
ing are used in the proper manner and within the established procedures. Raw
materials should not be used in production until they are approved by the
quality unit to assure that they meet the established specifications. Imagine
the possible outcomes if this procedure is not followed and a raw material is
used before approval by the quality unit-and the material is received in a
damaged drum with possible contamination, or the drum is painted or dirty
with the possibility of paint or dirt falling into the raw material when the
drum is opened, or a raw material fails to meet a certain specification. The
routine usage of raw materials prior to disposition being assigned by the qual-
ity unit does not lead to a process that is in control.
API labeling also should be used following procedures designed to pre-
vent mix-ups and mislabeling. Good judgment should be exercised to provide
assurance that the time and expense allocated to an intensive process valida-
tion program are not lost by poor labeling control with the possible outcome
of drums being mislabeled.
There are many more issues to be covered in an audit of an API manu-
facturing facility. The items above provide a good beginning and framework
by which to establish a program that can be suited in format to the individ-
ual's requirements.
THE AUDITORS
The discussions above have included the need for SOPs to cover many areas
of a manufacturing operation, including internal and external audits. There is
more than one type of audit of an API manufacturing facility, and this issue
will be addressed here. SOPs should enumerate "what" is to be audited and al-
lowed to be audited, "who" does the audit, and "how often" the audit is done.
This relates to audits done in-house by a department of the API manufacturer
that does not have direct responsibility for producing and testing/releasing
product (internal audits). Such audits can also be performed by a third party,
as an external function. In either case, responsibilities should be defined.
Written reports should be issued on the completion of an audit, deficiencies
should be taken seriously and followed-up and corrected. It is most important
that specific problems not be addressed but rather the systems that encom-
pass these problems be evaluated. These systems should be corrected, rewrit-
ten, or written as necessary to prevent problems. Individual problems are only
symptoms of more serious systems failures.
There are other audits that are performed, two of major importance be-
ing done by customers (i.e., dosage form manufacturers or agents) and by reg-
ulatory authorities. There should also be SOPs for these types of audits,
explaining the system of areas that are permitted to be audited and other ar-
eas that may be proprietary and the responsibilities of API personnel in lead-
ing the audit team. It is especially important in this case, and also for
internal/ external audits, that API personnel be adequately trained in the
SOPs and their responsibilities. Poorly trained and unknowledgeable API per-
sonnel can cause a lot of damage in not providing correct information and
not representing the API manufacturer properly, in addition to the poor im-
pression created.
BE PREPARED
The best advice to be given in advance of an audit is to be prepared. An API
manufacturer should perform their daily operations as though an audit will
be conducted every day. The best preparation for no surprise in an audit is to
keep the operation under tight control and to train all personnel in their re-
sponsibilities. A manufacturer that does otherwise, and has loose control over
the plant, will encounter difficulty at some point in time (GMP Trends 1998a,
1999a-f; The Gold Sheet 1994, 1995, 1997, March 1999, April1999). The issue
will not be "if" an audit discloses a problem but rather "when" a problem will
be disclosed.
SOME COMMON PLANT ISSUES

It is appropriate to note some common API manufacturer deficiencies/obser-
vations that have been identified in facility audits by regulatory authorities
and other qualified people. Some of these concerns have been raised during
FDA inspections (GMP Trends 199Sa-c).
• It is a common occurrence that some manufacturing processes are not

validated. It is important for an API manufacturer to create SOPs
and protocols for process validation-to document retrospective
and concurrent programs for current products and a prospective
program for new products. Also, new products should be substanti-
ated by documentation, such as development reports.
• Product batches are sometimes reworked or reprocessed because they do
not meet specifications. This operation should be defined as to
whether it is a repetition of steps in sequence in a manufacturing
process, repetition of a step out of sequence, or additional process-
ing taken based on laboratory results. A manufacturing process that
describes in-process controls and tests, and allows for operations
to be performed (and repeated) based on laboratory findings, is
acceptable provided that the entire process has been described in the
master batch records and validated. It is unacceptable to perform
operations that are not described (in sequence) in the master batch
records for a validated process without first performing revalidation.
• The manufacturing procedure included in a DMF should be the same as
for the master and executed batch records. As above, the manufactur-
ing procedure used in routine production should be the same as the
one in the DMF and that has been validated. This includes the se-
quence of steps and the flow scheme for the final purification step.
• There should be written reports of investigation into product failures. It
is important to investigate a product failure to meet specifications
and to document that investigation-both as a corrective action
and to prevent recurrence. Investigation includes a review of batch
records for the out-of-specification batch and successful batches
and also a discussion with manufacturing, laboratory, and other ap-
propriate personnel.
• The lack of a formal procedure to track product complaints is observed
in many organizations. A written procedure is needed, with a cor-
responding log record and assigned personnel responsibilities.
• Adequate cleaning procedures are oftentimes not in place and validated.
This is especially important for nondedicated equipment and will
help prevent cross-contamination of different products.
• There must be a sufficient number of quality unit personnel in order to
establish and implement a quality assurance program. This obser-
vation is self-explanatory.
• Equipment calibration programs are sometimes not written and imple-
mented. Measuring equipment and instruments that are used in
production and laboratory operations should be calibrated rou-
tinely in a defined, written program to assure that they are func-
tioning properly. This includes devices such as thermometers,
gauges, speed of movement mixers and conveyors, and laboratory
instruments.
• No stated retest date or shelf life and no stability data are observations
that appear frequently in audits. Just as for finished dosage forms,
it is important to define a date after which laboratory testing
should be repeated to assure that an API has not undergone a
change, based on stability data.
• Poor labeling control is often an understated deficiency. Packaging with
the proper labeling is one of the most controllable phases of a man-
ufacturing operation, yet it is also an operation that results in a
significant number of deviations. It is critical to control the label-

ing operation to assure that the correct labeling and identification
is placed on the final bulk container.
• Lack of (quality unit) release of the finished (bulk) product is a step that
is sometimes not assigned to the quality unit. Final release, which
is an authorization to ship to a customer, should be controlled so
that one final check can be exercised following company procedure
before a batch is shipped. This control should be assigned to the
quality unit.
• The need for personnel training is a common citation. It is very im-
portant that personnel be trained in company procedures, SOPs,
and regulatory requirements so as to implement and use the docu-
mentation and practices established by company management. All
too often, companies have excellent systems and procedures, but
personnel do not use or follow them because either the people are
not aware of the systems and procedures or they do not understand
them.
• A mechanism for a company's self-improvement, such as through inter-
nal audits, is an important responsibility only sometimes utilized. A
smart organization will monitor itself and solve and prevent prob-
lems through appropriate systems, before being audited by a cus-
tomer or regulatory agency.
• A formal change control procedure does not exist oftentimes. There
should be a written SOP describing the mechanism to change a pro-
duction or laboratory procedure, or any company procedure. Con-
sistent production and product quality, to conform to regulatory
requirements, is based on established written procedures that
should not be changed without proper documentation and autho-
rization.
• Some companies do not have a formal, written quality assurance proce-
dure. This document will establish the commitment to quality by
top management and will serve as a template for all employees to
follow. Quality products may not happen without top manage-
ment support and a written procedure for all employees to follow.
PREPARATION AIDS
There are many documents that are available and procedures and practices
that can be used to help provide the philosophy and framework for GMP to
an API manufacturer. Some of these have been discussed earlier in this chap-
ter, but a list is provided here for ready reference:
• SOP for internal and/or external audits

• Plant GMP and Validation Committee
• FDA compliance guides (FDA 1990, 1993, 1994)
• FDA draft guidance on GMP (FDA 1998b)
• FDA inspection guide (FDA 1992)
• FDA EIRs (Establishment Inspection Reports)
• UK monograph for APis (IQA 1992)
• IPEC (International Pharmaceutical Excipient Council) guideline
for GMP (IPEC 1995)
• "Code of Federal Regulations" for finished dosage form GMP regu-
lations (Parts 210 and 211) and the new drug regulations (Part 314)
(21 CFR)
• ICH (International Conference on Harmonization) guidelines on
stability, impurities, and analytical procedures validation (FR 1996)
• ICH draft guideline on GMP (ICH 2000)
• United States Pharmacopeia (USP 2000)
• Listen to your auditors and evaluate their comments, written and
verbal
REFERENCES
Berry, I. R. 1981. Process validation of raw materials. Pharm. Tech. 5 (2):38.
Berry, I. R. 1988. Process validation: Practical applications for pharmaceutical prod-
ucts. Drug Dev. Ind. Pharm. 14 (2 and 3): 377.
Berry, I. R. 1993. Process validation of raw materials. In Pharmaceutical process valida-
tion, 2nd ed. New York: Marcel Dekker, Inc.; p. 203.
Berry, I. R., and R. A. Nash, eds. 1993. Pharmaceutical process validation, 2nd ed. New
York: Marcel Dekker, Inc.
21 CFR. Code of Federal Regulations, Title 21, Parts 210, 211, and 314. Washington,
D.C., USA: U.S. Government Printing Office.
FDA. 1990. Sterile drug process inspections. Program #7356.002A, FDA Compliance Pro-
gram Guidance Manual. Rockville, Md., USA: Food and Drug Administration.
FDA. 1992. Guide to the inspection of foreign phannaceutical manufacturing plants.

Rockville, Md., USA: Food and Drug Administration, Office of Regional Opera-
tions, International Programs and Technical Support Branch.
FDA. 1993. Process validation requirements for drug products subject to premarket approval.
Section 490.100 (Compliance Policy Guide #7132c.08), FDA compliance policy
guide manual. Rockville, Md., USA: Food and Drug Administration.
FDA. 1994. Preapproval inspections/investigations. Program #7346.832, FDA compliance
program guidance manual. Rockville, Md., USA: Food and Drug Administration.
FDA. 1996. Guidance for industry-Q2B Validation of analytical procedures: Methodology.
FDA. 1998a. Investigation out of specification (OOS) test results for phannaceutical produc-
tion. Draft guidance. Rockville, Md., USA: Food and Drug Administration.
FDA. 1998b. Manufacturing processing, or holding active phannaceutical ingredients. Draft
guidance. Rockville, Md., USA: Food and Drug Administration.
FDA. 1998c. BACPAC I: Intennediates in drug substance synthesis-bulk actives postapproval
changes: Chemistry, manufacturing, and controls documentation. Draft guidance.
FDA. 1998d. NDAs: Impurities in drug substances. Draft guidance. Rockville, Md., USA:
FDA. 1998e. Stability testing of drug substances and drug products. Draft guidance.
FDA. 1998f. ANDAs: Impurities in drug substances. Draft guidance. Rockville, Md., USA:
FDA. 1999. Changes to an approved NDA or ANDA. Guidance for industry. Rockville, Md.,
FR. 1996. International Conference on Harmonization. Federal Register 61 (3):372.
GMP Trends. 1995a. Manufacturing-Bulk phannaceutical chemicals. Boulder, Colo.,
USA: GMP Trends: January 15, p. 3.
GMP Trends. 1995b. Manufacturing-Bulk phannaceutical chemicals. Boulder, Colo.,
USA: GMP Trends: January 15, p. 3.
GMP Trends. 1995c. Manufacturing-Bulk phannaceutical chemicals. Boulder, Colo.,
USA: GMP Trends: May 15, p. 3.
USA: GMP Trends: December 1, p. 3.
USA: GMP Trends: February 1, p. 3.
GMP Trends. 1999b. Manufacturing-Active phannaceutical ingredients. Boulder, Colo.,
USA: GMP Trends: March 1, p. 3.
GMP Trends. 1999c. Manufacturing-Active phannaceutical ingredients. Boulder, Colo.,

USA: GMP Trends: April 15, p. 3.
GMP Trends. 1999d. Manufacturing-Active phannaceutical ingredients. Boulder, Colo.,
USA: GMP Trends: May 15, p. 3.
GMP Trends. 1999e. Manufacturing-Active phannaceutical ingredients. Boulder, Colo.,
USA: GMP Trends: July 1, p. 3.
GMP Trends. 1999f. Manufacturing-Active phannaceutical ingredients. Boulder, Colo.,
USA: GMP Trends: August 15, p. 3.
The Gold Sheet (March 1994): 28. Chevy Chase, Md., USA: F-D-C- Reports.
The Gold Sheet (April 1995): 29. Chevy Chase, Md., USA: F-D-C- Reports.
The Gold Sheet (April 1997): 31. Chevy Chase, Md., USA: F-D-C- Reports.
The Gold Sheet (March 1999): 33. Chevy Chase, Md., USA: F-D-C- Reports.
The Gold Sheet (April1999): 33. Chevy Chase, Md., USA: F-D-C- Reports.
ICH. 1995. Guideline for industry, text on validation of analytical procedures. Geneva,
Switzerland: International Conference on Harmonisation.
ICH. 2000. Good manufacturing practice guide for active phannaceutical ingredients Q7a.
Draft 7. Geneva, Switzerland: International Conference on Harmonisation.
IPEC. 1995. Good manufacturing practices guide for bulk pharmaceutical excipients. Inter-
national Pharmaceutical Excipient Council.
IQA. 1992. Bulk pharmaceutical chemicals-Pharmaceutical quality group monograph.
Newnorth Print Limited, Kempston, Bedford, England: Institute of Quality
Assurance.
ISPE/FDA. 1995. Phannaceutical engineering guide, A guide for new facilities-Volume 1:
Bulk phannaceutical chemicals. Rockville, Md., USA: International Society for Phar-
maceutical Engineering and Food and Drug Administration.
Madan, P. L., and A. Komotar. 1979. Quality Control of Pharmaceuticals. Drug Cosmet.
Ind. 124 (4):66.
Martinez, E. R. 1994. An FDA perspective on bulk pharmaceutical chemical GMPs,
control, and validation. Paper presented at the National Association of Pharma-
ceutical Manufacturers Workshop on APis, 8 March, in New York.
PMA. 1994. Concepts for the process validation of bulk phannaceutical chemicals. Pharma-
ceutical Technology Europe, PMA QC Section, Bulk Pharmaceuticals Committee,
p. 37.
USP. 2000. The United States phannacopeia. 24th rev. Taunton, MA: Rand McNally.
14
QUALITY ASSURANCE SYSTEMS
Fred C. Radford
Alert Consultants, Inc.
Byron Center, Michigan
From the time of ancient China's bureaucratic and centralized state control,
to today's open and empowering fourth or fifth wave of discipline, and from
simple tools and handicrafts to complex drugs produced with biotechnology,
the assurance of quality has always been a part of government, industry, and
society (Qiupeng et al. 1995).
As is true today, many innovative quality programs resulted from infor-
mal and voluntary efforts to create and meet competitive pressures. As is also
true today, an ever-growing government bureaucracy issued formal and im-
plicit regulations based on societal and government-mandated laws or de-
crees. Most people feel it is the role of government and industry with their
many supporting "quality assurance" or compliance systems to minimize the
likelihood of undesirable situations. We would like a risk-free environment so
we can live in tranquility and the pursuit of happiness.
But ... the problem ... is us. We have the primary inputs to
processes and also the propensity for error.
We read about human achievement throughout history and call it

progress. The United States is certainly one of the greatest successes, even
though its future seems tenuous at times to the most pessimistic. However,
throughout history neither men nor their various unions, companies, na-
tions, or unions of nations have succeeded totally in preventing poor quality,
industrial failure, deception, or fraud. In overreaction, governments have fre-
quently made more laws and regulations and added police and armies to
369
bring all into compliance, order, and tranquility. But as glimpses of insight
surface, so does the idea that we have found the problem, and it is us. We
have the primary inputs to processes and also the propensity for error.
Look at the U.S. quality during its beginnings. The early settlers in Amer-
ica carried on basic manufacturing techniques largely based on those devel-
oped over many centuries in Europe. After gaining independence, the
colonies gradually moved from agriculture production to implement and im-
prove on these manufacturing capabilities. Along with the skill itself, the mas-
ter craftsman passed on to an apprentice his or her particular method of
quality control, usually some form of inspection Ouran 1995).
Taylor's system of "scientific management" gave rise to the
use of independent inspection departments early the last
[1900-2000] century Ouran 1995).
With seemingly unlimited natural resources and a strong entrepreneur-
ial spirit, these new Americans soon entered the Industrial Revolution that
had also begun in Europe. We saw the simultaneous introduction of the cot-
ton gin, interchangeable parts, and new firearms. American innovation
through Frederick Taylor's system of "scientific management" (he did not call
it scientific) gave rise to the use of independent inspection departments early
in the last century Ouran 1995). Taylor's unconventional system of mass pro-
duction played a major part in U.S. productivity leadership, especially as
adopted by Henry Ford.
Today where quality assurance or control is still perceived as a
force or entity distinctly outside the production pathway, we still
find an obvious or sometimes subtle adversarial relationship.
But this system also had a long-term negative effect that we feel to this
day. It separated designers and engineers, in development and planning, from
those supervisors and workers who were responsible for the execution of
manufacturing. A rivalry developed between the inspector and the inspected.
This adversarial relationship continues to have significant negative effects in
product development and manufacturing as well as overall product quality.
Today, where quality assurance or control is still perceived as a force or entity
distinctly outside the production pathway, we still find an obvious or some-
times subtle adversarial relationship.
Inspection will undoubtedly always be with us in some form
or other, by manual and high-tech approaches.
For the past decade, attempts to eliminate this inspector-inspected sepa-
ration and the sometimes bitter opposition it fostered have been the goal of
professional management, regulatory agencies, such as U.S. the Food and
Drug Administration (FDA), and the regulations and policies they promul-
gate. Inspection will undoubtedly always be with us in some form or other,
Quality Assurance Systems 37:1.
both by manual and high-tech approaches. But inspection has taken a sec-
ondary position to the recent emphasis on building quality into processes and
end products. We see transition into a worldwide movement toward total
quality management (TQM), a process and systems approach, and continuous
improvement.
In the 1960s, the United States was initially shocked into a refocus on
quality. After the WWII production experience, it seemed that nothing could
stop us. We were "the only game in town." But at the same time a new concept
of total quality and continuous improvement was being taught to the recover-
ing Japanese by American statisticians W. Edwards Deming and Joseph M. Ju-
ran. Several decades later, U.S. markets were flooded by Japanese products, and
major companies began to ask, "If Japan can do it, why can't we (NBC 1980)?"
Deming and others led the quality march through their speaking, writ-
ing, seminars, and hands-on guidance of industry clients. Many industry
leaders surged toward this new direction. Philosophies, definitions, and tech-
niques were developed with a myriad of acronyms-JIT (just in time), TQM,
TPM (total process management), CIS (continuous improvement systems).
Many U.S. industries were quick to adopt and improve on TQM. The concepts
of verification of true quality gradually shifted from inspection data to the
validation of processes and the use of statistical process control (SPC). Simi-
larly, the bearer or owner of the responsibility for quality throughout the pro-
duction cycle changed. According to Juran,
During the 1980s there emerged in the United States a major

trend toward assigning quality management work elements to
the functional line departments rather than the quality de-
partments.... As of the late 1980s, this trend (to assign qual-
ity management work elements to the line personnel) has
been gaining in momentum and has probably become irre-
versible (Bongiovanni 1994).
Operations also have trended toward a team approach in establishing

standards and solving problems and toward assigning responsibility for com-
pliance to the department doing the work. Formerly, hierarchical organiza-
tions have begun to "downsize" the middle layers and flatten out. The new
management theory emphasizes leading instead of threatening or dictating,
and the view that people at all levels of an organization have the same needs
for participation in corporate vision and organizational learning. Those fo-
cused on control began to change their thinking and adopt a posture of lead-
ership and team decision making. But even here a number of experiments,
such as quality circles, came in as lions and went out like lambs as this now
very dynamic art and science of quality programming advanced.
The pharmaceutical industry, however, was earning a lot of money in
the two decades between 1965 and 1985, even during periods of economic re-
cession. Product inspection emphasis in the corporate organization for FDA
approval and continued marketing sustained adversarial postures in true Tay-

loristic fashion (Deleers 1994). Under new regulations and early interpretive
policies, the problematic separation persisted. Typically Quality departments
were not involved in the development process or the transfer of technology to
production. But then those very Production departments were inspected and
audited by the somewhat out-of-sync Quality departments.
Numerous quality issues had surfaced publicly, but sporadically, in the
pharmaceutical industry some 40-50 years ago, which resulted in a stronger
regulatory mandate to protect public health. Current concepts of quality as-
surance appeared a few years later driven by the FDA's own Good Manufac-
turing Practices (GMP). The concept of GMP was based on the realization that
the quality of highly complex pharmaceutical products cannot be controlled
by endproduct testing alone. Experience had shown that assuring the safety,
purity, and efficacy also depends on the manufacturing process and its vali-
dated ruggedness and control of critical variables (Heir 1994). This process in-
cludes all of the GMP elements shown below:
• Organization and personnel
• Buildings and facilities
• Equipment
• Control of components and drug product containers and closures
• Production and process controls
• Packaging and labeling control
• Holding and distribution
• Laboratory controls
• Records and reports
• Returned and salvaged drug products
Food and drug legislation and regulations evolved. Major additions were
developed in reaction to a number of domestic and foreign tragedies. Some
people view parts of this legislation as political overreaction, resulting in
added bureaucracy and unnecessary control. In the United States, in 1937,
107 people died after taking an elixir of sulfanilamide incorrectly formulated
with the very toxic diethylene glycol. The result was the 1938 Food, Drug,
and Cosmetic Act (FD&C Act) that introduced a registration system for new
drugs and an FDA system of factory inspection. But we did not see the phrase
good manufacturing practice in legislation until passage of the Kefauver-Harris
Amendment to the FD&C Act in 1962 (Heir 1994).
In Europe, in 1959, the thalidomide tragedy resulted in much tighter
controls on new drug substances and formulations. GMPs were still some
time in development. The European Pharmaceutical Industries Association
(PIA) first published voluntary GMP guidelines in 1968. The World Health Or-
ganization (WHO) published its GMP guidelines in 1969. These were followed
worldwide outside the United States. The Pharmaceutical Inspection Conven-
tion (PIC) was established in 1970 by the European Free Trade Association
(EFTA) and followed the WHO text in its GMP guide. The most recent WHO
guidelines are a mix of guides from the European Economic Community
(EEC) and the ISO 9000 quality system guidelines of the International Orga-
nization for Standardization (Heir 1994).
The various international GMP requirements, objectives, and foci are
similar but differ considerably in their legal status. Some are legally binding,
and some are in the form of guidelines. Comparison is difficult, however, be-
cause of the varying rigor of implementation by industry and unlike relation-
ships between companies and the government agency inspectors. However,
for the U.S. domestic products and foreign products for import, it is still the
FDA that sets the standards. Manufacturers of active pharmaceutical ingredi-
ents (APis) must keep current with the FDA's inspection program and the strict
enforcement of GMP as linked with their New Drug Application (NDA) and
Abbreviated New Drug Application (ANDA) preapproval inspection. The FDA
has made GMP the major issue for the pharmaceutical industry (Heir 1994).
The FDA's drug GMPs, as currently applied to APis, along with
their much more specific 1998 draft guidance on APis, place
most of the emphasis on the critical parts of the process for
producing a quality product.
But the difference in this long list of rapidly developing regulatory con-
trols is more than status or expected level of enforcement. A key distinction
that must be kept in mind is the compliance approach, or the point of appli-
cation of the varying quality systems and standards. ISO 9000, for example, is
primarily applied to the product produced, with only a minimal emphasis on
how this is done. The ISO has not required a new corporate philosophy or cul-
ture change. If your process is very good at a certain point, you can set a spec-
ification and measure or test for compliance. This may meet the customer's
delivered product specification. You may appear to have a good process that is
under control, even though a significant quantity of end product is rejected
through some form of inspection. Certification may be achieved even though
competence is lacking. Once certified, a company can forget about continu-
ous improvement (Hawkins 1996). In contrast, the FDA's GMPs as currently
applied to APis place most of the emphasis on the critical parts of the process
for producing a quality product. Required quality control and auditing prac-
tices should result in improvement of formulations and processes. The FDA
places less weight on inspection criteria.
In the last two decades, new combinations of social, economic, regula-
tory, and competitive pressures have become major challenges for the phar-
maceutical industry. With the growing additional emphasis on reducing
healthcare costs and the expiration of many patents, both the industry and
the FDA have focused on functional quality as it related to product equiva-

lency. They, along with most other industries, are responding with programs
of TQM and continuous improvement of processes (Deleers 1994).
At the same time, in the aftermath of the U.S. generic drug scandal,
generic and pioneer drug company GMP deficiencies, plant shutdowns, and
consent decrees, the FDA has placed a major emphasis on GMP, starting in
product development and continuing through approved formulation. API
manufacturing plays a large part in the related preapproval inspections. The
validation of all processes, equipment qualification, and materials analysis
used in commercial production is both required and closely scrutinized dur-
ing plant inspections. The generic scandal gave the FDA the social impetus it
needed to rapidly implement new and tougher enforcement practices. This
change in the regulatory environment has been both a major challenge and
opportunity for most companies. It has brought on the demise of others un-
able to meet the challenge. All of this says that the importance of quality sys-
tems and procedures cannot be emphasized enough. Implementation of and
ongoing commitment to total quality systems and procedures results in effi-
ciently run manufacturing facilities on which U.S. companies and regulatory
agencies may rely (Weissinger 1994).
We are all continually faced with a series of great opportuni-
ties, brilliantly disguised as insoluble problems (Bajaria and
Copp 1991).
The FDA has now emerged from a postscandal black box, or perhaps put
more kindly, a cocoon. It has the attention of industry. But now FDA leader-
ship and the administration are recognizing additional internal and external
customers. Industry thought the pace of change was about to slow down. The
FDA's internal government and administration customers are demanding a
continuously reengineered FDA. External customers on the domestic side are
making demands from a political agenda that sets high priority to fast track
and user fee-related drugs. International demands provide molds for the har-
monization of product standards, dossier format, and related clinical testing
data extent and integrity. The U.S. generic industry struggled with the applica-
tion of standards from the International Conference on Harmonisation (ICH
1997). They will probably be affected by ongoing GMP standardization discus-
sions between Japan and the European Union (EU). This is the new global en-
vironment for the production of APis used in FDA-approved products.
In conclusion, (1) inspection as a quality assurance tool has always been
with us and with only less emphasis will remain so; (2) when quality assur-
ance is a department outside the production pathway, its personnel are usu-
ally seen as an adversary to some extent; (3) Japan's postwar recovery and
quality improvement with the help of quality gurus caught an overconfident
American industry offguard; (4) new management theory emphasizes leading
over threatening or dictating, and the view that people at all levels of an
organization have the same needs; and (5) the FDA's recent initiatives are
based on the quality management and validation of processes and only sec-
ondarily on in-process and endproduct inspection.
DEFINITION AND DECISION

There are many tangent industries that supply raw materials and processing
aids to the pharmaceutical industry as it moves from discovery of a New
Chemical Entity (NCE) to an approved new drug. One of the key support and
supply industries is the manufacturing of both NCEs and the well-character-
ized and off-patent APis. In regulatory terminology, these are known as bulk
pharmaceutical chemicals (BPCs), "active ingredients" or "drugs" or "drug
substances," and, more recently, APis. Having looked briefly at the state of the
global political, regulatory, and quality scene, we now look more specifically
at the determination and implementation of quality programs for APis.
The assumptions are that these analyses and summaries are general and
cover the continuum of small to large organizations, older and recently con-
structed or even envisioned facilities, and the use of outside laboratories and
contract manufacturers (e.g., for micronization). This is an overview describ-
ing various ways of overlaying the specific GMP and validation requirements
on somewhat unique companies. All API manufacturing or processing opera-
tions require the following:
• Quality assurance oversight and quality programs
• Good development practices and documentation
• Continuous internal and external auditing
• Periodic process and product review
• Superior transfer of technologies
• The required validation
• Packaging and labeling controls
The context is global marketing goals and a myriad of terms, interpreta-
tions, varied emphasis on compliance, ever-changing standards, and intense
competition. And as we look at the numerous overlapping requirements that
may be implemented for APis, the question is whether what we see coming at
the end of the tunnel is a light or a freight train. The most obvious problem
for the manufacturer is to determine what quality means as it relates to the
company's strategy for business.
From the FDA's viewpoint, both legislative and regulatory qual-
ity requirements for drugs cover an API from development,
through scale-up, to final production and distribution and are

fairly well defined.
In the narrowest sense, what constitutes Current Good Manufacturing
Practice (cGMP) and the total quality program for the API manufacturer?
From the FDA's viewpoint, both legislative and regulatory quality require-
ments for drugs cover an API from development, through scale-up, to final
production and distribution. They are fairly well defined by cGMP regulations
for finished dosage forms, by guidelines for all types of validation, by FDA
policies and procedures, and finally by current state-of-the-art practice in the
industry. This liberal approach is taken by the FDA, even though both the
FDA's internal API guidance and the preamble to the original21 CFR Parts 210
and 211 state that APis are not specifically the subject of these regulations.
The FDA's only specific policy statement of its enforcement posture is found
in its Guide to Inspection of Bulk Phannaceutical Chemicals:
As a general rule, however, it is reasonable to expect GMP con-
cepts to start to become applicable at that point where a start-
ing material enters a biological or chemical synthesis or series
of processing steps, where it is known that the end product
will be an API (FDA 1991).
In addition, all peripheral systems having an effect on this API synthetic
or biological pathway must comply with certain general and other very spe-
cific FDA regulations, guidelines, and policies (FDA 1991). At present, the eco-
nomic pressures both to market the bulk chemical and to gain FDA approval
make it difficult to oppose the investigator who takes a more liberal position
regarding his or her authority. The more recently issued draft guidance for in-
dustry is a clear and explicit application of those practices to APis (FDA 1998).
If the corporate driving force stated clearly is an unqualified

"total quality vision and mission," the job is easier.
Another problem is the actual determination, interpretation, and appli-

cation of requirements of quite an assortment of overlapping quality pro-
grams and the priority for implementation. If the corporate driving force
stated clearly by top management is an unqualified "total quality vision and
mission" the job is easier. The requirements can be identified, prioritized, and
complied with, though still requiring a lot of hard work, extensive resources,
and several years. Expect minimal communication difficulties and greater per-
sonal enthusiasm. On the other hand, when managers stress economic and
other factors or send mixed messages about the corporate aims and philoso-
phy, the task is much more difficult.
Another difficult decision is the process, systems, job functions and tools
a company will adopt to implement and maintain compliance with the se-
lected set of quality elements. As mentioned above, there is an abundance of
literature available. However, the majority of companies follow the approach

of W. Edwards Deming and his disciples. His lectures and publications are the
most often quoted and the most comprehensive. There is still much support
for the soundness of his theories and practical advice.
Deming developed a management philosophy described in a set of 14
guiding principles and a strong emphasis on systematic analysis. In the im-
plementation phase, a company may also include a wide range of simple to
very sophisticated statistical and management tools. These are brought to-
gether with a competency in the particular manufacturing art to form a body
of what Deming calls "profound knowledge," which is necessary for consis-
tent production of quality product. Deming's 14 points are as follows:
1. Create consistency of purpose for improvement of product and
service.
2. Adopt the new philosophy.
3. Cease dependence on mass inspection.
4. End the practice of awarding business on price tag alone.
5. Improve constantly and forever the system of production and service.
6. Institute training.
7. Institute leadership.
8. Drive out fear.
9. Break down barriers between staff areas.
10. Eliminate slogans, exhortations, and targets for the workforce.
11. Eliminate numerical quotas.
12. Remove barriers to pride of workmanship.
13. Institute a vigorous program of retraining and education.
14. Take action to accomplish the transformation.
The other key functional piece of the Deming philosophy is the Plan-
Do-Study-Act (PSDA) cycle for implementing principle number five and sev-
eral others. The goal in applying PDSA cycle pictured in Figure 14.1 is
continuous learning and improvement (Latzko and Saunders 1995).
Some people would like to think that the pharmaceutical industry is dif-
ferent from any other industry. It may be easily argued that it is one of the
most regulated. And these regulations are motivated not only by considera-
tions of control or consumer safety but also by a very highly lobbied political
structure in a very emotional public. The regulatory authorities thus have a
statutory duty to police the industry intensely. With each new concern or
crisis, public pressure has imposed more and more regulatory controls
Figure 1.4.1. PDSA Cycle
The old way is:
1. Design 2. Make 3. Sell
... ...
The new way is:
4. Adopt change or run 1. Plan a change

in several different
environments
3. Study the results 2. Try it out
concerning practically all aspects of the business (Heir 1994). This supports
the need for TQM.
And now in the past several decades, customers have taken the quality
issue to a new level beyond the availability, safety, and efficacy of the end
product. They want companies they can trust. Customers want agreements
and long-term relationships infused with trust and dependability (Popcorn
1991). They want to see Dr. Stephen Covey's "7 habits" in action.
• Be Proactive-recognize we are free to choose.

• Begin with the End in Mind-identify our personal mission and goals.
• Put First Things First-act on our priorities.
• Think Win-Win-seek alternatives that allow everyone to win.
• Seek First to Understand, Then to be Understood-listen deeply.
• Synergize-explore differences together.

• Sharpen the Saw-daily cultivate all of the above (Covey 1993) .
Personal character and honesty embellish these "habits" as the founda-
tion of leadership and corporate effectiveness (Covey 1993). Economic factors
come in second. A company· planning to survive over the next decade must
factor these ethical elements into its mission and plans.
In this context, it is unrealistic to say "we will install the minimal com-
pliance elements" to pass inspection and be on with our business. It is unreal-
istic because it seems that the FDA and other agencies throughout the world,
as rules and policies evolved, have implemented significant parts of a TQM
system. This is particularly true with the shift of emphasis from quality
through inspection and endproduct testing to development and process in-
tegrity verified by rigorous process validation. Validation and GMP have be-
come two inseparable concepts and major contributing factors of quality
assurance (Adamson 1992). A company that only does what the legislation re-
quires, and only shows the auditor what it is required to show, is taking a po-
sition of high risk.
Because of this kind of narrow focus on the end product, some experts
feel quality systems, such as ISO 9000, when implemented, may do little to ef-
fect improved process quality. For this reason quality leaders in the auto in-
dustry addressed this perceived weakness with the development of their own
standard, QS 9000, which will place more emphasis on the whole system or
process rather than on a mere meeting of specifications with the material re-
leased for distribution.
Further, a strategy of minimal requirements is in contradiction with cur-
rent quality and ethical management concepts. It leads to mistrust and, some-
times, a misplaced confidence by the customer. And, as emphasized, trust is
needed to come to a mutual understanding and acceptance of approaches
worldwide. Unfortunately, this difference in attitude is reflected in the differ-
ing approaches to inspections by European and U.S. authorities (Meyer and
Korteweg 1994). The FDA's intensive NDA review and Preapproval Inspection
(PAl) grew out of just a short season of rightful mistrust.
Applying inspection specifications to in-process product and only plac-
ing on the production report the numbers of the product meeting the stan-
dard is deceptive and inconsistent with the total quality concept. As
mentioned above, such a "compliance-driven" management falls short in to-
day's commercial manufacturing environment that demands a broader over-
lay of quality management as seen in TQM. We see this expressed in some of
the latest GMP guidelines, both domestic and international:
For product development, the application of quality manage-

ment concepts not only offers means to optimize regulatory
compliance process control and resulting product quality in a
relatively complicated environment, but it also provides an
essential first step in the quality management system extend-

ing from product design through commercial manufacture to
the customer (Heir 1994).
In conclusion, the random or statistical sampling and testing for re-

leasable product may significantly affect subsequent customer service and ma-
terial returns. The days of producing one failing batch in every six, for
example, are becoming history. The entire process must be under control
and continuous review. The FDA discusses this concept in its "bulk guide" on
page 7.
A good starting point for the BPC [API] inspection is a review

of product failures evidenced by the rejection of a batch that
did not meet specifications, return of product by a customer,
or recall of the product. The cause of the failure should have
been determined by the manufacturer, a report of the investi-
gation prepared, and subsequent corrective action initiated
and documented. Such records and documents should be re-
viewed to ensure that such product failures are not the result
of a process that has been poorly developed or one that does
not perform consistently (FDA 1991).
FDA REQUIREMENTS ARE CENTRAL
As stated above, it is explicit in the regulations that GMP must be imple-

mented in all functions or parts of functions that impact on the manufacture
of the API. A second implicit concept is the logical extent of implementation.
This involves identifying the clearest boundary around the API operation and
applying appropriate GMP in the strictest sense within that boundary. This
area may be defined by walls or cubicle or by the whole facility. It may be
largely defined by computerized systems. The point is that if both APis and
excipients or other chemicals are made within the minimally definable API
boundaries, then apply the most conservative GMPs and quality assurance to
all products made in that area. Under such a system of control, APis, excipi-
ents, and finished product will be fit for their intended use.
This involves identifying the clearest boundary around the

API operations and applying appropriate GMP in the strictest
sense within that boundary.
For most companies that hold compliance and change as a high priority,
the interpretation of GMP in the strictest sense is secondary to the way in
which these requirements are currently applied by the FDA. In fact, even
when the FDA seemingly incorrectly interprets GMP, or as with the recent
Barr decision bases its application on a judge's ruling, the reasonable thing to
do as a company is go along with it. When most companies follow an inter-
pretation, even a questionable one, the FDA considers it state of the art or cur-
rent GMP. The new requirement will hold until clearly shown in a data-based
approach as no longer necessary, or when a more effective alternative is pre-
sented and scientifically defended.
If issue is to be taken, it is more appropriate, more effective,

and much safer for individual companies if it is presented by a
trade association as the industry consensus.
The same is true at the international level. With the harmonization of

GMP regulations, and their enforcement, it is still the FDA's application of
cGMP, and related guidelines and policies, during foreign company inspec-
tions that will determine if U.S. drug and biological applications are ap-
proved, and whether, once established, the importation of a drug substance
can continue following a failing inspection of the API manufacturer. If is-
sue is to be taken, it is more appropriate, more effective, and much safer for
individual companies if presented by a trade association as an industry
consensus.
In summary, historical experience and the immediate environment of
regulatory development on a global scale seem to point the wise corporate
leader toward emphasizing GMPs for APis in the broader framework of total
quality system. Chief executive officers (CEOs) and general managers are be-
ginning to see that they can realize their economic goals only along with ap-
plication of a total quality system to the entire company's business-
processes, R&D, marketing, manufacturing, sales, finance, and so forth. This
will result in improved efficacy, higher productivity, and a better company
image. Above all, the company will realize an increased flexibility and prof-
itability needed to face the challenge of world competition (Deleers 1994).
THE INSPECTION FOCUS
Quality is a characteristic of the product, but it is built in by the system or

processes that produce it. On the other hand, one can have phenomenal sys-
tems and processes and produce poor quality product. It is the combination
of cGMP, validated and robust formulations and processes, and the context of
an adequate quality assurance system that produces quality products.
Validation and GMP have become two inseparable concepts and

major contributing factors of quality assurance (Adamson 1992).
Many companies still try to "just get by." Others have been over-
whelmed by the rapid pace of change over the last decade and have or will
remain in a catch-up mode for some time. It seems unfortunate that some will
never catch up. And that fact raises the potential of more incidents of failure
and further damage to an otherwise healthy industry.
The international inconsistency of regulations and enforcement men-
tioned above only adds to the difficulty. Regulatory inspections of manufac-
turing facilities may last hours or months, may be announced or
unannounced, may be formal or relatively informal, may be by qualified or
unqualified inspectors, or they may not take place at all in some countries.
The penalties for noncompliance may include the following:
• Practically none
• Withdrawal of manufacturing licenses
• Withholding of registration approvals
• Prosecution of the company or individuals often under criminal
rather than civil law (Deleers 1994)
In the United States, the FDA's enforcement powers were significantly
increased by the introduction of the PAl program, linking the NDA or ANDA
approval to GMP compliance. Withholding an approval is a very severe
penalty and can be very damaging to a company. The FDA has tied this au-
thority and priority to the API manufacturer as a key player in this drug li-
cense approval.
The key objectives of the FDA's PAl program were stated as follows:
• Evaluation of the establishment's compliance with cGMP require-
ments, including coverage of the specific batches used to demon-
strate bioequivalence
• Evaluation as to whether the establishment has adequate facilities,
equipment, procedures, and controls to manufacture the product
in conformance with application commitments
• Audit of the accuracy of the biobatch manufacturing and testing
information submitted with the application
• Collection of a sample of the biobatch from the bioequivalence test
laboratory (Heir 1994)
PAis are rigorous. The FDA's expectations are high. This can be seen by a
thorough review of the "bulk inspection guide" and the new draft guidance
(FDA 1998) and by the number of companies receiving a refusal to approve.
These inspections are specific to the NDA and challenge the integrity andre-
producibility of the API specifications in the NDA or ANDA. The FDA also ver-
ifies that the API process is as described in the Drug Master File (DMF)
submitted to the Center for Drug Evaluation and Research (CDER) in
Rockville, Md. If the data do not satisfy the FDA, then the investigator will
send a recommendation to CDER that the application for a specific API be
withheld from approval. Corrective action may be taken, but the time lost to
turn this type of situation around can have enormous economic conse-
quences (Heir 1994).
In conclusion, (1) quality must be defined in terms of corporate philoso-
phy, the specific standards the company decides to apply, and the needs of
the customer; (2) a TQM emphasis from top management makes implementa-
tion easier and the whole organization a more enthusiastic and effective
team; (3) a strategy of minimal meeting of requirements is of high risk and
leaves the company vulnerable to an outside auditor's strong criticism, which
is untenable even with a limited customer demand base; and (4) a new level
of ethical expectation within a company, and by numerous customers, ex-
ceeds a mere focus on expected quality characteristics.
BEYOND THE MANUFACTURING INSTRUCTION

Installing a quality system is obviously not the same as installing a new mix
tank. The key difference is that the mix tank, once qualified and in operation,
may perform its designated tasks with appropriate maintenance for years with-
out much further attention. To push the analogy, its customer is the specific
validated process of which it is a part. In contrast, with a quality system, the
"equipment" is the process along with all persons, equipment, facilities, and
regulatory and commercial customers." The activity of all these "customers" cre-
ates an environment both creating and requiring continuous change. The qual-
ity system must be kept current with the demands of these many customers,
some selected, and some part of the pathway to market, if a consistent quality
product is the goal. Quality is what each "customer" currently sees it to be.
GMP requires that in the company organization the Quality Assurance
or Quality Control department report to upper management and be a separate
entity from operations. But recently, a number of companies have also
formed a separate a Compliance division. The quality control focus is usually
on raw material, intermediate, and finished API testing. The Compliance de-
partment may spend most of its time on validation and stability testing. Qual-
ity assurance could quite logically also be responsible for final records review
and finished goods release as well as overall responsibility that all the quality
and production functions are audited periodically, with reports going to top
management (see Figure 14.2).
So, what is TQM and how does this concept join with, overlap, or rein-
force the historical quality assurance or quality control function in an API
plant? As implied above, it is a preferred alternative to the term quality assur-
ance for a number of good reasons. But confusion has also arisen in applying
and understanding of terms quality control, quality assurance, quality manage-
ment, and total quality management. The name Quality Assurance Department
has been a source of confusion. Specific nomenclature may differ depending
on the organizational evolution. In some companies, the name is intended to
Figure 14.2 Sample Company Management Flowchart
VP Quality Assurance
Compliance Manager
VP for Quality
Quality Assurance Purchasing
Compliance Research & Development
Quality Control Information Services
Technical Services Maintenance
mean broad responsibility over the entire quality function, as defined on page
S1 of the FDA's guidance (FDA 1998). In other companies, the term quality as-
surance is used in a narrower sense to designate the specialized activities of
conducting audits and preparing summary reports for managers (Plettenberg
1994). There is also a sense in which the term total quality is preferred to total
quality management, as the latter may imply that only management has con-
cern for quality.
Consider TQM as just one of many variously defined quality terms that a
company needs to consider. Terms vary and so do philosophical approaches
and checklists for methods and tools. For example, under TQM, on which
philosophy will a company base its actions? Which criteria will they plan to
satisfy? Deming's 14 points? Juran's list of criteria? Others? What about ISO
9000? Lastly, do we "reengineer" for new processes or new facilities? As
we move closer to U.S. fundamental practices and requirements, should we
also look at the ICH requirements and the European Community (EC), the
Japanese, and other GMP programs? What about Far Eastern or Oriental pro-
grams? A clear mission and a broadly based team effort will be necessary what-
ever the selected criteria.
The application of existing regulations to APis is enigmatic as well. The
interpretative extensions and variety of enforcement emphases are still a
moving target. Most FDA field managers and investigators have been quite
clear recently in stating their position that current GMP regulations for fin-
ished dosage forms found in 21 CFR Parts 210 and 211 are applicable to APis
since the FD&C Act states that all"drugs" are covered by cGMP. Other FDA'ers
have agreed with the GMP preamble text itself, which refers to bulk drug
GMPs being developed in another time and place or published as a Guidance
for Industry (FDA 1998). And finally, about 60-80 percent of our drug sub-
stances are imported, adding to the definitional problem the differences in
language and cross-cultural exchanges.
Whatever the interpretation inside or outside the FDA, the finished
dosage form GMPs and this new very specific guidance, as well as guidances
covering inspections and validation, are being applied vigorously to API man-
ufacturing today by the FDA. As mentioned above, the FDA's leverage is huge,
as this enforcement is tied directly to the ANDA/NDA PAl program and covers
APis, excipients, contract labs and facilities, and any other facilities listed in
an NDA.
In summary, top company management must first bring into focus its
overall purpose and strategy for the long term. This begins with its intended
market and available resources. For example, if a company intends to market
APis in the United States, the requirements are currently fairly well defined. If
the market also includes the EC or Japan, the differences and additional re-
quirements, even if only in documentation formatting, must be determined
and made part of the implementation plan. Adding compliance programs
later can be very difficult.
TANGENT CONSIDERATIONS
If the APis under consideration include those where contamination or innate
toxicity is of much greater concern, this presents an even greater challenge
(e.g., antibiotics, cytotoxics, steroids, biologicals, pesticides, herbicides [Gins-
bury and Bismuth 1994]). Likewise, if the current product line includes excip-
ients or inactive ingredients, this must be factored into the overall equation.
Secondly, if customers are requesting ISO certification, for example,
other terminology, documentation, or systems must be part of the implemen-
tation plan. These are considerations beyond our scope. However, it should be
noted that most of these approaches prescribe a leadership philosophy and
the type of culture that is desirable from the standpoint of the primary cus-
tomer, the FDA, and the particular country's culture from which employees
will be drawn.
Thirdly, for the most efficient implementation of a quality program, the

company should have a well-defined strategy going out 3-5 years. It may be
closely tied to adding value and bolstering the company's future competitive
position. Leadership must focus on and communicate its attitude so as to cre-
ate that quality culture. Such a strategy may include implementation of the
similar, overlapping, or differing requirements of United States, the EC, Japan,
the Far East. If the focus is exclusively on U.S. requirements for the manufac-
ture of bulk APis, then it is best to maximize the use of the FDA's nomencla-
ture and jargon, including its broader definition of quality assurance, to keep
the investigators' learning curve to a minimum.
Fourthly, as stated in the "bulk guide" and expanded in the newer
guidance,
It is important that a firm utilize a quality control unit inde-

pendent from production that has the responsibility and
authority to reject in-process materials not meeting specifica-
tions. Such responsibility and authority should also extend
beyond testing to include overall quality assurance activities
such as procedure approvals, investigation of product failures,
process change approvals, and product record reviews (FDA
1991, 1998).
And lastly, the Quality Assurance unit, however organized with respect
to product testing or compliance activities, is assigned authority not only to
assure that all of the actions required under cGMP are being taken, but that
the quality assurance and control departments are performing in compliance
with their organizational responsibilities.
Change is the primary context and goal of all quality programs. The
FDA's new guidance devotes several pages to its scope (FDA 1998). It must be
given a top priority in the corporation. Change, whether reactive or proactive,
should be oriented toward continuous improvement in products and
processes in the context of a continuous monitoring of regulatory and cus-
tomer requirements. Change is the greatest challenge in our environment,
and we need to give it appropriate priority. Organizations with management
systems engineered for a quality outcome must have change as their primary
goal as an extension of continuous improvement. Leadership and an appro-
priate corporate quality philosophy are key elements in the implementation
of such a TQM system. As noted above, there are many different definitions of
TQM. Variations in the detailed formulations occur from year to year. One
author (Cohen 1995) lists the following definitions of the seven major aspects
ofTQM:
1. Leadership
2. Information and Analysis
3. Strategic Quality Planning
4. Human Resource Development and Management

5. Management of Process Quality
6. Quality and Operational Results
7. Customer Focus and Satisfaction
Another source lists four and another five. In continuing the use of TQM
or "total quality" jargon, one may also replace the "implementation" cliche
with the concept of "quality function deployment" (QFD). This is a very help-
ful method of matching the "whats" and the "hows" in the development of a
quality system that complies with a wide variety of criteria found in the FDA
agenda for the review and approval of new and generic drug entities (Cohen
1995). Most approaches to TQM employ such linkages.
In any total quality model, these general areas (the seven listed above)
must be linked to customer needs and to each other to form a coherent pro-
gram. Questions such as the following are typical:
• How are the company's quality objectives translated into the work
unit's operations plans?
• How are quality values integrated into the company's management
system?
• What is the approach for each type of competitive comparison and
benchmarking?
• How are performance-related results and quality feedback analyzed
and translated into actionable information for developing priorities
in operations?
• How does the planning process create a framework for customer
satisfaction and leadership?
• How does the planning process drive improvement in operations
and processes?
• How are plans communicated to work units and suppliers (Co-
hen 1995)?
In summary, (1) TQM concepts and terms, even though various, form a
workable framework for implementation and optimization of the FDA's
quality assurance requirements in both the broadest spirit of the law and
narrowest regulatory particular; (2) TQM implementation language eases
communication in the context of changes in personnel or in dealing with
customers more familiar with ISO or the various international systems; and
(3) the Deming approach seems most broadly fundamental and sound.
PLAN, DO, STUDY, ACT

Once a quality system is implemented, change must remain a top priority for
management. Changes will be required as new customers surface (e.g., an-
other Barr decision) or are purposefully identified in the planning process.
Upstream systems can be designed for minimal disruption with change.
Changes can be anticipated from the wide range of customers that are poten-
tial but not current. Nevertheless, early customer identification is critical to a
quick implementation and minimization of later changes. A customer-driven
company must consider the needs and demands of all of its customers. Tom
Peters takes us one step farther in saying that not only must we meet the
needs, but that we must "delight" the customers to maintain long-term rela-
tionships.
By now, most of us are aware not only that change is a great challenge
but also that we now live in an information culture or society. Further, the
sheer volume of information we must find, decipher, and control is growing
as are the customers that generate it. What we may not have considered is
that a program for finding, obtaining or sharing, updating, understanding,
and communicating new information throughout our organization is a pro-
gram that should be written down, implemented with clear accountability,
and reviewed annually by the appropriate high level manager or quality as-
surance committee.
The requirements of the U.S. consumer are defined in the most specific
sense by Congress. They are implemented by policy, regulations, guidelines,
guidances, and inspectional practices of the FDA and its state and local coun-
terparts. The FD&C Act and CFR Title 21 are central with the previously noted
list of support documents, including the GMP revisions covering change con-
trol. Their coverage may be broad or narrow as their requirements affect the
primary goal of producing safe, effective, and pure products under cGMP con-
ditions and with validated processes (Barret al. 1993).
We have discussed the broader framework for a quality system. We also
have obtained the pertinent regulations and guidelines. How do we deal with
the second problem-interpretation, understanding, and keeping current?
With the state of CD-ROM (compact disk, read only memory) and on-
line technology and the rate at which documents related to FDA requirements
are becoming available in electronic form, the job of keeping current has be-
come much easier. Most of the regulations, required documents, interpretive
court cases, media coverage of meetings and hearings, hearing transcripts,
warning letters, and congressional and agency speeches are freely available
in electronic form on the Internet. As the technology improves, becomes
easier to use, and, most of all, becomes less expensive, any quality-focused
company can install a function to access and review all pertinent literature as
part of planning for a new product, a facility change, or a new process or spec-
ification.
I am writing this chapter in the midst of an ongoing information revo-

lution. We have paid hundreds or even thousands of dollars for subscriptions,
on-line services, and, most recently, for CD-ROM availability of our "cus-
tomers' " requirements in documents from the government and the various
commercial publishers. Now we can find most of these even very large docu-
ments, monographs, and guidances and download them in several minutes
from the Internet. We can then search and manipulate them conveniently
with a lightweight laptop computer.
All new personal computers (PCs) now have one or more large capacity
hard drives (fixed disks) and come with CD-ROM readers. Manufacturers have
introduced competitively priced PCs with a drive also capable of creating a
CD-ROM. Optical scanners used in conjunction with even the least expensive
of optical character recognition (OCR) software allow rapid conversion of
graphics and text of internal and external documents into electronic form
stored on easily reproduced CO-ROMs for distribution throughout an organi-
zation.
Today there is a PC on nearly every desk or workstation. These are linked
through local networks and Intranet databases. Internal communications,
E-mail, and document access can be facilitated and instantaneous. Couple
this to the worldwide easy access to the Internet, and the possibilities are be-
yond imagination. In the case of the Internet, there is an incredible competi-
tion between government agencies, information suppliers, industry-related
information vendors, and private individuals to get the latest documents,
indexes, and finding aids posted for easy searching and downloading.
It's a new world. However, sifting through and prioritizing this informa-
tion for a company's management and technical personnel requires a knowl-
edgeable and experienced person(s) to keep the company current and
competitive. A viable alternative may be the use of a consultant.
The FDA is rapidly upgrading its systems. For example, it started with a
small and unfriendly electronic bulletin board over a decade ago and then in-
troduced a CD-ROM. The FDA now has an Internet Web page and system
links to a myriad of related information sources. This trend will continue. Do
you want to search the full text of the Federal Register? All pages of all issues
since January 1, 1994, are up and searchable on the Internet. And it's free!
For that very specific and highly specialized information, there are many
consultants, many readily accessible though expensive on-line databases, and
information brokers available to do the searches and recover needed docu-
ments. Any agreement with a consultant should include his or her providing
the source(s) of all key information of either a commercial or public nature.
The goal of such an approach is not only a rapid filling of your needs but also
an option for a total system adjustment if feasible. As the quality system is
planned and implemented, due consideration must be given to options for
making use of this mountain of data and information available on-line. It is a
considerable undertaking just to catalog what bibliographic, statistical, and
full text information is available. Add to this the challenge of keeping it cur-
rent and identifying the changes, for example, when the FDA "posts" an up-
dated version on its Web page.
A second and critical part of the information element of a quality pro-
gram is membership in trade associations and, minimally, the attendance by
regulatory. and quality people at periodic updates and technical committee
meetings. The general updates on industry changes are critical for planning
and continuing compliance. Involvement in scientific committees is for in-
formation, but, more importantly, for the making of contributions to the so-
lutions of shared problems. Such contributions can be extended or slanted for
maximum benefit to each individual company.
Trade associations are also helping companies by developing their own
specialized CO-ROMs and Internet Web sites for the purpose of listing key
documents, schedules, and announcements. These systems usually include
message boards or "listservs" for all members to browse, interact, and solve
problems. You list your question, and then wait usually a short time to read
one or more replies from your peers. The American Society for Quality (ASQ),
for example, maintains an Internet Web site and a CD-ROM containing the
full text of previous years of their Progress magazine. The Nonprescription
Drug Manufacturer's Association (NOMA) has placed all of the historical over-
the-counter (OTC) drug review documents and numerous other FDA and in-
dustry publications on CD-ROM. Other organizations will likely follow suit
with back issues of newsletters, press releases and other relevant, though
presently archived, documents. Full text commercial services such as News-
page.com allow keyword or phrase searching of key pharmaceutical trade
journals, such as "the Pink Sheet" for as little as $29.95 a month. For added
convenience, Newspage lets you set up a keyword profile that will automati-
cally search each day's new articles and send headlines or full text to your E-
mail account.
Regulatory and technical seminars and meetings covering general or
very specialized regulatory, quality, and related technical topics occur
throughout the year. Networking at these gatherings of industry colleagues
can be extremely beneficial to quality staff. No person or company is an is-
land-these meetings are a must for either personal representative attendance
for the larger API producers, or by a link to customers, suppliers, consultants,
or trade associations. Another option is to buy tapes or proceedings from such
meetings. This information and material should be reported on by a reviewer
in as much detail as possible. Responsible managers should study, analyze,
communicate, and implement relevant changes. For complex issues, copies of
reports and proceedings may be indexed, archived, or scanned into databases
for future use as needed. As you perhaps suspected, most of these conferences
are now listed on the Internet by category, date, and location.
An aggressive company will maintain a library of these materials that is
easily accessed. Doing this up front can save money in the long run that may
be spent not only in finding answers but in knowing the questions. Money
saved in consulting and legal fees can quickly and greatly exceed the cost of a
highly organized professional secretary, documents clerk, or even a profes-
sional librarian.
Depending on the product line and company size, it may be wise to de-
velop a working relationship with a reputable and experienced law firm. Over
time, teach them all the ins and outs of how you do things. When a situation
gets "sticky," an experienced regulatory lawyer can be of great help in prob-
lem solving and decision making. We pay them well to know the subtle con-
nections among the legislation and case law, regulations, and cGMPs. In that
same situation, an outside attorney can perform an audit of your company's
systems, and his or her findings are protected under attorney-client privilege.
A good firm is usually found by word of mouth, by attending a regulatory
conference or training program, or perhaps by "surfing the Internet."
Another important information source is your customers. Part of there-
lationship with customers is to know their exact needs. Sharing regulatory
and quality expectations from the product end is an important role for cus-
tomers. It is critical to put in writing in as detailed manner as possible the in-
formation you will both need, monitor, and share. This is fundamental to
TQM. It is just a part of a corporate information system which in today's
world is almost limitless in what support it can provide.
Many of the companies producing APis on a contract basis would be
considered "small businesses" by U.S. standards. In the last few years, they,
along with the rest of the pharmaceutical industry, have been in a continuous
catch-up mode as the FDA radically changed its posture, expectations, and
methods of inspection. As stated above, the most critical factor in this agency
change was the PAl tied directly to the approval of an NDA or ANDA. During
these crucial inspections, the currency and accuracy of DMFs and the ability
of the plant described to produce finished materials are the key reasons for
FDA acceptance.
To other sectors, it seems that such broad changes have decreased in fre-
quency, with issues and changes occurring now only in peripheral or highly
specialized areas of products. At a recent manufacturing controls industry
meeting, it was observed by many that this was the first meeting in half a
dozen years that focused almost entirely on the future and improvement
possibilities and new technologies as opposed to sorting through a "large
bag" of compliance and technical problems. Now there is an opportunity for
each company to take both a futuristic, an environmental, and an inward
look. And with that begin to plan for improved quality through marginal im-
provements, for the installation of a total quality system, and, in some cases,
a total reengineering of old and archaic processes. The goal is to have a sys-
tem in place that will satisfy the FDA when they come in on a preapproval
inspection. Reasons for the FDA to recommend withholding of approval are
listed below:
• Plant not capable

• Failure to meet GMPs
• DMF or regulatory actions
• Control methods issues
• Stability issues
• Impurity issues
This list shows that auditing against cGMP, the new API guidance, and
the "bulk drug inspection guide" is critical, and that the supportive docu-
mentation from the selected intermediate stage through scale-up and com-
mercial production is needed to satisfy the FDA. The Quality Assurance
department should play a major role in the planning and auditing of these
documents. Its observations should be carefully evaluated by appropriate
technical staff members to determine what improvements need to be made.
Results of a critical nature should be communicated immediately to all cus-
tomers who have used the specific API, or another active produced in that fa-
cility, in a submission. Feedback from these important customers can be very
valuable in making system adjustments.
A number of alternative approaches to auditing can be chosen. A team
can be formed to review requirements and plan changes. An outside auditing
person or persons can be contracted to do and report an independent audit
against appropriate standards. Broad, telltale signs of a problem company are
as follows:
• Negative compliance record

• Quality decreases
• Process time increases
• Number of inspections increases
• Experienced workers leave
• Number of meetings increases
• Blaming nourishes
• Customer complaints increase
Another critical area for Quality department involvement is in the trans-
fer of technology. The importance of analytical technology transfer is increas-
ing. The FDA is asking companies to use internal certification to verify the
completed transfer between departments. The evidence that this and each
of the above FDA requirements is satisfactorily met will be based on audit re-
sults of a well-designed total quality system. Considerable emphasis may be
placed on
• the analytical and control areas of the operation,

• a comprehensive review of raw data associated with analytical
methods development and validation,
• compliance of methods with pharmacopeia! guidelines,
• a demonstrable evidence of understanding the process,
• a solid basis for specifications,
• an on-track stability program, and
• an aggressive quality assurance program.
With the requirements and standards identified and current practices

audited against those requirements, filling the resulting gaps in performance
can be prioritized and a plan for implementation developed. A key part of
quality is a sense of urgency to identify, find solutions, and implement those
solutions in a cost-effective and timely fashion (see Figure 14.3).
In conclusion, apply the above concepts and specifics to the internal
and external customers. Continuously cycle through planning, doing, study-
ing, and acting. Audit and reaudit with the goal of continuous improvement.
Treat the customer audits as another opportunity for enhancement of current
systems. Be delighted with your customers, suppliers, and their needs, and
they will be delighted with you (see Figure 14.4).
If the cGMP compliance is adequate, the development process has fol-
lowed sound scientific principles, and the preparation and conduct of the PAl
meets the needs of the investigator, then the inspection should be completed
without any significant adverse findings. Timely approval of NDAs and
ANDAs will be received, and competitive credibility, visible integrity, and de-
sirable profitability will be the outcome. The effectiveness of your quality
system will have been comprehensively demonstrated.
Figure 14.3 The API Quality System
~ API ~
~ Q ~
u
~ A ~
~ L ~
I
~ I
~
~ T ~
y
~
~ s ~
y ~
s
~ T
~
~ E ~
~ M
Figure 14.4 PDSA Cycle
REFERENCES
Adamson,]. R. 1992. An approach to validation. Pharmaceutical Engineering (Septem-
ber/October): 16-22.
Bajaria, H.]., and R. P. Copp. 1991. Statistical problem solving: A team process for iden-
tifying and resolving problems. Garden City, Mich., USA: Multiface Publishing
Company.
Barr, D. B. et al. 1993. FDA regulation of bulk pharmaceutical chemicals production.
Pharmaceutical Technology (September): 54-70.
Bongiovanni, ]. ]. 1994. Continuous improvement: A strategy for implementation.
Drug Information Journal 28 (4):943-948.
Cohen, L. 1995. Quality function deployment. Reading, Mass., USA: Addison-Wessley
Publishing Company.
Covey, S. R. 1993. The seven habits of highly effective people (audiotape). Provo, Utah,
USA: Covey Leadership Center, Inc.
Deleers, M. 1994. From quality control to total quality management: A logical evolu-
tion. Drug Information foumal28 (4):917-920.
FDA. 1991. Guide to inspection of bulk pharmaceutical chemicals: Materials and Training
Aids for investigators. Rockville, Md., USA: Food and Drug Administration, Center
for Drug Evaluation and Research.
FDA. 1998. Guidance for industry: Manufacturing, processing, or Holding active pharmaceu-
tical ingredients. Rockville, Md., USA: Food and Drug Administration.
Ginsbury, K., and G. Bismuth. 1994. Compliance auditing for pharmaceutical manufactur-
ers. Buffalo Grove, Ill., USA: Interpharm Press, Inc.
Hawkins, P. 1996. Is ISO 9000 diminishing the Baldridge Award? Quality Management
1904:2.
Heir, R. S. 1994. Good manufacturing practice: An historical overview and actual sta-
tus. Drug Infonnation Journal28 (4):957-963.
NBC. 1980. If Japan can ... why can't we? Executive director, Reuven Frank (videocas-
sette, 80 min.). New York: National Broadcasting Company, Inc.
ICH. 1997. Internationally hannonised guide for active phannaceutical ingredients: Good manu-
facturing practice. Geneva, Switzerland: International Conference on Harmonisation.
Juran, J. M. 1995. A history of managing for quality in the United States of America. In
A history of managing for quality, edited by]. M. Juran. Milwaukee, Wis., USA: Qual-
ity Press.
Latzko, W. ]., and D. M. Saunders. 1995. Four days with Dr. Deming: A strategy for mod-
ern methods of management. Reading, Mass., USA: Addison-Wesley Publishing
Company.
Meyer, P., and M. Korteweg. 1994. Introduction: Quality management in pharmaceuti-
cal development: From molecular design to drug approval. Drug Infonnation Jour-
na/28 (4):915-916.
Plettenberg, H. D. 1994. Quality-related terminology in "good practice" regulations
and ISO standards. Drug Infonnation Journal28 (4):921-929.
Popcorn, F. 1991. The Popcorn Report (audiotape). New York: Simon & Schuster, Inc.
Qiupeng, ]., C. Meidong, and L. Wenzhao. 1995. Ancient China's history of managing
for quality. In A history of managing for quality, edited by]. M. Juran. Milwaukee,
Wis., USA: Quality Press.
Weissinger, J. 1994. A systems approach to quality auditing. Drug Infonnation Journal
28 (4):1085-1087.
15
CLEANING FOR ACTIVE
PHARMACEUTICAL INGREDIENT
MANUFACTURING FACILITIES
William E. Hall
Hall and Associates
Winterville, North Carolina
Cleaning processes for active pharmaceutical ingredient (API) facilities can be

very complex due to the complicated nature of the manufacturing process it-
self. As discussed in previous chapters, these processes tend to be multiple
step processes involving both chemical and physical changes. Because chemi-
cal reactions occur during the process, there are many more potential residues
or contaminants to be concerned about in the development of cleaning pro-
grams, protocols, and procedures. A list of potential contaminants includes
precursors, by-products, desired actives, solvents, microbes, endotoxin, and a
host of other equipment-related materials, such as equipment linings, gaskets,
filter agents, and lubricants.
REGULATORY REQUIREMENTS
An important aspect of cleaning in API facilities is the regulatory expectations.
These regulations drive cleaning programs in the entire pharmaceutical indus-
try, including API facilities. Regulatory requirements are very dynamic and
may change considerably from year to year. The current Good Manufacturing
Practices (cGMP) Regulations continue to change as various guidelines,
397
guidance documents, and amendments are issued by the Food and Drug Ad-
ministration (FDA). Since pharmaceutical products are shipped internation-
ally, there is a desire that global regulations be developed. To this end, the
International Conference on Harmonisation (ICH) is addressing global require-
ments for the manufacturing, packaging, and holding of APis. Undoubtedly,
the subject of cleaning will be addressed in these forthcoming regulations.
However, many differences currently exist both in the regulatory requirements
of different countries and cultural differences. These differences will require
years of negotiations before a single set of standards will be finalized.
In the interim, the FDA has published a guideline document (Guide to In-
spection of Bulk Phannaceutical Chemicals, 1991) that, along with the cGMP
Regulations, is used as the official basis for current inspections. In this con-
text, the term bulk phannaceutical chemicals (BPCs) applies to APis. This docu-
ment specifically states, "There are basic differences between the processes
used for production of BPCs and the processes used for the production of fin-
ished products." These differences will be apparent in the cleaning processes
as well as the manufacturing process. However, many inspectors continue to
note in their presentations that the present cGMP regulations do not distin-
guish between dosage forms and BPCs.
Other sections of this document instruct the FDA inspector to evaluate a
BPC facility for the potential for cross-contamination from any source as well
as the relative ease and thoroughness of cleanup.
The BPC guideline also addresses the need for detailed cleaning proce-
dures, sampling plans, analytical methods, and cleaning limits, and the
reader is referred to this document for the specific statements on these issues.
However, these concepts and requirements will be incorporated throughout
this chapter.
One of the most significant sections of the BPC guideline is the section
dealing with limits. The guideline states that residue limits should be "practi-
cal, achievable, and verifiable." This is very encouraging as opposed to requir-
ing that a level of zero residue be achieved, which is impossible to achieve in
actual practice because of the tremendous sensitivity of modern analytical
methods. This concept will be expanded in a later section of this chapter.
Another document that addresses cleaning in an active ingredient facil-
ity is The Manufacturing, Packaging, and Holding of Active Phannaceutical Ingre-
dients. This document was issued by the FDA in 1998 and was issued as a
"discussion document" not for implementation. Although not official, this
document embodies the current thinking of the FDA regarding the expecta-
tions for controls for the production of APis as well as the cleaning processes
associated with them. This document includes sections on equipment clean-
ing and maintenance procedures, equipment cleaning methods, and clean-
in-place (CIP) methods. The most significant section of the document in
regard to cleaning is titled "Validation of Equipment Cleaning Methods."
This section states "equipment cleaning methods should be validated, where
appropriate." The document recognizes that the various purification and
Cleaning for API Manufacturing Facilities 399
recrystallization steps in an API manufacturing process may affect the allow-

able residue limits. It also recognizes the difference in early steps versus ter-
minal steps in the manufacturing process by stating, "In early synthesis steps,
it may be unnecessary to validate cleaning methods where residues are re-
moved by subsequent purification steps." This is a major difference in FDA
expectations when compared with dosage form manufacturing, where no
such distinction would be made between early and terminal steps in the man-
ufacturing process.
Another important legal precedent, which impacts cleaning in an API
manufacturing facility, is the U.S. v Barr Labs court decision. The major impact
of this decision on cleaning programs is that the court held that the pharma-
ceutical company must provide or make available data that demonstrates that
any cleaning agent is effectively removed from the manufacturing equip-
ment. The cleaning validation programs must then be extended to include
cleaning agents. This would, therefore, require validated analytical methods
for the cleaning agent(s). In the context of the legal definition, a cleaning
agent is not restricted to a soap or detergent but would also include other
materials such as organic solvents, if the solvent is specifically used for clean-
ing and is not a solvent used in the next manufacturing step. In the latter case
(i.e., where the solvent is a part of the next manufacturing step [usually a
recrystallization process]), the solvent would not be considered a cleaning
agent but still could be considered a potential impurity if carried over into
finished product.
Another document often impacting certain API manufacturers is the
Biotechnology Inspection Guide (FDA 1991b). Since this guide was derived from
the BPC guideline, it bears remarkable similarity in conceptual approach, and
the reader is referred to it for cleaning concepts for biological manufacturing
systems.
A major reason for pointing out the regulatory requirements for cleaning
validation is that the various guidelines available instruct the FDA inspector
to investigate the cleaning program of the company and, more specifically,
give specific questions for the inspector to ask. In the Preapproval Inspection
(PAl) process, cleaning validation is a "drop dead" issue, meaning that a com-
pany will be denied approval of their New Drug Application (NDA) or Abbre-
viated New Drug Application (ANDA) for lack of a satisfactory cleaning
validation package or plan. There is also a general expectation that cleaning
will be an issue for both API and dosage form facilities during a PAL
MULTIPLE USE VERSUS DEDICATED EQUIPMENT

A major consideration is whether equipment is used for multiple products or is
dedicated to a specific product. In some cases, a combination of situations
may exist where certain equipment is dedicated for a single product or step in
a process, whereas in other parts of the facility, equipment may be used for
multiple products. This is important to the FDA and will be an early "up-front"
question of the inspector. It is also important for the manufacturer of actives
to give some thought to this concept in order to develop an appropriate clean-
ing program that addresses areas where cross-contamination can occur.
It is an FDA requirement that separate facilities be used for the manufac-
ture of penicillin and cephalosporins. It is also encouraged that separate facil-
ities and air handling systems be used for the production of certain steroids,
alkaloids, certain hazardous or toxic drugs, pesticides, chemicals, and/or start-
ing materials.
In this context, it is desirable at an early stage of developing a cleaning
program to develop a matrix of equipment that demonstrates what products
may potentially be run in the equipment. Table 15.1 demonstrates a simple
matrix for a given manufacturing module. These matrices are valuable for giv-
ing an overall preliminary review of a facility prior to creation of a master
plan. Much valuable information can be gained from a matrix. It allows the
viewer to easily identify the most likely points of cross-contamination. For ex-
ample, by review of the matrix in Table 15.1, it can be seen easily that the
filler is used only for a single product, Product C, and is thus a dedicated piece
of equipment. As dedicated equipment, the cleaning program for this product
would be minimal or at least much less stringent than for the reaction vessel,
since the latter is involved in four products and represents a major potential
source of cross-contamination.
Another valuable use of the matrix is to determine quickly if any piece of
equipment is being overlooked in establishing the cleaning program. A later
section of the chapter discusses the "worst case" approach, whereby a single
product is selected to represent a group of products. This approach allows the
viewer to determine if, by choosing a single product, any piece of equipment
is overlooked, and thus there might be no data developed to indicate the
equipment could be cleaned. It is highly desirable to have at least some data
Table 15.1 Product-Equipment Matrix
Product A Product B Product A Product B Product C

Equipment Step 1 Step 1 Step 2 Step 2 Step 5
Reaction Vessel X X X X
Holding Tank X X X
Crystallizer X X X
Grinding/Screening X X
Filler X
on all the equipment in a facility. Thus, if the worst case product did not con-
tact an infrequently used piece of equipment, it would be desirable to choose
an additional product that was actually run in the equipment not covered by
the primary worst case product. Samples could be taken and assayed for the
secondary worst case product after cleaning to verify that the equipment was
suitably cleaned by the cleaning procedure. Using this approach would guar-
antee that there was actual cleaning data for all equipment and that no equip-
ment was missed by the primary worst case approach.
THE UNIQUE NATURE OF APis
An earlier section noted that manufacturing processes for APis differ signifi-
cantly from those for dosage forms, i.e., finished pharmaceutical products.
This section will expand on and explain these differences in more detail.
Table 15.2 shows a comparison of the manufacturing processes for APis and
dosage forms.
The differences between APis and dosage forms illustrated in Table 15.2
have a major influence on cleaning programs and procedures developed for
APis. Since the manufacture of APis involves chemical synthesis, the potential
cleaning residues may contain precursors and by-products, in addition to ac-
tives and residual solvents. Since any cleaning program must first identify
what potential contaminants are present, there are generally more potential
contaminants in API processes than for dosage form manufacturing. In addi-
tion, the precursors and by-products often have medical or toxicological activ-
ity in the human body and, thus, their presence as a contaminant is more
serious than an excipient residue from a dosage-form manufacturing situation.
Table 15.2 also indicates that purification is an important part of the
manufacturing process for APis. Typically, chemical reactions occur in the early
steps, and the final steps are a combination of recrystallizations, filtrations,
and other purification steps. Since residues from early steps may be subse-
quently removed by the purification in the later steps of the process, cleaning
requirements should be more flexible in the early stages of the manufacturing
process and less flexible (i.e., more stringent) in the final stages of the process.
Table 15.2 Comparison of API and Dosage Form Manufacturing
APis Dosage Forms
Both chemical and physical changes Physical changes only

Significant purification (terminal steps) No further purification (usually)
MULTIPLE LEVELS APPROACH TO CLEANING

There are so many different types of cleaning situations in the API manufac-
turing process that each cleaning situation may be quite unique. There are
batch-to-batch changeover cleanings, changeovers from early steps to inter-
mediates within a given product sequence, changeovers from intermediates
of one product to intermediates of a different product, changeovers from in-
termediates from one product to final products of a different type, and
changeovers from one finished product to another different finished product,
to name only a few possibilities. In a nondedicated facility, several companies
utilize an approach whereby different cleaning procedures are used depend-
ing on the location of the manufacturing step in the overall manufacturing
sequence and the nature of the next manufacturing event scheduled to occur
in the same equipment. This approach might result in a multilevel approach
to cleaning as follows.
Level 1 Cleaning
Level 1 cleaning is used only between steps in the same manufacturing process.
For example, in the manufacture of pseudoephedrine, there may be five steps,
and the overall process could be represented as a simple flow diagram.
Step A ~ Step B ~ Step C ~ Step D ~ Step E
If, for a given piece of equipment, on a specific occasion, step A of the
first batch in a campaign was to be followed by manufacturing a second batch
(i.e., a repeat of step A for a second identical batch of the same product), then
a level 1 cleaning would be required.
Level 2 Cleaning
Level 2 cleaning is used when cleaning between steps in the same manufactur-
ing process. In the above example, a level 2 cleaning would be used if step B
was to be performed immediately after step A for the same product line (pseu-
doephedrine in this case). The same would be true if step D for pseudo-
ephedrine was carried out after step C for pseudoephedrine, step E after step D,
and so forth. In all these cases a level 2 cleaning would be used if no other
product were manufactured in the equipment between the two steps involved.
Level 3 Cleaning
A level 3 cleaning would be performed when cleaning after an intermediate or
final product step of one product in preparation for production of an inter-
mediate step of another product. As an example, consider the manufacturing
of pseduoephedrine and guaifenesin. Assume that the two processes can be

represented by the following simplified flow diagrams.
Step A (pseduoephedrine) Step A (guaifenesin)

J, J,
Step B (pseduoephedrine) Step B (guaifenesin)
J, J,
Step C(pseudoephedrine) Step C (guaifenesin)
J, J,
Step D (pseduoephedrine) Step D (guaifenesin)
If step C of guaifenesin were run immediately after step B of the pseudo-

ephedrine process, then a level 3 cleaning would be appropriate.
Level 4 Cleaning
A level 4 cleaning would be used when cleaning after any intermediate or fi-
nal product step of one product in preparation for production of a final prod-
uct step of another product. In the example above for the level 3 cleaning, if
step C for pseudoephedrine was followed by step D for guaifenesin, a level 4
cleaning would be required. The important difference between the level 3 and
level 4 cleaning is that in the latter case, the next production will be for a fi-
nal product step.
Philosophy of Cleaning
The four levels of cleaning would differ in the thoroughness of the cleaning
process, the cleaning conditions, the level of verification of cleaning, and the
level of risk associated with a potential contamination in the order:
Ievell < level2 < level3 < level 4

(lowest risk) (highest risk)
(higher limits) (lower limits)
(less extensive cleaning) (more extensive cleaning)
(visual verification of clean) (analytical testing)
This philosophy allows the cleaning effort to be directed to situations where

contamination would have the greatest potential to cause harm and allows
a less stringent effort to early steps where there is less risk from cross-
contamination. This philosophy is only a general one and would not be
appropriate for every manufacturing and cleaning situation. For example, it
may not be appropriate or desirable to base the cleaning of a cytotoxic facility
on this same approach.
NATURE OF CONTAMINANTS
It is very important to know the nature of the potential contaminants in-
volved in the manufacturing of APis. Many of the potential contaminants are
highly reactive chemical compounds that were chosen as starting materials
largely because of their highly reactive chemistry. It is important to remember
that the same properties that make a chemical highly reactive in the process
reactor also make the chemical highly active from the biological standpoint
in the human or animal body. It is generally true that the more chemically ac-
tive materials will also be more toxic to the patient. It is also important to
note that potential contaminants may be either starting materials (precursors)
or they may be by-products of the various chemical synthesis reactions, ac-
cording to the general scheme:
precursors ~ final product + by-products

(reactants)
Of course, the total list of potential contaminants would also include

cleaning agents, lubricants, solvents, bacteria, endotoxin, filter media, filter-
ing agents, gasket materials, and tank linings such as glass and polymers.
In the past, most analytical technologies concentrated on detecting
what was expected to be present, rather than what materials should not be
present. Cleaning programs require a somewhat different orientation, in that
the concern must be about what should not carry over to subsequent product
and thus what should not be present on clean equipment. In order to evalu-
ate cleanliness, extensive physical, chemical, and biological testing is
required. The testing should be based on a knowledge of all potential conta-
minants. This is important since many of the analytical testing techniques are
so specific that if the proper method is not chosen, the contaminant will not
be detected.
The FDA and industry have concern for the impurities present in the raw
materials used in manufacturing active ingredients. In the industry's quest to
control cost, the quality of starting raw materials is sometimes unknowingly
compromised. Even though materials meet specification, there is often very
little knowledge of the nature of the impurities present.
The same concern is true for cleaning agents. Cleaning agents are simple
physical mixtures of various components, such as alkalis, acids, surfactants,
antifoam agents, and various other chemicals. The quality grades of these
components vary greatly according to the source and quality grade (e.g., tech-
nical grade, reagent grade, analytical grade, etc.).
The United States v Barr Laboratories, Inc. court case focused attention on
the cleaning agents used in pharmaceutical facilities. As a result of this case,
the FDA is now looking into cleaning in the API industry as well as the dosage
form industry.
The cleaning validation program for actives should be designed to

demonstrate the removal of cleaning agent(s) down to an acceptable level.
Cleaning agents may be materials typically considered to be cleaning agents,
such as soaps, detergents, surfactants, alkali, or acids; they may also be or-
ganic solvents. Regardless of the nature of the cleaning agent(s), there must be
documented evidence to demonstrate that the material is not present on
"clean" equipment beyond a level justified by science and practicality. If the
cleaning agent is not readily removable from manufacturing surfaces, then, in
the view of the FDA, the wrong cleaning agent was selected.
PRODUCT GROUPINGS AND

SELECTION OF A WORST CASE
It has been common practice in developing cleaning program philoso-

phies for dosage form manufacturing to group very similar products into a
single group and then choose one or more worst-case examples to evaluate for
cleaning validation purposes. The same general philosophy can be applied to
cleaning programs for APis; however, the basis for the groupings may be
slightly different. In dosage form manufacturing facilities, the grouping is
according to the dosage form (i.e., all tablet formulations together, all
petrolatum-based ointments together, etc.). For API manufacturing facilities,
the groupings must be based on factors other than dosage form. The follow-
ing philosophical approaches are typically used for API facilities:
• Worst case according to product
• Worst case according to equipment
• Worst case by a combination of product and equipment
If a family of products tends to be manufactured in the same common
"train" of equipment, then a worst-case product may be selected on the basis
of potency, toxicity, solubility, stability, and difficulty of cleaning.
In other cases, because of the unique nature of the chemical synthesis
process, there may be variation of equipment used from one manufacturing
event to the next and there is not always a uniquely defined equipment train.
In these cases, it is more rational to identify a worst-case piece of equipment
and demonstrate that it is cleaned by carrying out appropriate sampling and
testing. There may also be unique equipment surfaces such as glass-lined
tanks, or plastics such as Telfon® or Nalgene®, which require specific testing.
If a solely product-oriented approach were used, these materials could be
missed.
In other cases, some large API facilities may use literally dozens of
similar pieces of equipment. In these cases, a combination of product and
equipment considerations is often employed. For example, one approach is to

group similar equipment such as reactors and determine a worst-case reactor.
Then, the products made on that equipment are considered, and a worst-case
product is selected for cleaning studies. This combination approach is quite
logical and rational for this type of facility.
In any event, the criteria for the selection should be incorporated into a
written scientific rationale that describes the selection process. It is a given re-
quirement that the same cleaning procedure must be used for the products
and/or equipment in the group; otherwise, the comparison would be an "ap-
ples versus oranges" type of comparison and impossible to defend with a sci-
entific rationale.
Companies that employ multiple types of cleaning, such as described in
the previous section, usually validate at least one suitable product for each of
the types or levels of cleaning. There would be a worst case for levell, a worst
case for level 2, and so forth.
There has been a tendency for companies to stretch the concept of worst
case beyond what regulatory officials will accept. Indeed, several companies
have received Form FDA 483 citations or Warning Letters for overdoing the
grouping concept. This may be a case of either extending the concept beyond
what can be defended or of not preparing adequate scientific rationale.
It should be mentioned that the grouping and worst-case strategy has
been applied mostly to older, existing products. For New Chemical Entities
(NCEs) that are subject to the PAl program by the FDA, the expectation of
the inspector is that cleaning validation will be done on the all NCE prod-
ucts (i.e., that it will not be subject to coverage by a previous worst-case
product).
CLEANING TECHNIQUES
There are three types of cleaning used in API facilities: clean-in-place (CIP),
clean-out-of-place (COP), and manual.
CIP can be either controlled by automated programs or manually con-
trolled. CIP tends to be very reproducible and consistent and is readily vali-
dated. Even though a CIP system may be used, cleaning validation is still a
requirement. Samples must be taken, analyzed, and results documented.
After validation of the CIP cleaning process, suitable documentation
must be maintained that demonstrates that critical parameters, such as tem-
perature and rinse cycles, are still being achieved on a daily basis. These latter
records are typically incorporated into the batch record documentation. The
hardware and software controlling the cleaning process must also be vali-
dated.
COP is the term used when equipment is disassembled and taken to a
central washing machine. The washing equipment also requires validation to
demonstrate that the machine achieves the proper temperatures and cycle
times and that detergent is dispensed in the proper amounts. An inherent ad-
vantage to this type of cleaning is that the equipment is disassembled during
each cleaning event and, thus, can be visually inspected during the reassem-
bly process. However, the loading pattern of equipment into the washing ma-
chine should be taken into account in the development of protocols for this
type of equipment since larger pieces of equipment can "shield" other pieces
and prevent adequate exposure to the cleaning solutions.
Almost all API facilities have at least some manual cleaning processes.
While some may argue that manual cleaning processes are not validatable,
the consensus opinion of experts is that manual cleaning processes are capa-
ble of and must be validated. The key issue for manual cleaning is the level of
detail in the cleaning procedures themselves and the quality of the training
program. Most difficulties for manual cleaning processes can be traced back
eventually to inadequate training.
As with all validated processes, it is important that the processes not be
changed once they are validated. A subtle change in a wash temperature, cy-
cle time, detergent, or drying condition can undermine the validated clean-
ing process. Any change in any of these parameters should be subjected to a
change control process for evaluation of validation impact and possible
revalidation.
SAMPLING
There are many different types of sampling for cleaning purposes. There are
swab sampling, solvent rinse sampling, rinse water sampling, placebo sam-
pling, sampling of following products, direct surface monitoring, coupon sam-
pling and other methods that are combinations of these types. Even within a
given category of sampling, there are subtypes of sampling. For example, there
are dry swabs and wet swabs that are moistened with water or other solvent.
However, the list of sampling methods acceptable to the FDA appears to
have been reduced to swab sampling, rinse sampling, and solvent rinse sam-
pling (since these terms are referred to in the various inspection guides uti-
lized by FDA inspectors).
The FDA has a strong preference for swab sampling because it believes
that some residues need a mechanical or physical action to remove the
residue and that rinse samples might give a false indication that the equip-
ment was clean. When product contact surfaces lend themselves to easy ac-
cess by the sampler, swab sampling is easily accomplished. However, there
are product contact surfaces that do not lend themselves to easy access, such
as the inner surfaces of hoses, transfer pipes, filters, condensers, and small in-
tricate equipment such as micronizers, microfluidizers, brushes, and numer-
ous other examples. Also, tanks and other "closed" systems may not have
ports large enough for entry for sampling purposes. In the cases of wire
screens or sieves or brushes, swabbing simply is not appropriate because of
the nature of the material. In these cases, it is reasonable and acceptable to
use either solvent rinses or rinse water sampling. Because residue tends to be
trapped in the overlapping areas of metal screens, a better sampling program
would involve soaking the screen in the solvent for which the residue is
known to be soluble.
The main concern of the FDA regarding the use of rinse sampling is that
if large volumes of rinses are used, the residue can be diluted to the extent
that it will not be detected by the analytical method. To overcome this poten-
tial difficulty, the volume of the rinsate should be kept as low as possible. If
large volumes of rinses were used, then the rinse samples may be concen-
trated by evaporation of some or all of the solvent after sampling. The evapo-
ration would have the effect of increasing the sensitivity of the analytical
testing. In some cases, a sufficiently sensitive analytical method is available so
that evaporation is not required.
Regardless of the sampling methodology, a sampling protocol should be
developed that demonstrates the locations from which samples will be taken.
Normally, a schematic diagram of the equipment is prepared, and the sam-
pling locations may be marked directly on the diagram.
The sampling locations should include all areas that are known to be dif-
ficult to clean. It is also a good idea to include some of the "easier to clean" ar-
eas for calculation purposes. The sampling protocol should indicate what type
of samples (rinse, swabs, etc.) will be used and should include the details of
exactly how the samples will be obtained and processed. For example, the
protocol should address such items as
• the volume of rinses (if rinse sampling is used);
• the specific areas sampled;
• the specific type and size of swab to be used;
• the number of strokes of the swabs;
• the direction of swabbing (i.e., either horizontal or vertical or
both); and
• how the samples should be labeled and transported to the analyti-
cal facility.
For CIP systems, it is advisable to disassemble the equipment during the
cleaning validation for sampling purposes, even though the equipment is not
normally disassembled during use. The disassembly not only facilitates sam-
pling but also allows the sampler to visually examine the inner product con-
tact surfaces to determine if there is gross contamination that remains
undetected by the sampling and analytical technique.
It is impossible to overemphasize the importance of the sampling

process. Even the most sophisticated instrumentation and skilled analyst can-
not compensate for improper or inadequate sampling. Swab sampling, in par-
ticular, is very technique dependent.
ANALYTICAL METHODS
Analytical methods used for cleaning samples must be carefully chosen ac-
cording to the specific residue, type of sample, and cleaning situation. The
most common error is in choosing a method that is not sensitive enough. The
sensitivity required depends upon the acceptable limit, which, in turn, de-
pends on the potency or toxicity of the potential residues. A common error
associated with the sensitivity is the assumption that "none detected" is equal
to zero. It is important to remember that "none detected" is not equal to zero
but instead is equal to the sensitivity of the analytical method as reflected in
either the limit of detection (LOD) or the limit of quantitation (LOQ).
Another factor to remember is that the analytical method used for testing of
cleaning samples must be validated itself, a concept often referred to as meth-
ods validation.
Because of their codependency, it is often highly desirable to develop an-
alytical and sampling methodology concurrently. If the sampling will be done
by swabbing, then one of the first activities for the analytical department
should be to determine the recovery from the surface of the equipment. This
is usually done by spiking known amounts of the expected residue on surfaces
of the same material (e.g., stainless steel, glass, plastics) as the equipment to
be sampled. The recovery would be simply defined as:
amount detectedxlOO
percent recovery=-----------
amount spiked onto surface
The question often arises as to what is an acceptable percent recovery.

There is no regulatory requirement for recovery and, indeed, the range of val-
ues reported varies greatly. Values as low as 15-20 percent have been reported
by biotechnology companies. This is neither good nor bad but instead is a
function of the nature of the materials, levels of residue encountered, and
may be the maximum attainable for such residues as poorly soluble materials
such as proteins. For very soluble materials, the percent recovery may be as
high as 99.9 percent. Most typical recoveries fall somewhere in between these
extremes, and typically would be in the range of 50-70 percent.
One way to enhance poor recoveries is to use a piece of filter paper satu-
rated with solvent as the swab. This wetted filter paper may be placed directly
on the equipment surface and then rubbed on the back with a glass rod or a
rubber "policeman" and also allowed to stay in contact for several minutes.
This method offers a combination of the physical action of swabbing plus the
solvation action of the solvent and may give good recoveries in some situa-
tions. A list of analytical methods typically used for cleaning validation sam-
ples is shown in Table 15.3.
Table 15.3 also illustrates whether the method is specific or nonspecific
in nature. This is significant since several of the regulatory guidelines refer to
the use of specific analytical methods. While many of the simpler methods
such as visual, pH, conductivity, and total organic carbon (TOC) are nonspe-
cific in nature, they still render valuable information relative to the level of
cleaning and the presence of any possible contaminant. The trade-off is that
many of the nonspecific methods are extremely sensitive and rapid. Due to
these properties, they can often be very effective to evaluate cleaning as well
as offer a valuable monitoring application, since they lend themselves to in-
line or on-line application. For several years, heat distillation stills have been
equipped with conductivity monitors that automatically either shuts down
the still or dumps water to drain that does not meet the standard pro-
grammed into memory. Extension of this concept to include on-line
Table 15.3 Analytical Methods for Cleaning Validation

Analytical Method Specific Nonspecific
Visual Examination* ./
Gravimetric Analysis ./
pH ./
Conductivity ./
Microscopy ./
Titration ./
Thin Layer Chromatography ./
Lowry Protein ./
SDS-PAGE ./
Capillary Zone Electrophoresis ./
ELISA ./
lon Chromatography ./
Fourier Transform Infrared (FTIR) ./
Near Infrared (NIR) ./
HPLC* ./
Total Organic Carbon (TOC)* ./
* Indicates the most commonly used analytical methods for cleaning validation
monitoring of pH and TOC in addition to conductivity is presently used in

several new facilities. This same concept of using these three nonspecific ana-
lytical methods in tandem has considerable merit when applied to cleaning
samples. Even though each method has individual disadvantages or limita-
tions, together these three methods cover a vast array of potential contami-
nants, and there is a synergy of using the nonspecific analytical methods
concurrently. The conductance measurement would detect any inorganic,
ionic contaminant; the pH measurement would detect any residue having
acidic or basic character; and the TOC measurement would detect any organic
contaminant.
Although originally there was great reluctance by FDA inspectors to ac-
cept any analytical method that was not product specific in nature, there has
been some moderation in this position. In some cases, the nonspecific meth-
ods may actually give a much better indication of the clean condition of the
equipment. An example of this is in biotechnology manufacturing. In some
instances, biotechnology manufacturing may involve more than 100 compo-
nents (buffers, salts, media, products). Although it may be impractical to test
for all 100 components by individual, product-specific methods, the status of
the equipment can be quickly evaluated by TOC. If only a few product-
specific assays were performed, it is quite possible to have anomalous results
that seem to indicate the equipment is clean, when, in fact, the equipment
was not clean but simply was not assayed for the specific contaminant(s)
present. A simple summary of this concept is that "if you don't assay for the
correct contaminant, you will simply not detect it."
Another stimulation to nonspecific analytical methods was given when
the U.S. Pharmacopoeia adopted TOC analysis as an alternative for testing
water for oxidizable substances.
Visual Examination
Although a nonspecific method, visual examination is probably the most pop-
ular and easy to use analytical method of all. Some companies have carried out
studies to make this technique quantitative for their particular application. In
contrast to the other analytical methods, this method gives the observer the
most complete and immediate indication of the condition of cleanliness in
the equipment. For situations where the entire product contact surface can be
observed (e.g., a large manufacturing tank), the entire surface can be evaluated
visually. If the manufacturing equipment is a transparent S L glass flask
(biotechnology manufacturing), the visual examination of the equipment un-
der good lighting is a valuable means of determining whether the equipment
is clean. This simple method thus bypasses the difficulties of taking a finite
sample from a limited location or series of locations. It also does not suffer
from recovery difficulties as do swab sampling or rinse sampling.
Various modifications of visual examination have been utilized in the

pharmaceutical industry. Visual examination has been enhanced by the use of
ultraviolet light where the potential contaminant has fluorescence properties,
much as a dentist uses dyes that bind to protein to enhance the detection of
plaque on teeth during a dental examination. For areas that are difficult to ac-
cess, such as areas behind tank baffles or inside transfer pipes, companies have
used various creative approaches such as fiber optic probes and video cameras.
Visual examination of equipment should be a component of all cleaning
validation programs regardless of whether additional testing methods are
used. It is actually quite common practice to perform both visual examination
and chemical/biological testing of cleaned equipment during the validation
process. Another benefit of visual examination is that it will allow the ob-
server/operator to detect gross amounts of contamination concentrated in a
small area, which could go undetected with "normal" sampling programs.
Analytical Techniques for Biotechnology Cleaning Validation

There is a family of analytical techniques that is widely used in cleaning vali-
dation for biotechnology products. It consists of Lowry protein, sodium do-
decyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), capillary zone
electrophoresis, enzyme-linked immunosorbent assay (ELISA), and TOC
analysis. These methods are particularly useful and appropriate, since many
of the products and potential contaminants occurring in biotechnology man-
ufacturing facilities are protein in nature.
High Performance Liquid Chromatography

High performance liquid chromatography (HPLC) has been the mainstay of
pharmaceutical analysis for many years. Most recently, analytical researchers
have developed a new generation of detectors for these instruments that has
extended the range of applicability to an even wider array of materials. The
new detectors, known as evaporative light-scattering detectors, are more uni-
versal in their response (i.e., they do not require a chromophore group on the
molecule as do ultraviolet detectors). For these detectors, all compounds pro-
duce similar responses, and there are no baseline drifts due to mobile phase
effects. These developments in analytical technology should make this tech-
nique even more significant for the evaluation of cleaning samples in the
years to come.
Microbial and Endotoxin Testing

Microbial and endotoxin contamination has become and will continue to be-
come even more significant both in dosage form manufacturing and API facil-
ities. Even though these testing methods were not listed in the table of
analytical methods, they are certainly important. This is especially important
for products derived from natural sources, biotechnology products, and
aqueous-based processes. Currently, the APis used to manufacture sterile
dosage forms are subjected to validation of the critical parameters responsible
for controlling microbial and endotoxin levels in the finished API. Many
experts believe this expectation should also be applied to nonsterile API facil-
ities. One of the current difficulties is in establishing meaningful limits for
these residues.
Total Organic Carbon Analysis

The newest member on the analytical scene is TOC analysis. By this method,
the carbon atoms in the analyte are oxidized to carbon dioxide, which exists
in aqueous solution as the bicarbonate anion:
residue + oxidizing agent ~ (HC0 3t
The bicarbonate anion is then detected by various types of detectors,

typically infrared or conductometric types. The essential analytical
instrumentation is basically very simple, but it has been automated with mi-
croprocessors that determine when the sample is completely oxidized, and
subtract off inorganic carbon (that due to the presence of carbon in the water
itself as carbonate or dissolved carbon dioxide). These instruments are auto-
mated so that the multiple samples can be run unattended.
TOC offers great promise for verification and validation of the cleaning
process. It is extremely sensitive (one instrument supplier claims SO ppt [i.e.,
SO parts of carbon per 1,000,000,000,000 parts of solution]). It also involves
minimal development time compared to other analytical methods. The in-
strument run time is extremely rapid, thus enabling a laboratory to generate
literally hundreds of data points from an unattended instrument running
overnight.
There are two disadvantages to analysis by TOC. The first was referred
to previously, namely, that this is a nonspecific analytical method. The sec-
ond major disadvantage is that the material to be analyzed must first be dis-
solved in water, which requires the substance to have at least a minimal
aqueous solubility.
It remains to be determined whether these disadvantages will prevent
this analytical method from being utilized as an analytical method of choice
for cleaning sample analysis. In any event, many companies are already using
the technique Qenkins et al. 1996; Baffi et al. 1991).
Two possible manners of immediate application of TOC are quite readily

apparent. One is to use the technique as a screening method whereby the
equipment would be sampled, samples assayed by TOC, and the resulting
data used to screen the equipment to determine the general level of cleaning
and identify the most difficult to clean locations. This could then be followed
by product-specific assays with particular attention to the areas identified as
hard to clean. This type of study, often referred to as a process capability
study, would ideally be completed prior to cleaning validation and would pro-
vide extremely useful information to identify areas difficult to clean or to give
the confidence that the cleaning procedure is going to work effectively and be
easily validated during the formal validation of the cleaning process.
The second potential application of TOC is to use the technique to do
the cleaning validation itself. When used in this manner, it is necessary to
carefully prepare a scientific rationale because of the nonspecific nature of the
technique. In this case, the scientific rationale essentially states that all car-
bon residue detected will be assumed to have resulted from the most toxic
possible material present, normally the active ingredient. If the actual clean-
ing samples give results that are less than the limits established for the most
toxic material, then the actual identity of the contaminant is not necessary
since the worst-case rationale was used. If the actual results happen to exceed
the previously established limits, then a product-specific assay could be used
to establish whether the residue was due to active ingredient(s), excipients,
cleaning agents, preservatives, or other ingredients in the formulation.
The only case when this argument would be scientifically flawed would
be if the toxic material was not an organic (i.e., carbon-containing)
compound or if the active could be entrapped by other insoluble ingredients
and thus not available to be dissolved and not detected analytically. It should
be noted, however, that this is also a potential problem with all the analytical
methods, specific as well as nonspecific.
LIMITS AND ACCEPTANCE CRITERIA
Regardless of the cleaning approach or strategy, the question inevitably arises

as to what is clean enough or "how clean is clean"? There is no single, com-
prehensive answer to this question. It is quite clear that a level of zero residues
is neither practical nor possible due to the tremendous sensitivity of analyti-
cal technology.
The cleaning limit, although very important, should be only a single
component of the cleaning validation program or protocol. Other parts are
the requirements that equipment should be visibly clean, that training
records should be accurate and current, and that the cleaning procedures
should reflect accurately the procedures actually used by the operators to
clean the equipment.
The most important aspect of arriving at a cleaning limit is the journey

itself, not the destination. The "journey" refers to the process of arriving at
the limit, specifically the scientific rationale that supports the limit chosen.
Several companies are still using a limit of x ppm because they heard this
number mentioned at a meeting and decided to apply it to their operation.
Needless to say, this will not and should not be acceptable to the FDA.
A good scientific rationale should be logical, practical, verifiable, and
achievable. The actual numerical limit should be based on one or more of the
following:
• Therapeutic dosage levels

• Toxicity of the material
• Solubility of the potential residue
• Difficulty of cleaning
• How the products will be used
• The nature of other products made in the same equipment
• The batch size of other products made in the same equipment
For a finished pharmaceutical dosage form or for drug substances, the

limit is often based on allowing not more than a fraction of a therapeutic dose
to be present in subsequent products. Often, for oral dosage units (tablets,
capsules, caplets, etc.), a fraction of the smallest therapeutic dose, (e.g.,
1/1000th) is used as the numerical limit. The 1/1000th in this case becomes a
"safety factor." The safety factor should be a measure of a reasonable degree of
risk for the given situation. That reasonable degree of risk will be different for
APis and dosage form manufacturing situations. It will also be different for
tablet manufacturing versus production of sterile products. It will also be dif-
ferent for topical products compared with ophthalmics.
In this era of risk, statisticians can actually quantitate the probability of
a golfer being hit by lighting while on the golf course. Patients with terminal
diseases, such as AIDS and cancer, have been able to convince lawmakers that
a patient with a terminal disease should be able to make an informed consent
about risk in their medication. Presently, the FDA is trying to establish new
policies that will take into account different degrees of risk for different med-
ication situations.
To carry the concept of risk into cleaning residue limits determination,
there is no reason that risk cannot be related to the nature of how the product
is going to be used. For calculations of risk for dosage form manufacturing
based on therapeutic doses, it may be feasible to adjust the safety factor based
on the dosage form and to develop a continuum of safety factors as indicated
in Table 15.4.
It is apparent from Table 15.4 that the risk, as expressed in the safety fac-
tor, is different for different dosage form situations. The risk is higher for
Table 15.4 Safety Factor Continuum
Dosage Form Safety Factor
Research Compound 1/100,000 to 1/10,000

Intravenous Products 1/10,000 to 1/5,000
Ophthalmic Products 1/5,000 to 1/1,000
Oral Dosage Forms (tabs, caps, caplets) 1/1,000 to 1/100
Topical Products 1/100 to 1/10
research compounds, because little is known about the toxicity of the mater-
ial or the effect on the body in the diseased state. Therefore, a greater safety
factor is applied (i.e., a smaller fraction is allowed to carryover), and the limit
will be lower for these cases. At the other end of the continuum is the dosage
form of lowest risk (i.e., the topical dosage form). Since there is far less risk for
contamination to cause medical problems for this dosage form, the safety fac-
tor is appropriately less (i.e., a larger number). Of course, the majority of the
dosage forms will fall somewhere in between these two extremes, as indicated
in Table 15.4.
Calculation of Limit Based on Smallest Therapeutic Dose

As an example of a simple limit calculation, assume product A is manufac-
tured and the equipment subsequently cleaned before manufacturing other
products. Assuming that the product will ultimately be used as an oral tablet
and that the smallest therapeutic dose is 100 mg, a safety factor of 1/1000 is
applied. This means the next product would contain not more than:
100 mg x 1/1000 = 0.1 mg per daily dosage
If it is known, for example, that the following product B will have a max-
imum daily dose of 1000 mg (for example, 10 tablets each containing 100 mg
of active) and a batch size of 300 kg, then it is possible to calculate the limit
using a simple proportion as follows:
300 kg= 300,000,000 mg
0.1 mg = ___x_m--""g_ _
1000 mg 300,000,000 mg
Solving for x yields 30,000 mg.

It is important to note that the 30,000 mg limit appears to be quite large;

however, this is the total residue allowed for all manufacturing and packaging
equipment. It should be noted that this is only one simple example of a way
to calculate a limit based on smallest therapeutic dose.
Some companies use a worst-case approach for this calculation. In the
above example, the calculation would be modified by using the smallest
batch size of any product made in the same equipment and the largest daily
dose of any product made in the same equipment. This allows a single limit to
be set instead of having different limits depending on the parameters of the
following product. For the above example, if the smallest batch size for any
other product made in the equipment is 100 kg, and the largest daily dosage
of any other product made in the same equipment is 1500 mg, the limit cal-
culation would be as follows:
100 kg= 100,000,000 mg
0.1 mg xmg
1500 mg 100,000,000 mg
x = 6,667 mg
In this case the limit is calculated to be 6.667 g.

It is important to understand that it is not a case where one of the above
methods of calculation is correct and the other incorrect. By the first method,
a different calculation would be required for each and every product which
followed product A. Thus there would be a different limit if product B fol-
lowed product A, if product C followed A, if product D followed product A, if
product A followed B and so forth, for every possible combination and se-
quence of manufacturing events. This would become very unwieldy to man-
age, and, thus, many companies choose the second approach (i.e., of using
smallest batch size and largest daily dose for all products made in the same
equipment) for that very reason.
One obvious limit to this method of calculation is that in order to use it,
there must be an established therapeutic dose. This is not always available, es-
pecially for API facilities. For example, there are no therapeutic doses for pre-
cursors, by-products of chemical synthesis, and cleaning agents (detergents).
Therefore, a method of calculating limits is needed that is based on some pa-
rameter other than therapeutic dose. One method, which can be used in these
instances, is based on toxicity of the various materials.
Calculation of Limit Based on Toxicity

The toxicity method of calculation is based on the use of animal toxicity data
to determine limits. As mentioned earlier, this method is particularly suited
for determining limits for materials that are not used therapeutically. This
method is based on the concepts of acceptable daily intake (ADI) and no ob-
served effect level (NOEL) developed by various scientists in the U.S. Environ-
mental Protection Agency (Dourson and Stara 1983), the U.S. Army Medical
Bioengineering Research and Development Laboratory (Layton et al. 1987),
and the Toxicology Department at Abbott Laboratories (Conine et al. 1992).
Basically, these workers were attempting to determine the amounts of
chemicals that the human body could ingest on a daily basis without undue
risk and toxicity. In the process, they found that this level of ADI could be cal-
culated from the toxicity of the materials expressed as an LD 50 . These data are
widely available on Material Safety Data Sheets and other references in which
toxicity data can be found.
The NOEL is calculated from the LD 50 by the mathematical relationship
as follows:
NOEL= LD 50 X 0.0005
where the 0.0005 is a constant derived from a large toxicology database. Once
the NOEL is known, then the ADI can be calculated by the relationship:
ADI =NOEL/SF
where SF is an appropriate safety factor.

And finally, the maximum allowable carryover (MACO) can be calcu-
lated from the relationship:
MACO = ADI x BIR
where B is defined as the smallest batch size of any other product made in the
same equipment and R is the largest normal daily dosage of any product made
in the same equipment.
As an example, consider a fictitious chemical substance, X. If it is as-
sumed that the following toxicity, batch size, and dosage information is
known, then the MACO can be calculated as follows:
LD 50 = 419 mg/kg (oral) and 85 mg/kg (IV)

Smallest batch size made in same equipment (B) = 40 kg
Largest normal daily dosage (R) = 300 mg
NOEL= 419 mg/kg X 0.0005 = 0.2095 mg/kg/day
For a normal adult of 70 kg,

NOEL= 0.2095 mg/kg X 70 kg= 14.665 mg
ADI = NOEL/SF
Using a safety factor of 100 (for the oral route) gives

ADI = 14.665/100 = 0.147 mg
0.147 x 40,000,000 mg
MACO= ADI x B/R = 300 mg
= 19,600 mg or 19.6 g
Similar calculations for the intravenous (IV) route of administration are
as follows:
NOEL= LD 50 X 0.0005 = 85 mg/kg X 0.0005

= 0.0425 mg/kg/day
Again, converting for a 70 kg adult weight gives the following:
NOEL= 0.0425 mg/kg/day X 70 kg= 2.975 mg/day
ADI =NOEL/SF= 2.975/5000 = 0.000595 mg/day
(Note: 5,000 represents a safety factor for the intravenous route of
administration)
MACO= ADI x B/R = 0.0005957 x 40,000,000 mg = 119 mg
200mg
This calculation illustrates a couple of additional points. First, the
MACO calculation will utilize different LD 50 values depending on the route of
administration of the other products manufactured in the same equipment. If
all of the products manufactured in the equipment were used by the oral
route of administration, then the limit used would be 19.6 g. However, if
any of the products made in the same equipment were to be eventually
incorporated into an IV dosage form, then the limit would be 119 mg (i.e., the
most conservative of the two calculations).
Another important aspect of limits calculations is that the values calcu-
lated represent the total amount of allowable residue on all pieces of equip-
ment in the manufacturing "train." Often, for practical and logistics purposes,
it is necessary to divide, or prorate, the limit among the various pieces of
equipment.
Table 15.5 illustrates how the limit is prorated for a specific manufactur-
ing setup. From the table, it is apparent that the total limit is divided or pro-
portioned based on it's percentage of the total surface area.
If rinse sampling is used and the entire equipment is rinsed, then the
limit can be used for the individual piece of equipment. However, if the
equipment will be sampled by swab sampling, it is necessary to factor the
limit even further. For example, if 6 areas of the manufacturing tank will be
sampled by swab sampling and each swab will represent an area swabbed of
12 in. by 12 in., then the total area swabbed is 6 square feet. (Note: the total
Table 15.5 Dividing a Total Residue Limit Among Various Pieces of Equipment
Name of Equipment Surface Area (Sq.Ft.) %of Total Limit (Oral) Umit(IV)
Manufacturing Tank 23 6.34 1.24007 0.0075

Transfer Tank 23 6.34 1.24007 0.0075
Holding Tank 98 27.03 5.28378 0.0322
Centrifuge 45 12.41 2.42623 0.0148
Predryer 116 31.99 6.25428 0.0381
Dryer 28 7.72 1.50965 0.0092
Transfer Piping 27 7.45 1.45574 0.0089
Line Filters 2.6 0.72 0.14018 0.0009
Totals 362.6 100% 19.5500 0.1190
area of the equipment was 23 ft2). The total allowable residue for all
6 swabs (summed together) is as follows:
limit for total area swabbed (oral)= 6/23 x 1.24007 = 0.3235 g

limit for total area swabbed (IV)= 6/23 x 0.0075 = 0.002 g or 2 mg
To determine the residue allowed per swab, it is necessary to divide these

results by 6, that is
limit for single swab (oral)= 0.3235/6 = 0.0539 g

limit for single swab (IV) = 0.002/6 = 0.0003 g
or 0.3 mg or 300 meg
CLEANING VALIDATION DOCUMENTATION

All of the topics previously discussed in this chapter (e.g., analytical methods,
sampling methodology, determination of limits) come together in the process
of validation of the cleaning procedure. Validation of the cleaning process is
the accumulation of documentation of testing which demonstrates that the
cleaning process consistently reduces the levels of residues remaining on
equipment to previously determined acceptable levels. Frequently, the clean-
ing validation is included in an overall"master plan" for validation of an en-
tire facility, as represented in Figure 15.1.
It may be useful to consider where cleaning validation of APis fits in the
overall big picture. This is especially true for instances where limits are
Figure 15.1 Components of a Facility Master Plan

1. Validation of Manufacture of Active Pharmaceutical Ingredients (APis)
A. Equipment Validation
• Installation Qualification (IQ)
• Operational Qualification (OQ)
• Calibration Program
• Preventive Maintenance Program
B. Manufacturing Process Validation Process Qualification
C. Cleaning Validation
2. Validation of Manufacture of Dosage Forms
A. Equipment Validation
• Installation Qualification (IQ)
• Operational Qualification (OQ)
• Calibration Program
• Preventive Maintenance Program
B. Manufacturing Process Qualification (PQ)
C. Cleaning Validation (Dosage Form Manufacturing Equipment)
3. Validation of Packaging of Dosage Forms
A. Validation of Packaging Process
B. Cleaning Validation of Packaging Equipment
calculated for a total manufacturing operation (including production of ac-

tive[s] and dosage form) and then are subdivided or prorated into individual
components.
The documentation resulting from cleaning validation may be volumi-
nous but can be divided into two categories:
• protocols
• final validation reports (often referred to as validation packages or
finished validation packages)
Protocols
The protocol is the experimental plan that will be followed to demonstrate
the capability of the cleaning process. This experimental plan usually con-
tains some or all of the following elements.
Scope
The scope is a verbal description of the products and processes to be covered
by the experiments outlined in the protocol.
Objective
The objective is a statement of what is to be accomplished by the experi-
ments. It is typically a short general statement expressing the purpose of the
study-to demonstrate that the cleaning procedure will successfully and con-
sistently reduce the levels of residue to a predetermined level of acceptability.
Description of Process
A brief description of the manufacturing process naming the equipment used
in manufacturing the product is often included in this section as well as a de-
tailed description of the cleaning process or a reference to the number of the
Standard Operating Procedure (SOP) or other procedure. This would be an ap-
propriate section in which to list the equipment used in the manufacturing
process and any special auxiliary cleaning equipment such as high pressure
rinsing equipment, cleaning agents, and washing machines. It is also appro-
priate to distinguish whether the cleaning process is CIP, COP, or manual in
nature.
Identification of Critical Parameters

For every process, including cleaning processes, there are parameters that
must be controlled for the process to deliver consistent results. These parame-
ters are known as critical parameters, and they must be both controlled and
measured during the validation procedure. Examples of critical parameters for
cleaning processes are temperature of the cleaning solutions concentration of
cleaning agent(s) volume of cleaning solution, extent of disassembly of the
equipment flow rates of cleaning solution (especially important for CIP sys-
tems) drying conditions training of personnel and storage conditions. This
list is not extensive and certainly not complete, but it gives the reader a gen-
eral idea of the types of factors that may differentiate a good cleaning process
from a totally unacceptable cleaning process.
Test Functions
After the critical parameters are determined, the next step is to develop the ac-
tual tests that will be used to validate the cleaning process and determine if
the cleaning procedure is adequate and validatable. An example of test func-
tions is the visual examination of the equipment to verify that the equipment
is visually clean. If equipment is not visually clean, then it cannot be consid-

ered clean and there is little reasonto proceed with chemical testing. Another
value of physical examination of equipment is that often it is possible to de-
tect residue when chemical analysis alone might fail because not all surfaces
were swabbed or rinsed. Visual examination allows quick evaluation of large
surface and intricate surfaces and is perhaps the simplest of all tests.
Another important test function is training. It must be demonstrated
during the validation process that personnel have been properly trained in
the cleaning procedure. This is particularly important for manual cleaning
processes, since there is the potential for significant differences in the way
various individuals might interpret and actually carry out a given procedure.
There are also analytical test functions. These would be required for the
quantitative determination of the amount of product and cleaning agent
residues. As mentioned previously, it is very important that the analytical
procedures for trace amounts of actives and cleaning agents be sensitive
enough to detect the residues and that the analytical procedures themselves
be validated.
Description of Sampling Process

The sampling process is described in this section of the protocol and would
typically include a detailed description of what type of sampling (swab, rinse,
or other) is to be used, how samples would be obtained, and how they are to
be stored until analysis. A sampling diagram is often included, which indi-
cates the location of all sampling sites with an emphasis on the difficult-to-
dean areas (hot spots and critical sites).
Description of Analytical Methods

A detailed description of the analytical process or a reference to an associated
document, which gives the details of the analytical method, is given in this
section of the protocol. This section should also indicate that the analytical
method itself is validated and, therefore, capable of detecting residue levels
at the concentration levels established by the limits calculations. It should
also address recovery studies that establish the effectiveness of the samp-
ling process in removing residues and delivering them to the analytical in-
strument.
Limits and Acceptance Criteria

Limits and acceptance criteria are perhaps the most important and the most
scrutinized portion of the entire protocol. In it should be found the scientific
rationale that supports the actual numerical limit as well as the other accep-
tance criteria. It is important that the limit not be arbitrary but, instead, that
it be based on medical dosage levels, medical effect levels, or the toxicity lev-
els for the particular residue substance. The rationale should also define what
the basic approach is (i.e., whether a total residue [the so-called train concept]
approach will be the basis for pass or fail or whether there will be separate, in-
dividual limits for each piece of equipment).
There may be multiple requirements for acceptability. For example, it
may be a requirement that the total residue not exceed a certain level, as well
as that the concentration of contaminant not exceed a prescribed concentra-
tion (usually expressed as parts per million, ppm). There are usually addi-
tional requirements such as requiring that the equipment be visibly clean
when examined with a "black" light (ultraviolet).
A good rationale will also address assumptions or conditions that may be
present that can affect the risk of contamination. For example, if the equip-
ment is dedicated completely or in part to the production of a single product
or intermediate, the risk is much less than for a multiproduct situation, and
this should be stated in the rationale. Many companies assume that if a
residue were to occur in a particular piece of equipment, such as a mixer, that
it would be uniformly distributed in the following product. Assumptions of
this nature should be stated in the rationale.
If there are calculations or equations used in determining quantitative
limits, they should be described in detail, and each term and step in the cal-
culation should be fully explained in detail. In many cases, it is appropriate to
include a sample calculation.
Documentation
The documentation section of the protocol indicates exactly what documen-
tation must be a part of the final validation report. This would include items
such as original analytical records, charts, reports,· signed statements by man-
agement ·of the analytical department that the analytical methods are vali-
dated, and signed statements by production supervision that personnel were
properly trained in the cleaning procedures.
Analyses and Conclusions

The data are summarized in the analyses and conclusions section of the pro-
tocol, and any deviations or failures are fully explained or addressed. There
should be at least three sets of data, since all validation requires at least three
experiments (runs). In order to be acceptable, there must be three consecu-
tive, successful trials.
Approval
The protocol should be formally approved by appropriate signees represent-
ing appropriate expertise qualified to determine if the experimental plan will
test the process as desired. One of the signatures should be a representative of
the Quality Assurance/Quality Control unit.
Final Validation Report

Just as the protocol represents the experimental plan to be followed, the final
validation report represents the result of carrying out the experimental plan.
There should be a nearly perfect "fit" between the protocol and the final vali-
dation report (i.e., the report should be organized in the same order as the
protocol). Indeed, many companies incorporate a copy of the protocol into
the final validation report for convenience of reference. The components of
the final validation report would be exactly the items required by the protocol
and could include some or all of the following:
• Copy of the original protocol
• Sampling verification report (signed and dated by the person[s] per-
forming the sampling)
• Original analytical data (signed and dated by analyst and his or her
supervisor)
• Analyses and conclusions (evaluation of data, explanation of any
deviations, and statement that all acceptance criteria were met)
• Approval sheet (written signed approval by appropriate manage-
ment, including Quality Assurance, that all conditions of the pro-
tocol were met and that the cleaning process may be considered
validated)
Often at this point of completion of validation, a cleaning process be-
comes subject to change control. Often, the equipment and batch records are
labeled as "Validated-any change requires prior approval before implemen-
tation of the change." A statement to this effect may also be included in the
final validation report.
EMERGING TRENDS IN CLEANING IN

THE PHARMACEUTICAL INDUSTRY
Many companies are experimenting with new cleaning methods and new
cleaning technology in an effort to clean more efficiently and to a lower level.
Previously, many cleaning procedures were not product specific (i.e., the same
cleaning procedure was used for all products in a given facility or all products
manufactured in a certain piece of equipment). As cleaning has become more
scientific, there has been a realization that the cleaning technique used must
be directed toward the specific equipment and the products made in that
equipment.
Some companies have modified their use of cleaning agents. Particularly
for manufacturers of active ingredients, there has been a recent trend away
from the use of organic solvents for cleaning purposes, especially in the final
stages of the manufacturing process because of the toxicity of the organic sol-
vents. Some companies have found that aqueous-based cleaning is safer than
organic solvent cleaning in terms of potential carryover of the toxic organic
solvent residuals into the next product. Since organic solvents must be recov-
ered or disposed of, they also present an environmental impact.
Some companies have moved to the use of more product-specific clean-
ing agents, while others have moved away from cleaning agents in an attempt
to simplify their cleaning methodology. Many of the older cleaning methods
that were developed many years ago were quite arbitrary but became en-
trenched in our procedures. A commonly heard comment was, "That is the
way we have always done it." Some companies are finding that hot water is as
effective as any other cleaning method for their products.
Still other companies are experimenting with high pressure water clean-
ing. These devices function in a similar manner to those used in the "do-it-
yourself" car washes, except that they may involve considerably higher
pressure. These devices may be particularly appropriate for hard to remove
residues such as proteins. Any user of this technique should be aware of the
safety factors that these devices present; fingers and limbs have been lost by
careless use of these high pressure devices.
Another emerging trend is in the indirect visualization of hard to access
areas such as pipes, transfer hoses, or small intricate pieces of manufacturing
equipment. The fiber optic probe allows the viewing of surfaces that cannot
be accessed in any other manner.
Some companies are experimenting with the use of video cameras to ex-
amine equipment after cleaning. The cameras come equipped with a light
source and can be placed on a central post inside the tank. The device is in-
dexed and covers the entire inside surfaces of large tanks and may actually
prove to be superior to having a worker climb inside the tank. It is also safer
(no fumes) and less likely to lead to further contamination from the entry
process. The tapes can provide visual documentation should problems arise
later on.
An analytical trend in companies is the use of TOC for evaluation of
cleaning samples. This technique will undoubtedly have a major impact on
pharmaceutical analysis in general, and water and cleaning validation in par-
ticular. Newer analytical technology will continue to develop. Also, there is
ongoing research to develop newer and faster techniques to evaluate biobur-
den and endotoxin.
REFERENCES
Baffi, R. 1991. A total organic carbon analysis method for validating between products
in biopharmaceutical manufacturing. f. Parenteral Sd. Technol. 45:13.
Code of Federal Regulations, Title 21, Part 211, Current Good Manufacturing Practices for
finished phannaceuticals. Washington, D.C.: U.S. Government Printing Office.
Conine, D. L., B. D. Naumann, and L. H. Hecker. 1992. Setting health-based residue
limits for contaminents in pharmaceuticals and medical devices. Quality Assur-
ance; Good Practice, Regulation, and Law 1:171.
Dourson, M. L. and]. F. Stara. 1983. Regulatory history and experimental support of
uncertainty (safety) factors. Reg. Toxicol. Phannacol. 3:224.
FDA. 1991a. Guide to inspection of bulk phannaceutical chemicals. Reference materials
and training aids for investigators. Rockville, Md., USA: Food and Drug Adminis-
tration, Center for Drug Evaluation and Research.
FDA. 1991b. Biotechnology inspection guide, Washington D.C.: U.S. Government Print-
ing Office.
FDA. 1998. Guidance for Industry, Manufacturing, Processing, or Holding Active Phannaceu-
tical Ingredients. Rockville, Md., USA: Food and Drug Administration.
Jenkins, K. M., A.]. Vanderwielen, J. A. Armstrong, L. M. Leonard, G. P. Murphy, and
N. A. Piros. 1996. Application of total organic carbon analysis to clearing valida-
tion. PDA f. Phann. Sci. Technol. 50:6.
Layton, D. W., B.]. Mallon, D. H. Rosenblatt, and M. ]. Small. 1987. Deriving allowable
daily intakes for systemic toxicants lacking chronic toxicity data. Reg. Toxicol.
Phannacol. 7:96.
United States v Barr Laboratories, Civil Action No. 92-1744, United States District Court
for the District of New Jersey.
16
VALIDATION OF STERILE APis
Robert V. Kasubick
Oakwood Laboratories
Oakwood, Ohio
The manufacture of drug substances and drug products has been regulated
since the enactment of the federal Food, Drug and Cosmetic (FD&C) Act in
1906. The FD&C Act was expanded, most notably, in 1938, and again in
1962. The 1962 amendment included requirements for current Good Manu-
facturing Practices (cGMPs). The procedures for the control of cleanroom op-
erations and aseptic processing stem from the requirements posed by cGMPs.
The requirement for the validation of a microbiological control process
is embedded in 21 CFR 211.113(b), Control of Microbiological Contamina-
tion, which states,
Appropriate written procedures, designed to prevent microbi-

ological contamination of drug products purported to be ster-
ile, shall be established and followed. Such procedures shall
include validation of any sterilization process.
The validation of sterile bulk pharmaceutical chemicals (BPCs) (drug

substances) was addressed in July 1994 by the U.S. Food and Drug Adminis-
tration (FDA) (FDA 1994a) and in August 1995 by a Pharmaceutical Research
and Manufacturers of America (PhRMA) position paper (Lazar 1995). The
FDA's document was a guide to inspectors of a sterile drug substance manu-
facturing facility and indicates areas that the FDA considers necessary to in-
vestigate for potential deviations. Validation was 1 of 12 sections in the
guide. The PhRMA paper was intended to provide an industry position on
validation practices when producing a sterile drug substance.
429
Validation of an aseptic process should be designed to provide assurance,

through appropriate testing, that all phases and activities of the process re-
main sterile (aseptic), and that the aseptic process is controlled within the
predetermined parameters. The validation effort should take into account not
only the facility environment but also all materials and personnel introduced
into the aseptic core as potential causes for the loss of sterility. The validation
of drug substances generally follow the principles established for sterile drug
products.
For all processes, a validation plan should be generated. This plan should
include four items:
1. Installation qualification (IQ): The equipment is shown to per-

form with the specifications set by the manufacturer.
2. Operational qualification (OQ): The reliability of the equipment
has been demonstrated with at least three consecutive runs.
3. Product validation: The term product stability is more frequently
used to refer to the determination and documentation that the
product will consistently meet the established criteria for accep-
tance. The product has been shown to be stable under the condi-
tions of the process under consideration. This is usually done
during the scale-up trials and should appear in the development
report.
4. Process validation: The documentation to show that the process,
when functioning under the control parameters, will consistently
produce a product that will meet release criteria. The policy for
three consecutive runs definitely applies for process validation.
Note that the Guideline on General Principles of Process Validation (FDA
1987b) states "it is important that qualifications simulate actual production
conditions, including those which are 'worst case' situations," and that "tests
and challenges should be repeated a sufficient number of times to assure reli-
able and meaningful results." The FDA has not recommended any specific
number of "runs," but expects multiple tests to simulate actual operating
ranges and to establish consistency. The often-cited "three consecutive batch"
recommendation is intended for process validation rather than equipment
qualification or validation. However, it is our practice to follow the three-run
criteria for validation across the board.
In this chapter the assumption has been made that the IQ, the OQ, and
the product validation have been completed. This chapter is intended to
cover the validation of the microbiological aspects of the conversion of a drug
substance into a sterile drug substance. No attempt will be made to address
the validation of the synthesis of a drug substance. This subject is adequately
covered elsewhere in this book and in papers by the PhRMA (Lazar 1993) and
the FDA (1998).
Validation of Sterile AP/s 431
REGULATORY ASPECTS
Aseptic processing has been defined in several documents. Among these doc-
uments are the 21 CFR Part 211 cGMP regulations (1993), Federal Standard
209E (1992), and the FDA Guideline on Sterile Drug Products Produced by Aseptic
Processing (1987a). The basics for validation are set forth by the FDA Guideline
on General Principles of Process Validation (1987b). These documents have es-
tablished the conditions that must be met and validated for aseptic process-
ing. A summary of these conditions is given below.
• Microbial limits should be statistically established for environmen-
tal monitoring.
• Environmental control limits should include maximum levels for
viable and nonviable organisms.
• All equipment must be sterilized before each use.
• All personnel must be monitored for microbial contamination. The
monitoring must be done each day for all operating shifts.
• Particulate monitoring must be done on each operating shift.
• Sampling locations should represent conditions throughout the
controlled areas.
• Media fills must simulate production operations, especially regard-
ing number of personnel, equipment used, and the process followed.
• The aseptic process must be validated on a periodic basis.
The demonstration and documentation that these conditions are being met
by the manufacturing process controls is the intent of validation.
VALIDATION PROTOCOL FORMAT

The first step in any validation process is to generate a protocol that defines
the process to be validated, how the process will be tested, and the acceptance
criteria for the results obtained from the testing. The validation study will in-
clude the facility, conditions, and controls under which the drug substance is
manipulated. The protocol should include the following eight items:
1. An introduction defining the objectives of the study
2. Identification, location, and description of all equipment and
processes being validated
3. Identification of test and support equipment being used
4. Identification of Standard Operating Procedures (SOPs) being used
5. Identification and description of the test methodology

6. Process parameter acceptance criteria
7. Diagrams or figures for equipment, heat penetration studies, and
so on
8. Sampling criteria
The inclusion of all of these items in a protocol with test methods and accep-
tance criteria requires that the process being validated is understood in detail.
The basis for the validation acceptance criteria will be found in the develop-
ment report issued by the research group at the time of the technology trans-
fer from research to production.
GENERAL MANUFACTURING PROCESS DESCRIPTION
The general process for converting a nonsterile drug substance to a sterile

drug substance can be divided into nine operations (Figure 16.1). These oper-
ations generally are carried out in four distinct areas.
1. A nonsterile, but controlled, atmosphere environment where a
nonsterile drug substance is dissolved in a solvent (aqueous or non-
aqueous) in preparation for sterilization by filtration.
2. An aseptic, controlled atmosphere environment where the nonsterile
bulk solution is sterilized by filtration. The sterile solution is collected
in an aseptic reactor for precipitation or crystallization. Filtration or
centrifugation can isolate precipitated or crystallized solids.
3. An aseptic, controlled atmosphere environment in which the sterile,
wet drug substance is dried to remove solvents. Depending on the
operation, the dried material may be milled and/or blended to pro-
duce the bulk material in preparation for final testing and packaging.
4. An aseptic, controlled atmosphere environment where the sterile
bulk is sampled for final quality control testing and packaged into
containers.
FACILITY
Now that the process has been defined in general terms, the specifics must be
addressed. The general process described above must be evaluated in terms of
the following parameters:
• Room classifications
• Airflow patterns
Validation of Sterile APis 433
Figure 16.1 General Process for The Production of Sterile Bulk Drug Substances
Area 1
Dissolution
Area 2
~-·····-····--------·-···- -------·-·····-----------------------------------------------------··-----·---------·--·-·-···-------------------------···-·----1
Sterilization Precipitation
Isolation
"" Crystallization
,.
~-----····----------------
Area 3
---------------------------------------------------·-·-··················--···············-·-···-···----·-·····-----------------i
Drying ... Milling Blending
Area 4
··-·-···-·····-···-···-···, ··-·······-·····-········ ····-·········-·····-···-·-·········-···-·····-···-·-
Sampling Packaging
• Pressure differentials
• Personnel flow patterns
• Material flow patterns
Room Classification
Room classifications are assigned according to Federal Standard 209E (1992).
This standard establishes room classification according to the number of par-
ticles less than 0.5 ll-m found in a cubic foot of sampled air. Thus a Class 100
area is one that has ~100 particles, a Class 10,000 area has ~10,000 parti-
cles, and a Class 100,000 area has ~100,000 particles per cubic foot that are
~0.5 ll-m in size. The status of the room when the particle count is established
is not specified by the federal standard. However, Section 5 1.2.1 of 209E states
that the status of the clean room during collection of the samples shall be re-
ported as one of the following conditions: "as-built," "at-rest," "operational,"
or as otherwise specified. Generally, the validation data are reported as taken
under the "at-rest" condition, since the introduction of people and operating
equipment quickly introduces nonreproducible quantities of particles. The
"at-rest" condition provides the best opportunity to develop trend data on
the operational capabilities of the area under consideration. Federal Standard
209E provides in-depth details for collecting samples, evaluating results, and
so on; therefore, these actions will not be discussed.
Figure 16.2 is a simplified representation of a typical aseptic suite. The
Class 100 areas are the areas directly over the portions of the operation where
the product has the potential of exposure to the environment. A Class 100
condition is required by the cGMPs for any area where the product has the
potential of exposure to the environment. Surrounding these Class 100 areas
are areas that are generally put into a Class 10,000. Frequently these areas ex-
ceed the Class 10,000 requirement and are actually closer to a Class 1000 area.
This is the segment of the suite where autoclaves are unloaded, materials are
staged, sterilized items are transported, and so on. Class 10,000 areas are those
from which the critical or Class 100 areas are reached. Next to the Class
10,000 areas are the Class 100,000 areas where items are cleaned and prepared
for sterilization, and materials are weighed, formulated, and so on. The Class
100,000 also includes the site for personnel to have initial entry into the asep-
tic processing suite.
The validation protocol for the air system should include details of how
the air samples will be taken and tested to verify each classification. As indi-
cated above, most of the data will be generated under the "at-rest" condition,
but situations will occur where "operational" data, i.e., when personnel or
equipment are in motion, may be required. In areas where dry powders are
being processed, "operational" particle data will not be of value because the
particles introduced to the environment will be inherent to the process and
will not represent the capabilities of the environmental control system.
Figure 16.2 Area Classifications
Corridor 2
Area 3 Area 4
Gowning3 Corridor 1
Class 100,000
0
Class 10,000 Class 100
Areas that must be monitored and validated in a nonactive mode ("at-

rest") will be the Class 100 laminar flow hoods in the filling suites and stor-
age areas. For Class 10,000, the secondary gowning anterooms, corridors, air
locks, sealing and staging areas, and cleaning closets must be considered. For
Class 100,000 areas, the initial entry anteroom for gowning, equipment
preparation areas, equipment cleaning areas, and storage areas must be vali-
dated. The area used for the dissolution of the drug substance, in preparation
for sterile filtration, is Class 10,000 and should be validated as such. Valida-
tion during activity at the site (operational) must be done for Class 100 hoods
used for filling liquid products. If the sterile drug substance is to be sent to
European facilities, the European Community (EC) guidelines must be con-
sidered when determining the acceptance criteria (EC 1993).
Airflow Patterns and Pressure Differentials

Besides maintaining the area classification, airflow and pressure differential
patterns among critical (Class 100), controlled (Class 10,000 and Class
100,000), and uncontrolled areas must be given consideration. The airflow
must be outward from the Class 100 area where the sterile drug substance is
or may be exposed to the environment. The pressure differential between
adjacent classification areas is required by the cGMPs to be a minimum of
0.05 inches of water. The above criteria dictate that the airflow will be from
each of the processing areas into the access corridors and gowning/degown-
ing areas before exiting to the uncontrolled areas.
For most manufacturers of sterile drug substances, the flow pattern de-
scribed in the previous paragraph must be modified. Since most drugs exist in
a powder or crystalline form they are easily introduced into the environment.
Therefore, the portions of the aseptic suite not directly involved in manipu-
lating the dry drug substance must be protected from potential contamina-
tion by the drug substance. The potential contamination of areas where the
dry powder is not manipulated can be achieved by having the airflow toward
the powder processing.
Figure 16.3 is a representation of validation criteria for the airflow direc-
tion and pressure differentials in a typical aseptic suite used for filling a pow-
der product. The values displayed are pressure differentials in inches of water
pressure relative to the uncontrolled areas, which are considered to be at zero
inches of water. The arrows show the direction of airflow.
The cGMPs dictate that the airflow must be outward from the Class 100
area where the sterile drug substance is, or may be, exposed to the environment.
Therefore, the direct packaging (filling) site in Area 4 should be under
laminar flow and have a static rating of Class 100. The actual airflow will be
from the Class 100 area into Area 4 to control exposure for the sterile drug
substance. However, the overall airflow will be from the corridor into Area 4
Figure 16.3 Airflow Pattern
p =0.05 p = 0.07
p = 0.10
t t
Area 1 Area 2 Area 3 Area4
I I
I
I
-o
II
0
0
-
-o
II
0
0
' -o
II
0
0
- .
lr
-o
II
0
0
l
(11 CX> CX> CX>
I
' ll
= 0.10
GovJning Gowning 2
, Gowning 3 p
p = 0.02 p =0.05 p = 0.07 -

to control the potential of particle contamination of the environment. Area

3, where the drug substance is dried, will have a similar airflow pattern to
control particles. Areas 1 and 2, as typical controlled areas, have the air flow-
ing into the corridors and then into the gowning areas. Airflow is generally in
the reverse direction of personnel and material flow.
A Center for Drug Evaluation and Research (CDER) guideline (FDA
1987a) requires that the pressure differential between classes be a minimum
of 0.05 inches of water. The guideline further recommends that the pressure
differential measurement be taken with connecting doors closed. If the pres-
sure differential meets the minimum requirement of 0.05 inches of water be-
tween air classification areas, the outward flow should be sufficient to
minimize the ingress of contamination when the doors are open. Pressure
gauges must be in place to monitor the differentials constantly, and the out-
put should be recorded periodically.
The conditions represented in Figure 16.3 meet the cGMP requirements.
For example, going from Class 100,000 to the uncontrolled area is to go from
Area 1 through the degowning area. The drop in pressure across both rooms
(a single classification) is 0.05 inches. A drop of 0.03 inches of pressure occurs
between Area 1 and the degowning room, and another drop of 0.02 inches of
pressure occurs between the degowning room and the uncontrolled area.
The validation of these factors will require gathering sufficient data to
display the stability of the system both "at-rest" and "operational." The sys-
tem should be monitored for validation purposes over several days under
both conditions to display stability.
The velocity of airflow is a key parameter for validation. The CDER
guideline (FDA 1987a) states that the airflow must be sufficient to provide ap-
proximately 20 volume changes per hour. Also, Class 100 air velocity is de-
fined by Federal Standard 209E and by the FDA (1987a) to be 90ft/min at the
filter face. This velocity is to be considered the starting point for achieving
laminar flow at the work area. Each operation should be validated for para-
meters most suitable for the geometry of the equipment used. The efficiencies
of high efficiency particulate air (HEPA) filters also are determined as part of
the validation procedure.
Besides validating the air classification of the aseptic area, airflow veloc-
ity, and airflow patterns, the temperature and humidity conditions must be
considered. Normally, the temperature should be maintained at 68°-72°F and
the relative humidity at 30-60 percent. These parameters should be met un-
der conditions with all personnel present and operating the equipment.
Personnel Flow
For personnel entering the aseptic suite, the entry is in Gowning Area 1
(Figure 16.4). From here they go to Gowning Area 2 to don a gown (jumpsuit)
to minimize the ingress of potential contaminants into Area 1. For those
personnel going into other areas, additional gowning is required and
Figure 16.4 Personal Flow
ll I' ~
Area 1 Area2 Area 3 Area4
t • ~
Gowning Gowning 2 Gowning3
accomplished in Gowning Area 3. This additional gowning would consist of

another jumpsuit, a hood, rubber gloves, and goggles. This second gowning
assures that minimal skin area is exposed to the aseptic environment.
The use of correct techniques in putting on sterile gowns is essential to
minimize the likelihood of personnel-borne contamination entering the asep-
tic environment. Two areas must be stressed and validated. First, operators
must be sufficiently trained that during the process of putting on the sterile
gowns no transfer of microorganisms occurs from the operator to the gown.
Second, operators must constantly monitor their gowning to assure that no
skin area becomes exposed to the environment.
The personnel gowning process must be validated. Personnel monitor-
ing is done by monitoring the exterior surfaces of gowned personnel. The
most common form of monitoring is to press the gloved fingertips onto a
petri dish containing a solid agar media. This method should be validated to
maximize recovery. RODAC™ (replicate organism detection and counting)
(i.e., plate) samples should be taken from all gown joints and the zipper area
of gowns. These are the most frequently touched areas and, therefore, the
most likely to be contaminated. The validation process should also include
the process of leaving the aseptic area and regowning, either totally or par-
tially, to reenter the aseptic area. During the sampling procedure, care must be
taken that the operators do not subject their gloves to disinfectant wash be-
fore samples are taken.
Material Flow
Material flow will follow the same pattern as indicated for personnel. Con-
tainers going into Area 1 must be clean to assure minimum potential for the
introduction of microorganisms. For materials transferred from Area 1 to Ar-
eas 2, 3, or 4, the controls must be more extensive. Procedures must be in
place to assure that no possibility for the introduction of contamination has
been overlooked.
Materials will enter the aseptic core by either using the same air lock
system as personnel, or entry through sterilizing ovens or sterilizing fil-
ters. For equipment or materials entering through the air lock system,
sufficient contact plate testing must be conducted to assure that all possible
areas for contamination have been disinfected. Corners and joints are the
most difficult spots to clean and are the most likely places to harbor micro-
organisms.
If materials enter through sterilizing ovens, the ovens must be validated
to show that all configurations will be exposed to minimum sterilization con-
ditions. An excellent review of the points that must be considered for oven
validation is presented by the FDA document entitled Sterilization Process Val-
idation (1993a). Since the materials will be in sterile storage for some time, val-
idating the ability of the materials to remain in an aseptic condition for the
maximum anticipated storage time will be necessary.
The ability of the filter to sterilize the drug substance solution, and any
other liquid or solution passed through the filter, must be validated. The man-
ufacturers of the filters will certify that filters rated at 0.2 Jl.m will remove 10 7
organisms per centimeter squared. Using only the manufacturer's certification
that the filter will remove this quantity of organisms is no longer sufficient.
Each filter must be validated for the specific solution being filtered. The major
filter manufacturers have developed programs for validating filters with spe-
cific solutions.
SUPPORT SYSTEMS
Water Systems
Foremost among the support systems are the water and air systems. The water
system has received considerable attention. A good overview of what may be
expected from an FDA inspector can be found in the Guide to Inspections of
High Purity Water Systems (1993b). This guide does not specifically address val-
idation but does provide background and guidance for items that must be
addressed.
The objective of water system validation is to provide assurance that the
system eliminates endotoxins from the incoming water and prohibits the
formation of endotoxins during usage. The validation is conducted in five

steps:
1. System description, including specifications
2. Installation qualification
3. Operational qualification
4. Validation to prove that the system will reproducibly deliver Water
for Injection (WFI)
5. Documentation and monitoring
The concepts for the these five steps were published in 1983 (Carleton et al.).
This section will focus only on the actions necessary to accomplish Step 4. A
simplified WFI system is shown in Figure 16.5. In the system depicted, the
validation protocol should require testing at the six points shown as A, B, C,
D, E, and F.
The purpose of testing and establishing action limits or levels is to assure
that the water system is under control. The major consideration in the valida-
tion of high purity water systems is the acceptance criteria. Consistent results
throughout the system over a period of time form the primary element.
Any action limit established will depend on the overall system and fur-
ther processing of the finished product and its use. In general, the FDA prefers
100-300 mL for water samples. Sample volumes less than 100 mL are unac-
ceptable. The major concern in a water system is endotoxins. Because water
can pass the Limulus Amebocyte Lysate endotoxin test and still fail the mi-
crobial action limit, it is important to monitor water systems for both endo-
toxins and microorganisms.
To assure that the system is not stressed, the quality of the incoming
water must be monitored (Point A). The quality of water introduced into
most facilities varies considerably. The acceptance criteria for incoming
water must, at a minimum, meet the U.S. Environmental Protection
Agency regulations for drinking water. The variation allowed in the para-
meters can be defined only after the system has been operated for a period
of time and determining the effect of the test parameters on the overall
ability of the system to produce WFI that consistently meets U.S. Pharma-
copoeia (USP) specifications. If the feedwater is from a municipal water
system, reports from the municipality testing can be used in lieu of in-
house testing.
The ability of multimedia filters, softeners, and the reverse osmosis sys-
tem to remove most of the contaminants to a consistent level must be docu-
mented. This documentation will be achieved by showing that the
pretreatment system provides constant quality water to the stills (Point B) de-
spite the fluctuations in incoming water quality.
The ability of the distillation system to produce WFI, as defined by the
USP, must be documented. The testing at Point C should be conducted over a
Figure 16.5 Simplified WFI System
Multimedia Softener
City Water Filters System
Reverse
Osmosis
System
still No.2
Still No.1
Storage Tank
D Use Point Use Point
sufficiently long period to assure obtaining representative samples of the sys-

tem's capabilities to deal with a variety of events and conditions. Conductiv-
ity meters used to monitor water systems provide information only on the
chemical quality and have no meaning regarding microbiological quality.
The loop system must deliver pyrogen-free WFI at the use points (D and
E). Maintaining the loop and the storage vessel at 80°C and continually mov-
ing WFI through the system will generally maintain the system pyrogen free.
Lower temperatures may also be adequate and may be considered acceptable
if the firm has data to show that a lower temperature works as intended (i.e.,
the water remains pyrogen free on storage). Any validation effort should in-
clude studies at the lower range of the temperature that can be maintained in
the loop and storage tank.
A validation report for a WFI system should include a description of the

system along with a blueprint. The drawing needs to show all the equipment
in the system, from the city water feed point to the points of use and the re-
turn loop. The report should contain a diagram showing all sampling points.
The diagram must be compared with the actual system to confirm its accu-
racy. These diagrams are necessary to provide the testing microbiologist infor-
mation on where the most appropriate test points are. The validation of the
water system may be considered complete when the firm has a full year's
worth of data. This amount of data is necessary to show that seasonal varia-
tions in the feedwater do not adversely affect the operation of the system or
the water quality. A major consideration in the validation procedure is the ac-
ceptance criteria. Consistent results over an extended period are primary in
generating a report that adequately validates the system.
Air Systems
The second area of concern is the air system. The air supplied to the aseptic core
is usually filtered through 0.2 1-Lm HEPA filters to remove particles from the in-
coming air. Therefore, incoming air, if the filters are working properly, is seldom
the source of contamination. Two other possible sources of contamination are
1. the environment, i.e., the room and equipment surfaces; or

2. people, who are usually the main source of airborne bacteria.
As indicated above, the air filtration system must provide particle reduction.
The acceptance criterion for the validation of the HEPA filter system is a mini-
mum of a 99.99 percent reduction of incoming particles. The degree of reduc-
tion can be determined and validated by introducing a dioctyl phthalate
(DOP) aerosol into the duct system a short distance upstream from the filter.
The concentration of the DOP should be in the neighborhood of 80 to 100 1-Lg
per liter of air at the filter's designed airflow rating. The scanning probe on the
downstream side of the filter should be capable of a sampling rate of at least
1 ft 3 of air per minute. The downstream probe should be positioned 1 to 2 in.
from the filter face. The validation protocol should, besides validating the ca-
pability of the filter to remove the appropriate amount of particles, provide a
method to show that the frame holding the filter in place will not pass any air.
This phase of filter validation testing is generally conducted with no activity
in the area.
The air introduced into the area under consideration is intended to min-
imize the exposure of the sterile material to contamination from the environ-
ment. These Critical or Class 100 areas should be supplied with a HEPA-
filtered laminar or unidirectional flow of air having sufficient velocity to
sweep particulate matter away from the filling/dosing operation. The velocity
of the air exiting a filter intended to provide a Class 100 condition is specified
by the FDA (1987a) to be a minimum of 90 feet per minute (FPM). In actual-

ity, the appropriate velocity is determined empirically and may be higher
where equipment or surfaces disrupt the laminar flow pattern. Typically, ve-
locities of 110 FPM or more may be required to provide a continuous and un-
obstructed laminar flow pattern across the work area. When conducting the
studies, a general rule is to take a velocity measurement for each 0.5 ft2 of fil-
ter surface. The validation acceptance criterion is generally ±20 percent of the
minimum velocity determined to provide laminar flow.
The laminar flow pattern should be initially determined without activity
in the area. It should be subsequently determined with personnel performing
normal operations to assure that the introduction of containers, hands, and
so on does not affect the laminar flow sufficiently to prevent the removal of
particles from the area containing the sterile drug product. Smoke studies
may be conducted to verify the patterns.
The flow pattern can be affected by the following four general factors:
1. Vertical surfaces
2. Horizontal work surfaces
3. Equipment or materials, stationary and in motion
4. Personnel, stationary and in motion
The position of the air inflow relative to each of these factors, obviously, will
affect the areas that need special attention.
When the air is introduced to provide a laminar flow down a vertical sur-
face to a horizontal surface, the area where the vertical surface meets the hor-
izontal surface, as might be found in the rear of a laminar flow cabinet, will
produce a stationary vortex. To avoid such vortices the sidewalls must be de-
signed with openings to prevent the generation of dead air pockets. Introduc-
ing the vertical laminar flow from the center of a bench or work area will lead
to a stagnation point in the middle of the bench. The addition of a produc-
tion filling unit into the laminar flow introduces more complication. De-
pending on the geometry of the vertical and horizontal surfaces, horizontal
laminar flow may result in less turbulence. However, in production condi-
tions vertical flow is more frequently used. In some cases decreasing the flow
rate instead of increasing it may eliminate a stationary vortex. The optimum
flow rate can be determined empirically only by trial and error.
The smoke patterns will show that changing the position of an arm from
a waist position to a higher position will drastically affect the flow patterns.
The patterns also will be different for objects in motion as opposed to station-
ary objects. The use of video cameras to record the results greatly simplifies
the documentation of this task. Class 10,000 and Class 100,000 areas are not
required to have laminar flow. The validation acceptance criterion for the air
velocity at the filter face in these areas is generally ±20 percent of the original
installation values.
For those individuals who are interested in designing a facility, Ljung-

quist and Reimiiller (1997) gives an excellent presentation on the theoretical
aspects of the dispersal of airborne contaminants. The text does not specifi-
cally address validation issues but provides a better understanding of the dif-
ficulties encountered with laminar flow conditions.
Equipment Sterilization
Equipment used in the processing of sterile bulk substances presents special
problems. This equipment, which includes items such as crystallizing tanks,
centrifuges, and dryers, is intended to be sterile before use. Sanitation, usually,
is not acceptable to the FDA. However, the FDA does recognize that some
equipment is not amenable to sterilization. In those cases, the validation of
the sanitation process is extremely critical. The acceptance criteria for the san-
itation process must be narrow, and the support data must be well docu-
mented. The validation program should show the effectiveness of the
disinfecting program for this and all subsequent processing areas. If a se-
quence or rotation of disinfecting agents is used, the validation program
should be sufficiently long to cover the use of all agents.
The method of choice for sterilizing large equipment and associated
transfer lines is saturated clean steam under pressure. The validation process
must prove that the steam being delivered meets the USP criteria for WFI, py-
rogens, and bioload. The validation must also prove that the steam is steriliz-
ing all surfaces. When validating the ability to sterilize equipment, heat
distribution studies in the autoclaves must be done to determine the cold
spots where condensate could accumulate. The point of steam injection and
discharge must be part of the testing pattern, including any low spots. As with
the WFI system, the validation effort should be over a period sufficiently long
to allow the system to go through several cycles. It is necessary to show that
the steam-in-place (SIP) cycle is reproducible and capable of achieving ade-
quate sterility at the extremes of the operating conditions.
The validation of the sterilization or depyrogenation of equipment out-
side the aseptic core is essentially the same for both drug substance and drug
product. This validation procedure has been thoroughly covered by an FDA
guideline (FR 1993). Standard items, such as load mapping at a minimum of
10 points showing a uniform and stable heat distribution throughout the
chamber demonstrating that the coolest position remains above the mini-
mum temperature for the minimum run time and biological challenges with
a minimum of 1,000 endotoxin units per measured site with a reduction ac-
ceptance criteria of not less than three logs, must be covered. In addition to
these items, the hot air ovens must be validated for particles introduced dur-
ing the sterilization operation. The number of particles should be determined
by sampling after the oven has reached the set depyrogenation temperature.
The validation of any sterilizer or depyrogenation oven is not considered
acceptable unless three consecutive runs that have met all acceptance criteria
have been completed. There should be three consecutive runs at both the
maximum and minimum load configurations.
Another area that must be included in the validation protocol is equip-
ment cleaning. Procedures must be developed to remove any previously used
chemicals or materials from the equipment. The cleaning procedures must be
validated to demonstrate that the level of residual materials present after
cleaning is acceptable. The criteria applied to the cleaning procedure to deter-
mine acceptable residual levels is as follows:
The residual level of any material should be sufficiently small

so that when the drug substance is used for normal therapeu-
tic purposes, the amount present will be below known toxicity
levels.
The analytical method used in the detection of residual materials must be

shown to be reproducible, and so on, the same as for other methods used for
in-process testing.
Clean Steam System

The validation of the clean steam loop follows the procedure used for the WFI
system. The water going into the clean steam generator should be WFI. Using
WFI as the water source eliminates the need to have a separate validation of
the quality of incoming water, as was done on the WFI system validati9n. The
clean steam loop must be validated to show that the system has no low point
where condensate could collect and allow microorganisms to grow. The abil-
ity of the system to maintain the necessary temperature must be demon-
strated. Samples should be taken at each injection leg to assure the lack of
microbial growth while the injection port is closed.
Filtration Systems
All process gases entering the aseptic core must be validated as sterile and par-
ticle and pyrogen free. Therefore, validating the ability of the in-line filters to
remove microorganisms will be necessary. An adequate sample is required to
evaluate the pyrogen potential. The pyroburden should have a sample size of
30-40 L of gas. Additionally, the nonviable particle count should be done on
a sample of not less than 1 ft3 of gas. There are no set limits for nonviable par-
ticles in a gas stream. The specification will be set based on the data generated
during the OQ and IQ operations. The validation of the process gases must be
run separately from any media trials conducted, to show the ability of the sys-
tem to provide aseptic media. Bioburden data on the incoming gas stream will
be necessary to show control of the incoming material and to show that the
in-line filters will not be stressed beyond their capabilities to remove organ-
isms. The validation process must also include the sterilization of the filters to
be used in the gas lines.
There are two types of filters to be considered when establishing the val-
idation protocol: gas and fluid. Gas filters will be required on all incoming
process gases and on all system vents. The validation procedure will need to
cover the sterilization of the filters and their installation. Since the potential
exists that a filter may have to be changed during the processing of a drug
substance, the validation should also cover the procedure of removing and in-
stalling a filter while maintaining aseptic conditions.
The validation of the filters used to sterilize incoming solutions and sol-
vents is considerably more involved. The protocol for these filters must con-
sider not only the effect of the bioburden of the incoming solutions but also
the effect of viscosity, pH, ionic strength, osmolarity, flow rates, temperature,
and pressure on the ability of the filter to remove microorganisms. If organic
solvents are to be employed in the process, their effect on the filter's ability to
function must also be documented. Filter validation must be conducted in
the manufacturing facility. The testing can be contracted to an outside labo-
ratory. Several filter manufacturers have programs to validate filters. However,
care must be taken that the protocol meets FDA criteria. One criterion is that
the actual manufacturing conditions must be simulated. The FDA has noted
(1994b) that the potential for the drug product to cause a reduction in mi-
croorganism size must be considered. Therefore, conducting the filter valida-
tion with the actual drug substance solution presents a situation that is in line
with the FDA's views. The FDA further states that in the cases where a preser-
vative has been added, conducting the validation with the preservative ex-
cluded from the formulation is acceptable.
Filter manufacturers have developed what they call a matrix approach to
validation. However, the FDA has gone on record to say that the matrix
system proposed by filter manufacturers may not be adequate (Ben Venue
Laboratories 1994). The FDA's major concern with the matrix approach, as
proposed by filter manufacturers, is that the approach does not take into con-
sideration any interactions between variables that would decrease the ability
of the filter to retain microorganisms. Again, this concern of the FDA is elim-
inated if the actual drug substance solution is used in the filter validation.
Other items that must be included in the validation study are the
bioburden of the drug substances, procedures for determining the integrity of
the filters before and after use, and several changes of the filters to cover the
potential for filter failure and appropriate replacement.
Heat Exchangers
Certain portions of processing will require heating or cooling, which is the
function of a heat exchanger. The quality of the heating or cooling media is
generally less than the quality of the process.stream. Controlling the heat ex-
change system to assure no passage of the heating or cooling media into the
process stream is critical. This control is generally accomplished by having the
heating or cooling media at a lower pressure than the process stream. The val-
idation protocol must include a section to document that the pressure moni-
tors are functioning as designed.
Vacuum Systems
The primary concern with vacuum systems is that nonsterile gas is not drawn
into the system, either during the application of the vacuum or after the com-
pletion of the vacuum cycle and the subsequent adjustment to atmospheric
pressure. The validation procedure must document that the system does not
leak under the operating conditions. The procedure also must verify that all
system vents prevent the ingress of nonsterile gases.
MANUFACTURING PROCESS VALIDATION

So far, the discussion on validation has concentrated on equipment and facil-
ities used in the processing of the drug substance. This phase of the validation
effort is generally the more difficult phase to accomplish because of the size of
the equipment and facility involved. However, the validation procedure will
not be complete until the process (the actual manipulation of the drug sub-
stance through the system) is shown to produce a sterile material. This phase
of the validation is achieved by showing that the drug substance remains ster-
ile throughout its handling, and that the controls for the process perform the
tasks expected of them. For a drug product, the maintenance of sterility is
demonstrated by processing a growth medium through the system. This use
of a growth medium to simulate the drug product can be done, because the
processing of a drug product involves a solution. With the drug substance
process, most of the process is generally the handling of a solid material. The
exception to this would be for a lyophilized drug substance. When this is the
case, media runs will be expected for the process up to the point of placing
the material into the lyophilizer {dryer). Since the process for lyophilization
up to drying in the vacuum chamber is liquid, processing a solution of media
to show that the process is aseptic is possible. If the drug substance is
lyophilized, conducting three consecutive media trials that show no growth
after a 21-day incubation period will be necessary.
During the dissolution of the drug substance, the primary concern is to

document that the bioburden introduced either with the drug substance or
the solvents is controlled. Therefore, bioburden data are necessary for all ma-
terials consumed in the process. Acceptance criteria will be based on historical
data and should be set to reflect the bioburden levels found. For example, if
the bioburden for a drug substance was found to be 1 colony forming unit
(CFU), an acceptance criterion of 20 or 25 CFUs would not be acceptable
to the FDA. The acceptance criterion, in this case, should be in the range of
3-5 CFUs. The FDA would probably accept this range. The position taken by
the FDA on setting acceptance criteria is that sufficient control must be ex-
erted on the incoming materials to assure that the bioload introduced into
the system is minimal and will not result in stressing the sterilizing filters.
If organic solvents are used in the dissolution of the drug substance, the
FDA has not accepted the argument that the solvent will kill any organisms
introduced. Although organic solvents may be lethal to microorganisms, the
lethality is too sporadic to be considered as an assurance of sterility. The FDA
wants to use an external factor (i.e., filtration) to assure the removal of all or-
ganisms. As mentioned earlier, the filter must be validated to show that with
the particular solution used in the process, the filter will remove sufficient mi-
croorganisms to achieve a minimum of a six-log reduction. Also, the filter
must be shown not to degrade in the presence of the drug substance solution,
nor contribute extractables to the solution.
The precipitation or crystallization of the drug substance is generally ac-
complished in a closed system with little exposure to the environment.
Therefore, the validation at this point would primarily consist of environ-
mental monitoring to assure that the support systems are acting to minimize
the potential of contamination. A typical program will include multiple sam-
pling and testing schemes. Besides nonviable particle monitoring, several
types of microbiological samples should be collected. The most important re-
quirement in all the sampling and testing is to have a consistent procedure.
The isolation of the wet drug substance is the first time that the sterile
material may be exposed to the environment. The actual collection process of
filtration or centrifugation is generally done in a closed environment. Thus,
the same criteria are applied as were applied to the precipitation operation. If
the filtration is not done in a closed environment, the isolation equipment
area should be kept under Class 100 conditions. In any event, the removal of
wet solids from the collection unit will expose the drug substance to the envi-
ronment, and it must be provided protection to maintain aseptic conditions.
The protocol must be designed to demonstrate that the movement of the
drug substance from the collection unit (filter) to the next processing unit
maintains the sterile condition of the drug substance.
Although the drying, milling, and blending phases of the process are in-
tended to start under the Class 100 conditions described earlier, maintaining
class status and laminar flow conditions, and controlling the introduction of
drug substance particles into the environment, is almost impossible. The vali-
dation of this phase of the process will show that the manufacturing facility
system controls the environment reproducibly and minimizes the number of
particles in the atmosphere, while maintaining the inward airflow to prevent
the contamination of other areas of the aseptic suite. Because of the drug sub-
stance particles being introduced into the atmosphere, and subsequently
being deposited on room surfaces, validating the procedures for removing
the drug substance from the walls, floors, and equipment will be especially
critical.
In the area dedicated to packaging the drug substance in containers for
shipment, the validation will be directed toward environmental control, as
was done in the milling area and other areas. The validation should also show
that if an equipment failure occurs, the procedures in place are adequate to
have the equipment removed, repaired, resterilized, and reintroduced into
the aseptic areas without compromising the sterility of the environment or
the drug substance.
VALIDATION MAINTENANCE
Once all aspects of the aseptic process, facility, and operations have been val-
idated, any changes proposed for these areas must be reviewed to determine if
the changes will affect any of the parameters covered during the validation. If
the changes will affect a parameter, that parameter must be revalidated once
the change has been made. The implementation of minor changes in the field
without prior review and approval has caused severe problems when the FDA
has inspected the facility. A validation program can only guarantee the effec-
tiveness and quality of a process when that process is operating according to
the procedures and acceptance criteria in the initial validation effort.
REFERENCES
Ben Venue Laboratories. 1994. Private communication.
Carleton, F.]., D. Conrad, R. Myers, S. Chrai, and R. Kieffer. 1983. Design concepts for the
validation of a water for Injection system. Technical Report No. 4. Bethesda, Md.,
USA: Parenteral Drug Association
CFR. 1993. Current Good Manufacturing Practices for finished pharmaceuticals. Code
of Federal Regulations Title 21, Part 211, pp. 81-100.
EC. 1993. Rules and guidance for pharmaceutical manufacturers. London: HMSO.
FDA. 198 7a. Guideline on sterile drug products produced by aseptic processing. Rockville, Md.,
FDA. 1987b. Guideline on general principles of process validation. Rockville, Md., USA:
Food and Drug Administration, Center for Drugs and Biologics and Center for De-
vices and Radiological Health.
FDA. 1993a. Sterilization process validation. Rockville, Md., USA: Food and Drug Ad-
ministration, Center for Veterinary Medicine and Center for Drug Evaluation and
Research.
FDA. 1993b. Guide to inspections of high purity water systems. Rockville, Md., USA: Food
and Drug Administration, Division of Field Investigations.
FDA. 1994a. Guide to inspections of sterile drug substance manufacturers. Rockville, Md.,
FDA. 1994b. Human drug CGMP notes. Rockville, Md., USA: Food and Drug Adminis-
tration.
Federal Standard 209E. 1992. Airborne particulate cleanliness classes in clean rooms and
clean zones. Washington, D.C.: U.S. General Services Administration.
FR. 1993. Guideline for submitting documentation for sterilization process. Federal
Register 58:63996.
Lazar, M. S. 1993. Concepts for the process validation of bulk pharmaceutical chemi-
cals. Pharm. Techno!. 17 (12):32-40.
Lazar, M. S. 1995. Sterile bulk pharmaceutical chemicals: A position paper. Pharm.
Techno!. 19 (8):38-42.
Ljungqvist, B., and B. Reinmtiller. 1997. Clean room design; minimizing contamina-
tion through proper design. Buffalo Grove, Ill., USA: Interpharm Press, Inc.
17
VALIDATION OF BIOTECHNOLOGY
INGREDIENTS
Rob Murphy Robert J. Seely

Amgen Center Amgen Boulder
Thousand Oaks, California Boulder, Colorado
This chapter is an introduction to the validation of bulk biopharmaceuticals.

The application of validation to biotechnology processes is different from tra-
ditional pharmaceutical validation, yet the theory and principles of valida-
tion outlined in previous chapters are consistent. The reason the application
is different is because the technology is different. Different technology means
different operations, equipment, controls, and procedures. As the application
of validation to biopharmaceutical manufacture is discussed, the principles of
validation from the viewpoint of a biopharmaceutical manufacturer are also
discussed. This chapter uses examples to show how the theory and principles
of validation are applied to biopharmaceutical processes.
The subject matter is presented in the order the validation activity
should be performed. A short discussion on master planning and equipment
qualification is presented first. These topics are not unique to biopharmaceu-
tical manufacture, so the sections focus on problems that have been encoun-
tered and biotech examples of the solutions to these problems. The main
focus of the chapter is on validating the manufacture of bulk biopharmaceu-
ticals. Cleaning validation, consistency validation, and validation of fermen-
tation and purification processes are also discussed to illustrate the unique
aspect of validating a biotechnology process and to give the reader some sug-
gestions on how this validation has been performed previously.
451
MASTER PLANNING
The Master Plan is the first document to be written, the first one to be referred
to in carrying out a validation program, and is commonly the first one to be
requested during a regulatory inspection. This document gives an overview of
what is to be validated and can include information on how specific systems
will be tested, when these activities will take place, and who will perform the
various validation studies. It can contain the specific variables of a given
process or it can be generic and apply to any protein and any site. In the lat-
ter case, the nature and scope of the process validation approach are de-
scribed. A second document, the Validation Protocol, will be required when
validating a specific product. The protocol usually includes a detailed process
description, the testing strategy, and acceptance criteria.
The generic approach provides a governing document that helps the val-
idation team (or an inspector) initially visualize the general scope. And, as
each process is different, the Validation Protocol will list defined variables and
scales. This document is written and signed by those responsible for doing the
work.
The Master Plan should state areas of responsibility-who, by depart-
ment, will be charged with the responsibility of completing the validation ac-
tivity. The team that actually performs most of the process validation is an ad
hoc team that initially begins in the process development area. Members from
clinical manufacturing, Quality Control (QC), and Quality Assurance (QA) are
included for broader input and because validation activities impact these
other areas. Process Development and Manufacturing provide the bulk of the
scientific guidance, and are assigned, as system owners, one or more unit op-
erations for which they are directly charged to monitor and evaluate the data.
QC is included so that they have an early warning system for sample load
and timing, and also to provide assurance that the most appropriate assays are
being chosen by the process members. A goal of the team is to generate well-
defined protocols, with a minimum numbe-r of the most relevant samples. We
wish to avoid obtaining data from the QC group only to realize later that the
wrong polyacrylamide gel electrophoresis procedure, for example, was used,
or the specified high performance liquid chromatography (HPLC) procedure
was developed specifically for final bulk product and upstream samples show
interference.
QA is included to assure compliance with applicable regulations and
guidelines. Their role is to review the protocols for completeness, and to
review the reports to ensure the protocol was followed as written and the con-
clusions are supported by the data obtained, and to make sure the documen-
tation meets the applicable regulatory requirements. They are free to suggest
alternative or more extensive analyses, and their comments are to be ad-
dressed by the validation team.
Validation of Biotechnology Active Pharmaceutical Ingredients 453
EQUIPMENT QUALIFICATION
Equipment qualification documentation helps ensure quality because it
serves to provide evidence that engineering specifications were followed and
that these specifications meet the demands of the manufacturing process. In
simpler terms, the documentation should provide evidence that what you
bought was installed and operates correctly. The principles are that simple.
The effect of not having this information is obvious; less consistency, less con-
trol. The methods of collecting this information are just as simple. Most of the
information contained in the qualification documentation probably exists
anyway.
When a piece of equipment, a software program, or a manufacturing
process is used, it serves a function. Prior to the design of the equipment, the
program, or the process, the function must be defined. If not, how would one
know they purchased the correct equipment, wrote software correctly, or cre-
ated a process that is effective? In order to define the function, certain re-
quirements are necessary. In this chapter, these requirements are called
functional requirements. Functional requirements are the cornerstone of the
equipment qualification process. The requirements dictate how equipment or
systems need to operate to produce the desired output. The output may be
Water for Injection (WFI) or a database, but the principles remain constant.
Basing the installation qualification (IQ) and operational qualification (OQ)
on the functional requirements of the system gives an absolute base from
which to work. The requirements are usually documented and given to the
vendor or design engineer when a project begins. If specific functional re-
quirements are not documented, check any design documents or purchase
specifications. These documents should outline what the equipment is de-
signed to do. They may not be clearly illustrated but the requirements of the
system were most likely considered before the purchase specification was writ-
ten. A design qualification (DQ) can be a significant portion of the IQJOQ and
is done up-front before the actual purchase is made. This phase of the qualifi-
cation documents the exact requirements of the system.
Once the functional requirements are written, a traditional validation
approach can be applied. An IQ document can be used to provide informa-
tion that equipment is installed per the requirements and design documenta-
tion. An OQ document can be used to illustrate that equipment operates as
defined in its functional requirements and design documentation. Further-
more, a performance qualification (PQ) document can assess the performance
of an equipment or system as defined in its functional requirements.
Installation Qualification
Like other manufacturing processes, biopharmaceutical processes need equip-
ment that is installed properly to assure proper operation. Biopharmaceutical
manufacturers use IQ documentation to help prove their processes are in a
state of control, to keep track of things like change parts and spare parts, to
know what utilities are used, to know what process instrumentation needs to
be calibrated, to make sure current drawings are on file, and, most important,
to assure equipment is installed according to its requirements. Table 17.1 il-
lustrates the information that may be included in an IQ document.
Operational Qualification
Biopharmaceutical manufacturers need equipment that operates per require-
ments to ensure consistency and quality. OQ documentation is the means to
capture such information. Many of the requirements outlined in the design
documentation can be tested to prove adequate op~ration. Procedures used to
operate the equipment can also be checked during the OQprocess. Table 17.2
is an example of what can be included in an OQ document.
Performance Qualification
If the performance of equipment or systems can be measured, the results can
be documented. This is called a PQ document. The difference between OQ
and PQ lies in the testing strategy. The OQ shows that equipment/systems op-
erate as intended by design. The PQ shows the equipment/systems can per-
form (i.e., clean, sterilize) as intended using a challenge representative of the
process in which it will be used. Performance testing can be combined with
operational testing documentation.
CLEANING VALIDATION
Cleaning processes used in the manufacture of biopharmaceuticals can be val-
idated using simple sampling techniques and a combination of analytical
techniques used to detect specific and nonspecific contaminants (Murphy
1996). The key to understanding what sampling and analytical methods to
use lies in an understanding of how the specific unit operations react to
potential contaminants and how the quality of the product may be affected if
these residues are not removed to appropriate levels.
Upstream processing steps, such as fermentation or cell culture opera-
tions, contain many different compounds that may be left behind following
processing. Adequate cleaning of these residues helps assure batch-to-batch
consistency and can aid in preparing process equipment for sterilization.
Most of the potential contaminants found in biotechnology are carbon based
making a nonspecific test method, such as total organic carbon (TOC), a
valuable tool in assessing the cleanliness of equipment. Other nonspecific test
methods, such as pH and conductivity, can also be used to detect the
Table 17.11nstallation Qualification Information

Subject Description
System Application The system application section describes the function

of the system or piece of equipment_ A detailed
system application section can be used to detail the
functional requirements of the system_
Equipment Description This section is used to identify the equipment or

Manufacturer system that is being qualified. The information
Model Number contained here can be tracked and modified over the
Serial Number life of the system if deemed necessary_
Equipment Number
Materials of Construction
Process Instrument Description The process instrument section is used to track

Manufacturer instrumentation associated with equipment. These
Model Number(s) instruments can be traced back to the design drawings
P&ID Reference Number and the list can be used to track the future calibration
Calibration Reference Number needs of the instruments_
Utility Hook-Up Description The utility requirements of the system can be traced
Pressure Requirements back to the design requirements of the equipment.
Temperature Requirements can be used to The IQ check that the proper
Estimated Usage connections were made_
Type and Size of Connection
Drawing Reference Number
Electrical Requirements
Spare Parts A spare parts list can be generated during the IQ

process and be used in the future for tracking spare
parts used in maintenance.
As-Built Drawings on File Drawing references can be included to show the

equipment or system design.
System Manual Reference Manuals that are included with equipment or systems
can be referenced to show manufacturer
recommendations were considered during installation.
Design Specification Reference The design specifications can be referenced.
Functional Requirements Reference The functional requirements of the equipment or system

can be referenced.
adequate removal of cleaning agents. Bioburden and endotoxin testing can

also be performed to prove removal or to give an assessment of the bioload
prior to sterilization. Rinse water samples following or during cleaning can be
tested for each of these assays_ These analytical tests combined with a visual
inspection of the product contact surfaces are sufficient to prove upstream
processes are cleaned effectively.
The validation of downstream processing steps such as recovery and pu-
rification is similar to validating the upstream steps. Rinse water sampling can
be tested to provide evidence of equipment cleanliness. Protein specific assays
can be used to detect residual product and several nonspecific assays can be
Table 17.2 Operational Qualification Information

Subject Description
Operational Description This section can be used to describe the

operational requirements of the
equipment per the design specifications.
References Information that is used to test the

Related Procedures operation of the equipment or system can
Functional Requirements be referenced.
Calibration Check Process instrumentation should be

checked to see that it is calibrated prior to
testing for operation.
Process Operating Variables The variables that are to be checked

during the OQ can be outlined to illustrate clearly
the testing strategy used to check
the operation of the system.
Operation Testing Protocol Process operating variables should be

tested to assure operation.
System Alarms Alarms can be tested to assure operation.
used to detect carbon, cleaning agents, and microbial contaminants. Visual

inspection can also be used to support analytical data.
Surface sampling methods are also commonly used when validating bio-
pharmaceutical cleaning operations. One common method is surface sam-
pling for total organic carbon. Surface sampling can often quantitate visual
observations or the lack thereof. When potential contaminants do pose a risk
(e.g., downstream multiproduct processing), a combination of surface sam-
pling, rinse water sampling, and visual inspection are often used.
Another testing strategy involves "worst-case testing." This is where all
of the inputs, or controlled factors, that may influence the analytical results
are set to challenge the limits of the cleaning process. Common examples of
worst-case inputs involve using the highest concentration of a product and
delaying the time between use and cleaning. Testing strategies that include
both of these worst-case inputs show that equipment can be cleaned effec-
tively when equipment hold times are challenged and when using the hardest
to clean concentration of product.
EQUIPMENT STERILIZATION
Equipment sterilization is probably the most studied and understood process

that is validated in the biotechnology industry. Therefore an in-depth discus-
sion is not presented here. Trying to decide what equipment and processes are
to be sterilized can be more of a concern than how to validate the steriliza-

tion. A common approach in deciding which equipment to test includes the
method of grouping like tanks together in the same protocol and challenging
only the most difficult tanks to sterilize. Factors that make tanks more diffi-
cult to sterilize include tank size and tank design.
PROCESS VALIDATION
Unlike the IQ/OQ of equipment validation, process validation is usually
much less defined. Cleaning validation, also, is relatively straightforward in
that the physical/chemical principles are easy to comprehend, and once the
appropriate protocols are executed, the program is finished. The same proto-
cols essentially apply to any piece of equipment, any system, at any site. By
contrast, process validation deals with the microbiology and biochemistry of
a dynamic process. As such, it is a long-term program that begins in the labo-
ratory and continues through commercial manufacturing.
Basically, the main focus of the purification process validation program
is to demonstrate and document (1) removal of host cell contaminants, (2) re-
moval of process additives, (3) consistent product purity and identity, and
(4) consistent process yields.
The ultimate goal is to establish, and document, a well-understood
process that consistently performs to expectations, and produces a product of
consistent quality. Adequate in-process controls are essential in producing a
product of consistent quality. Final bulk purity assays are used to verify this
and further ensure quality.
During the evolution of a process a number of well-known procedures
are followed and landmarks reached (Martin-Moe et al. 2000). First, a process
is developed to be cost-effective, scaleable, and robust. This is done to ensure
adequate amounts of material with minimal batch failures. The key to achiev-
ing this is process understanding, or process characterization. Experiments are
run to make improvements or troubleshoot upsets. Thorough process devel-
opment increases process understanding. Second, the process is often scaled
several times to meet increased production demands for clinical trials and
eventually to meet market needs. During scaling and campaigning, more data
on process performance are gained. If these activities are well documented,
the process is largely validated already. There are a few additional protocols
that should be performed to extend process understanding, but basically the
validation program is well underway.
Full process characterization is of enormous value to manufacturing, in
terms of maintaining a smooth-running plant and minimizing lost batches. It
is also of great value to Quality Assurance in providing supporting informa-
tion to justify lot release for batches that have drifted slightly at some point
during manufacturing. In actuality, full process characterization is a more en-
compassing program than process validation. When the former is completed,
a subset of data is culled to demonstrate process consistency and define in-

process controls. That subset will form the basis of a validation report for reg-
ulatory filings.
Process validation has been adequately defined elsewhere (FR 1996). Our
definition is that subset of a more comprehensive process characterization
package that fully describes each step in the process, demonstrates consis-
tency, and set in-process controls. This section will describe the essentials of a
process validation package for bulk recombinant proteins, with example pro-
tocols and consistency data.
Timing
At minimum, the critical components of facilities validation need to be essen-
tially complete by the manufacture of product for Phase I clinical trials. This
is necessitated by the requirement that the product be manufactured in com-
pliance with current Good Manufacturing Practices (cGMP). Process valida-
tion should be underway at that point, with any critical issues identified and
addressed. There should be a minimal program in place to (i) show process
consistency from batch to batch and (ii) prevent unauthorized changes in the
process. For Center for Biologics Evaluation and Research (CBER) filings, the
process validation needs to be completed prior to the license submission. At
that time, all aspects of process validation should be finalized and docu-
mented, with the obvious exceptions of (and specific references to) ongoing
validation and revalidation.
In recombinant protein production, process validation frequently is ne-
glected until late in clinical development. This is understandable due to a va-
riety of reasons. The drug may not show favorable clinical results in late stage
trials, so why invest the time or money before it is a proven product candi-
date? Process validation is often seen as a perfunctory activity solely per-
formed for regulatory agencies. Finally, there may be a fear that the process
will change dramatically and early validation will be negated. As a result of
these misunderstandings, the process validation activity can be diagrammed
as in curve A of Figure 17.1; very little effort until Phase 3 clinical testing,
when a mad dash is made to gather data to support the Biologics Licensing
Application (BLA).
We hope to demonstrate here that the above perceptions are ill-founded
and early process validation is of great value to manufacturing, not just in sat-
isfying Food and Drug Administration (FDA) requirements. Curve B (Figure
17.1) illustrates a more reasonable approach to validation. There is a higher
amount of effort during process development and initial scaling activities. It
will be seen later that this effort is in effect already going on by the develop-
mental scientists and engineers. These activities are not necessarily dedicated
to establishing process validation data, but one should merely capture and
document data as they are generated when establishing a workable process.
Figure 17.1 Schematic diagram of process validation activity

100
90
80
t: 70
0
:t:
w 60
.
c
0
as
:5!
50
40
/
e/
~ 30
/
/
20
/
10
0
Lab Tox II Ill Mkt
Phase of Development
Note also in curve B the level of activity is spread out over time, lessen-
ing the painful dash at the end, and more importantly, early process under-
standing will actually assist in process development and help prevent batch
failures in subsequent clinical material manufacturing. Further, the area un-
der curve B is greater than that of A, meaning a more complete characteriza-
tion package, a more substantial database to assist plant troubleshooting and
to support proposed process improvements; in sum, a more thorough under-
standing of the process.
Process Variables
Every bulk protein process contains several unit operations and a host of vari-
ables, or parameters. It is convenient, and meaningful, to divide them into
two distinct groups. The set of parameters that can be preset and are used to
run the process can be thought of as operational, or input parameters. These
are commonly found in the manufacturing procedures or associated Standard
Operating Procedures (SOPs). These parameters, such as flow rate, tempera-
ture, pressure, time, mixing speed, and raw material weights, define the
process and, when followed as prescribed, should result in a consistent
process and consistent final product quality. These parameters are usually
very controllable, often within very narrow ranges.
Another class of variables, the performance variables, are the output pa-
rameters. These are not directly controllable and the resulting values depend
on how closely the operational variables are maintained and interact. Exam-
ples of these parameters are step yields, purity at each step, and other step
characteristics that the process development biochemist or engineer feels are
useful in describing the performance of a given unit operation.
Each of these classifications will be described further, in detail, with spe-
cific examples for some typical unit operations in a recombinant protein pro-
duction process.
Operational Parameters
Operational parameters, or input variables, are usually controllable, and often
merely require demonstration of consistency, within some prescribed range.
The list of these input variables, however, can become quite large. Therefore,
the number should be limited to only those that can be reasonably expected
to affect the operations of a given step. The mixing rate during a refold step
might have a dramatic bearing on the outcome of that step. This variable,
then, should be addressed for process validation purposes. During develop-
ment of that operation, the development scientists will have altered the rate,
perhaps in conjunction with varying other parameters, and settled on a speed
that gives an acceptable yield and purity. This mixing rate can then be speci-
fied and controlled, within a reasonable range, during the manufacturing
process.
The ranges at the time of beginning manufacturing may be considered
provisional, as they may have been established by limited development stud-
ies, past experience, and general scientific judgment. During the course of
manufacturing for early to midphase clinical trials, monitoring these parame-
ters begins the validation process and substantiates that the chosen ranges are
acceptable or need to be shifted.
A given process may involve hundreds of operational variables. Al-
though all the variables are important, not all are critical. We reserve the use
of the term critical to apply to variables that either are difficult to control or
are near an edge of failure (Seely et al. 1999). Most operational parameters are
easy to control within narrow ranges and are not near a failing point. With
thorough process characterization and robustness, there should be only a few
critical variables in a process.
Returning to the example of refolding tank mixing speed, the first level
of validation, and frequently the only level that needs to be covered for vali-
dating the operational parameters, is to document that when mixing is main-
tained within a defined range, the expected yield and purity result, within
some range. If either side of that range is near a limit of failure, further vali-
dation may be required. Additional studies might include running the
process at lab scale at that limit and determining what happens to the prod-
Validation of Biotechnology Active Pharmaceutical Ingredients 461.
uct. One may wish to examine the interaction of multiple variables. This ap-
proach is often very informative when based on statistical experimental
design (Kelley 2000). The number of possible interactions in a protein pro-
duction process can become astronomical and only those that are expected to
have significant interactions and consequences should be so thoroughly
investigated.
Chromatography is most certainly affected by pH, temperature, and
ionic strength, and all three will show interactions. However, it is reiatively
uncommon for minor fluctuations in any one, or in all three, to lead to major
process upsets. A common approach here is to record the exact data for these
variables and analyze by trend charts or maximum/minimum values after
multiple runs are done for a variety of other reasons such as in the production
of product for toxicology or stability tests. Often the extremes of the specified
ranges will be reached at some time, and the yield and purity data from those
runs can be reviewed for acceptability.
We maintain that each extreme need not be specifically tested for the
sake of demonstrating acceptability. The ranges were originally set by a com-
bination of sdentific judgment and previous experimental results. The final
justification comes after many, many runs, at full scale, and will combine
other variables not previously envisioned. Recall the concept that process val-
idation is an ongoing process of a growing body of data. This requires an on-
going in-process sampling and data monitoring program to be in place. The
program need not be cumbersome, but should encompass recording discrete
data points for each of the operational variables, and at least a yield calcula-
tion and purity assay at each step in the process. Here again it can be seen that
capturing process data during development and early clinical manufacturing
can provide significant validation data.
Performance Parameters
Performance parameters are a set of select output variables, such as step yields
and purity, that while they are not directly controllable, are a measure that
the unit operation did indeed perform as expected. These are individually
chosen by the unit operation owner to be the most useful, from a multitude
of possibilities that exist for any given step.
These performance, or output, parameters take many runs to define sta-
tistically. Data gathered in the early stages of development and technology
transfer can serve to set preliminary or provisional control limits. Once the
process is at the commercial manufacturing scale, operational and perfor-
mance values can be recorded for as few as three consecutive runs to show
consistency. These are commonly referred to as the conformance, or qualifi-
cation, lots. Process data from these runs can be compiled into a final process
validation package. Additional studies, such as plasmid stability and process
pool stability are required and will be discussed later.
Examples of typical performance parameters are given in Table 17.3.

Since final performance control limits are often not established until more
runs are completed, the calculation of the control limits will be deferred to
the "Process Monitoring" section.
Impurity Profile
An important element of demonstrating process consistency is tracking the
product-related impurities. For proteins, these are trace amounts of species
that are oxidized, acetylated, dimerized, cleaved, and so on. The relative
amounts of these species should be consistent from batch to batch. Rarely are
they fully identified before process validation is performed, but they can
merely be numbered and the levels (in area percentage of the total chro-
matogram) can be tabulated or graphed.
Although consistency of the main peak is important to monitor, the
trace impurities provide a very sensitive tool for monitoring unit operation
Table 1.7.3 Example List of Performance Parameters for a Typical Recombinant

Protein Process
Step Parameter Units
Seed Flask Growth Time hours
Seed Fermentor Growth Time hours
Main Fermentor Time to Induction hours
Rnal Density 00660
Expression g/L
Plasmid Marker Loss percent
Cell Harvest Sludge Percent Solids percent
Solids Yield percent
Debris Removal Homogenate Percent Solids percent
Solids Yield percent
lon Exchange Yield percent
Product Concentration g/L
HPLC Purity percent
Hydrophobic Interaction Yield percent
Chromatography (HIC)
Product Concentration gjL
Host Protein Level ppm
Diafiltration Yield percent
Water Aux Recovery percent
Cone. Bulk Time to Concentrate minutes
performance. In addition, when a process change is proposed, demonstrating

that the impurity profile does not change significantly lends increased sup-
port to substantiate the change.
Additional Studies
Thus far, we have stressed validation data that are gleaned directly from ob-
serving the process. This is where the majority of the validation package will
be derived. We have also seen that significant process data are generated dur-
ing development, scale-up, and manufacturing for various phases of clinical
trials. If these data are adequately captured and documented, they automati-
cally contribute to the process validation program. There are a number of side
issues, however, that need to be explored and incorporated. A typical list of
protocols for validating a recombinant protein process is given in Table 17.4.
In this example, Protocol 01 for monitoring the process at large scale is
described above. The others provide validation information that either is in-
cluded in the final package submitted as part of a BLA or provides additional
data to justify that the process is sound. These will not be further discussed
here. An example of a protocol is given in Appendix 17.1 to show an accept-
able format and degree of detail required.
The Final Package

The first and primary report to support process validation begins with moni-
toring the three to five conformance or validation runs. This report docu-
ments the consistency of the runs and is typically written into the Chemistry,
Table 17.4 Example List of Protocols Needed for a Typical Recombinant Protein
Process
Number Title
PV-01 Extensive Monitoring of the Process in Building No. _ _

PV-02 Cleaning Validation; Recovery Off Stainless Steel Surfaces
PV-03 Inclusion Body Stability at-•c
PV-04 Validation of Sterilizing Filter
PV-05 Chromatography Column Cleaning Validation; Mock Gradients
PV-06 Postcampaign Evaluation of Chromatography Column Resins
PV-07 Postcampaign Evaluation of Diafiltration Membranes
PV-08 Buffer Stability; Validation of Extended Hold Times
PV-09 Process Pool Stability; Validation of Extended Hold Times
Manufacturing, and Controls section of the BLA. It is also found to be quite

useful in troubleshooting possible process drift and supporting a proposed
process change.
The validation report summarizes the consistency of the operational
variables, either in tabular or graphical form. Little more is said of these vari-
ables unless a change in the operational range is suggested or if reproducibil-
ity was shown to be a problem. The performance parameters, however, are
described in more detail, in terms of why those specific variables were chosen
to reflect process performance, how the control limit values will be calculated,
and what steps will be taken if the control limits are exceeded.
A second report summarizes pool and buffer stability, and general
bioburden control. A third shows the process consistency in terms of impu-
rity tracking throughout the process, and a fourth addresses issues of ex-
tended reuse of materials such as chromatography resins and ultrafiltration
membranes.
These four report summaries comprise the basis of the process validation
sections of the BLA. A reviewer or an on-site inspector may have additional
questions and can request additional documentation. To provide more de-
tailed data and answers, the process validation team leader or QA personnel
should be able to quickly retrieve appropriate protocols, reports, and even raw
data. If the four primary summaries are thorough and complete, reviewer
questions will be largely limited to points of clarification.
Process Monitoring
In a well-designed process, sufficient data can be gained from the above pro-
tocols, and from at least three production plant runs, to allow assemblage of a
complete process validation package. However, continued monitoring is re-
quired to accumulate adequate data on the performance parameters. At least
12 data points, preferably 30, are needed to calculate the upper and lower
control limits (UCL and LCL). These data are then plotted as control charts,
and the UCL and LCL are projected for upcoming production runs. The new
data, as they are received, are plotted directly on these plots so the manufac-
turing personnel can immediately see if they are in control or if an excursion
or trend is occurring. An example of a control chart for the yield on a chro-
matography step is shown in Figure 17 .2.
If the control limit values cannot be specified at the time of BLA filing, it
should be clearly stated in the process validation section which parameters
will be control charted, how many data points will be required, and how the
limits will be calculated.
The control limits are commonly calculated as ±3 standard deviations of
the population (Trubinski and Majeed 1984). Calculation based on the aver-
age moving range is reported to provide more discrimination between normal
process variation and that caused by special factors, for which an assignable
cause can usually be found (Gershon 1991; Greer and Halteman 1991). This
calculation is
X ± (2.66)(mR)
where, X is the mean of the first 12-24 data points, mR is the average moving
range with a running window of 2, and 2.66 is a factor that brings the control
limits to approximately ±3 standard deviations.
Once the control charts are in place for each identified performance pa-
rameter, the ongoing monitoring consists of plotting the new data points for
every subsequent batch. Recalculation of the control limits should not be nec-
essary unless there is process drift that cannot be otherwise explained or, of
course, if there is an implemented process change. An example is given in the
Revalidation section.
Every excursion outside of a control limit requires an investigation at
that step in the process, and perhaps at previous and subsequent steps, a for-
mal report as to the nature of the cause and any actions taken to correct it.
The batch is not necessarily discarded; rather, disposition is based on the
cause found and is evaluated on a case-by-case basis. We would become
Figure 17.2 Control chart for the yield at a chromatography
90
UCL
i. •
()
85
• •
Gl
e:. • • •
c
...J
w 80 • •
s::
•
75 LCL
70 +----+----+----+----+----+----+----+----+----+----+---~
2 3 4 5 6 7 8 9 10 11 12
BATCH NUMBER
concerned with the development of a definite trend in the data, within the
control limits, although we have not formally implemented trend definitions,
such as the Western Electric (1956) control rules.
Change Control
An important component to validation that is often overlooked is an ade-
quate change control program. Clearly, once a process is validated, there
needs to be a strong program in place to ensure the process is not changed,
even in minor ways, without prior authorization by the appropriate individu-
als. The program needs to be well documented so changes can be clearly
traced, but it need not be overly cumbersome.
Even in the early stages of development, process changes need to be
recorded. Good documentation can be very useful later in development and
scale-up. Written descriptions as to what is being changed and why adds to
process understanding. Knowing things that do not work well is often as in-
formative as knowing those that do.
A particular filter membrane material may be replaced by one that hap-
pens to bind some level of DNA. If this information were to become lost dur-
ing process transfer, the plant might revert to the previous material for cost
reasons and the process would be different, with unknown effects down-
stream.
At some stage of development, the process becomes basically fixed. Re-
finements have been made to provide a robust and cost-effective process. This
usually occurs by the time of pivotal Phase 3 clinical trials for biotechnology
products. Thus, the process is known, describable, and the operational para-
meters such as flow rate, temperatures, and pressures are clearly defined. The
performance parameters, such as step yields, are necessarily specified within
wide limits until extensive production data are accumulated.
Further changes are expected to be required as the process is scaled up
for Phase 2 and 3 manufacturing. Most are based on necessities of scale, but
some will be based on further refinements for increased purity, ease of
production, and increased robustness. Indeed, such changes can be imple-
mented well after licensure, and with proper documentation and authoriza-
tion should not be automatically avoided.
The required documentation is basically a justification, based on solid
data, that the proposed change does not significantly alter the manufacturing
process and results in product of the same bioequivalancy. By not altering the
manufacturing process, we mean the same basic physical and chemical princi-
ples are involved. Changing a type of cation exchanger is clearly less of a sub-
stantive change than switching to an anion exchanger, or, more drastically,
using an entirely different separation mechanism such as liquid-liquid extrac-
tion. With the latter, severe changes can certainly be made, but more data and
documentation would be required, and the process might be considered
sufficiently different to require preapproval by the FDA or even a new Investi-

gational New Drug Application (IND).
There should be an SOP, controlled by the document control division, to
establish the philosophy and procedures for the inevitable modification that
will be made to the process during development and manufacturing.
The current FDA trend of relying on final product testing for a well-
characterized biologic does not lessen the emphasis on process validation to
assure quality and consistency of the product. A process may not be fully val-
idated in the early stages of manufacturing for material for clinical trials. The
process should, however, be characterized to the extent that appropriate unit
operation data are gathered on an ongoing basis as a comparative tool in eval-
uating future scale-up and development.
Material intended for use in human clinical trials must be first subjected
to animal testing to determine toxicity profiles in one or more species. It is
therefore essential that the material used for both animal toxicity studies and
human clinical trials be produced by a similar, well-defined, and controlled
process to assure quality and consistency. Materials intended for use in an an-
imal toxidty study must thus be processed with appropriate standardized
techniques and controls.
Changes in a process should be traceable, just as are changes in a Stan-
dard Analytical Procedure. Thus, a numbering system is the first requirement.
This can be a simple system such as XX99.02, where XX is the product identi-
fication code, and 99.02 represents the second reiteration of the process that
was introduced in 1999. Such a numbering system, while simple, conveys a
lot of information.
When a process modification, or a scale or site change, is proposed for the
next production campaign, a proposal will be written that describes the nature
of the change, past data (if applicable) to justify the change, the number of
batches needed to generate suffident data to evaluate the change, and how the
evaluation will be made. The proposal indicates precisely what samples and
data will be required, and if possible, some preidentified acceptance criteria
should be set. The proposal is then reviewed and signed by the appropriate
process team members, manufacturing, regulatory (if applicable), and QA.
If the proposal is found acceptable, the corresponding manufacturing
procedures and SOPs are issued, with a new process number, such as XX95.03.
Upon completion of the requested number of batches, the data are analyzed as
specified in the proposal and a report is written. It is important that the report
be reviewed and signed by the same individuals who approved the proposal.
If the change is implemented after the process has been validated, some
degree of revalidation will be necessary. The extent of revalidation will de-
pend on the nature of the change (see "Revalidation" section). The data col-
lected during the test runs may be sufficient, or a protocol for extended data
collection can be issued.
The material produced by the test batches is quarantined until the final
report is reviewed and signed. This is to allow time to ensure the material was
made by a process of equal or better consistency, and is bioequivalent at each

in-process step as well as at the purified bulk stage.
The above procedures provide a formal mechanism for requesting, im-
plementing, and documenting a process modification. They do not, however,
prevent an unplanned change from becoming integrated into the process.
Someone may rewrite an SOP, change the specification of a raw material, or
replace a piece of equipment without knowing that it could alter the process.
One method to provide a means to help prevent this is to have a key person
in development receive copies of all document change requests and all rele-
vant work orders.
This, too, does not absolutely prevent process drift, but it does provide
an additional layer of safety. It also provides documented evidence that the
company is conscientiously concerned about change control.
Revalidation
Revalidation of a process need not follow the concept of revalidation of a fa-
cility and equipment or cleaning validation. That is, once it is validated, there
is no need for revalidation unless there is a change. In the absence of changes,
there is normally a low level of equipment and cleaning revalidation rou-
tinely performed on an annual or biennial basis. Process revalidation can
merely be a formal review of the performance parameters, the nature and fre-
quency of excursions of these parameters, and operational variables. Such a
review could be included as part of the annual product review.
When a change is proposed, it may or may not have a significant impact
on the process or product quality. The proposed change does, however, need
to be reviewed by a process scientist or process engineer in order for that de-
termination to be made. Many changes, such as like-for-like filters, might
have no effect on the process, but the final call should be from a process bio-
chemist or engineer and not just QA.
If the change affects the process or quality, some degree of revalidation
will need to be performed. The specifics will vary with the process and the
change, but the Master Plan can give some guidance on this issue. That docu-
ment might state that the unit operation owner is to review the original
process validation report and draft a protocol to readdress all or pertinent
variables of the step in question, and set the number of runs to be monitored.
A decrease in wash buffer volume at a chromatography step might be
proposed to decrease process waste volumes and decrease process time. This
change holds a reasonable chance of affecting quality, and some preevalua-
tion would be required to justify acceptability (see "Change Control," above).
Beyond that, the process owner should issue a protocol to monitor the vol-
umes used, to sample for in-process purity assays, and to track the process per-
formance parameters already in place. At the end of the monitoring program,
an addendum to the process validation report is written and signed by the rel-
evant persons. It is important to keep the revalidation reports associated with,
but distinct from, the originals. Previous data are not superseded; rather,
process validation documents are freestanding, nonevolving documents that
can be added to, but not changed. Another way of stating this is that all
process validation documents have unique numbers with no provision for re-
visions.
Making a change that is expected to shift the value of a performance pa-
rameter requires more extensive revalidation. One that decreases the purity at
a specific step is most troublesome, and substantial data showing recovery of
purity downstream, and certainly demonstrating biochemical equivalency at
the final bulk stage, is absolutely necessary.
On a particular Escherichia coli process, we defined the performance of a
seed flask growth step in terms of the time it took to reach the transfer optical
density of 2.0 at 660 nm. This growth time was useful in describing that step
as it verified proper nutrient composition, temperature, aeration, and am-
poule inoculation volume. When the time came to begin using a new seed
lot, it was known the initial cell density was slightly lower and that the LCL
would be frequently violated.
A protocol was issued to implement the new seed lot, suspend the for-
mal enforcement of control limit excursion, and monitor the new growth
times to allow recalculation of the control limits (both upper and lower). This
required 12 runs to complete the protocol, and the step was considered reval-
idated, with new control limits.
REFERENCES
FR. 1996. Current Good Manufacturing Practice: Amendment of certain requirements
for finished pharmaceuticals; proposed rule. Federal Register 61 (87):20103-20115
(3 May 1996).
Gershon, M. 1991. Statistical process control for the pharmaceutical industry.]. Parent.
Sci. Techno/. 45: 41-50.
Greer, D. A., and E.]. Halteman. 1991. The Swiss army knife of control charts. In Proc.
Joint Statistical Meeting. San Francisco, pp. 1-5.
Kelley, B. D. 2000. Establishing process robustness using designed experiments. In Bio-
phannaceutical process validation, edited by G. Sofer and D. W. Zabriske. Marcel
Dekker: New York, pp. 29-59.
Martin-Moe, S., W. H. Kelsey, ]. Ellis, and M. E. Kamarck. 2000. Process Validation in
Biopharmaceutical Manufacturing. In Biophannaceutical process validation, edited
by G. Sofer, and D. W. Zabriskie. New York: Dekker, pp. 287-298.
Murphy, R. 1996. In Cleaning and cleaning validation: A biotechnology perspective, edited
by]. Voss. Bethesda, Md., USA: PDA, pp. 91-106.
4 70 Validation of Active Pharmaceutical Ingredients
Seely, R.J., H. V. Hutchins, M.P. Luscher, K. S. Sniff, and R. Hassler. 1999. Definining crit-
ical variables in well-characterized biotechnology processes. BioPharm 12 (4): 33-36.
Trubinski, C.]., and M. Majeed. 1984. Retrospective process validation. In Pharmaceu-
tical process validation, edited by B. Loftus and R. Nash. New York: Marcel Dekker,
pp. 149-179.
AT&T. 1956. Statistical quality control handbook. (This handbook is no longer available
through commercial sales. Inquiries may be addressed to AT&T Technologies,
code 700-444, Indianapolis, In 46219.)
Validation of Biotechnology Active Pharmaceutical Ingredients 4 71
APPENDIX 17.1
Process Validation Protocol PV-08:

Validation of Buffer Hold Times for the _ _ _ Process, as Run in Building
Introduction
Validating the stability of each buffer held for an extended period is an im-
portant part of process validation. This will be done by purposely holding
each buffer in its respective hold tank and testing for maintenance of the
chemistries given in the appropriate manufacturing SOP for each buffer, and
for presence of bioburden and endotoxin.
Purpose
This protocol will define the procedures to perform the extended hold testing,
with data sheets to be completed for each buffer. The protocol will demon-
strate that the buffers are stable for up to 18 days.
Scope
This protocol is general in nature, to be used for all buffers expected to be held
for greater than 24 hours. Individual data sheets will be completed for each
test, with data entry slightly different for each buffer. The stability program
applies to the process as run in building _ __
Stock solutions, such as 6 N HCl, are not addressed here; the expiration
dates arrived at in Amgen Center are used.
The solubilization buffer is also not examined. This solution is prepared
over a relatively long time period (9 h), tested, but then is used within the
next 24 hours.
The monitoring of stability will be performed for the three time periods
given below, and for two consecutive batches.
Responsibilities
1. Process Development
1.1 Write initial protocol.
1.2 Ensure that every buffer identified in the Scope section is
tested.
1.3 Obtain most of the required samples and complete the in-
formation on the data sheets and work closely with oper-
ators to obtain some samples.
1.4 Perform the pH and conductivity tests, using the same in-
struments used in manufacturing at point of use.
1.5 Compile and report the results.
1.6 Control the finalized documents.
2. Manufacturing
2.1 Prepare the buffers at full scale.
2.2 Assist Process Development in obtaining some of the
samples.
2.3 Perform the initial tests outlined in the buffer specific
SOP for buffer release.
3. Analytical Resources
3.1 Log in and route the samples submitted.
3.2 Perform the endotoxin assay.
3.3 Perform the bioburden assay.
3.4 Supply the results to the protocol originator.
4. Quality Assurance
4.1 Review and sign protocol and report.
4.2 Control a scanned copy of the documents and raw data.
Procedure
Buffer tanks will be labeled with the date of preparation and the date for the
10-, 14-, and 18-day elapse times. This will be done by Process Development.
1. For each buffer and time point, enable buffer transfer and flush at
least 4 L of buffer through the sample valve at the point of use and
remove 40 mL in a polypropylene tube. Label"PV Chern." and in-
clude date, initials, time point, and name of buffer. This sample is
for pH and conductivity.
2. Also collect a 10 mL sample into a polystyrene tube. Label "PV
LAL" and include date, initials, time point, and name of buffer.
This sample is for endotoxin.
3. Also collect 100 mL in a polypropylene container. Label "PV BB"
and include date, initials, time point, and buffer name. This sample
is for bioburden.
Validation of Biotechnology Active Pharmaceutical Ingredients 4 73
4. Complete the data sheet.

5. Submit sample request forms with the samples to Analytical Re-
sources.
6. Repeat the above for a second batch of buffers.
7. Table A. Specifications for Each Buffer
Buffer Name Composition pH Conductivity lAL Bioburden
Acceptance Criteria
Each buffer will be validated for stability up to 18 days if all the buffer chem-
istry, endotoxin, and bioburden criteria in Table A are met.
8. Table B. Buffer Stability Data Report Table
Buffer N a m e - - - - - - - - - - - - - - - - - - - - - - - -
Buffer C o m p o s i t i o n - - - - - - - - - - - - - - - - - - - - -
Procedure N o . - - - - - - - - - - - - - - - - - - - - - - -
Lot No. (Date of P r e p . ) - - - - - - - - - - - - - - - - - - -
Date _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __
Initials - - - - - - - - - - - - - - - - - - - - - - - - - -
Date and Initials When

Days Elapsed Performed pH Conductivity LAL Bioburden
Zero (Transfer)
10 days
14 days
18 days
Other
18
MICROBIOLOGICAL ATTRIBUTES
OF ACTIVE PHARMACEUTICAL
INGREDIENTS
Karen Zink McCullough John Shirtz

MMI Associates Catalytica Pharmaceuticals, Inc.
Whitehouse Station, New Jersey Greenville, North Carolina
Active pharmaceutical ingredients (APis) are the building blocks of finished

drug products, which are subject to Good Manufacturing Practices (GMPs) for
Finished Pharmaceuticals (21 CFR 211, 1998). These finished drug products
are held to stringent microbiological and chemical specifications and are sub-
ject to precise testing by compendia! methods. In the absence of definitive
compendia! or regulatory guidelines written specifically for the production of
APis, it is prudent for manufacturers to follow the general principles outlined
in the current Good Manufacturing Practices (cGMPs) for finished pharma-
ceuticals, as the quality of the finished drug product obviously reflects the
quality of its component parts. Paul Motise, speaking for the U.S. Food and
Drug Administration (FDA), states,
the definition of "drug" in the Food, Drug and Cosmetic Act
encompasses bulk pharmaceutical chemicals, and Section
SlO(a)(2)(B) of the Act also requires that all drugs be manu-
factured, processed, packed, and held in accordance with
CGMPs. No distinction is made between APis and finished
pharmaceuticals in the Act, and failure of either to comply
with CGMP constitutes a violation of the Act. (Motise 1995).
475
4 76 Validation of Active Pharmaceutical Ingredients
In March 1998, the FDA issued a document titled, Guidance for Industry:
Manufacturing, Processing, or Holding Active Phannaceutical Ingredients (U.S.
DHHS 1998). Though this document was issued as a draft for comment pur-
poses only, it begins to provide guidance to industry by expanding on Mo-
tise's earlier comments, and by clearly outlining the FDA's philosophy
regarding the relationship between API manufacture and the application of
relevant GMPs. Broadly speaking, the FDA views validation and documenta-
tion of processes and test methods as key to assuring quality and purity of
APis. More specifically, the FDA expects that applicable GMPs will be applied
more stringently as API production proceeds from synthesis through purifi-
cation and (where applicable) sterilization. 21 CFR, 211.113, "Control of mi-
crobiological contamination" (1998), states,
(a) Appropriate written procedures, designed to prevent objectionable

microorganisms in drug products not required to be sterile, shall be
established and followed.
(b) Appropriate written procedures, designed to prevent microbiologi-
cal contamination of drug products purporting to be sterile, shall
be established and followed. Such procedures shall include valida-
tion of any sterilization process.
When developing a plan for the application and implementation of
GMPs pertaining to microbiological control, an API manufacturer must con-
sider the type of API that is being produced (sterile or nonsterile, preserved or
unpreserved, bacteriostatic/bacteriocidal) and the intended route of adminis-
tration. For example, an API intended for a parenteral formulation will be held
to a different, more stringent, microbial and endotoxin standard than mater-
ial intended for oral dosage forms. If the material is a compendia! article,
microbiological specifications may already exist. If the material is noncom-
pendial, an understanding of the ultimate use of the API and good judgment
based on a thorough knowledge and understanding of the manufacturing
processes and their capabilities will provide a direction for establishing
appropriate in-house microbiological specifications. When developing speci-
fications, the laboratory must consider not only the total numbers of mi-
croorganisms that can be present per gram or milliliter of the material but also
the types of microorganisms that can be present. Defining objectionable or-
ganisms based on the U.S. Pharmacopeia (USP) Microbial Limits Test and de-
scriptions provided in the general chapter, Microbiological Attributes of Non
Sterile Pharmaceuticals, is important when developing microbiological speci-
fications or profiles for any material.
Once an acceptable microbiological profile is determined for the final
API, the manufacturer can work backward and consider
• the source of the raw materials used for the API (organic, inorganic,
synthesized), including establishing microbiological profiles for
each key material;
Microbiological Attributes of Active Pharmaceutical Ingredients 4 77
• the quality of the water necessary to produce a material that meets

chemical and microbial specifications (USP 1999c);
• the microbiological quality and profile of the environment needed for
the production of the API (PhRMA 199Sa-c, 1997; USP 1999h); and
• process validation for the API including the definition of steps in-
tended to reduce numbers or types of microorganisms and endo-
toxins and the identification of processing steps that are likely to
introduce microorganisms.
APis may be produced by chemical synthesis, recombinant DNA tech-
nology, fermentation, enzymatic reactions, recovery from natural materials,
or some combination of these processes (FDA 1991b; Brocklebank and Deo
1996, USP 1999g). Because the quality of the input material affects the qual-
ity of the final processed bulk, microbiologists are concerned about the qual-
ity of the starting raw material, including its origin and how many and/or
what kinds of microorganisms are present. Even though APis frequently un-
dergo significant chemical change during processing and purification, those
materials that are derived from nature or natural sources (plants, animals, fer-
mentations, some recombinant processes, etc.) are likely to be sources of a
range of microorganisms and bacterial endotoxins. APis that are derived from
chemical syntheses are not as likely to contain significant levels of microor-
ganisms or endotoxins because the microorganisms usually don't survive in
the harsh environments that are characteristic of such processes.
Once the raw materials are received and manufacture has begun, ana-
lysts are concerned with the microbiological quality of the manufacturing en-
vironment, including the air, product contact surfaces, personnel, and water.
Obviously, poor quality air and water or ineffective cleaning and/or sanitiza-
tion can contribute significantly to the final bioburden in the API. Manufac-
turing should be carried out wherever possible in an environment that is
capable of producing material that conforms to the microbiological specifica-
tion and complies with the principles outlined in cGMPs (FDA 1991b; PhRMA
199Sa-c, 1997; CFR 1998; U.S. DHHS 1998). The design and construction of
the manufacturing facility is important, as reasonable steps should be taken
to avoid overt or potential microbial contamination of the product.
Finally, analysts are concerned with the microbiological quality of the fi-
nal API product. While there are well-defined microbiological test methods
and specifications in the USP for both sterile and nonsterile finished drug
products and some drug substances, APis are not always compendia! materi-
als. If the material has been assigned a specification that contains a sterility
requirement, microbial limit, definition of objectionable organisms, or endo-
toxin limit, it must be tested in accordance with the appropriate chapters in
the USP or FDA guidelines (USP, 1999a, 1999b, 1999d, 1999e; FDA 1987a,
1991a). If the API is a noncompendial article that is to be used in a nonster-
ile formulation, the testing methods, monitoring schemes, and specifications
that are utilized or referenced in the industry are very often extrapolations or
adaptations of the established methods for finished drug products. Since there
is no set of rules that specifically governs the API industry, the benchmarks,
testing standards, methods, and data interpretations used in the microbiolog-
ical analyses of the bulk material are not uniformly applied throughout the
industry. Unfortunately, the microbiological quality of APis between and
even within manufacturing environments may vary significantly.
PRELIMINARY ISSUES
Standard Operating Procedures

Standard Operating Procedures (SOPs) provide users with consistent, compli-
ant methods to examine products, interpret test data, and to determine con-
formity with established specifications for the material. cGMPs clearly state
that written procedures designed to "prevent objectionable microorganisms"
or "prevent microbiological contamination of drug products purporting to be
sterile" shall be established and followed (CFR 1998). Where applicable, SOPs
should be aligned with USP methods or the principles established by USP ref-
erence methods and general chapters. Where deviations from established pro-
cedures are necessary or desired, documentation including methods
validation should be referenced, providing a rationale for such deviations. If
alternative methods are used, the laboratory is cautioned to assure that the
product will pass the USP test, if required.
SOPs should contain
• an objective or reason for testing,
• a listing of materials and reagents needed to conduct the test,
• a description of the test procedure,
• a provision for the proper documentation, interpretation, and eval-
uation of test data including out-of-specification (OOS) results;
• direction in conducting investigation of OOS results; and
• a list of references including compendia! and regulatory citations as
well as cross-referenced in-house SOPs.
Examination of Microbiological Media for Sterility

and the Ability to Support Growth
Before using any microbiological growth medium for the purposes of water
testing, microbial limits testing, environmental monitoring, or sterility
testing, each lot of prepared medium must be tested for sterility and the abil-
ity to support the growth of a panel of indicator organisms (USP 1999b).
Sterility of each lot can be assured by incubating a portion of the lot at the
Microbiological Attributes of Active Pharmaceutical Ingredients 4 79
appropriate temperature (22 ::±:: 2.5°C or 32 ::t 2.5°C) for not less than 14 days
and examining test specimens for the presence of growth. No observed
growth indicates that the lot of medium is sterile and suitable for use.
In the growth promotion portion of the test, each lot of medium is in-
oculated with fewer than 100 colony forming units (CFU) of each of a general
panel of microorganisms described in the USP Sterility Test (USP 1999b), or
indicator organisms appropriate to the particular selective medium under test
(e.g., Salmonella used to test Brilliant Green Agar, Escherichia coli used to test
MacConkey agar, etc.). After incubation, plates are examined for evidence of
growth on general-purpose media and proper reactions on selective media.
Documented recovery and appropriate biochemical reactions of all test or-
ganisms coupled with the lack of growth on the sterility portion of the test al-
lows for the release of the medium for use in the laboratory.
MICROBIOLOGICAL QUALITY OF WATER

Water is one of the most widely used raw materials in the manufacture of
APis, intermediates, and finished drug products. The USP, as well as other in-
ternationally known compendia such as the British Pharmacopoeia (BP) and
Japanese Pharmacopoeia GP), include descriptions and guidance for many
types of water used in the processing of pharmaceuticals. Specific mono-
graphs in USP include Purified Water, Water for Injection (WFI), Sterile Water
for Injection, Bacteriostatic Water for Injection, and Sterile Water for Irriga-
tion (USP 1999c). Water used in the early stages of the production of drug sub-
stances, or water that is used as the feed water for more purified water, must
meet the requirements of the National Primary Drinking Water Regulations
(NPDWR) (40 CFR 141) issued by the Environmental Protection Agency (EPA).
Comparable regulations for drinking water of the European Union or Japan
are considered acceptable (USP 1999c). The API manufacturer should verify
that the potable water is tested routinely to assure compliance with chemical
and microbiological standards, including the absence of pathogenic microor-
ganisms. In many cases, sufficient data may be available from the municipal
water authority to support the use of the water, and only periodic monitoring
may be necessary by the API manufacturer (FDA 1991b).
Deionizers, charcoal beds, ultrafiltration (UF) apparatus, and cold sys-
tems such as reverse osmosis (RO) are notorious for providing an excellent en-
vironment for microbial growth. The validation and control of these systems,
including periodic regeneration, cleaning, and monitoring for microbial pro-
files, are necessary components of a properly maintained water system.
Appropriate control methods include the establishment of water quality spec-
ifications and corresponding alert and action levels, plans for remedial action
when microbial action levels are exceeded, and adequate validated mainte-
nance procedures such as periodic regeneration and sanitation/sterilization.
Specifications for microbiological quality, including alert and action lev-

els, should be established, periodic sampling should be conducted according
to a consistent schedule, and testing should be performed by means of stan-
dard methods of analysis (Greenberg et al. 1992). The particulars of the sam-
pling frequency and the stringency of the test specifications will vary
depending on the stated quality of the water (drinking water, Purified Water,
WFI, etc.) and the point in the process at which the water is being used. For
example, drinking water may be used in the early stages of chemical synthe-
sis and in the early stages of the cleaning of pharmaceutical manufacturing
equipment. However, if the water is used as a final wash of the centrifuge cake
for a nonsterile API that may ultimately be used in the manufacture of a ster-
ile product, a higher water quality standard than normally specified for Puri-
fied Water should be considered. Water used in the manufacture of
parenterals must have limits for total microbial count and endotoxin. Water
used for topicals and oral products has less stringent requirements than does
WFI, since endotoxin is not an issue for these products, and sterility is not an
end product specification (FDA 1991b).
Water test results should be compared with established alert and action
levels as soon as the data become available, and reaction to excursions should
be implemented immediately. Proliferation of contaminants in water systems
or water system points of use can accelerate rapidly over the multiday incu-
bation period for microbiological water tests, so by the time these results are
available, the offending location may already be out of control. Periodic
trending of water system test data is also an important tool that can be used
since isolated OOS results may appear rather innocuous by themselves. How-
ever, when compared with other test results from the same time period or
with test results from the same location over a long period of time, these aber-
rations may highlight seasonal or event-related spikes that can be managed
and possibly eliminated in a more effective manner.
For the manufacture of parenteral APis where there is a concern for the
levels of endotoxin and microorganisms in the final product, WFI should be
used. WFI should be used not only for the formulation of products ultimately
slated for parenteral use but also for the final washing of components and
equipment used in their manufacture. Distillation and RO are the only ac-
ceptable methods currently listed in the USP for producing WFI, although the
feed water must comply with the EPA NPDWR or with comparable regulations
of the European Union or Japan (USP 1999c). Modern multieffect distillation
units generally elevate the temperature of the feed water to the point of boil-
ing, the vapor produced is separated and conveyed to a compressor, and then
condenses on the outside surface of stainless steel distilland tubes, thus leav-
ing behind numerous impurities in the process. These systems are usually
very reliable in producing WFI, but they are not infallible. Failure of these
units will often result in carryover of endotoxin into the final distillate, a
situation that could persist unchecked unless tested for. RO units are usually
less reliable than stills because they generally operate under cold or ambient
Microbiological Attributes of Active Pharmaceutical Ingredients 481
conditions, and they rely on a semipermeable membrane, which can fail, so

they are usually used in a series of at least two (Weitnauer and Comb, 1996).
Some API manufacturers have installed heat exchanger units immediately
downstream of the RO units to heat the processed water to 7S-80°C to mini-
mize microbial contamination (FDA 1993). UF, a method that excludes parti-
cles based on molecular weight, may be employed to minimize endotoxins in
water as well as in those drug substances that are to be administered par-
enterally (FDA 1991b). In addition, some nonparenteral sterile products such
as ophthalmics, orals, and even topicals may have formulation concerns that
would dictate the use of a better quality water such as WFI, along with
processes similar to those used for sterile products, to minimize the potential
for product contamination, especially for products whose formulation may be
conducive to microbial proliferation.
The USP and the FDA have published microbial count expectations for
drinking water, Purified Water, and WFI (USP 1999c; FDA 1993) (Table 18.1).
These should not be considered pass/fail limits, but rather they should be con-
sidered as action levels. When exceeded, the firm must investigate the cause
of the problem, take action to correct the problem, assess the impact of the
microbial contamination on products manufactured with the water, and doc-
ument the results of their investigation. To minimize the possibility of action
violations, alert levels of a more conservative number, e.g., S CFU/100 mL,
should also be considered as a warning signal for a system trending out of
control.
In addition to total microbial count, the presence of objectionable mi-
croorganisms in water systems is another concern for API manufacturers. In
fact, the presence of a specific contaminant could be more significant to an
API manufacturer than the total number of microorganisms. Manufacturers
are cautioned to not simply focus in on just those objectionable microorgan-
isms listed in specific USP monographs. It is up to manufacturers to
• establish a microbiological profile of their water through frequent

monitoring and trending,
Table 18.1 Microbial Count Expectations

Water Type Action Level*
Drinking 500 CFU/ml

Purified 100 CFU/ml
WFI 10 CFU/100 ml
*Based on a sample size of 100-,300 ml
Note: A CFU is a colony forming unit, or a bacterial colony that arises from one bacterial cell.
• evaluate their water systems against a set of established standards,

• examine the ways in which both the water and product are manu-
factured, and
• establish acceptable action (and possibly alert) levels based on the
highest risk product manufactured with the water (FDA 1993; USP
1999c).
The presence of these contaminants should be evaluated in terms of the
source water, the nature of the product, the ultimate use of the product, and
the potential harm of the contaminant to the user.
Validation/Qualification and Maintenance of the

Water Purification, Storage, and Distribution System
The suitability of the system to consistently produce water of acceptable qual-
ity should be validated, and appropriate operating and testing controls should
be in place before the water is used for routine manufacturing. Once a water
system is validated, criteria for controlling and maintaining the microbial
quality of Purified Water and WFI should be established. These criteria may
vary from process to process or manufacturer to manufacturer according to
the particulars of the water's production, storage, distribution, and use. There
are generally few problems that arise regarding the chemical purity of WFI of
Purified Water. In contrast, however, maintaining the microbiological purity
of the water system requires continual surveillance. In recognition of this con-
cern, USP 24 includes a lengthy discussion on the microbiological considera-
tions of water systems including guidance on methods for testing,
identification of contaminants, and establishment of alert and action levels
(USP 1999c).
Validation of the water system should include Installation Qualification
(IQ) to verify that the installation meets the design requirements and Opera-
tional Qualification (OQ) to verify that the equipment and its system controls
are reliable and that appropriate response levels have been established. Finally,
Performance Qualification (PQ) will confirm that the unit can consistently
meet critical process control parameters. The validation program should also
include a mechanism for change control so that any modification is evaluated
for its impact relative to the validated process for the entire system.
Documented, written procedures should be established for the opera-
tion, preventive maintenance, and control of critical water systems. These
procedures should include a description of the system, including schematics;
identification of all outlets, use points, and sampling ports; and requirements
for routine preventive maintenance of the system. It should also include pro-
cedures for flushing of the outlet prior to sampling in a manner similar to
that used prior to using the outlet for production, training of operators or an-
alysts in appropriate sampling techniques, documented test procedures and
specifications including detailed methods of analysis, and microbial alert

and/or action levels for each water type. These procedures should also in-
clude guidance on the steps to be taken in the event microbial action levels
are exceeded. This guidance should include procedures for resampling (usu-
ally by a second person) and retesting either of a volume in excess of the orig-
inal sample volumes or additional replicates. If the retests confirm the
original test result, an investigation should be conducted on the water system
in an attempt to isolate and eradicate the cause of the problem.
Given that the microbiological quality of the feedwater may fluctuate
seasonally (warmer months can pose particularly challenging problems), or
with demands that are often made on the municipal system (e.g., construc-
tion, water main breaks, etc.), pretreatment of the feedwater is recommended
by most manufacturers of distillation and RO equipment. Pretreatment may
consist of multimedia filtrations, declorination, and other processes designed
to prepare consistently good water for stills and RO systems. These pretreat-
ment systems are also usually very effective at protecting the equipment com-
ponents and prolonging the useful life of the still or RO system.
Continual monitoring of water systems for evidence of microbial conta-
mination is essential for proper maintenance. WFI systems should include a
hot (65-80°C) circulating loop to "self sanitize" and should be made of high
quality stainless steel with sanitary butt-welded connections (FDA 1993). One
common problem with the piping layouts in either hot or cold circulating
high-quality water systems is that of "dead legs." A dead leg is generally con-
sidered a length of piping, at least six pipe diameters in length, that extends
from, but is not in the pattern with, the circulation loop and is therefore not
subject to the positive effects of continuous water circulation (FR 1976). Wa-
ter can collect in dead legs, providing an opportunity for the formation of
biofilm and growth of microorganisms. Dead legs should be prohibited in cir-
culating water systems, and there should be validated routine sanitization pro-
cedures in place to assure adequate cleaning and maintenance of the system
(FDA 1993).
If the API is purported to be endotoxin free or sterile, or if it will be used
in the preparation of parenteral products, the water system must be validated
to demonstrate control of both microorganisms and endotoxin (FDA 1993).
Routine testing should be conducted according to standard methods for mi-
crobiological qualities such as total plate count and Bacterial Endotoxin Test-
ing (BET) to document this control (FDA 1987a, 1990; Greenberg et al. 1992;
USP 1999a). In addition, the USP requires Total Organic Carbon (TOC) and
conductivity testing, and some foreign compendia require additional tests be-
yond these to be performed.
Starting in the mid-1980s, the BET has gradually replaced the USP (rab-
bit) Pyrogen Test for water and most raw materials and finished products due
to its simplicity and specificity for bacterial endotoxin. The most simplistic
form of the BET is the gel-clot test in which small portions of the water sam-
ple and a specific reagent are incubated for one hour and then examined
for the formation of a clot. This is considered a semiquantitative test since
dilutions of the sample can be tested and an endotoxin concentration range

determined. More elaborate quantitative versions of BET involve endpoint or
kinetic methods, some utilizing chromogenic substrates (discussed later in
this chapter). These alternative methods may be suitable for some testing, es-
pecially when knowledge of a more specific endotoxin concentration is de-
sired. These methods are also useful for trending of water data over long
periods of time to evaluate for drifts in endotoxin quality.
Microbiological total plate count testing, including incubation of the
test samples, usually takes at least 48 hours. By the time the data are reviewed,
the manufacturing process for the affected product is usually complete. Re-
view of data, therefore, is retrospective. If results are observed that are out of
specification (OOS), these data should be reviewed with regard to the partic-
ular lot of drug substance formulated from the day the water sample was
taken. A decision regarding further processing (rework), rejection, or release
of the product will depend on the numbers of microorganisms observed, the
presence of a specific undesirable contaminant, the subsequent manufactur-
ing process, and the end use of the product. A comprehensive investigation
report including a description of the problem, the action taken by the Qual-
ity Assurance (QA) department, the results of any retesting, the justification
or "logic stream" used in making the decision, and any resultant follow-up ac-
tivities should be prepared by the QA department. Investigations of individ-
ual excursions may not provide a complete examination of the consistency of
the water quality, but trending of water data over a period of time (week,
month, year) will usually bring out the weak points in the system.
BIOBURDEN
The microbiological profile of the material, sometimes referred to as the

bioburden, must be understood and controlled for routine processing of both
sterile and nonsterile APis. The impact of the bioburden for incoming raw
materials, water, processed materials, and manufacturing equipment on the
quality of the finished API can be considerable, especially if the material is in-
tended to be used in the manufacturing of a sterile drug product. Though
only general guidance currently exists for API production, the FDA expects
that GMPs for finished pharmaceuticals will be applied as appropriate to the
manufacture of APis (U.S. DHHS 1998). For bioburden, this means the
validation and control of processes designed to reduce or eliminate microor-
ganisms during manufacture and screening key raw materials and process in-
termediates as well as final product for numbers and types of microorganisms,
particularly those organisms considered to be objectionable.
Microbiological monitoring of raw materials should be part of the over-
all quality program. Those raw materials derived from plant or animal
sources are particularly important, since these classes of materials naturally
may have high background levels of microorganisms and/or endotoxins.

Depending on the source of raw materials, the manufacturing process, and
the intended use of the product, monitoring of key points in early and in-
termediate phases of production may be performed to track bioburden lev-
els throughout production. Any processing steps designed to reduce
bioburden should be validated to demonstrate efficiency and consistency
from batch to batch.
The frequency and scope of the testing program depends on the in-
tended use of the product and the philosophy of the company. Some materi-
als may require simply a total count, while others may need a screen for
particular objectionable microorganisms. The USP Microbial Limits chapter
lists four objectionable microorganisms: Escherichia coli, Pseudomonas aerugi-
nosa, Staphylococcus aureus, and Salmonella species (USP 1999e). These four mi-
croorganisms are generally referred to as "indicator microorganisms," and
their presence in raw materials or finished products suggests a poor quality
produ~t. Although these four microorganisms are listed by name, they are
merely representative of a broader panel of microorganisms that may be ob-
jectionable (e.g., Enterobacter species, some other Pseudomonads, other
Staphylococcus species, and some Streptococcus species). Depending on the
product, or the intended use of the API, the manufacturer should consider
screening for organisms that are objectionable for the intended administra-
tion. For example, APis intended for oral administration should be screened
for the presence of Salmonella and Escherichia coli; topicals should be tested for
Staphylococcus aureus and Pseudomonas aeruginosa; and substances intended for
rectal, urethral, or vaginal administration should be examined for the pres-
ence of yeasts and molds (Schmitz et al. 1995; USP 1999f).
Testing methods used to determine the bioburden in nonsterile APis, in-
termediates, and raw materials should comply, as closely as possible, with the
methods and interpretation of data described in the Microbial Limits chapter
of the USP (1999e). This chapter is intended to be a general guide for the "es-
timation of the number of viable aerobic microorganisms present and for free-
dom from designated microbial species in pharmaceuticals of all kinds from
raw materials to the finished forms" (USP 1999e).
The API manufacturer often purchases raw materials. In addition to pur-
chase price and delivery schedule, the contract will usually stipulate product
quality specifications for each material. These specifications describe the at-
tributes that the API manufacturer feels are achievable by the raw material
supplier and necessary to guarantee the quality of the final product. While
specifications regarding the chemical quality of the raw material are custom-
ary, specifications regarding the microbiological quality of raw materials are
becoming more common as API manufacturers recognize that the microbio-
logical profiles of the starting material "building blocks" affect the quality of
the end product.
If an API manufacturer accepts any certificate of analysis (CofA) from a
supplier, it is the firm's responsibility to audit the vendor to assure that test
methods and data interpretation are consistent with industry and (where ap-
plicable) compendia! standards. Validation of a supplier's test methods and
the lot-specific documentation of test data should be requested. A vendor au-
dit is a prudent measure even if the API manufacturer performs its own con-
firmatory testing of the data presented on the CofA. When performing a
vendor audit, including contract manufacturers and contract testing labora-
tories, assume that the laboratory providing the CofA is an extension of the
API manufacturer's own laboratory. Contract laboratories and suppliers
should be held to the same standards (training, methods validation, SOPs,
documentation, investigation of OOS results, etc.) to which an in-house lab-
oratory would be held.
Because they are generally unblended, microbial contamination of in-
coming raw materials or process intermediates is rarely consistent across the
batch or lot of product but rather is very often found in "pockets" within the
batch. Since microorganisms are ubiquitous in the nonsterile manufacturing
environment, these pockets of microorganisms can be formed by exposure of
the API or intermediate to operators and/or the environment. Frequently,
however, pockets are formed as the result of improperly cleaned and dried pro-
cessing equipment. Improper cleaning can result in contamination of the first
portion of a batch with a bolus of microorganisms. As the process continues
and the system is purged, later stages of the batch will contain fewer microor-
ganisms. Likewise, a mechanical intervention due to equipment failure or a
system shut down could result in an intermediate portion of the batch being
contaminated. Testing of large samples taken as composites across the batch
are suggested to increase the probability that any large pockets of contamina-
tion will be sampled and detected.
API PROCESSING
One of the primary objectives in the manufacture of sterile or nonsterile APis

is to minimize or eliminate the potential for microbial contamination in the
final bulk substance or intermediate. This objective requires special attention
to the microbiological quality of the environment in the facility, including the
cleanliness of processing equipment, the quality of the raw materials used in
the process, the validation of manufacturing processes, the validation of the
cleaning process, and the training of the operators involved in the production.
The starting point in the synthesis of APis is usually a relatively simple
chemical or group of chemicals, which undergo a series of reactions to pro-
duce one or more intermediates that ultimately become the final API. The
production of APis is usually a "batch" process, with separate steps that usu-
ally include crystallization, separation, and drying, or some combination
thereof. To fully assess the microbiological impact, a thorough knowledge of
the process used in the manufacture of the final substance is important. The
point during manufacture where the process evolves from a series of chemi-
cal reactions to a recognizable API is the point at which strict adherence to
cGMPs becomes an issue for the API manufacturer (FDA 1991b; Brocklebank
and Deo 1996; PhRMA 1995a-c, 1997).
It is important for the API manufacturer to recognize that once a sterile
powder is made, there is no further processing to remove contaminants or im-
purities such as particulates, endotoxins, or degradants. Therefore, it is very
important to understand those practices and processes that may affect the mi-
crobial profile of the sterile bulk powder during its manufacture.
Nonsterile liquid APis are often rendered sterile by filtration through a
sterilizing filter. Powdered APis are reconstituted, filtered, and dried again
downstream of the sterilizing filter. FDA expectations for filtration efficiency
and validation are clearly defined, and have remained virtually unchanged
for many years (FDA 1987b).
Routine processing of sterile APis usually involves the transfer of the
nonsterile liquid material from a manufacturing vessel into a sterilized hold-
ing vessel through one or several sterilizing filters. Many companies utilize the
concept of redundant filtration on the premise that filter failure is usually a
highly unusual event, so a failed filter would generally be supported by an ac-
ceptable filter and therefore minimize the risk of microbial contamination.
The filtration process must be capable of removing at least 107 microorgan-
isms per cm2 of filter area. Several major filter manufacturers have described
the mode of filtration as a "sieving" process, and this concept has been con-
firmed through the use of scanning electron microscopy to examine filter sur-
faces. This microscopy demonstrated that after filtration of a liquid
containing bacteria, the membrane surface is not covered by a monolayer of
cells, but rather consists of a multiple layer sieve effect with some layers of
cells on the surface of the filter acting as a sieve to exclude other bacterial cells
and large particulates, some of which penetrated as deep as 30 J..t.m into the
membrane (Osumi et al. 1996).
All filters must pass a bubble point (or pressure hold) test, which is a
means to demonstrate integrity of the filter. The purpose of this is twofold:
(1) to provide the API manufacturer assurance that the filter used for steril-
ization is devoid of flaws before being used in the process, and (2) to provide
demonstration of the integrity of the filter after it was used for processing.
Testing is performed by pressurizing the upstream side of the filter and ob-
serving for bubbles in water out of the downstream side. If no bubbles are
seen when pressure is applied up to the manufacturer's recommended bubble
point value (usually in terms of pounds per square inch), the filter is consid-
ered acceptable for use. Filter manufacturers usually have technical experts
who are willing to assist in the selection of the appropriate filter medium de-
pending on the composition of the API (e.g., materials with high solvent con-
tent, extreme pH, etc.) to provide a filter medium and configuration with
construction materials that will not be attacked or damaged by the material
being filtered.
Filter suppliers often perform physical and microbiological validation

studies on the sterilizing efficiency of the filter as a service to the customer.
The indicator microorganism used to test the efficiency of the filtration
process should be from a strain that is physically small enough to present a
challenge to the ability of the membrane to provide retention. Pseudomonas
diminuta is often used as the indicator microorganism for the validation of
sterilizing filters. In the presence of the product being filtered, the filter mem-
brane may be altered in a way that would allow passage of microscopic cells,
so the filter matrix is usually challenged after is has been exposed to the ex-
tremes of the routine processing conditions. Once validated, the filter type
should be used exclusively for the manufacture of the product until a new fil-
ter medium is validated.
Some API processes involve subjecting the filtered solution to aseptic
crystallization, precipitation, and/or drying of the material resulting in a ster-
ile powder. Processes using organic solvents may eliminate or reduce micro-
bial contamination and/or endotoxin due to the harsh chemical environment
provided by the solvents used in the process. Any API process intended or
purported to reduce microbial populations or endotoxin in the material must
be validated to demonstrate this feature. This method, however, involves
more handling, transfer, and manipulation of material by operators than
other methods, and therefore has a higher potential for microbial contami-
nation during processing (FDA 1987b).
FACILITY AND EQUIPMENT CONSIDERATIONS

FOR THE PRODUCTION OF STERILE APis
The production of sterile APis poses special challenges to the manufacturer.

Sterile APis by definition must be free of viable microorganisms, and if labeled
"nonpyrogenic" or "pyrogen free," must meet specific standards for endo-
toxin content (discussed later in this chapter). Therefore, it is imperative that
the building and the production equipment not contribute to actual or
potential contamination of the API (FDA 1991b). Facilities used for the
manufacture and/or filling of sterile APis should share some of the same de-
sign features that are generally employed in facilities designed to produce
sterile finished products. The materials used in the construction of the walls,
floors, and ceilings must be designed to withstand frequent sanitization with
a variety of harsh chemicals. Recovery of the final API should take place in an
environment with little or no exposure to airborne contaminants such mi-
croorganisms, dirt, dust from other drug substances, or industrial chemicals.
The sterile API processing area should be devoid of all unnecessary
equipment, so storage of blenders, trays, containers, etc. should be handled
outside the aseptic area. There must be strict surveillance to forbid the use of
any materials that would provide a growth medium for microorganisms such
as wooden pallets, pads of paper, cardboard, and any other materials that can-
not be adequately sanitized.
Equipment coming in contact with the API product must be rugged, eas-
ily cleanable, and inert to the product. Equipment should have smooth sur-
faces with curved corners and no seams to facilitate cleaning. Any sterile
holding vessels should be equipped with microporous hydrophobic vent fil-
ters to prevent the inadvertent introduction of microbial contamination
through the vent. Manufacturing equipment may be used for several prod-
ucts, or it may be dedicated to a single product. If used for more than one
product, careful attention should be given to cleaning between campaigns to
prevent "crossover" of dissimilar products. Validation of cleaning agents and
cleaning procedures is an important part of any API process to assure not only
that there is no residual product remaining after cleaning, but also to assure
that the cleaning process is effective against any bacteria that might be part of
the normal bioburden.
Depending on the process, equipment used in the production of APis
may require sterilization after cleaning. The method of choice for the steril-
ization of equipment and transfer lines is saturated clean steam under pres-
sure (FDA 1994). Appropriate sterilization cycles for all items used in the
manufacture of the product must be developed as part of the validation of the
process. For the sterilization cycle to be valid, the bioburden (both numbers
and types of microorganisms) of the product should be determined and eval-
uated for its resistance to the proposed sterilization cycle. The development
and validation of steam sterilization revolves around the use of F0 values, D-
values, and z-values to describe the efficiency of the sterilization process
(Pflug 1980). The term F0 is defined as the actual time of sterilization in terms
of its equivalence to 121.1 oc, the D-value is the time it takes to reduce the chal-
lenge microorganism population by one log (90 percent), and the z-value is
the number of degrees of temperature necessary to cause the D-value to
change by a factor of 10. These three parameters are used routinely in the
evaluation and validation of steam sterilization processes.
Thermocouples and resistance thermal devices (RTDs) are routinely
used to monitor the temperature at various locations within the sterilization
chamber in order to demonstrate the uniformity of heat distribution and
penetration in the empty chamber and throughout the load being sterilized.
Some of the more sophisticated sterilizers can be programmed to monitor the
level of sterilization at various points within the chamber by means of imbed-
ded RTDs, and they can be programmed to terminate the cycle at the moment
the coldest part of the chamber reaches the appropriate combination of tem-
perature and exposure time.
Biological Indicators (Bis) are carriers that usually contain large popula-
tions of bacterial spores known to be resistant to the effects of the sterilant,
which in this case is moist heat. Bls are used to support the physical monitor-
ing (F0 , D, and z-values) of the sterilization process and provide a biological
demonstration that the sterilization cycle is effective against even the most
resistant microorganism. If the process is capable of sterilizing the BI, it can

then be assumed that the resident bioburden, which usually has considerably
less resistance to the sterilant (moist heat) than the specific BI microorgan-
isms, will also be effectively sterilized. Under certain circumstances, it may be
successfully demonstrated that a sterilization process is effective even though
one or more of the Bis survives the process. In this case, it would have to be
demonstrated that a sufficient population of a challenge microorganism with
adequate resistance was killed.
Sterilization cycle development for all items used in the product must be
developed as part of validation of the product. For the sterilization cycle to be
valid, the bioburden of the product should be evaluated for its population
count, and for its resistance to the sterilization process. In most cases, the
bioburden population and resistance of the presterilized material is usually
very low, but rarely is it nonexistent. This evaluation enables the processor to
be assured that the validated sterilization process will demonstrate an effec-
tive microbiological kill, and· include an adequate safety factor.
Most equipment sterilization can usually be performed in an "overkill"
cycle in which the time duration and chamber temperature are considered ex-
cessive relative to the time and temperature that would be necessary to steril-
ize the natural bioburden of the equipment. This approach is usually
developed using a BI with extreme resistance and high population. The se-
lected sterilization cycle is usually sufficient to kill the challenge BI plus some
level of additional sterilization in order to extrapolate a sterility assurance
level (SAL) usually to the level of w-6 , meaning there is a probability of fewer
than one nonsterile unit in every one million units. Once the overkill steril-
ization process is validated, the cycle can usually be routinely conducted with-
out any additional biological monitoring.
If the equipment or material being sterilized cannot withstand excessive
heat, the bioburden approach may be considered. This approach usually in-
volves a thorough characterization of the resident bioburden for both popu-
lation and resistance, followed by the development of a sterilization cycle of
adequate temperature and time duration to deliver a sterilizing effect suffi-
cient to kill this resident bioburden to a satisfactory SAL. Once established,
routine sterilization using the bioburden approach must be accompanied by
monitoring of the population and resistance of the resident bioburden to ver-
ify they are not in excess of the validated parameters.
One method for assessing the sterilization effectiveness is by means ofF0
determination. The F0 value for the process is determined by a calculation
with variables that include the D-value, the z-value, and the bioburden:
F0 = D12u (log A - log B)
where D 12 u is the D-value of the bioburden at 121.1 oc, A is the bioburden

per some predetermined unit, and B is the maximum acceptable SAL. For
example, if the bioburden of each gram of bulk API is 100 CFU, its D-value
is 0.5 minutes, and the desired SAL is at least 10-6 (no more than 1 CFU in
1,000,000 g) the Fa determination is 4.0 minutes:
Fa= D 12 u (log A -log B)
Fa = 0.5 (log 100 - log 10-6)
Fa = 0.5 (2.0 - (-6))
Fa= 0.5 (2.0 + 6)
Fa= 0.5 (8)
Fa= 4.0 minutes
This means the process must deliver the equivalent of 4.0 Fa (minutes of ster-
ilization at temperatures equivalent to 12l.l C) to assure a 6-log SAL due to
0
the bioburden population of this microorganism, which has a D-value of

0.5 minutes. If the bioburden were higher, e.g., 10,000 CFU/g (but the D-value
and SAL remained the same), the required Fa would be higher (5.0 minutes).
Conversely, if the bioburden were less, e.g., 10 CPU/container, the required Fa
would be less (3.5 minutes). Similarly, a higher D-value (e.g., 1.5 minutes) or
SAL (e.g., 10-8) would require a higher Fa; lower D-value or SAL would require
less Fa. Manufacturers will quite often monitor the sterilization process with
a BI containing a specific number of viable microorganisms with known re-
sistance to the sterilization process. If this specific process is capable of steril-
izing the BI, it can then be assumed the resident bioburden, which usually has
considerably less resistance that the BI, will also be effectively sterilized. In ac-
tual practice, many manufacturers will use the minimum determined Fa sim-
ply as a starting point and design their process to exceed that figure by some
percentage, e.g., 10 percent, 25 percent, SO percent, etc., in order to provide a
safety factor of sterility assurance. This philosophy is generally acceptable
provided the chemical/stability composition of the API being processed is
relatively unaffected by excessive heat. If the subject material is affected by
the sterilization process, the bioburden approach may be the better choice.
The microbiological quality of an API must take into consideration the
nature of the final product. If the final product is a liquid form, quite often
the manufacturer will be hesitant to claim sterility since most liquid bulks
will ultimately proceed to a sterile dosage form by means of a validated fil-
tration sterilization procedure. In many cases, the bulk liquid will have a very
low bioburden (quite often nonexistent), a level of quality considered by the
manufacturer as adequate for that particular stage of processing. However, if
the final bulk product is in a powder form ("sterile bulk"), the bulk API would
generally need to be certified at that point as "sterile" since there is usually
no further processing other than transfer of the powder to individual dosage
containers. This certification as sterile includes the requirement to validate

the sterile manufacturing process; however, manufacturers must also demon-
strate the ability to consistently produce a sterile bulk product. Although a
sterile media fill (FDA 1987b) is primarily designed to evaluate the aseptic as-
sembly process for final dosage forms, this process can also be modified and
used to evaluate the aseptic potential of the sterile bulk process. Since the
USP Sterility Test procedure requires the examination of only six grams of
material from what are usually kilogram quantities, the assurance of sterility
by conducting a Sterility Test is no better for bulk products than for finished
products unless special provisions are made to test larger quantities. There-
fore, sterility assurance of the manufactured sterile bulk may be more appro-
priately assessed by means of aseptic simulation, using a sterilized inert
material such as lactose instead of the product (which is then overlaid with
liquid culture media before stoppering), rather than attempting to apply the
limited examination of only 6 g, as required by the USP Sterility Test, to
batches produced.
Media fills (or process simulations) are usually conducted as part of
the validation to qualify an aseptic process, and they should include all of the
typical routine (and sometimes nonroutine) activities associated with the
production process as though the manufacture and filling involved a typical
production batch. The only difference is sterile culture media is substituted
for the product. After filling, the units are incubated and inspected for
contamination. The process is considered qualified provided the number of
contaminated units is within a minimum requirement (FDA 1987b; ISO
1998).
The material used to simulate the API in the media fill must be selected
very carefully. Dehydrated sterile microbiological culture media, which is
commonly used to simulate powder filling operations, is not often used due
to the difficulty encountered in simulating all of the normal production steps.
In addition, cleaning arrd removal of trace quantities of the media would be
nearly impossible and require very aggressive cleaning procedures (PhRMA
199Sa-c, 1997). Placebos, such as inert materials or buffer solutions, that rinse
the system and are then tested for microbial contamination may be suitable
choices for simulation provided they are tested for their microbial toxicity
and their ability to be adequately cleaned from the system. New production
areas or processes normally require three consecutive successful simulations
to qualify the process, and periodic requalification is thereafter expected on a
semiannual basis.
If the final product is a liquid, however, the bulk API may not necessar-
ily need to be certified as sterile since the material would usually be added to
an aqueous formulation that would be filter sterilized. Prefiltration bioburden
monitoring of these APis or manufacturing intermediates should be routinely
or periodically conducted, the frequency of which should be based on the
confidence of the process to produce a bulk of low microbial bioburden. The
key issue here is to assure the microbial load on the sterilizing filter does not
exceed that of the filter sterilization validation. All other forms of sterile
product (ointments, creams, suspensions, etc.) need to follow these same
considerations.
USE OF ISOLATOR SYSTEMS TO MINIMIZE

HUMAN CONTACT WITH STERILE APis
Modern manufacturing processes are being designed to minimize or elimi-
nate direct operator contact through the use of isolator systems that are de-
signed to facilitate the containment of entire manufacturing processes
(Carroll 1995). In many cases, the purpose of the isolator is to contain the
product to avoid cross-contamination. In other cases, the purpose of the iso-
lator is to limit exposure of the environment and operator to the product, as
in the handling of toxic materials, or to protect the product from viable and
nonviable contaminants, as in the production of sterile APis. Once validated,
isolator systems used for the segregation of manufacturing processes require
an extensive system of sensors, controllers, alarms, and other such safety de-
vices to assure continued reliability. In addition, isolator systems usually re-
quire a fair amount of routine maintenance for continual reliable operation
of the functional components. Cross-contamination as a result of leakage, ei-
ther into or out of the isolator, could have tremendous negative conse-
quences. An excellent review of current isolator technology may be found in
Isolator Technology, edited by Wagner and Akers (1995).
There are four basic types of barrier protection currently in use in the
manufacture of sterile APis (Table 18.2).
Containment
In general, the production of multiple APis in the same facility is not an ob-
jectionable practice. However, for certain APis such as penicillin, some
steroids, and other drug or toxic substances that could cause adverse or even
fatal reactions in some patients, there must be separate facilities and com-
pletely separate air-handling systems to isolate these materials from each
other. Documented regulatory guidance on this issue is uncharacteristically
limited, however, with the only known published citation being in the FDA
Guide to Inspections of Sterile Drug Substance Manufacturers (1994).
Isolation of two manufacturing processes does not necessarily mean that
production must take place in two separate buildings or in areas separated by
some significant distance. Separation may be achieved within a building (or
a plant) by effectively isolating and sealing off from one another these two
types of operations. Although many different methods of segregating pro-
duction activities have been used to effectively isolate them from others
Table 18.2 Types of Barrier Protection

Type Level of Protection Impact on Work Area Examples
Partial Minimum No sterile transfer capability available. Personal protective
Barrier Sterility of work area cannot be equipment, curtains,
assured during performance of equipment.
activity. Operators are not completely conventional clean
isolated from the process. rooms
Closed Limited opening and No sterile transfer capability available. Hospital isolators,
Barrier handling; better than Sterility of work area cannot be restrictive access
partial barrier assured during performance of barriers, glove boxes
activity. Operators are not completely
isolated from process. Closed barriers
are usually decontaminated or
sanitized, not sterilized.
Open Highly isolated Sterility of work area can be maintained Production isolators
Isolator process and transfer during performance of activity. with small openings
Overpressure helps ensure the for exiting of vials
integrity of work area in spite of
"mouse holes" or other such openings.
Transfer of materials in and out
through special transfer devices.
Closed Totally contained Closed systems. Sterility of work area Closed, leak-tight
Isolator process and transfer; can be maintained during performance isolators used for
highest level of of work and does not rely on over- batch production,
protection pressure. Transfer of materials in and QC testing, and
available out through special transfer devices. containment
applications
within the same facility, some production activities (e.g., fermentation and
purification of penicillins) can only be isolated through the use of separate
air-handling systems (Brocklebank and Deo 1996).
MONITORING THE ENVIRONMENT IN

API MANUFACTURING FACILITIES
A well thought-out and carefully constructed microbiological monitoring
program of the environment in any pharmaceutical production facility pro-
vides manufacturers with the ability to
• gather information on the quality of the environment during man-
ufacture of the product,
• prevent the release of a contaminated lot of product if specific qual-
ity standards are exceeded (e.g., sterility, microbial limits, freedom
from objectionable microorganisms, endotoxin limits), and
• prevent future contamination by establishing profiles and monitor-

ing trends (FDA 1999).
For example, monitoring of the air in a manufacturing site provides informa-

tion on the microbiological "cleanliness" of the air that may come in contact
with the product. The more miCroorganisms detected in the air, the higher
the potential that the exposed product will be adversely affected. Surface sam-
pling for microorganisms is really a check on the effectiveness of the disin-
fection/sanitization program for equipment, floors, and walls. Poor
sanitization of surfaces results in high microbial counts and indicates a po-
tential for contamination of exposed product. Product contact surfaces are es-
pecially important and deserve special attention in the monitoring program.
People are a significant source of contamination, especially in a clean or asep-
tic processing area. Therefore, training of operators in techniques that prevent
contamination of product coupled with microbiological monitoring of
gowned personnel working in aseptic areas will help define the degree to
which individuals add to the contamination potential of a manufacturing
process (Hyde 1998).
As with any process, microbiological control in the production of APis is
established through thoughtful and complete validation of processes and sys-
tems including
• the quality of air used in manufacturing areas,

• validation of the effectiveness of disinfection/sanitization of equip-
ment and surfaces used in processing,
• quality of raw materials and excipients used in the formulation
• definition of any step in the process designed to reduce or elimi-
nate microorganisms (bioburden), and
• definition of any step in the process that is likely to contribute
microorganisms.
Once control has been established, an environmental monitoring

program may be implemented to help in maintaining control by predict-
ing excursions through trend analyses and providing clues for corrective
action.
Monitoring of Classified and Critical Areas: Manufacturing

and Support for Products and APis Produced Aseptically
There are a number of excellent reference documents available that will pro-
vide guidance for the microbiological monitoring of classified areas. Among
these are USP general chapter <1116>, Microbiological Evaluation of Clean
Rooms and Other Controlled Environments (USP 1999h); the Parenteral Drug
Association's Technical Report #13: Fundamentals of a Microbiological Environ-

mental Monitoring Program (PDA 1990); and the FDA's Guideline of Sterile Drug
Products Produced by Aseptic Processing (FDA 1987b). These documents describe
agency and compendia! expectations and industry standard sampling plans
for classified production and support areas in which the manufacture of asep-
tic materials takes place.
Monitoring of Unclassified Areas:

Nonsterile Dosage Forms and APis
Unlike classified areas used in the manufacture and support of sterile prod-
ucts, unclassified areas used to manufacture nonsterile dosage forms or APis
have no official guidance or even well-defined industry consensus defining
programs and data interpretation for microbiological monitoring (PhRMA
199Sa--c, 1997). Though most companies manufacturing in unclassified areas
do perform some type of microbiological monitoring, the magnitude of the
program will depend largely on
• the final route of administration of the material;

• any compendia! or in-house requirements and microbiological pro-
file of the material, including specifications for microbial limits
and/or definition of objectionable microorganisms;
• the microbiological profile of the manufacturing area based on lon-
gitudinal analysis of data collected over time (trends); and
• the risk of product contamination (analysis/validation of produc-
tion and support processes).
Site Selection and Frequency of Testing

The focus of any microbiological monitoring program should be the identifi-
cation and monitoring of those specific areas that pose a risk of product
contamination through exposure to the environment. For an aseptically pro-
duced material, exposure to the environment may result in contamination
and rejection for the lack of assurance of sterility. For solid dosage forms and
APis produced in unclassified areas, exposure may result in a bioburden that
exceeds microbial limit specifications or a product that becomes contami-
nated with objectionable microorganisms. Therefore, monitoring intensity
and frequency generally increase as
• the product becomes more purified or nears its final form,
• the classification of the environment increases (in order from un-
classified through Class 100),
• the product is exposed to surfaces or air, and

• the product is handled extensively by operators.
When first developing a plan for the microbiological monitoring of a
manufacturing area, it is important that sites ultimately chosen for the pro-
gram will provide meaningful data. As a preliminary exercise, the firm should
consider conducting a general survey of the area to be monitored and include
many sites that could impact on product quality. The survey should be broad
enough to include data gathered over seasonal changes, normal shutdowns,
routine cleaning procedures, and routine or emergency mechanical interven-
tions. Careful analysis of the survey data will not only provide the firm with
an idea of the normal microbiological flora in the area (baseline), but will also
assist in decisions to choose representative worst case sampling sites based on
history, the nature of the manufacturing process, and the identification of
sites with maximum product exposure.
Microbiological Monitoring of Air

One of the major routes of microbial contamination in any pharmaceutical
production facility is the air. Air quality in controlled and critical manufac-
turing areas is usually described in the United States in terms of "class" as de-
fined by Federal Standard 209E (1992). The number in the classification
description represents the limit of particles :::::0.5 IJ.m that may be present in a
one cubic foot sample of air. Therefore, the lower the number in the class de-
scription, the "cleaner" the air. Class 100 rooms are considered to be critical
areas or zones where sterile product or containers come in direct contact with
the environment. Class 10,000 describes the air quality in rooms immediately
outside of Class 100. These rooms are usually storage rooms, corridors, and
other rooms with service or support functions within the aseptic core. Class
100,000 describes the air quality for preparation areas, compounding areas,
and any other area immediately adjacent to the aseptic suite.
Air-handling equipment for any controlled or critical area should be
sized to provide adequate volumes of incoming and exhaust air in order to
achieve and maintain appropriate air quality. Air quality should be commen-
surate with the type of process (aseptic or nonsterile), risk of product expo-
sure to the environment, and criticality of microbial limit expectations. For
aseptic manufacturing, this typically means a minimum of 20 air changes per
hour, and a positive pressure differential of at least 0.05 inch of water (with
all doors closed) relative to adjacent uncontrolled areas (FDA 1987b). The pur-
pose of these requirements is to establish and maintain the conditions neces-
sary for providing process air that is free of viable (living) and nonviable
particulates in the areas where the product, and containers into which the
product is transferred, are handled. Properly installed and maintained sys-
tems of this type significantly inhibit the intrusion of contaminants into the
immediate and adjacent areas in which the product or containers into which
the product is being transferred are handled.
The air in critical areas should be supplied as high efficiency particulate
air (HEPA)-filtered laminar flow air (FDA 1987b). HEPA filters must be certi-
fied prior to use and should be recertified at least semiannually for critical ar-
eas. The dioctyl phthalate (DOP) aerosol test is the method of choice for
challenging and certifying HEPA filters. A DOP aerosol is introduced up-
stream of the filter, and a probe is positioned downstream of the filter to de-
tect any particles that get through the filter medium. Readings equivalent to
a 0.01 percent penetration of the challenge particles indicate a significant
leak.
There are two ways to sample the air and test it for the presence of mi-
croorganisms. The preferred method is described as "active" sampling, which
involves the intake of a specified volume of air into an instrument, and ex-
posing it to a plate or plastic strip containing sterile microbiological growth
medium. The number of microorganisms that are observed on the growth
medium after incubation is indicative of the number of microorganisms pre-
sent in the sampled volume of air. Popular instruments used for active air
sampling are the slit to agar sampler, sieve-type samplers, and the centrifugal
air sampler. Generally speaking, slit to agar instruments sample a larger vol-
ume of air than centrifugal air samplers. The use of slit to agar samplers in
nonsterile areas can result in a grossly overgrown plate due to exposure to a
large volume of nonsterile air. In these areas, the use of a carefully directed
and carefully timed centrifugal air sampler can provide enumeration of mi-
crobial counts in a specific volume of air without overgrowth.
In passive sampling, settling plates, which are petri dishes filled with ster-
ile microbiological growth medium, are placed in areas on the floor and equip-
ment in the controlled area, and are allowed to sit open for some specified
period of time, usually one hour. Longer exposure times are possible or even
desirable depending on the manufacturing conditions. It should be noted that
in any air sampling technique, care must be taken not to overexpose the
growth medium to too much air, as desiccation of the medium can affect re-
covery of microorganisms. Since there is no active intake of a specified volume
of air, the microorganisms that fall onto the surface of the plate find their way
there through the forces of gravity and air movement in the room. This
method is less well defined than active sampling procedures in that counts
cannot be correlated with a specific volume of air, and is subject to inadver-
tent contamination by spills, operator error, etc. However, settling plates,
when properly distributed and analyzed, can provide a general picture of the
microbiological quality of the air in both classified and unclassified areas.
In any air sampling method, the firm can utilize either a general pur-
pose growth medium such as soybean casein digest (SCD) medium to get a
broad picture of the quality of the air or various selective growth media to
look for specific types of microorganisms such as the utilization of Sabouraud
dextrose agar (SDA) or potato dextrose agar to select specifically for fungi.
No matter what method is used to sample the air, the firm must set a
limit for the number of allowable CFU per cubic foot, cubic meter, or (in the
case of settling plates) per hour of air in the controlled area. The limits are
usually linked to the classification of the room (Class 100 rooms have the
lowest limit) and the specific activity that takes place in the room. In the
General Information Chapter <1116>, Microbiological Evaluation of Clean
Rooms and Other Controlled Environments, the USP has proposed limits
for active air sampling in classified areas of 0.1 CFU per cubic foot of air for
Class 100 rooms, 0.5 CFU per cubic foot of air for Class 10,000 rooms, and
2.5 CFU per cubic foot of air for Class 100,000 rooms (USP 1999h). Al-
though no official limits have yet been established for unclassified areas, a
survey conducted by PhRMA suggests that many companies involved in
monitoring these areas set action and alert limits for total counts based on
the history of the area and the intended use of the product (PhRMA
1995a-c, 1997).
After incubation of exposed growth media, colonies are counted and the
total number of CFU per cubic meter, cubic foot, or hour of exposure is
recorded. Representative colonies are screened for the presence of objection-
able microorganisms. In Class 100 and some Class 10,000 areas, representa-
tive colonies are generally identified to the species level because of the
criticality of potential product exposure to the environment. For Class
100,000 areas and unclassified areas, representative colonies are identified by
at least a Gram stain and may be identified at least to the genus or even
species level depending on the criticality of the process and the eventual
route of administration of the product. Identification of representative
colonies serves a number of purposes.
• It provides a profile of normal flora present in the manufacturing
area (baseline).
• It provides a mechanism for screening for objectionable organisms.
• It provides a benchmark when investigating batches that have
failed microbial limits or sterility testing.
• When trended, it serves to alert QC/QA/manufacturing to drifts
away from the normal operating condition and prevent product
failures by early intervention to correct potential problems.
Microbiological Monitoring of Surfaces

The purpose of sampling surfaces in areas used for the manufacture of phar-
maceutical products is to evaluate the effectiveness of cleaning and sanitiza-
tion procedures. Two methods are utilized for sampling surfaces-contact
plates, sometimes called RODAC (Random Organism Detection and Count-
ing) plates; and swabs. Contact plates are used to sample flat surfaces such as
walls and floors and also large flat surfaces on equipment. Swabs are used to
sample small irregular surfaces such as nooks and hard-to-clean areas of
equipment, grates, and corners where walls or walls and floors meet.
Contact plates are small petri dishes (25-30 cm 2) filled with sterile mi-
crobiological growth medium. The plates are slightly overfilled so that the
surface of the medium rises above the rim of the plate. The exposed agar is
pressed against the surface in question, picking up resident microorganisms.
After sampling, care must be taken to wipe the area clean to remove any resid-
ual growth medium from the surface.
As with media used for the microbiological analysis of air, contact
plates can contain either general growth media or selective growth media.
Contact plates usually contain neutralizing agents such as lecithin and
polysorbate 80 to counteract the bactericidal or bacteriostatic effects of resid-
ual disinfecting or sanitizing agents that may remain on equipment, walls,
or floors after cleaning. Contact plates are considered to be quantitative, as
colonies that are recovered from surfaces can be easily enumerated after in-
cubation. As with air sampling plates, representative colonies are chosen for
identification to establish a baseline of normal flora and screen for objec-
tionable microorganisms.
Alternatively, two different incubation techniques using only SCD
agar supplemented with lecithin and polysorbate 80 have been described
as giving equivalent or better recoveries of yeast and mold than using the
selective SDA agar (Marshall et al. 1998). In the first technique, SCD
medium supplemented with lecithin and polysorbate 80 is incubated
first at 30-35°C for 70-72 hours and shifted to 20-25°C for an additional
70-72 hours. In the second technique, supplemented SCD medium is in-
cubated only at 30-35°C for 72 hours. It must be remembered that growth
promotion testing must mimic the particular incubating technique that is
routinely used by the laboratory. For example, if a lab chooses to monitor
using SCD and shift incubation temperatures after 72 hours, each lot of
medium must be "growth promoted" using bacteria, yeast (Candida albi-
cans), and mold (Aspergillus niger) and shifting the temperature as in rou-
tine use.
Not all surfaces are amenable to sampling using contact plates. For ir-
regular or hard-to-sample surfaces, a sterile swab is moistened with sterile wa-
ter and is rubbed over an area of the surface or crevice that is roughly equal
to the area of a contact plate (25-30 cm 2). Swabs may be incubated directly
in liquid bacteriological growth medium containing neutralizers, in which
case the result is recorded as "growth" or "no growth." Alternatively, the
swab may be temporarily placed in a measured volume of sterile transport
medium containing neutralizers, and once returned to the lab, the transport
medium can be plated so that the number of CFUs that are picked up by the
swab may be enumerated. As with contact plates, swabs may be transported,
plated, and incubated in selective media to encourage the growth of particu-
lar microorganisms.
Microbial limits for surface sampling as listed in USP general chapter

<1116> are set based on the classification and use of the room. The USP de-
fines limits for classified areas as 3 CFU /plate for Class 100 rooms, 5 CFU /plate
for Class 10,000 rooms, and 10 CPU/plate for Class 10,000 floors (USP 1999h).
There are no official limits recommended for the monitoring of surfaces in
unclassified areas. However, many firms sample product contact surfaces reg-
ularly, with the limits and sampling intervals largely dependent on the man-
ufacturing process, design of the facility, and the final route of administration
of the API (PhRMA 199Sa-c, 1997).
Microbiological Monitoring of Operators

The skin of humans normally is home to a range of microorganisms. As skin
particles are shed, so are the associated organisms, making humans a signifi-
cant potential contributor to contamination in the production of pharma-
ceutical products. As APis destined for aseptic products work their way
through synthesis, purification, and sterilization, contamination via contact
with humans becomes more important. Monitoring of personnel involved in
the aseptic manufacture of APis for the presence of microorganisms should be
a routine part of the environmental monitoring programs for aseptic produc-
tion. Contact plate samples taken from the outer garments and gloved hands
of gowned operators are incubated and analyzed for total microbial count and
the presence of objectionable microorganisms. Many companies use the re-
sults of this type of personnel monitoring to evaluate gowning procedures
and even to exclude people from working in the aseptic area, if it is found that
they are excessive microbial"shedders."
Trending Data Obtained from Environmental Monitoring

Tracking total counts and microorganism identification helps the firm to
trend the quality of the environment in the manufacturing area over time
and correlate high counts or the presence of specific undesirable microor-
ganisms with seasonal changes, activity in the room, the level of nonviable
particulates, etc. Should the sterile API ultimately fail a sterility test, or
should the nonsterile API exceed the allowable microbial limit, the microor-
ganism(s) recovered from the test can be compared with the microorganism
profile in the area at the time of manufacture to help determine the source
of the contamination.
Analyses of trended data help the manufacturer to set logical alert and
action limits based on historical data and process capability. Once these lim-
its are set, examination of the trend can help to predict excursions and sug-
gest corrective intervention before the process is compromised and product is
lost due to OOS microbiological data.
MICROBIOLOGICAL TESTING OF FINISHED STERILE APis
Sterility Testing
Sterile API batches are usually tested for the presence of microorganisms us-
ing a composite sample taken from several containers across the batch. The
Sterility Test consists of reconstituting powdered API or pooling a liquid ma-
terial in a suitable diluting fluid and filtering the resulting solution through
one or more 0.45 J.Lm filters. The filter(s) are then incubated in two different
bacterial growth media, and are examined periodically for growth, which is
evidence of microbial contamination of the material (Shirtz 1987; USP
1999b). For those products that are insoluble, the USP allows for a "direct
test" where the product is introduced directly into tubes containing the
growth medium. As with the membrane filtration test, tubes are examined pe-
riodically for evidence of growth.
Validation of the Sterility Test requires that the specimen be proven in
preliminary testing not to interfere with the sterility test process. In this pre-
liminary testing, called "bacteriostasis and fungistasis" (B/F), the sample
quantity is diluted and, if necessary, inactivated in such a manner to render
it ineffective against potential contaminating microorganisms. The effective-
ness of this inactivation must be demonstrated by suitable growth of several
strains of indicator microorganism in the final test media vessels.
The USP and most international compendia require the use of two dif-
ferent culture media for the Sterility Test, one for the detection of aerobic mi-
croorganisms and the other for anaerobic microorganisms, each with its own
incubation requirements. The media vessels are visually examined periodi-
cally after testing for evidence of contamination, which is usually shown by
the development of turbidity or by the development of fungal structures. If
none is present, the batch from which the sample is taken is considered as
having met the requirements of the sterility test. However, if the media ap-
pears turbid or if there appears to be evidence of fungi, the sample is consid-
ered to have failed. Extenuating circumstances may, under specific conditions
where analyst or other testing error can be proved, allow for a repeat test. It is
incumbent on the manufacturer to provide convincing documentation via a
well-documented investigation to allow this retesting (USP 1999b). Such doc-
umentation may consist of evidence the test procedure was flawed in some
way so as to influence the outcome of the test, and that the positive result was
more likely to have occurred through analyst error than via the product itself.
Sterility testing is usually performed under a laminar flow hood in a
Sterility Test suite, which is a classified/controlled area. This area should be
cleaned, monitored, and held to the same specifications and requirements as
classified areas used in production. Since the Sterility Test is a very labor in-
tensive task that is prone to contamination by inadvertent analyst error, many
parenteral manufacturers and contract laboratories are electing to use isolator
systems for sterility testing. The isolator system is regarded as the current state
of the art in the microbiology laboratory, as its use nearly eliminates potential
contamination of the test by operator error (Shirtz 1995; Wood 1995). The
driving force for the movement to isolators for sterility testing is the restric-
tive nature of the FDA's stance on retests as defined in their 1987 Aseptic Pro-
cessing Guideline (FDA 1987b) and reference to current USP procedures (USP
1999b).
Few tests in the compendia have the limitations of the sterility test.
cGMP requirements demand an extremely low contamination rate for aseptic
processing, which is proven through careful process validation and strict en-
vironmental control. Examination of data on the probability of a sterility re-
jection suggests that the sterility test does not, in fact, assure sterility in a
batch. Data published for the probability of detecting sterility failures in fin-
ished vials provides an excellent source of guidance when interpreting steril-
ity test results from APis (Table 18.3).
Table 18.3 indicates that while the current USP sterility test has difficulty
detecting low-level contamination, it will usually detect grossly contaminated
product (Shirtz 1987; Wood 1995). Thus, the USP Sterility Test is not really a
check on the sterility of a batch of product or drug substance but rather is a
monitor for gross manufacturing breakdowns.
Testing of APis for the Presence of Endotoxin

A pyrogen is any substance capable of causing a fever if it comes in contact
with the bloodstream of a human or other mammal, and is thus considered
to be a serious contaminant in any parenteral pharmaceutical product or in-
termediate. Endotoxins, which are chemically defined as lipopolysaccharides,
are by far the predominant class of pyrogen found in parenteral preparations.
Endotoxins are characteristic components of the cell walls of a certain class of
bacteria called "Gram negative" (Pearson 1985a). These Gram-negative bacte-
ria are ubiquitous in nature, and find their way into formulation components
Table 18.3 Probability of Lot Rejection Based on Contamination Level and Sample
Size
% Contamination
Sample Size 0.1 1.0 5.0 10.0

10 0.01 0.09 0.40 0.66
20 0.02 0.18 0.65 0.89
50 0.05 0.34 0.92 0.99
100 0.09 0.63 0.99
300 0.26 0.95
and ultimately into finished dosage parenteral preparations primarily via wa-
ter systems. The presence of endotoxins in oral dosage forms is not consid-
ered to be a problem, because endotoxins do not pass from the intestinal tract
to the blood system.
Endotoxins are quite stable molecules. They can survive autoclaving and
can pass through sterilizing filters. Thus, a preparation may be sterile, but if
it was once exposed to Gram-negative bacteria, it may still contain endotox-
ins. Conversely, since endotoxins are unique components of Gram-negative
cell walls, a preparation may be nonsterile (i.e., contain numbers of viable
Gram-positive bacteria) but may be free of detectable endotoxins.
Official Test Methods for Pyrogens

Materials requiring a pyrogen test can be examined for the presence of bacte-
rial endotoxins by either of two official methods: the compendia! Pyrogen
Test (USP 1999d), or the Bacterial Endotoxins Test, also known as the LAL test
(FDA 1987a, 1991a; USP 1999a).
In the Pyrogen Test, a solution of the product under test is injected into
the marginal ear vein of each of three laboratory rabbits. The temperature of
each rabbit is monitored for a period of three hours, and the maximum rise
in temperature for each animal from the baseline is calculated. For an article
to be "pyrogen free," no individual rabbit may show a temperature rise of
0.5°C or more. If any rabbit demonstrates such a temperature rise, the test
may be continued on five more rabbits, for a total of eight animals. In this
case, not more than three of the eight rabbits may show a temperature rise of
0.5°C or more, and the total temperature rise for all eight rabbits may not ex-
ceed 3.3°C (USP 1999d). The USP Pyrogen Test was introduced with the pub-
lication of USP XII, and although it is not the current method of choice for
the testing of most substances, it is still included as a chapter in the USP as a
suitable method for those materials that are not amenable to the LAL test. The
USP Pyrogen Test (rabbit test) is also used as one of the tests in a toxicology
panel used for the screening of new active ingredients, excipients, and raw
materials.
The Bacterial Endotoxins Test is the preferred method for the detection
of endotoxins in water, APis, manufacturing intermediates, raw materials,
and finished drug products (McCullough 1988). LAL reagent, or Limulus ame-
bocyte lysate, is derived from the circulating blood cells of the North Ameri-
can horseshoe crab, Limulus polyphemus. In nature, and in vitro, the animal's
blood cells respond to the presence of endotoxin by forming a clot. In the
crab, this clotting mechanism is the basis of its immune system, protecting it
from infection by Gram-negative bacteria found in the sea environment. In
the laboratory, the clotting of the LAL reagent indicates the presence of en-
dotoxin in the preparation under test. Successful testing using LAL reagent re-
quires that the pH, divalent cation levels, and sodium level of the
product/lysate mixture be at optimal levels (Pearson 1985b; Cooper 1990).
The unit of measurement for bacterial endotoxins is known in the

United States as the "endotoxin unit" or EU. The EU is a measure of the bio-
logical activity of the endotoxin, not the weight of the endotoxin. Interna-
tionally, this unit of activity is referred to as the "international unit" or IU.
The equivalency of the EU and IU has been demonstrated, so for international
testing purposes, EU = IU (Poole et al. 1997).
Users may purchase gel clot reagents in different sensitivities depending
on the endotoxin specification for the product under test. Currently, the most
common gel clot reagents are labeled 0.125 EU/mL, 0.06 EU/mL, or
0.03 EU/mL, meaning that they will clot in the presence of at least
0.125 EU/mL, 0.06 EU/mL, or 0.03 EU/mL, respectively. Methods for the val-
idation and use of the gel clot test are described in the Bacterial Endotoxins
Test chapter in the USP and in the FDA's 1987 Guideline for Validation of the
Limulus Amebocyte Lysate Test as an End Product Endotoxin Test for Human and
Animal Parenteral Drugs, Biological Products and Medical Devices (FDA 1987a;
USP 1999a). Generally speaking, validation of the bacterial endotoxins test re-
quires that endotoxin be added to the material under test ("spiked"), and that
recovery of the added endotoxin be demonstrated. Both the FDA guideline
and the USP acknowledge that most materials interfere with the clotting of
the reagent. Although this interference is frequently related to pH, it may also
be affected by the presence or absence of suboptimum levels of divalent
cations, residual organic solvents, natural inhibitors, and heavy metals. APis
may display interference patterns with the LAL test that are different from the
interference patterns seen in the final drug formulation. In fact, many APis
will be more interfering when tested as a single chemical entity rather than as
a fraction of a larger formulation. Interference in the LAL test is most easily
and conveniently eliminated through dilution in water that has been shown
to be free of detectable endotoxin (Laboratory Reagent Water [LRW]). Of
course, dilution to relieve interference also dilutes any endotoxin that might
be present. The FDA has provided for the calculation of a maximum valid di-
lution factor (MVD), which depends on the endotoxin limit for the material,
the concentration of the material, and the sensitivity of the reagent or assay.
Dilution beyond the MVD is invalid.
Quantitation of endotoxin by LAL requires the continuous monitoring
of the change in color or turbidity of standards and samples over time. Stan-
dard curves are constructed in these kinetic chromogenic or kinetic turbidi-
metric tests by plotting the log of the time it takes for each of a set of standards
to reach a predetermined optical density (onset or reaction time) as a function
of the log of the endotoxin concentration. Endotoxin content in unknowns is
calculated by measuring the onset time for each specimen and interpolating
endotoxin content from the referenced standard curve. Quantitative LAL
methods are capable of detecting as little as 0.001 EU/mL. The FDA's 1991
supplement to the 1987 guideline, titled Kinetic LAL Testing: Interim Guidance
for Human Veterinary Drug Products and Biologicals, as well as lysate manufac-
turers' product inserts, which are legal documents, provide the user with a
guide specifically written for the validation and use of quantitative LAL test
methodologies (FDA 1991a).
Of the two tests (the rabbit pyrogen test or the LAL test), the LAL test is
the preferred method for the detection of endotoxin in APis, intermediates,
raw materials, water, and finished pharmaceutical dosage forms. Characteris-
tics of the LAL test that make it the pyrogen test method of choice over the
rabbit test include the following:
• The LAL test is specific for endotoxins, the primary pyrogenic con-
taminant in pharmaceutical preparations.
• The LAL test is considerably more sensitive and certainly more con-
sistent in the detection of endotoxin than the rabbit pyrogen test.
• Endotoxin levels in products under test can be quantitated using
LAL, which facilitates trend analyses to monitor the quality of any
process over time.
• LAL testing is less time and labor intensive than rabbit pyrogen
test, meaning that associated costs of LAL testing are lower than is
the USP rabbit pyrogen test.
Endotoxin Limits
The concept of the endotoxin limit defines a maximum allowable level of en-
dotoxin in the product. The endotoxin limit for a dose of a parenteral prod-
uct is 5 EU/kg (FDA 1987a; USP 1995a). This 5 EU/kg limit or the "threshold
pyrogenic dose" was determined experimentally in rabbits and defines a level
of endotoxin above which is likely to cause a fever (Tsuji et al. 1980; Dabbah
et al. 1980). Endotoxin levels below the threshold pyrogenic dose are clini-
cally insignificant, as they are too low to cause a fever in an animal. There is
no way to measure for the absence of endotoxin in a drug product; the sensi-
tivity of the test method provides a minimum detection level.
The endotoxin limit for any drug product and/or compendia! drug sub-
stance is dependent on the maximum human dose of the drug product or
substance, and is calculated using the formula,
K
M
where K = the threshold pyrogenic dose of 5 EU /kg, 0.2 EU /mL
for intrathecals, and M = the maximum human dose in units/kg.
Those substances with high dosages have relatively low endotoxin lim-
its; those substances with low dosages have relatively high endotoxin limits.
The FDA has calculated endotoxin limits for most compendia! drug products
and drug substances, and has listed these limits in the "Appendix E" to its
1987 Guideline (FDA 1987a). USP monographs for most parenteral drugs and
some APis also specify endotoxin limits.
Setting Endotoxin Limits for Noncompendial Articles

Some APis have their own monographs in the USP. For example, the mono-
graph for human insulin produced using recombinant DNA technology
specifically states that the insulin bulk may not contain more than 10 EU/mg
of material. The insulin finished product, Insulin Human Injection, has a dif-
ferent endotoxin limit-not more than 80 EU/100 units of insulin. For those
articles with established compendia! endotoxin limits, testing is rather
straightforward and should follow the FDA's 1987 Guideline and/or the 1991
Interim Guidance supplement (FDA 1987a; McCullough 1988; FDA 1991a).
Setting endotoxin limits for noncompendial articles can be elusive and
frustrating. If there is no monograph for the material, or if the endotoxin limit
for the material is not listed in Appendix E of the FDA Guideline, a logical limit
must be projected based on the manufacturer's knowledge of the intended use
of the material. The API manufacturer or user has two options in this case:
(1) Set limits based on the specific use of the material in the final formulation,
or (2) set general limits based on the most conservative usage that can be pro-
jected (McCullough 1988). For those substances that are in development, the
most conservative (i.e., highest) dose should be predicted by the product de-
velopment group or clinicians. Until a final dose is determined, this predicted
value should be used as M in the endotoxin limit formula (as already
discussed).
An API or other raw material vendor may wish to provide a CofA for ma-
terial that addresses the uses of the material and needs of its customers. This
approach, of course, is difficult as the supplier must either understand or an-
ticipate the specific uses of the material in any of a number of different man-
ufacturing environments. For example, a supplier of bulk magnesium sulfate
who wishes to certify this product for use in parenteral products may impose
an endotoxin limit on the material based on the limit for finished magnesium
sulfate for injection. In this case, the compendiallimit for the injectable prod-
uct is 0.09 EU /mg of magnesium sulfate.
Another approach is to provide the customer with a range of qualities of
material, with each grade of the product possessing certain certifiable charac-
teristics. To extend the magnesium sulfate example, one might imagine sell-
ing bulk magnesium sulfate in a grade that is not intended for use in the
production of parenteral products but rather may be used primarily for oral
dosage forms. In this case, the material would likely not be tested for endo-
toxin, would not purport to be pyrogen or endotoxin free, and would be la-
beled for "nonparenteral use only." Therefore, a manufacturer of APis, raw
materials, and excipients may choose to sell material certified against differ-
ent test specifications depending on the ultimate usage.
Dextrose is another example of an API used throughout the pharmaceu-
tical industry as a component of both sterile and nonsterile drug products.
Dextrose is a natural product that can be purchased in many grades, each
with its own set of chemical and biological characteristics. Food grade dex-
trose may be considered acceptable for oral dosage products. This material
might need to be tested for total microbial count and for the presence of ob-
jectionable microorganisms, but it does not need to be tested for endotoxin.
Recognizing that dextrose is a natural product that may contain some level of
endotoxin, customers for parenteral grade may have in-house specifications
that are passed on to the supplier requiring low bioburden and low endotoxin
in the lot of material to be purchased. Purchasers may ask for preshipment
samples to confirm the manufacturer's certification and assure themselves
that the lot of material to be shipped is acceptable for the intended purpose.
Endotoxin specifications for noncompendial articles may be set by the
user based on a "back calculation" from the endotoxin limit that has been es-
tablished for the final product (McCullough 1988). For example, assume a
mythical formulation consisting of four general components: an active ingre-
dient that is derived from recombinant technology, an organic stabilizer, and
a preservative, all in a buffer solvent. Each of these components is a potential
contributor of endotoxin to the final formulation: the active ingredient is a
product of a recombinant process and is considered a natural product; the sta-
bilizer may be extracted from a plant or animal source and is a natural prod-
uct; the preservatives are probably synthetics; the chemicals that are used in
the buffer solution are inorganics; and the water is a very important raw ma-
terial used in the production of this or any product. Since the active ingredi-
ent and stabilizer are derived from natural sources, they should each be
considered as a significant potential source of endotoxin, and should be given
a priority for validation and endotoxin testing. Microorganisms generally do
not grow in or on purified inorganic chemicals, and so the salts used in the
preparation of the buffer should be given a lower priority in the testing hier-
archy since these materials will likely contribute little or no endotoxin to the
final formulation. Water is a major raw material and must be monitored for
endotoxin levels, particularly if the water has been given the label of WFI or
other categories of water with established compendia! endotoxin limits.
The easiest way to assign endotoxin limits to the four fractions (active
ingredient, stabilizer, preservative, and buffer) is to take the limit for the final
formulation and divide it by four. Using this method, the amount of active
ingredient in 1 mL of the formulation could contribute up to 25 percent of
the total allowable endotoxin (endotoxin limit); the stabilizer could con-
tribute up to 25 percent; the preservative could contribute up to 25 percent;
and the chemicals used to prepare the buffer could contribute up to 25 per-
cent. If WFI is used in the formulation, its contribution should be less than
the compendia! 0.25 EU/mL limit. If water other than WFI is used, its poten-
tial contribution may be significant and needs to be taken into account. For
this example:
• The final formulation is allowed 4 EU /mL.
• Each component is allowed to contribute 25 percent of the allow-
able load, or 1 EU/mL.
Microbiological Attributes of Active Pharmaceuticallngredients 509
• Dividing the assigned limit by the concentration of the material

per milliliter of the final formulation results in a specification in
EU /unit of each component.
However, since both the active ingredient and stabilizer in the mythical
drug product are both derived from natural sources, and since the preserva-
tives and chemicals in the buffer are inorganic and not likely to contribute
significant amounts of endotoxin, the firm might decide to assign most of the
allowable endotoxin load to the two natural components. Based on historical
data, the firm might assign 40 percent of the endotoxin limit to each of the
two natural fractions, and divide the remaining 20 percent among the inor-
ganic fractions. For example:
• Formulation is allowed 4 EU/mL.

• The active and stabilizer portions of the formulation are each al-
lowed to contribute 40 percent or 1.6 EU /mL.
• Preservatives and inorganics are each allowed to contribute 10 per-
cent or 0.4 EU/mL.
• Dividing the assigned limit by the concentration of the material
per milliliter of the final formulation results in a specification in
EU/unit of each component.
Yet another way to look at the problem, particularly if the active ingre-
dient is produced in a Gram-negative host, is to assign virtually all of the en-
dotoxin load to the active ingredient, regardless of its concentration in the
final formulation, because it is the fraction that is most likely to contribute
endotoxin to the final product. There is no one "right way" to assign endo-
toxin limits to noncompendial materials. However, no matter which method
is ultimately chosen for the assignment of endotoxin limits to formulation
components, specifications and alert/action limits should be assigned based
on a solid logic stream, sound scientific principles, and where possible, on
historical data and the origin of the component in question.
Testing of AP/s for the Presence of Endotoxin

If a bulk API is to be used in the preparation of a sterile dosage form, and if
it is purported or labeled to be pyrogen free, it is the responsibility of the
manufacturer to certify via appropriate validation and testing that the lot of
material in question has indeed been screened for the presence of endotoxin,
and that the level of endotoxin meets the specified limit. In fact, suppliers of
APis will frequently provide customers with a CofA that reports endotoxin
levels in their products as a service. Supplying this CofA is frequently a posi-
tive marketing strategy for suppliers of raw materials, and may be a valuable
service to the customer as a certification of quality and, after a thorough ven-

dor audit and appropriate validation, a potential saving in time and money
required for the lab to routinely test incoming material.
As a general rule, all endotoxin testing for APis should follow the vali-
dation and testing requirements for final dosage forms that are outlined in
the 1987 LAL Guideline/1991 Kinetic Guidance (FDA 1987a, 1991a). This test-
ing package can be divided into three parts, all of which must be documented
by appropriate SOPs:
• Initial quality control of the test includes verification of the

reagent's label claim (lower limit of detection of the reagent), quali-
fication of any analysts that will be performing the test, and docu-
mentation of the standardization of the control standard endotoxin
(the secondary standard) against the reference standard endotoxin
(the primary standard) for each unique combination of endotoxin
lot and reagent lot in use in the lab.
• Validation of the test method with three lots of material assures
that the substance does not interfere with the LAL test.
• Methods for the routine testing of the material should include pro-
visions for benchmarking against an established endotoxin limit
for the material, and a provision for an investigation of the testing
and manufacturing process if the endotoxin detected in the mate-
rial exceeds the prescribed limit.
SUMMARY
For many years, the FDA has recognized the significance and importance of
stringent requirements for the manufacture of pharmaceutical dosage forms.
These requirements, or cGMPs, were originally designed to be applied to fin-
ished products only. In recent years, however, the FDA has stated frequently
the intention to extend these requirements to drug components, including
APis. This extension of the requirements is pushing the cGMP concepts fur-
ther back in the process, forcing API manufacturers to consider many of the
same current microbiological concerns involved with finished product pro-
cessing, holding, and distribution.
Many of these issues have applied for years in the sterile API area, espe-
cially with those for which no further sterilization processing is required.
These considerations, however, may be somewhat new to nonsterile API man-
ufacturers. Primary among these are the water systems used for API process-
ing. Since water is an integral part of most processes including the
formulation, processing solutions, and equipment washing, every effort
should be made to assure its continual microbiological quality. Likewise, the
quality of incoming materials should be assessed for their potential to add
microbiological contaminants to the process rather than assuming the process

will effectively deal with them. And finally, the overall API facility must be de-
signed, controlled, and qualified with many of the same features as finished
dosage forms in order to assure reliable, consistent microbiological quality of
the final drug substance.
API manufacturers must also consider the significance of endotoxin in
the final drug substance. If the intended drug product is a nonsterile formu-
lation, there is no reason for concern. If the final drug product is a parenteral,
however, the process must assure the absence of endotoxin below certain ac-
ceptable levels. Some nonparenteral sterile formulations may also require the
absence of endotoxin. Routine reliable manufacturing processes and controls
must be developed and validated to support end product testing for the ab-
sence of endotoxin.
GLOSSARY
Active Pharmaceutical Ingredient The active ingredient in the final dose
form product (Brocklebank and Deo 1996).
Aer~bicMicroorganism A microorganism capable of growing in the presence
of atmospheric oxygen (Prescott et al. 1993).
Airborne Particulate Cleanliness Class The level of cleanliness specified by
the maximum allowable number of particles per cubic meter (or cubic foot)
of air (Federal Standard 209E 1992).
Anaerobic Microorganism A microorganism capable of growing in the ab-
sence of atmospheric oxygen (Prescott et al. 1993).
Bacteriostatic A substance or environment capable of inhibiting the growth
and reproduction of bacteria (Prescott et al. 1993).
Barrier A device that prevents contact between operators and the aseptic
field enclosed within the barrier (Wagner 1995).
Bioburden A term used to describe the microbial content of a material, in-
cluding both the types and numbers of microorganisms present (Leahy 1986).
Biological Indicator (BI) A carrier containing a specific species of heat resis-
tant microorganism used to test the effectiveness of a sterilization process
(Leahy 1986).
Bubble Point Test A test to predict or verify the performance and integrity of
a filter (HIMA 1982).
CFU A colony forming unit is a macroscopically visible growth or cluster of
microorganisms on a solid medium (Prescott et al., 1993).
Compendia! Requirements Specific product monographs including specifica-

tions and test methods as described in the United States Pharmacopeia.
Containment The separation of the work area from the outside environment
to protect the people and the environment from potent or undesirable sub-
stances, or the execution of a process in a manner that prevents the discharge
of contamination to the outside environment (Wagner 1995).
Contamination Undesirable material (viable and nonviable particulates,

toxic or other undesirable substances) that are found in processed materials.
Contamination may come from raw materials, air, water, work surfaces, or hu-
man operators.
Controlled Areas Areas of a facility that are designed and maintained to min-
imize the amount of airborne particulates (Federal Standard 209E 1992).
Critical Areas Areas of a facility where sterile products or components come

in direct contact with the environment.
Differential Pressure The difference in pressure between the upstream and

downstream sides of the filter (HIMA 1982).
Distilland The material in a distillation apparatus that is to be distilled.
Distillation The process by which high purity water is manufactured, usually by

means of vapor compression in which feed water is heated in an evaporator to
boiling, and the vapor produced is separated and conveyed to a compressor that
raises the temperature to approximately 224°C. The vapor then condenses on
outer surfaces of distilland tubes and is drawn off as distillate (Gennaro 1985).
DOP Testing A method used to test the integrity of HEPA filters in a con-
trolled environment (FDA 1987b).
D Value The time (usually in minutes) at a given temperature needed tore-

duce the population of a challenge microorganism by 90 percent or one log
(Pflug 1980).
Endotoxins Pyrogenic, heat stable lipopolysaccharides found in the outer

membrane of the cell wall of Gram-negative bacteria (Prescott et al. 1993).
Endotoxin Unit A measure of the biological activity of an endotoxin.
F0 The actual time of sterilization in terms of its equivalence to 121 oc

(Pflug 1980).
Fungistasis A substance or environment capable of inhibiting the growth

and reproduction of fungi (Prescott et al. 1993).
HEPA Filter High efficiency particulate air filter, used to filter out at least
99.998 percent of the particles 0.3 JJ..m or larger from the air entering a clean
zone (Wagner 1995).
Isolator A barrier system that exchanges air with the outside environment
only through HEPA or equivalent filters, completely separating the process
from the operator of environment (Wagner 1995).
LAL Limulus Amebocyte Lysate, an extract from the circulating blood cells
of the North American horseshoe crab, Limulus polyphemus, used in the de-
tection of endotoxin in drug substances and drug products.
Laminar Airflow Airflow in which a whole body of air moves in the same di-
rection with uniform velocity in parallel flow lines (Wagner 1995).
Objectionable Microorganism Any microorganism that can cause infections
when the drug product is used as directed ("pathogenic") or any microorgan-
ism found in a sterile drug product. Sometimes, high numbers of less harm-
ful microorganisms may be considered as "objectionable" (FDA 1993).
Particulates Objects of solid or liquid composition, or both, generally be-
tween 0.001 J.Lm and 1000 J.Lm in size (Federal Standard 209E 1992).
Pretreatment Systems used to remove chlorine and other impurities from
source water prior to its introduction into a still, RO unit, or UF unit. Pre-
treatment systems usually consist of a carbon bed, sand filter, and bed of
mixed ionic material.
Pyrogens Any substance capable of causing a fever in a human or other
mammal.
Raw Material The starting materials used in the manufacture of an API.
Recombinant DNA Technology The techniques used in carrying out genetic
engineering (Prescott et al. 1993).
Reverse Osmosis A water treatment process in which the natural process of
selective permeation of molecules through a semipermeable membrane sepa-
rating two aqueous solutions of different concentrations is reversed. Pressure
is applied to overcome osmotic pressure and force pure water through the
membrane (Gennaro 1985).
Sterile The complete absence of viable microorganisms (Gennaro 1985;
Leahy 1986).
Sterilization A process by which all forms of viable microorganism, includ-
ing bacterial spores, are removed or destroyed based on a probability function
(Gennaro 1985; Wagner 1995).
Sterilizing Filter A filter which, when challenged with the microorganism

Pseudomonas diminuta at a minimum concentration of 107 microorganisms
per cm2 of filter surface will produce a sterile effluent (FDA 1987b).
Threshold Pyrogenic Dose A dose of endotoxin per kilogram of body weight
that is capable of the induction of a minimal, but unequivocal fever (Pearson
198Sa).
Ultrafiltration A process based on the sieving mechanism in which all com-

ponents smaller than the pore size of the filter membrane pass through it by
mean:s of either pressure applied to the solution side or by suction on the fil-
trate side (Gennaro 1985).
Validation The procedure substantiating to a high level of assurance that a
specific process will consistently produce a product conforming to an estab-
lished set of quality attributes (USP 24).
Z Value The number of degrees Celsius necessary to cause the D value to
change by a factor of 10 (Pflug 1980).
REFERENCES
Brocklebank, M.P. and P. V. Deo. 1996. GMP issues for bulk pharmaceutical chemical
plants. Pharm. Engin. Oanuary/February): 8-26.
Carroll, M. 1995. Microbiological monitoring and control in isolation systems. In Isola-
tion technology: Applications in the pharmaceutical and biotechnology industries, edited
by C. M. Wagner and J. E. Akers. Buffalo Grove, lll., USA: Interpharm Press, Inc.
Code of Federal Regulations. 1998. Title 21, parts 210 and 211. Current good manufac-
turing practices.
Cooper, James F. 1990. Resolving LAL testinterferences. f. Parent. Sd. Technol. 44(1):13-15.
Dabbah, R., E. Ferry, and D. A. Gunther. 1980. Pyrogenicity of E. coli 055:B5 endotoxin
by the USP rabbit test-a HIMA collaborative study. f. Parent. Drug Assoc. 34:212.
Federal Standard 209E. 1992. Airborne particulate cleanliness classes in cleanrooms and
clean zones. Washington, D.C.: General Services Administration.
FDA. 1987a. Guideline on validation of the limulus amebocyte lysate test as an end product
endotoxin test for human and animal parenteral drugs, biological products and medical
devices. Rockville, Md., USA: Food and Drug Administration.
FDA. 1987b. Guideline of sterile drug products produced by aseptic processing. Rockville,
Md., USA: Food and Drug Administration.
FDA. 1990. Compliance program guidance manual for bulk pharmaceutical chemicals.
Microbiologica/Attributes of Active Pharmaceutical Ingredients 515
FDA. 1991a. Kinetic LAL testing: interim guidance for human veterinary dmg products and
biologicals. Rockville, Md., USA: Food and Drug Administration.
FDA. 1991b. Guideline to the inspection of bulk pharmaceutical chemicals. Rockville, Md.,
FDA. 1993. Guide to inspections of high purity water systems. Rockville, Md., USA: Food
FDA. 1994. Guide to inspections of sterile dmg substance manufacturers. Rockville, Md.,
FDA. 1995. Human Dmg CGMP Notes 3(2):6.
FR. 1976. Current good manufacturing practice in the manufacture, processing, pack-
ing, or holding of large volume parenterals for human use. Federal Register 41
(1 June 1976), 212. 49.
Gennaro, A. R., ed. 1985. Remington's pharmaceutical sciences. Easton, Penn., USA: Mack
Publishing Co.
Greenberg, A. E., L. S. Clesceri, and A. B. Eaton, eds. 1992. Standard methods for the
examination of water and wastewater. Washington, D.C.: American Public Health
Association.
HIMA. 1982. Microbial evaluation of filters for sterilizing liquids, document #3, volume 4.
Washington, D.C.: Health Industry Manufacturers Association.
Hyde, W. A. 1998. Origin of bacteria in the clean room and their growth requirements.
PDA f. Pharm. Sci. Technol. 52(4):154-158.
ISO. 1998. ISO 13408-1, Aseptic processing of health care products-Part 1: General re-
quirements. Geneva, Switzerland: International Organization for Standardization.
Leahy, T. ]. 1986. Microbiology of sterilization processes. In Validation of aseptic phar-
maceutical processes, edited by F.]. Carlton and]. P. Agalloco. New York: Marcel
Dekker.
Marshall, V., S. Paulson-Cook, and]. Moldenhauer. 1998. Comparative mold and yeast
recovery analysis (the effect of differing incubation temperature ranges and
growth media). PDA J. Pharm. Sci. Technol. 52(4):165-169.
McCullough, K. Z. 1988. Process control: in process and raw material testing using
LAL. Pharm. Technol. 40.
Motise, P. ]. 1995. Human Dmg cGMP Notes, vol. 2, no. 3. Rockville, Md., USA: Food
Osumi, M., N. Yanada, and M. Toya. 1996. Bacterial retention mechanisms of mem-
brane filters. f. Parent. Sci. Technol. 50(1):30-34.
PDA. 1990. Technical Report# 13: Fundamentals of a microbiological environmental mon-
itoring program. Bethesda, Md., USA: Parenteral Drug Association, Inc.
Pearson, F. C. 1985a. Endotoxin. In Pyrogens: endotoxins, LAL testing, and depyrogena-
tion. New York: Marcel Dekker.
Pearson, F. C. 1985b. LAL assay. In Pyrogens: endotoxins, LAL testing, and depyrogenation.
New York: Marcel Dekker.
Pflug, I. j. 1980. Syllabus for an Introductory Course in the Microbiology and Engi-
neering of Sterilization Processes. St. Paul, Minn.: Environmental Sterilization Ser-
vices, p. 22.
PhRMA Quality Control Bulk Pharmaceuticals Work Group, Quality Steering Com-
mittee, PhRMA Science and Regulatory Section. 1995a. PhRMA guidelines for the
production, packing, repacking or holding of drug substances: part I. Pharm. Technol.
19(12):22-32.
PhRMA QC Section Bulk Pharmaceuticals Committee and Sterile Bulk Pharmaceutical
Chemicals Subcommittee, Sterile Bulk Pharmaceutical Chemicals. 1995c. A
PhRMA position paper. Pharm. Technol. 19(8):38-42.
PhRMA Quality Control Bulk Pharmaceuticals Work Group, Quality Steering Commit-
tee, PhRMA Science and Regulatory Section. 1995b. PhRMA guidelines for the pro-
duction, packing, repacking or holding of drug substances: part II. Pharm. Technol.
20 (1):50.
PhRMA Environmental Monitoring Work Group. 1997. Microbiological monitoring of
environmental conditions for nonsterile pharmaceutical manufacturing. Pharm.
Technol. 21(3):58.
Poole, S., P. Dawson, and R. G. Das. 1997. Second international standard for endo-
toxin: calibration in an international collaborative study. J. Endotoxin Res.
4:221-231.
Prescott, L. M.,j. P. Harley, and D. A. Klein. 1993. Microbiology, 2nd ed. Dubuque, Iowa:
Wm. C. Brown Publishers.
Schmitz, A. J., M. X. Cooper, T. E. Munson, and R. Dabbah. 1995. Microbiological test-
ing of nonsterile pharmaceutical articles-a review. Pharm. Forum 14(4):4163.
Shirtz, j. 1987. Sterility testing. Pharm. Engin. 7(6):35-37.
Shirtz, j. 1995. Isolation technology for sterility testing at Burroughs Wellcome Co.,
Greenville, NC. In Isolator technology, edited by C. M. Wagner and j. E. Akers. Buf-
falo Grove, Ill., USA: Interpharm Press, Inc.
Tsuji, K., A. Steindler, and S. Harrison. 1980. Limulus amebocyte assay for detection
and quantitation of endotoxin in a small volume parenteral product. Appl. Envi-
ron. Microbiol. 40:533.
United States Department of Health and Human Services (U.S. DHHS). 1998. Guidance
for industry: manufacturing, processing, or holding active pharmaceutical ingre-
dients. http://www.fda.gov/cder/guidance/index.htm.
United States Pharmacopeia! Convention, Inc. 1999a. The United States pharmacopeia
24. Chapter 85, Bacterial endotoxins test. Rockville, Md., USA: United States Phar-
macopeia! Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999b. The United States pharma-
copeia 24, Chapter 71, Sterility Tests. Rockville, Md., USA: United States Pharma-
copeia! Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999c. The United States pharmacopeia
24, Chapter 1231, Water for pharmaceutical purposes. Rockville, Md., USA: United
States Pharmacopeia! Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999d. The United States pharma-
copeia 24, Chapter 85, Pyrogen test. Rockville, Md., USA: United States Pharma-
United States Pharmacopeia! Convention, Inc. 1999e. The United States pharmacopeia
24, Chapter 61, Microbial limits test. Rockville, Md., USA: United States Pharma-
United States Pharmacopeia! Convention, Inc. 1999f. The United States pharmacopeia
24, Chapter < 1111 >, Microbiological attributes of nonsterile pharmaceutical
products. Rockville, Md., USA: United States Pharmacopeia} Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999g. The United States pharmacopeia
24, Chapter <1078>, Good manufacturing practices for bulk pharmaceutical ex-
cipients. Rockville, Md., USA: United States Pharmacopeia! Convention, Inc.
United States Pharmacopeia! Convention, Inc. 1999h. The United States pharma-
copeia 23, Chapter <1116>, Microbiological evaluation of clean rooms and other
controlled environments. Rockville, Md., USA: United States Pharmacopeia! Con-
vention, Inc.
Wagner, C. M., and J. E. Akers (eds). 1995. Isolator technology. Buffalo Grove, Ill., USA:
lnterpharm Press, Inc.
Weitnauer, A. C., and L. F. Comb. 1996. Reverse osmosis: two-pass RO for
pharmaceutical-grade purified water. Ultrapure Water. (March): 42-45.
Wood, R. T. 1995. Points to consider in the use of sterility testing isolators. In Isolator
technology, edited by C. M. Wagner and j. E. Akers. Buffalo Grove, Ill., USA: Inter-
pharm Press, Inc.
19
EXCIPIENTS: FACILITY,
EQUIPMENT, AND
PROCESSING CHANGES
Irwin Silverstein
International Specialty Products
Wayne, New Jersey
The term process change is used here to reflect changes made in facility,
equipment, or processing. (Note that terms appearing in bold are defined in
the glossary.) Change as it relates to the facility includes new locations or im-
provements to existing locations, while equipment change encompasses all
production hardware, such as vessels, agitators, and instrumentation. The
term processing covers all operating steps and parameters, set points, on-line
and off-line process controls, raw materials, and testing.
The issue of process change has significant importance to the customer,
whether or not the product is used in a pharmaceutical application. Manufac-
turers often claim that changes made in the facility, equipment, process, ma-
terials, or even test methods have resulted in a product that is "improved,"
even if the improvement is a reduction in manufacturing cost. However, expe-
rience has shown that such "improvements" or changes can have a deleterious
impact on product performance. This impact, in the pharmaceutical industry,
can range from subtle changes (e.g., a shortening of shelf life) to the dramatic
(e.g., the failure of a dosage form mixture to process properly or have the in-
tended therapeutic effect). Either effect can lead to a product recall.
The U.S. Food and Drug Administration (FDA) requires validation of the
facility, equipment, and process so that the impact of any such change will
not alter the consistency of the products supplied to the pharmaceutical
519
industry. The pharmaceutical customer seeks to protect the regulatory status

of its products by expecting advance notification of process change from their
suppliers so that the impact to the dosage form of a change in an ingredient
can be evaluated.
The manufacturers of active pharmaceutical ingredients (APis) and
bulk pharmaceutical excipients (BPEs) are often members of the chemical
industry. BPE manufacturers in particular typically derive far more sales rev-
enue from customers using these same chemicals in applications other than
pharmaceuticals. The chemical industry is pressured by intense competition
and regulatory oversight, which leads to efforts to reduce cost, improve prod-
uct quality, reduce by-products and pollution, increase product yield, and so
on Guran and Gryna 1988). Achieving these ends almost always results in
some form of process change.
Therefore, process change drives conflicting forces within the chemical
process industry. There is the manufacturer's need to stay competitive by ap-
plying the principle of continuous improvement to the quality of the product
and its cost. However, revalidation, as well as advance notification to and ap-
proval by the pharmaceutical customer, impedes these efforts. Thus, it is im-
portant to delineate those changes to facility, equipment, and processing that
are significant and thus require validation and communication to the cus-
tomer from those changes that do not.
The FDA has come to recognize that there are significant differences be-
tween manufacturing a bulk pharmaceutical and the finished dosage form
(The Gold Sheet 1995). The FDA has issued a series of guidance documents ti-
tled Scale-Up and Postapproval Changes (SUPAC) for dosage form manufac-
ture (drug product) and Bulk Active Chemical Postapproval Changes
(BACPAC) for the active ingredient (drug substance). These guidance docu-
ments suggest different evaluation criteria for process change in drug sub-
stance and drug product manufacture. From this it is apparent that the FDA
views the issue of process change differently for the dosage form manufacturer
and the bulk supplier. Any change in the facility, equipment, or processing by
the dosage form manufacturer not only requires validation but also often re-
quires prior approval by the FDA and also requires the updating of the docu-
ments supplied to the FDA in support of the drug application. Bulk suppliers,
however, must not only update their Drug Master File (DMF) but also con-
sider notification of their customers.
The FDA recently submitted for comment a draft guidance Changes to an
Approved NDA or ANDA (FDA 1999) that mandates notification to them for
just about all changes to the drug product and its components. This guidance
would mandate notification for virtually all postapproval changes to the API
and BPE, their components, composition, manufacturing sites, process, speci-
fication, packaging, and labeling. Even changes to specification made to
continue conformance to a revised U.S. Pharmacopeia (USP) monograph
would require FDA notification. Unless the change is considered minor,
FDA approval would often be necessary before such change is effected. The
Excipients: Facility, Equipment, and Processing Changes 521
ramifications of such a regulatory change are now being considered and a fi-
nal guidance is not expected for some time.
The FDA has proposed revisions to the Current Good Manufacturing
Practice 21 CFR Parts 210 and 211 (FDA 1996) that include the requirement
for a "quality assurance system" for change. The system would ensure revali-
dation whenever a change is made that might affect the safety or efficacy of
the dosage form. The quality control unit would have responsibility for "re-
viewing changes in product, process, equipment, or personnel, and for deter-
mining if and when revalidation is required." The quality unit would thus
implement the proposed FDA guidance (FDA 1999).
The FDA has specified that the bulk manufacturer should notify them
when a process change is "significant" and there is a DMF for the product.
Otherwise, companies holding DMFs are only required to provide an annual
update to reflect changes. However, in its guideline (FDA 1989) the FDA does
not attempt to define process change, let alone "significant," or to indicate
the need for updates beyond the statement to notify affected applicants of
pertinent changes (FDA 1989). In its draft guidance, BACPAC I (FDA 1998),
the FDA has proposed criteria for evaluating the significance of changes in the
manufacture of API intermediates. The International Pharmaceutical Excipi-
ents Council-Americas has prepared a guidance (IPEC-Americas 2000) for the
evaluation of change in BPE manufacture.
The FDA attempts to define changes in the manufacture of the dosage
form that require revalidation (FDA 1987). It states in the Guideline on General
Prindples of Process Validation that revalidation is required whenever a process
change "could impact on product effectiveness or product characteristics, and
whenever there are changes in product characteristics" (FDA 1987). The FDA
also specifies revalidation whenever there are adverse differences in raw mate-
rial characteristics. The document goes on to state that "tests and methods of
analysis which are capable of measuring characteristics" should be used to de-
termine "whether a process is slipping out of control" (FDA 1987).
The FDA also discusses the issue of change in its Guidance for Industry:
Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients (FDA
March 1998) in the section titled Change Control/Revalidation. This guidance
recommends that the manufacturer evaluate the impact of the change on the
chemical and physical properties of the API such as the chemical purity, im-
purity profile, and physical characteristics such as particle size and density,
moisture content, and susceptibility to microbial contamination. It further
suggests that the manufacturer classify the potential impact of the change on
the API as major or minor. A major change has a likely impact on the above
noted API attributes, whereas a minor change is unlikely to affect an attribute.
It is apparent that the FDA has been actively addressing the issue of
change in recent years. It is also evident that the guidance from the FDA in
this matter is addressed to API manufacture but is less appropriate to the ex-
cipient. Therefore, the IPEC guide (IPEC-Americas 2000) will be used to dis-
cuss the matter of process change in this chapter.
It would seem as though the FDA is allowing the manufacturer to assess

the effect of process changes on the consistency of process performance as
well its impact on the product. The International Pharmaceutical Excipients
Council in its Good Manufacturing Practice (GMP) guide for the manufacture
of BPEs (IPEC 1995) provides guidance on identifying significant processing
steps. These are divided into two types; steps involving energy transfer or
steps wherein the molecule undergoes a chemical change. The IPEC guide
notes that these steps are exemplified by phase changes, phase separation,
and changes that result from milling, agglomeration, or blending in the en-
ergy transfer category. Chemical changes involve steps such as pH adjust-
ment, hydration or dehydration of the molecule, salt formation, and
operations involving precision addition measurement of such items as excip-
ient components. The evaluation of process change, especially of significant
processing steps, to determine the need for revalidation is discussed under
"Identification of Significant Processing Change."
The FDA in their BACPAC I draft (FDA 1998) proposes that changes in
the impurity profile and physical properties are the two major characteris-
tics of the drug substance intermediate that should be evaluated. The results
of this evaluation are used to determine the need for notifying the FDA of the
change. IPEC-Americas (IPEC-Americas 2000) has proposed a broader evalua-
tion of BPE manufacturing changes. The rationale for the additional IPEC cri-
teria is the realization that the BPE typically is used in far more dosage forms
and formulations than is the API.
The drug product manufacturer may complete its evaluation of a process
change and find no basis for revalidation, thus the matter is closed. By con-
trast, for the bulk manufacturer there is still the matter of whether the change
is significant enough to justify advance customer notification and approval.
Guidance as to when a change requires customer notification will be de-
scribed in "Identification of Significant Processing Change."
Evaluation of the impact of a change in a BPE must address not only the
issue of conformance to the product specification but also of product perfor-
mance in every application. In assessing product performance, the bulk man-
ufacturer should consider the impact of all combinations of the bulk product
with the other chemicals with which it is combined to formulate every drug.
Clearly, the matter of product performance assessment is an almost impossi-
ble task without the assistance of the customer. Therefore, customer notifica-
tion is beneficial in assuring that significant changes do not adversely impact
product performance.
A personal survey of requests for notification of process change from 92
customers, regardless of their industry, is shown in Figure 19.1. This survey
found that changes to the production process were mentioned by 80 percent
of the customers as requiring their being informed. Almost SO percent of the
customers referred to a new site, and about 40 percent mentioned changes to
the specification or raw material supplier as examples where their notification
is needed. Customers referred to formulation changes 25 percent of the time,
Figure 19.1 Process Change Notification Requests: Analysis

Percent using Definition
100,--------------------------------------------------,
70
60
50
40
30
20
10
0
Process Site Raw Material Specification Formulation Unspecified tabei/Pkg
Definition
and packaging or labeling changes were mentioned by 10 percent. Of the cus-

tomers in the survey, only 15 percent did not define what they meant by a
process change.
It must be noted that an overly restrictive definition of process change
runs counter to the manner in which the chemical industry operates. The
Chemical Manufacturers Association Responsible Care code requires member
companies to improve processes so as to minimize emissions, pollution, and
waste. The philosophy of quality management as espoused by W. Edwards
Deming, Joseph Juran, and others instructs companies to continuously im-
prove manufacturing processes by improving process control. This is often ac-
complished through the application of such tools as statistical process
control (SPC), design of experiments Ouran and Gryna 1988), and improved
test methods.
The American Society for Quality (ASQ), Chemical and Process Indus-
tries Division, recognizes the importance of customer notification of
process change, especially as it relates to the potential impact on the cus-
tomer's product (ASQ 1996). The ASQ proposes that change notification
not inhibit continuous process improvement and should not be made
without adequate customer notification. Sufficient inventories of
prechange material should be available to allow adequate time for customer
approval.
APis are most often manufactured in a batch or semicontinuous process,

since they are often made on a scale too small to justify continuous process-
ing. In a batch process, the product is made from a discrete supply of raw ma-
terials present at the start of the reaction. In a semicontinuous process, some
raw material is added during the reaction. In either process, batch or semi-
continuous, no product is removed, so that at the completion of the reaction,
the vessel contains all product manufactured. Batch processing results in
product made from readily identified and traceable raw materials, and the
product usually has good uniformity throughout.
The manufacture of a BPE often involves continuous processing. A con-
tinuous process is one in which material, raw and/or in-process, is acided con-
tinually while finished product is removed for further processing or is
collected for packaging. A continuous process may involve manufacture in a
continuous reactor, where unique identification or traceability of raw materi-
als is not feasible. Continuous processing can involve a batch reaction, where
the identification of ~he reactants is clearly known but where further process-
ing, such as purification or drying, is done in a continuous fashion. The BPE
is often manufactured on a scale sufficiently large to justify continuous pro-
cessing, often because of their other nonpharmaceutical applications. When
continuous processing is utilized, uniformity of the finished material is gener-
ally not as good as for batch processing.
For either bulk material, API or BPE manufacture involves chemical syn-
thesis, isolation, and/or purification. However, the issues of process change
for batch versus continuous processing, as discussed in the equipment sec-
tion, are different due to the consistency of the product within each desig-
nated lot.
Manufacture of API and BPE products often involves several synthesis
steps. The FDA has established that GMP concepts apply from the point at
which the end product is synthesized or where a series of processing steps
leads to the drug substance (FDA 1994). Thus, the issue of process change and
validation clearly applies from this point in the process forward. However,
changes earlier in the process stream can have an impact on the final product.
Changes in the manufacture of a raw material, the storage conditions of a re-
actant, or processing conditions prior to the step where GMP applies, would
not necessitate validation. Since the intent of the GMP regulation is for such
changes to be assessed for their potential to alter product performance, the
prudent manufacturer also evaluates such changes.
IDENTIFICATION OF SIGNIFICANT PROCESS CHANGE

The preparation of a process validation protocol requires the identification
of the critical operating parameters. A critical operating parameter is one
that can impact a product quality attribute, either a specification parameter or
performance characteristic. The FDA requires validation as to the suitability of

the allowable ranges for these critical operating parameters. However, there is
no need for the validation of the other operating parameters. Therefore,
changes to critical operating parameters must always be evaluated to deter-
mine whether they result in a significant processing change.
A significant process change is defined as any change that alters a
product's physical or chemical property or that is likely to alter the product
performance in the dosage form. The FDA has proposed a guidance (FDA
1998) useful for evaluating changes in the manufacture of drug substance in-
termediates; that is the drug substance just prior to the final purification or
significant processing step. This draft guidance suggests that the manufac-
turer determine the equivalence of the intermediate's impurity profile and
physical properties before and after the processing change. Criteria for this
purpose are recommended in the proposed FDA guidance.
IPEC has suggested classifying the risk that the change to the BPE will im-
pact its use in the dosage form (IPEC-Americas 2000). When the risk of affect-
ing the dosage form is sufficient, the guidance suggests comparing the product
made before and after the change for the effect on the impurity profile and
physical property, as does the FDA guidance, but goes further to include chem-
ical properties, moisture content, microbial content, and functionality.
It is useful to apply statistical principles as objective criteria for the de-
termination as to whether or not there has been a significant change to a crit-
ical parameter, specification, or performance, such as results from a change in
raw materials, processing, or sampling plan and its impact on the product.
The comparison of the processing variation before and after the change is use-
ful for identifying when a significant change has occurred. SPC, which is
widely used in the chemical industry to monitor process performance, is the
preferred tool for this purpose.
SPC is the application of statistical graphical techniques for monitoring
process variation. In the application of this technique, the process data are
plotted versus time. If the points show a nonrandom pattern, it indicates a
process requiring the investigation and elimination of the cause for the lack
of randomness. This will return the process to a state where it behaves in a
consistent, predictable manner. A process operating with predictable varia-
tion will have charted points falling within the upper control limit (UCL) and
lower control limit (LCL). A useful approximation for these control limits is
±3 standard deviations about the process average.
A control chart using the process capability solution pH data is shown in
Figure 19.2. The chart plots the individual data points along with the average
line, the UCL, and the LCL. This chart clearly shows the process capability
and process average as the conditions were changed. The original capability
has been improved after the first process change at lot 125, as shown by the
width of the control limits; however, the average has dropped noticeably. The
impact of the last change was to bring the pH back to the original level and to
further narrow the control limits.
Figure 19.2 Solution pH control chart, December to June, 1995
pH
5.6
5.4
5.2
5
4.8
4.6
4.2
Lot Number
pH UCL LCL Avg

.
By using SPC charts, it is also possible to evaluate a change in raw mate-

rial source or quality or in equipment operation or processing to see if the
mean or variation is statistically different. Again, if there is no statistical dif-
ference in these measures, the change is not significant.
Another useful statistical technique is the process capability study,
which evaluates the relationship of the process output variation and its cen-
tering relative to the performance specification or expectation. The process
performance expectation is represented by the variation and centering
demonstrated by the process prior to the change.
Process capability is illustrated by presenting the processing parameter
or production output data, such as the pH of in-process material or lot analy-
ses of finished product, in a histogram format. The pattern of the histograms
for the process variables typically approximates a bell-shaped curve, often re-
ferred to as a normal curve, if the process variation is due to random causes.
The normal curve is overlaid onto the histogram along with the average line
and lines representing the ±3 standard deviations of the measurements. Fig-
ure 19.3 shows a process capability diagram.
In comparing the process capability of two processes, the first step is
to show that the process demonstrates normal or random variation. Then
histograms of the parameter or measurement can be prepared reflecting the
Figure 19.3 Solution pH process capability before process change, February, 1995
Frequency
Average
Upper Spec Limit
Normal
Curve
0
4.5 4.6 4. 7 4.8 4.9 5.0 5.1 5.2 5.3 5.4 5.5
pH
variation before and after the change. Finally, the average and standard devi-
ations of each process are determined. Figure 19.3 shows the process capabil-
ity for solution pH prior to a process change. The normal curve, also called
the Gaussian distribution, illustrates good process capability since it falls en-
tirely within the lower and upper specification or process limits.
Figure 19.4 is a process capability histogram after the process was
changed. Examination of the graph shows the normal curve is narrower than
before and continues to fall within the specification limits. However, the
process average has shifted downward from a pH of 5.0 to 4.8, so that it is no
longer centered within the limits. Therefore, this change appears to be signif-
icant, and validation is needed along with customer notification.
The effect of the final process change is illustrated in Figure 19.5. The
process is again centered at a pH of 5.0, and the normal curve falls comfort-
ably within the specification limits. Since the distribution is narrower than it
was for the original process, the only effect on the solution pH is a reduction
in its variation. Such a change is considered not significant, and neither vali-
dation nor customer notification is indicated.
In the series of changes reflected in Figures 19.3-19.5, visual examina-
tion was sufficient to determine objectively when the change was significant.
An even more objective evaluation can be made using statistical techniques.
The confidence level needed for this determination should be at least 95 per-
cent. Conducting at-test of the means using Student t distribution allows the
Figure 19.4 Solution pH process capability after process change, February, 1995
Frequency
1 Average
Upper Spec Limit
4~5 4.6 4.7 4.8 4.9 5.0 5.1 5.2 5.3 5.4 5.5
test of the null hypothesis that the averages are statistically different. Per-
forming an analysis of variance (ANOVA) of the distributions for the two
process results will identify whether the process variation is statistically sig-
nificant. If either statistical test for a critical characteristic or operating para-
meter indicates a statistically significant difference, there has been a
significant process change. As discussed, a reduction in variation requires no
validation. Computer software simplifies this evaluation. Quality Progress, the
magazine of the ASQ, prints a listing of statistical software each year in the
March issue.
While the use of statistical techniques provides an objective method for
evaluating process consistency and change, it has one serious shortcoming:
the analysis relies on production data alone to determine significance. As
noted, the FDA requires evaluation of the impact on the physical properties
and impurity profile (FDA 1998), whereas IPEC suggests considering the im-
pact of the change on the excipient chemical and physical properties, impu-
rity profile, moisture level, microbial contamination, and performance, as
reflected in functionality testing (IPEC-Americas 2000).
IPEC recommends measuring the effect of the change on the chemical
and physical properties that are specified for the product. The evaluation
Exdpients: Facility, Equipment, and Processing Changes 529
Figure 19.5 Solution pH process capability after process is centered, June, 1995
Frequency
10 Average
Lower Spec Upper Spec
8 Limit Limit
6
Normal
Curve
4
4.5 4.6 4.7 4.8 4.9 5.0 5.1 5.2 5.3 5.4 5.5
pH
should also take into consideration unspecified properties that may be altered
by the process changes such as the particle shape, surface area, or bulk density
of powders or the pH and viscosity of liquid products. The molecular distribu-
tion of polymer products should also be considered.
Both the FDA and IPEC require comparing the impurity profiles before
and after the process change to identify if there are significant differences in
the presence or level of impurities as a consequence of the process change.
IPEC goes further to suggest that the moisture levels should be examined,
since moisture is ubiquitous and often has an effect on the performance of
the product. Microbial contamination or susceptibility can be altered by
process change, and IPEC recommends that challenge testing of the product
after the process change be considered. Finally, the performance of an excipi-
ent can be affected by the process change. Therefore, it is recommended by
IPEC that the excipient be tested in model formulations to determine the im-
pact of the process change.
Since much work is required to thoroughly evaluate a process change,
the IPEC significant change guide (IPEC-Americas 2000) suggests risk levels
for consideration. A level 1 change reflects a minor risk that the new process
will result in a significant change in the excipient. As a result, the guide only
calls for the manufacturer to document the change and update the DMF, if
there is one, at the annual update, but customer notification is necessary.
A level 2 change might have a significant impact on the BPE perfor-
mance or properties. The manufacturer should evaluate the impact of the
change on the chemical and physical properties of the product as well as on
the impurity profile. If there are any changes in the postchange product, then
the manufacturer should notify the customers. However, preapproval of the
process change is not required.
Level 3 changes are always significant. Customers should always be in-
formed of the change as early as possible so that they can begin evaluating the
potential impact on their use of the ingredient. The manufacturer should
plan to build inventory of the prechange product since the customer will
probably need to evaluate the postchange product in its formulation.
The IPEC guide discusses the level of change that results from changes in
the site or scale of manufacture, equipment, process, packaging, and specifi-
cations. There are many examples used to help clarify the decision-making
process in reaching a determination of the level of change.
It is recommended that objective data be used wherever possible to mea-
sure the impact of a process change. The tests performed should provide vari-
able results and not attributes. The preferred data is that derived at the
production unit, but the batches should not be released until the statistics
have demonstrated that the change is not significant. Usually this will in-
volve making three production-scale batches using the changed process. At
least a comparable number of batches made prior to the process change
should be used for comparison.
The manufacturer must decide whether to keep the three production
batches under evaluation in quarantine or to release the lots upon quality
control approval. Holding the lots in quarantine is practical when demand for
the product is high and batches are made frequently. However, many API and
some BPE products are manufactured infrequently. Even so, the prudent man-
ufacturer will make every effort to manufacture three batches for evaluation
even though it means raising inventory levels and associated costs. When this
approach is not feasible, the only option left is to rely on the evaluation of
small-scale production or scientific judgment in considering the significance
of the change.
An alternative is to evaluate the change in a pilot unit that has a demon-
strable correlation to the production unit. If the statistical evaluation of pilot
scale data shows no statistical change, then full-scale production can proceed
without revalidation. However, the prudent manufacturer will confirm the
lack of impact on the product through statistical techniques.
Another approach is to rely on an understanding of the process chemistry
for evaluating the likelihood of a significant process change. A technical report
should document the reason why no significant impact on the product is an-
ticipated. Again, the judicious manufacturer will confirm this expectation.
The decision tree is a useful quality tool for visualizing the relationship be-
tween process change and validation. A decision tree developed by IPEC (IPEC-
Americas 2000) is shown in Figure 19.6. The major categories of change-site,
scale, equipment, process, packaging, and specification-are arrayed across the
top. Decision points are illustrated with a diamond shape. The response to the
question contained therein is used to determine the risk level of the change.
Processing change is divided into major change categories of process,
equipment, and specification. Changes in process control can be evaluated us-
ing the six criteria of IPEC (IPEC-Americas 2000) to compare the product
equivalency or by using statistical comparison of the process output to demon-
strate equivalence. If equivalent, validation would not be necessary. Equip-
ment changes are either replacement in kind or their impact should be
determined using the IPEC change criteria. Specification changes such as a raw
material from a new source or an improved test method should be evaluated
for their impact on the product. If a new raw material is to be used, a signifi-
cant change must have occurred because the process chemistry is now differ-
ent. If a revised specification or improved test method results in a product of
different quality, then the change to the product will be reflected in the pres-
ence of either new impurities or existing impurities at a new concentration.
FACILITY
Relocating production from one site to another, either in the same plant or to
another one, would seem to be an obvious example of a process change re-
quiring process validation and customer notification. Validation is required
because the new manufacturing location will probably use different equip-
ment, at least some different raw material sources, and different personnel.
The FDA suggests (FDA 1998) that site changes probably won't alter the API
intermediate since it will be purified to produce the drug substance. There-
fore, it suggests that installation qualification (IQ) and operational qualifi-
cation (OQ) be performed along with a comparison of the impurity profile
and physical properties. For excipient site changes, IPEC suggests (IPEC-Amer-
icas 2000) that a new site of manufacture will likely affect the BPE and thus it
is a level 3 change.
It is possible to use the same raw material sources as at the other site if
they are delivered to the site via rail or road, but any materials delivered by
pipeline will likely be from a new source. Clearly, process water falls into the
latter category, as do industrial gases. The IPEC-Americas guide (IPEC-Ameri-
cas 2000) classifies material changes as level 2 unless the new raw material is
bought to the same specification and is produced by the same manufacturing
process, wherein it is a level 1 change. The change in raw material source to a
new facility, even using the identical process, indicates the need for validation
and customer notification.
Figure 19.6 Quality Tool Decision Tree (page 1)
~
N
-~
~
......
a·
::J
0
.......
~
Manufacture Quality Control Intermediate Excipient
!:::!".
or Packaging Lab Spec Spec 05
Yes ~
Q.l
~
3
Q.l
8c:::
......
£"
..,
No ~
-
~
c-L~e12) Materials Equipment Manufacturing Q..
Process Yes (ii•
::J
Gb (ij
~·~
~No Yes
Figure 19.6 Quality Tool Decision Tree (page 2)
-o·(b"~
Materials Manufacturing
Process
;::,
1i!
Supplier Type Specification Process Process Steps Reprocessing ~
C")
Control
:::.:
'St
~
~-
•
Yes (!)
No ;::,
~ ( Level1 )
Scale
.:->
§
Q..
~
0
Level3
~
~)eves (J)
(J)
~-
9
~No Q)
;::,
Yes ~
(J)
"'
(Levell)
U1
w
w
It is not unusual in the chemical industry to rationalize production by

relocating the manufacture of a product to a more appropriate site. As noted
above, this would indicate the need for validation and notification to the cus-
tomer. However, it is also possible for the manufacturer to relocate production
back to a facility once used to produce the chemical. If the transfer back to the
original facility occurs within a short time frame, the process validation for
that facility could still be applicable and IPEC considers this a level 1 change
(IPEC-Americas 2000). If revalidation is not needed, customer notification is
probably not either.
Revalidation would probably be needed when a key raw material, one
that is known to affect product quality attributes, is now being purchased at
the new site with quality attributes statistically different as described earlier.
This validation is also needed when the original equipment has been signifi-
cantly altered so that the expected impact on the processing is a product
whose quality attributes differ statistically. These issues can only be ade-
quately evaluated by the manufacturer for their impact on the product. If
manufacturing equipment, raw materials, or processing changes indicate the
need for revalidation because of the site change, then customer notification
and approval are indicated.
While it is not a difficult task to notify the customers, their requirement for
prior approval could delay start-up of the new facility. The manufacturer would
have to validate the new site and make product for sampling to the customers
for their evaluation and approval. In the meantime, the facility could not pro-
duce product until customer approval is received. Under these circumstances, it
is important that the customer evaluation be completed expeditiously.
The approval of a process change by the customer can require consider-
able effort. The customer must demonstrate that the finished dosage form
continues to conform to the design presented in the New Drug Application
(NDA). It may be possible to complete this evaluation in a short period of
time, perhaps three months. However, the process change can have an impact
on the stability of the dosage form and thus the product's shelf life. Testing to
show that the change does not affect the dosage form stability can take many
months, especially if the product has a long shelf life. If customers require dif-
fering intervals to complete their approval process, a manufacturer can be
forced to produce the product at uneconomically low rates until all approvals
are received.
EQUIPMENT
Changes to the equipment involve modification or replacement of the pro-
duction or test equipment and control devices. Production equipment in-
cludes items such as reactors, agitators, and pumps, whereas control devices
are exemplified by thermostats, manostats, and automatic controllers. Test

equipment consists of the devices that indicate the operating conditions,
such as thermocouples, pH probes, and charge meters, as well as on-line ana-
lyzers. The Quality Control Bulk Pharmaceutical GMP Task Force of the Phar-
maceutical Research and Manufacturers of America (PhRMA) merely states
that the manufacturer must ensure any equipment modifications or repairs
return the equipment to a qualified state (Lazar 1995). Demonstration that
the equipment meets this condition is done by a statistical comparison of the
product variation observed before the repair was made with the product vari-
ation after the repair. PhRMA makes no mention of the need for revalidation
or notification of customers concerning such equipment changes.
The FDA treats equipment used in the manufacture of a drug substance
intermediate that is replaced with new equipment "not significantly different
from that previously used with no modifications to process parameters" (FDA
1998, p. 11) as routine and thus requiring only IQ and OQ. IPEC treats this as
a level 1 change (IPEC-Americas 2000). Both organizations consider the use of
otherwise different equipment as significant and requiring careful evaluation
of the impact on the drug product.
The normal operation of chemical manufacturing equipment makes it
susceptible to two types of change. There is normal wear and tear of mechan-
ical components as well as the deterioration of the chemical components,
such as catalysts. Each type of degradation can be responsible for gradual
changes in the finished product.
Changes to the equipment can either be progressive or sudden. Exam-
ples of progressive change are the gradual enlarging of the orifice of a spray
dryer nozzle or the blinding of the filter media in filtration equipment.
The consequence of the gradual widening of the spray dryer nozzle is a
heavier product stream entering the dryer section. This can result in a product
with a higher residual moisture level or alteration of the particle size distribu-
tion and give rise to a change in the physical characteristics of the product
that can lead to a change in performance. It may not be feasible to validate
the process over the entire range of subtle changes, such as orifice dimension,
especially if the orifice widening occurs over many weeks or months. This is
especially true if the equipment is part of a continuous process where the sub-
tle change in equipment variation is difficult to isolate from the variation
arising in raw materials and processing conditions.
The blinding of a filter occurs when particulate clogs the filter media.
This often results in an increase in the back pressure on the filter. As this back
pressure increases, it is possible that some of the material clogging the filter
can be blown into the filtered material. This can result in a product of varying
particulate composition. It is possible that this particulate can impact the
functionality of the bulk drug. The level of particulate can vary from lot to lot
due to the variation in porosity of different filters, or due to variation in filter
manufacture. Porosity of the filter media is dependent on the porosity of the
component used to make the filter, such as the fabric. It is unlikely for the
bulk pharmaceutical manufacturer to validate the variation of filter porosity,
but filtration performance should be monitored for conformance to process-
ing requirements.
Mechanical changes can also be sudden in nature, such as the collapsing
of the plates in a distillation column or the failure of a reactor seal. The col-
lapse of the plates in a column reduces the number of theoretical plates and,
thus, the efficiency of the separation during distillation. This can result in a
change in the purity profile of the distillate. As the purity profile changes, the
manufacturer will often adjust distillation conditions to maintain the desired
purity profile. This is sometimes done without even knowing that the deteri-
oration in separation is due to equipment failure. Even when known, the op-
erating conditions might be adjusted because of the inability to shut the unit
down for repairs. Equipment failure may become apparent only when main-
tenance is done on the column. Since the manufacturer cannot easily identify
when the collapse took place, it would be very difficult to know which lots of
product are affected and then to alert those customers. It is difficult to envi-
sion validating the process with this eventuality in mind.
Changes in the chemicals used in excipient manufacture can involve
catalysts, initiators, deionizer resins, carbon beds, and so on. This type of
change is almost always gradual.
Catalysts are often used in continuous reactors for reactions such as hy-
drogenation. These catalysts have a finite longevity during which their activ-
ity changes, often going through a maximum efficiency before gradual
decline. The manufacturer will compensate for this decline by gradually ad-
justing processing conditions such as reaction temperature and flow rate. The
effect of these changes in operating conditions is often reflected in a subtle
change to the impurity profile of the product. Since the catalyst life is often
measured in months, it must be recognized that gradual, but subtle, product
variation will occur. Finally, the processing conditions required may vary
somewhat from batch to batch of catalyst. Thus, the replacement of the cata-
lyst could also result in a subtle change in the purity profile. While it is possi-
ble to revalidate the process and notify the pharmaceutical customer of such
change, it is not possible to produce material matching the purity profile of
earlier material, since that catalyst has already been consumed. It is also an
unreasonable burden to expect the manufacturer to revalidate the process
every time the catalyst is replaced.
Carbon beds are used to adsorb chemicals, usually impurities from the
product stream. Virgin carbon is more efficient in adsorption, which can de-
cline with usage. When carbon beds are used in a continuous process, subtle
changes in trace levels of impurities can result in an unhomogeneous prod-
uct. The manufacturer must remain alert to lot-to-lot changes in the adsorp-
tion characteristics of the carbon and ensure the impurity levels remain
within established limits.
It is apparent that changes in equipment used in a manufacturing process

can occur with great frequency. Revalidation or customer notification would
place an undue burden on the manufacturer and escalate the cost to the cus-
tomer. The decision to revalidate or notify the customer is best left up to the dis-
cretion of the producer who should use the likelihood of a change in product
quality attribute or performance as the driver for validation and notification.
PROCESSING
The remaining aspects of change involve raw materials, production process-

ing, quality control analysis, and specifications. The implementation of an
ISO 9000 compliant quality system makes the identification of these changes
an easier task. The ISO 9000-certified manufacturer is required to thoroughly
document the production process. This documentation ranges from approved
raw material suppliers, to processing conditions, quality instrument identifi-
cation and calibration, laboratory analysis, specifications, and packaging.
Compliance with the Process Control section, number 4.9 of ISO 9000
(ISO 1994), requires that the process description be kept current and that all
changes receive appropriate approval. This ISO quality system requires the
documentation and approval of such changes, providing a mechanism for the
plant to notify the quality unit of the proposed change. This allows the qual-
ity unit an opportunity to evaluate the proposed change for its impact on the
critical processing parameters and its effect on the product. The quality unit
can then direct the revalidation of the process and/or the notification of the
customer for approval if appropriate.
The presence of a DMF for the product also facilitates the identification
of a process change. The maintenance of a DMF requires that it be updated
annually with any process changes. The FDA requires that it be notified
promptly of any significant process changes, but the document does not de-
fine significant change. It is suggested, as noted above, that statistical tech-
niques be used to indicate whether or not such a change has had a significant
impact on the product.
Customer evaluation and approval of a processing change relies on cus-
tomers learning sufficient details of the change from the manufacturer. It must
also be pointed out that the manufacturer will probably consider many of the
processing conditions to be proprietary. Therefore, while the manufacturer
may be willing to notify the customer of a processing change, the manufac-
turer will probably not offer much detail about the nature of the change. This
places a serious burden on the pharmaceutical manufacturer who must now
appraise the significance of a processing change without detailed information.
As a result, the drug manufacturer will probably have to formulate its finished
dosage form with the changed bulk product and observe the effect directly.
Both the FDA and IPEC consider the use of a new raw material in the
production process significant, as indicated by the FDA requirement for fil-
ing a prior approval supplement (FDA 1998) and IPEC assigning the
change a level 3 (IPEC-Americas 2000). IPEC considers a raw material from
a new manufacturer or plant as possibly significant and thus level 2, re-
quiring the evaluation of its impact on the quality of the product. Statisti-
cally significant changes to the product require validation and customer
notification.
However, sometimes the bulk manufacturer may find it difficult to iden-
tify when a raw material is being provided from a new supplier. API and BPE
products are often manufactured in quantities that are small by chemical in-
dustry standards. This may lead the manufacturer to purchase relatively small
quantities of raw materials, making it necessary to go to a distributor. Distrib-
utors usually purchase their chemicals from one source but will often switch
to another supplier when economics or availability dictates. A manufacturer
purchasing from a distributor is unlikely to be notified of a switch in source,
nor would the manufacturer necessarily notice a change, unless it became ob-
vious from use of SPC. If the bulk manufacturer is notified, there may not be
sufficient time to validate the change or to alert customers for their approval
prior to the switch over to the new supplier.
A similar scenario involving raw material sources concerns commodity
chemicals, those materials sold in large quantities for which there are indus-
try standard specifications. Chemical companies are known to conduct
exchanges where large volume commodity chemicals are involved. An ex-
change may occur between companies A and B for methanol, where company
B will agree to provide its methanol for the customer of company A in ex-
change for similar consideration by company A. The customer of company B
will probably not receive notification of the change in advance, if at all. Since
the manufacturer of the API is probably a small customer of the commodity
chemical, it cannot exert enough economic leverage with the supplier to pre-
vent exchanges. One final comment involving commodity chemicals is that
exchanges may involve product made overseas for domestically produced ma-
terial, again unknown to the bulk manufacturer. Under this circumstance,
neither revalidation nor customer notification is possible.
Manufacturers often list several approved suppliers wherever possible
but typically use one almost exclusively. The use of another approved source
of raw material in a validated process should not require revalidation if the
raw material continues to meet specifications and the raw material quality is
essentially identical to the source covered in the validation. As noted above,
the criteria for concluding the raw material sources are equivalent are the
demonstration that the mean and ::!::3 standard deviations for each supplier's
material is statistically the same.
Changes to process control should also be evaluated for their impact on
the product quality attributes. Such changes may include improvements to
existing instrumentation or new instrumentation, on-line analyzers, com-

puter-aided manufacturing, and SPC. If the process control shows an im-
provement, as reflected in a narrowing of the control limits, and is within the
validation parameters, then IPEC concludes the change is level 1 (IPEC-Amer-
icas 2000) and neither revalidation nor customer notification is necessary.
However, if the improvement in process control is outside the validated para-
meters or is accompanied by a statistically significant shift in the mean, or a
widening of the measured variation, then the change might be significant
and is an IPEC level 2 change. Revalidation would be needed.
The application of SPC to a process exhibiting random variation should
result in a significant reduction in lot-to-lot variation as reflected in the ±3
standard deviation- range. Such an improvement will be evident to the cus-
tomer who monitors such variation as reflected in the certificate of analysis
(CofA) provided by the supplier or by the performance of the chemical. How-
ever, this type of process improvement should not impact the performance or
conformance of the product and, thus, no revalidation or customer notifica-
tion is necessary.
The addition of instrumentation at the production unit represents an-
other form of processing change. The data from a new instrument can lead to
better control of the process and should only be treated as a change needing
revalidation if the mean of a product quality attribute changes statistically.
Another type of processing change involves in-process and finished
product testing. Analytical equipment and techniques are constantly improv-
ing, which results in easier and faster measurements as well as measurements
with greater sensitivity. When the results of improved analytical methods are
used for processing control, there is the possibility of altering the quality at-
tributes of the product. The FDA, in BACPAC I, requires only the routine up-
dating of filings and thus treats the change as minor. IPEC classifies any such
change made with the intent to improve product quality as probably signifi-
cant and level 3. Both organizations treat new testing with the sole purpose of
gathering information as minor change unlikely to affect the product. Statis-
tical analysis should demonstrate the equivalency of the product when the
change might impact the quality of the drug product to assure validation is
unnecessary.
An example of a process improvement where the mean is statistically
different is increasing product purity. This might also seem to be an example
of a change not warranting customer scrutiny. However, such purity improve-
ments can impact the performance of the product. This is very apparent when
the purity of a solvent is increased. Higher purity results in higher freezing
points that can have an effect on its use in the finished dosage form.
An example of another effect of higher purity involves glycerine. Process
improvements by the manufacturer led to a higher aldehyde content in an ef-
fort to improve the product. However, the pharmaceutical customer used io-
dine as a colorant for the product in combination with glycerine. The
"improved" glycerine resulted in a pharmaceutical with the desired color.

However, after a short time the color faded as the iodine was consumed, re-
sulting in a loss of product stability.
A final example of improved quality impacting the customer is a thio-
phosphate ester that was produced in higher purity. Unfortunately, the reduc-
tion in certain minor impurities that acted as an inhibitor resulted in a
finished dosage form of diminished stability.
While these two process improvements would have been revalidated,
the impact on the customer formulation went unnoticed. They clearly
demonstrate the importance of customer process change notification by the
chemical manufacturer to allow customers to evaluate the impact on their
finished dosage forms.
One last impact of processing change should be considered. Analytical
method validation must take into account the potential for impurities and
by-products in the analyte that may interfere with the measurement process.
Processing change can have a dramatic impact on the test method because of
increasing the interference caused by new impurities and by-products or a
significant change in their presence. Therefore, processing changes must be
given careful scientific scrutiny to ensure the change does not adversely affect
the analytical method. Otherwise, the analytical method must be revalidated
to show its continued predicable performance.
CONCLUSION
Process change validation and notification is a difficult issue for both the man-
ufacturer and the customer. The pharmaceutical industry must balance the
need for consistency of the product with the processing industry need for con-
tinuous improvement. It is evident that the bulk manufacturer needs clear, ob-
jective criteria to justify the effort involved in validation and customer
notification. While both the FDA and IPEC have begun to add clarity to the is-
sue of change, an attempt has been made to provide practical guidance to the
manufacturer and an understanding of the issue to both the maker and user.
As mentioned previously, statistical techniques, including SPC, can be a
useful tool in determining whether or not there has been a significant change
to the equipment or processing. The validation and customer approval result-
ing from process change places constraints on continuous improvement for the
bulk manufacturer. Variation in bulk chemical quality requires the drug formu-
lators to monitor their raw material quality, design more robust processes, and
monitor their finished dosage form quality more carefully. Reducing API and
BPE quality variability saves the pharmaceutical manufacturer these costs.
Therefore, process improvements by the bulk manufacturer should be encour-
aged where they can be shown to have a beneficial reduction in lot variation.
GLOSSARY
Active Pharmaceutical Ingredients (API): The active ingredient that is in-
tended to furnish pharmacological activity or other direct effect in the treat-
ment of illness.
Batch Process: A manufacturing process that produces the excipient from a
discrete supply of raw materials that are present before the reaction is com-
pleted.
Bulk Pharmaceutical Excipient (BPE): Any substance other than the active
ingredient that is included in the drug delivery system.
Continuous Process: A manufacturing process that continually produces the
excipient from a continuous supply of raw material.
Critical Operating Parameter: An operating condition that can impact a
product quality attribute, either a specification parameter or performance
characteristic.
Drug Master File (DMF): A compilation of technical data filed with the FDA
describing the manufacture, quality, and control of a product.
Drug Product: A finished dosage form.
Drug Substance: An active ingredient that is intended to furnish pharmaco-
logical activity or other direct effect in the treatment of illness.
Impurity Profile: A description of all of the impurities present in the product.
Installation Qualification (IQ): The documented verification that equip-
ment was installed according to an approved design.
Operation Qualification (OQ): The documented verification that equipment
performs as intended.
Physical Property: A quality parameter that can be measured solely with me-
chanical equipment.
Process Change: Changes made in facility, equipment, or processing of a
product.
Processing: All operating steps and parameters, set points, on-line and off-
line process controls, raw materials, and testing used in the manufacture of a
product.
Significant Process Change: A processing change that alters a product's
physical or chemical property or that is likely to alter the product perfor-
mance in the dosage form.
Statistical Process Control (SPC): The application of statistical graphical
techniques for monitoring process variation.
REFERENCES
ASQ. 1996. Specifications for the chemical and process industries. Milwaukee, Wis., USA:
ASQ Quality Press, pp. 127-128.
and Drug Administration, p. 12.
FDA. 1989. Guidelines for Drug Master Files. Rockville, Md., USA: Food and Drug Ad-
ministration Center for Drug Evaluation and Research, Dept. of Health and Hu-
man Services.
FDA. 1996. Current good manufacturing practice: Amendment of certain requirements for
finished pharmaceuticals; Proposed rule. Federal Register (May 3).
FDA. 1994. Guide to inspections of bulk pharmaceutical chemicals. Rockville, Md., USA:
Food and Drug Administration, Div. of Field Investigations (HFC-130), Division of
Manufacturing and Product Quality (HFD-320), p. 3.
FDA. 1998. BACPAC I: Intermediates in drug substance synthesis. Rockville, Md., USA:
Food and Drug Administration, Drug Information Branch (HFD-210), Center for
Drug Evaluation and Research.
FDA, March 1998. Manufacturing, processing, or holding active pharmaceutical ingredients
(Guidance for Industry). Rockville, Md., USA: Food and Drug Administration,
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Re-
search, Center for Veterinary Medicine.
FDA. 1999. Changes to an approved NDA or ANDA (Guidance for Industry). Rockville,
Md., USA: Food and Drug Administration, Drug Information Branch (HFD-210),
The Gold Sheet-Quality Control Reports. 1985. The Gold Sheet 29 (4):2.
IPEC. 1995. Good manufacturing practices guide for bulk pharmaceutical excipients. Arling-
IPEC-Americas. 2000. Significant change guide for bulk pharmaceutical excipients. Arling-
ISO. 1994. Quality systems-Model for quality assurance in production, installation, and ser-
vicing (ISO 9002:1994, ANSI/ASQC Q9002-1994). Geneva: International Organiza-
tion for Standardization.
Juran, J. M., and F. M. Gryna. 1988. Juran's quality control handbook, 4th ed. New York:
McGraw Hill, pp. 28.5, 28.22-23.
Lazar, M.S. 1995. PhRMA guidelines for the production, packing, repacking, or hold-
ing of drug substances: Part 1. Pharm. Techno!. (December): 30.
20
API TERMINOLOGY AND

DOCUMENTATION
Robert A. Nash
St. John's University
Jamaica, New York
According to the federal Food, Drug, and Cosmetic Act in the United States
Code of Federal Regulations under Title 21, the term drug means articles recog-
nized in the official United States Pharmacopeia (USP), the official Homeo-
pathic Pharmacopeia of the United States, or the official National Formulary
(NF) and their official supplements. This includes articles intended for use in
the diagnosis, cure, mitigation, treatment, or prevention of disease in man or
other animals; articles, other than food, intended to affect the structure or
any function of the body of man or other animals; and finally, articles in-
tended for use as components in the drug but not including devices and their
components.
According to the official definition of drugs, no such distinction is made
among auxiliary terms, such as drug product (pharmaceutical dosage form), ac-
tive pharmaceutical ingredients (API), inactive ingredient (excipient, inert compo-
nent of the drug product), and in-process material (mixtures of active and
inactive ingredients prior to the creation of the finished dosage form). All
four meet the definition of the term drug. Since by definition a pharmaceuti-
cal is a medicine or drug product, then Part 211 of the Code of Federal Regula-
tions-which covers current Good Manufacturing Practice for Finished
Pharmaceuticals (cGMP) applies to the drug in all its forms: drug product, ac-
tive ingredient, inactive ingredient, and in-process material. Furthermore,
since the basic concept of validation is incorporated within the meaning
of section 211.110 (a) and (b) and proposed section 211.220 of the cGMP
543
regulation, it follows that the legal basis for requiring validation documenta-
tion for both active and inactive ingredients has been properly established.
The former term, bulk pharmaceutical chemical (BPC), first used by the
Pharmaceutical Manufacturers Association (PMA, now called PhRMA) in their
December 1978 Guideline for the Production, Packing, Repacking, or Holding
of Bulk Pharmaceutical Chemicals, has no legal basis in the regulations
(Tuthill 1979). API has been defined as the ingredients or components (both
active and inactive) used in the manufacture of dosage form drug products.
According to Tuthill, such chemicals are usually made by chemical synthesis,
by processes involving fermentation, or by recovery (isolation, extraction, or
purification) from natural materials. In his article, Tuthill spelled out the re-
quirements of cGMPs for APis, including validation. The term bulk is most
likely derived from the term sterile bulk antibiotics, which are repacked from
their "bulk form" into dispensing containers without further processing. Ac-
cording to Fry (1984), such products, even in bulk form, are finished pharma-
ceuticals and, therefore, subject to cGMP regulations. However, sterile APis are
handled under a separate set of Food and Drug Administration (FDA) guide-
lines (7356.002A). Prior to 1978, APis were referred to as raw materials and
bulk chemicals (Byers 1966).
The regulatory priority of APis over inactive ingredients (especially key
excipients) is clearly established in the following FDA publications: Compli-
ance Program Guidance Manual for APis (7356.002F), Guide to Inspection of API
Manufacturing (revised September 1991), and Guidance for Industry-Manufac-
turing, Processing, or Holding Active Pharmaceutical Ingredients (draft document
issued March 1998).
The table of contents of the draft document issued March 1998 is as follows:
1. Introduction
2. Organization and personnel
3. Buildings and facilities
4. Process equipment
5. Control of raw materials
6. Production and process controls
7. Packaging and labeling controls
8. Holding and distributing of APis and intermediates
9. Laboratory controls
10. Records and reports
11. Validation
12. Change control/revalidation
13. R~processing/reworking of APis and intermediates
API Terminology and Documentation 545
14. Control of chemical, biological and physical contaminants

15. APis for clinical trials
A Drug Master File (DMF) is defined as a reference source providing de-

tailed information about a specific facility, process, or article used in the manu-
facture, processing, packing, or holding of a (drug) substance that is the subject
of an Investigational New Drug Application (IND), a New Drug Application
(NDA), an Abbreviated New Drug Application (ANDA), or Antibiotic Form 6 or
7. DMFs originated in 1943 with the submission of information of a chemical
substance to support a drug product application, apparently to ensure confi-
dentiality of the chemical process for making the chemical substance.
The basic requirements for a Type II DMF submission for an API, drug
substance intermediate, and material used in preparation of a drug product
consists of the following elements:
• Disclosure of the company and its operations

• Description of the facilities and equipment used in the manufac-
turing process
• Description of the sanitation systems on premises for cleaning and
disposal
• Organization, qualifications, and training of personnel
• Description of raw materials and packaging components, including
specifications and control procedures
• Description of manufacturing and packaging specifications, proce-
dures, and control documentation
• Description of quality control and testing procedures
• Description of sterile products manufacture and control, if applicable
• Description of quality assurance program
• Stability program documentation
• Environmental impact assessment statement
• Notification of changes or amendments to the DMF
• Letter of authorization to make reference to DMF
• Statement of commitment to comply with the information con-
tained within the DMF
The past resistance to the validation of APis is that much of the required
information and documentation should be contained within the scope and
requirements of a successfully completed DMF. However, a DMF document
does not have the legal weight of the cGMP regulations, which provide the
basis for requiring API validation documentation.
The FDA principle "You are what you claim you are" applies to APis as
well as to foods, drugs, and cosmetics.
Take, for example, dextrose. When dextrose is used as a sweetener in
baked goods, it is a food ingredient and subject to the requirements of food
products. When dextrose is used as an excipient in drug tablets or in liquid
preparations as a sweetener, it is an API. When it is used in the manufacture of
sterile dextrose injection, it is an active drug substance and an API but now
subject to assay and testing for bacterial endotoxins and 5-hydroxymethyl
furfural content.
Pharmaceutical excipients (inactive ingredients) are substances, other
than the active drug substance or the drug product, that have been evaluated
for safety and are included in the pharmaceutical dosage form (drug delivery
system) for one or more of the following functions:
1. Aid in the processing of the drug product during manufacture
(i.e., binder, disintegrant, lubricant, suspending agent, filtering
aid, etc.)
2. Protect, support, or enhance, stability, bioavailability, or patient ac-
ceptability (i.e., chelant, surfactant, sweetener, etc.)
3. Assist in product identification (i.e., colorant, flavor, film former, etc.)
4. Enhance any other attribute of the overall safety and effectiveness
of the drug during storage or use (i.e., inert gas, preservative, sun-
screen, etc.)
Like APis, pharmaceutical excipients are made by chemical synthesis,
fermentation, recovery from natural materials, etc. Often in the manufacture
of pharmaceutical excipients, such as clays, celluloses, starches, and natural
gums, purification procedures may not be employed. In addition, the physical
and chemical change of certain excipients during processing is not uncom-
mon. Unlike APis, many excipients have complicated chemical and physical
structures that do not yield easily to modern analytical and chromatographic
methods.
More than 200 monographs of pharmaceutical excipients appear in the
third edition of the Handbook of Pharmaceutical Excipients, published jointly
by the American Pharmaceutical Association (APhA) and the Pharmaceutical
Press (2000). In addition, more than 200 of the same pharmaceutical ingredi-
ents (excipients) are listed in NF 19 and cover more than 40 different exdpi-
ent categories, from acidulants to wetting agents. It has been estimated that
there are more than 1,000 different pharmaceutical excipients in use world-
wide at the present time.
The International Pharmaceutical Excipient Council in the United States
(L. Blecher, Chairman, 1361 Alps Road, Wayne, NJ 07470) has issued a GMP
guideline for excipient bulk pharmaceutical chemicals. The Council, in con-
junction with both the European and Japanese Pharmaceutical Excipient
API Terminology and Documentation 54 7
Councils, is currently engaged in establishing international harmonization

excipient monographs for the more popular pharmaceutical excipients. A list
of important and popular pharmaceutical excipients is given in Table 20.1.
Table 20.1 Harmonization Monographs for the Following Excipients Are in

Progress at the Present Time
Pharmaceutical Excipient Function
Magnesium stearate tablet lubricant

Microcrystalline cellulose tablet binder
Lactose tablet and capsule filler
Starch (corn, wheat, potato, rice) tablet disintegrant
Carboxymethylcellulose, Na, Ca suspending agent
Cellulose acetate phthalate enteric coating agent
Hydroxypropyl cellulose film former
Hydroxypropylmethyl cellulose film former
Ethyl cellulose tablet binder
Hydroxyethyl cellulose film former
Sucrose tablet binder
Povidone film former
Stearic acid tablet lubricant
Dibasic calcium phosphate tablet binder
Polyethylene glycol 400, 3350 cosolvent, stabilizer
Hydrochloric acid acidulant
Alcohol cosolvent
Benzyl alcohol preservative
Talc tablet glidant
Sodium chloride osmotic agent
Sodium starch glycolate tablet disintegrant
Sodium hydroxide alkali
Polysorbate 80 nonionic surfactant
Edetate Na2H2, Na2Ca chelant
Petrolatum lipid base
Colloidal silicon dioxide tablet glidant
Citric acid acidulant, buffer
Methylparaben preservative
Sodium saccharin sweetener
Titanium dioxide opacifier
ACTIVE PHARMACEUTICAL INGREDIENT
Presently, the overwhelming number of APis are organic, carbon-based,

chemotherapeutic agents prepared by either chemical synthesis, fermentation
techniques, or isolated from natural products. More than 90 percent of the ac-
tive drug substances are solids, the majority of which are white, crystalline,
and with a well-defined melting point or range. The rest are liquids at room
temperature, while a few are medicinal gases.
The organic chemical structures of most active drug substances are com-
posed of carbon, hydrogen, oxygen, and nitrogen atoms and may contain an
occasional sulfur, phosphorus, or halogen (fluoride, chloride, bromide, and
iodide) in the specific chemical configuration. Molecular weights of most ac-
tive drug substances range from 100 to 1,000 but tend to be about 300 dal-
tons. Melting points range between 100 and about 300°C.
APis belong essentially to one of the following four basic chemical
classes (see Table 20.2). They are listed as follows:
1. Weak acids and their salts (sodium sulfacetamide, potassium gua-

iacolsulfonate, calcium fenoprofen, magnesium salicylate, etc.)
2. Weak bases and their salts (nortriptyline hydrochloride,
phenelzine sulfate, chloroquine phosphate, scopolamine hydro-
bromide, tamoxifen citrate, etc.)
3. Organic nonelectrolytes (neutral molecules) (chloral hydrate, hy-
drocortisone, testosterone, mannitol, etc.)
4. Quaternary compounds (substituted ammonium salts) (metha-
choline chloride, mepenzolate bromide, phospholine iodide, etc.)
Table 20.2 Four Chemical Classes of Active Pharmaceutical Ingredients

Solubility
Types Structure Character pH Absorption
Weak acids & RM+ Weak acid neutralized 8-11 moderate acid: pylorus;
their salts (30%) with strong base to weak acids: small intestine
make water soluble salt
Weak bases RNH 2+x- Weak base neutralized 3-6 weak bases: pylorus;
& their salts RNWx- with strong acid to moderate base: small intestine
(45%) RWX- make water soluble salt
Neutral molecules R Requires cosolvency 5-8 stomach to rectum
(nonelectrolytes) to make water soluble
(15%)
Quaternary R4 wx- Soluble in water 5-8 active transport
compounds (10%)
Weak acids and weak bases and their salts account for about 75 percent
of the APis currently used in drug products.
Prodrugs are drug substances that are biotransformed in the body to ac-
tive metabolites and chemotherapeutic agents. Examples include sulfa-
salazine to sulfapyridine, phenylbutazone to oxy-phenbutazone, aspirin to
salicylate, and hetacillin to ampicillin. In some cases, like aspirin (ester) and
hetacillin (amide), hydrolysis in water releases the active drug moiety con-
tained within the basic structure of the prodrug.
The FDA often considers such simple, uncomplicated amides, lactams,
esters, and lactones as derivatives of the active drug substance in the same
way as it treats salts (electrolytes) and ion-pair complexes (nonelectrolytes) of
the same basic chemical structure.
COMPENDIAL STANDARDS
Compendia! tests and standards (USP/NF/European Pharmacopeia [EP]/Japan-

ese Pharmacopeia [JP]) and generally recognized analytical methods (AOAC
International) are used to establish the identity, purity, strength, potency, and
physical properties of pharmaceutical ingredients, including both APis and
excipients.
A listing of suitable test methods for the characterization of pharmaceu-
tical ingredients (both solids and liquids) follows. Such information, along
with detailed procedures, specification, and criteria for acceptance (not
shown here), forms the basis for establishing effective compendia! standards.
Not all of the items listed here must be carried out for each and every phar-
maceutical ingredient. Sufficient test methods and specifications, however,
must be developed to establish meaningful, and eventually, harmonized com-
pendia! monographs.
• Aspect and macroappearance, including color, odor, and taste

• Infrared and ultraviolet spectroscopy, including specific optical ro-
tation and refractive index
• Particle morphology, including scanning electron microscopy
• Particle size distribution, including light scattering methods and
optical microscopy
• X-ray diffraction
• Thermal methods of analysis, including differential thermal analy-
sis and differential scanning calorimetry (DSC)
• Chromatographic identity and purity, including thin layer chro-
matography (TLC), gas chromatography (GC), and high perfor-
mance liquid chromatography (HPLC)
• Loss on drying and moisture content (Karl Fischer)

• Residue on ignition
• Specific surface area (BET adsorption isotherm)
• Bulk or apparent powder density (loose and tap)
• Powder flow and compressibility characterization
• Heavy metals and arsenic content
• Solubility characteristics in suitable solvents, including color and
clarity evaluation
• pH value if pharmaceutical ingredient is soluble in water
• Microbial limits testing
Different properties, standards, and their test methods are important

during the various stages of the manufacture and end use of APis.
During the reaction stage, identification of the API is important. Identifi-
cation is established through chromatographic and spectrophotometric
analysis and special colorimetric tests.
During the crystallization and purification stages, the potency of the API is
established, again through the use of chromatographic analysis, particle mor-
phology, loss on drying, residue ori ignition, thermal analysis, and solubility
characteristics.
The performance of the API in the pharmaceutical dosage form is estab-
lished and maintained (lot after lot) through particle size analysis, specific
surface area, if applicable, powder density, flow, compressibility, moisture
content, and microbial limits testing.
It is important to remember that the API manufacturer, supplier, and
end user have different requirements and specifications when it comes to the
standardization and characterization of pharmaceutical ingredients (both ac-
tive drug substances and pharmaceutical excipients).
CHIRAL APis
According to the FDA's guideline for marketing chiral drugs (APis), issued in
May 1995, drug companies have the choice of whether to develop chiral drugs
as racemates (50 percent mixture of the D and L forms or enantiomers) or as
individual single enantiomers. Enantiomers have opposite rotational optical
activity in solution.
Most companies today have decided to move toward the development
of the pharmaceutically active, single enantiomer. If the racemate had been
approved alone or in pharmaceutical dosage forms, the development program
for the single active enantiomer can be shortened.
Certain chiral APis, however, are diastereoisomers and meso-compounds,

with two or more optically active centers (carbons) in the molecule (i.e.,
erythrose, threose, and meso-tartaric acid). In such cases, the simplification
between racemates and single enantiomers is often not readily apparent. The
conversion of racemates to active enantiomers can be accomplished using
one of the following reaction pathways.
• Lipase immobilized hollow-fiber membranes

• Asymmetric dihydroxylation
• Asymmetric epoxidation
• Fermentation methods for synthesis and resolution
• Reaction with cyclic lactam intermediates
• Reaction with glycine and aldolase
• Fractional crystallization
The following approved, first line, active drug racemates are candidates
for single enantiomer research at the present time:
• Cardiovascular drugs (atenolol, nicardipine, verapamil, diso-

pramide, etc.)
• Central nervous system drugs (meclizine, phenyl-propanolamine, flu-
oxetine, lorazepam, etc.)
• Anti-inflammatory and analgesic drugs (ketoprofen, dihydroxythe-
baine, ibuprofen, triamcinolone, etc.)
• Antiinfective and anticancer drugs (cytarabine, ciprofloxacin,
ofoxacin, norfloxacin, etc.)
• Cough and cold drugs (albuterol, terbutaline, astemizole, terfena-
dine, etc.)
• Hormonal drugs (calcitonin, estradiol, norgestrel, testosterone, etc.)
The advantage of the active enantiomer is that it has twice the activity of
the racemate and at least one-half of the toxic potential. The potency stability
of the active API enantiomer in both the solid state and solution is an impor-
tant concern to be addressed during the validation program.
CHEMICAL CONTROL REGULATIONS

The Premanufacturing Notice (PMN) is a document covering the manufacture
or import of a new chemical substance that is provided to the U.S. Environ-
mental Protection Agency (EPA) not more than 90 days prior to the start of
the activity. The PMN program is mandated by the Toxic Substances Control
Act (TSCA). Any substance that is not listed in the TSCA Inventory of Chemi-
cal Substances is classified as a new chemical substance. The significant new
use rule (SNUR) applies to new uses for an existing substance.
The following new chemical substances are not subject to the PMN re-
porting mechanism:
• The chemical substance is recognized as a drug (API), food additive,

or cosmetic.
• The chemical substance is formed during the manufacture of an ex-
empt article, manufactured solely for export, or found by incidental
or end-use reaction, or a by-product, mixture, or a nonisolated inter-
mediate in a chemical synthetic sequence [see 40 CFR 720.30(h)].
• Substances that are manufactured or imported that do not harm
civilians or the environment and where a low release and eposure ex-
emption (LoRex) application is submitted at least 30 days in advance.
• Substances are manufactured or imported in small quantities
(amount not stated) solely for research and development purposes
(not for sale) with a Low Volume Exemption Application (LVEA).
• Less than 10,000 kg (approx. 1 ton) of the substance is manufac-
tured or imported each calendar year and an LVEA is filed 30 days
before.
• The chemical substance is manufactured or imported solely for test
marketing purposes not less than 45 days after submitting a Test
Marketing Exception Application (TMEA).
• The chemical substance is a polymer, and the EPA is notified in time
prior to one year.
• The chemical substance is already listed in the TSCA inventory.
The only situation in which the manufacturer of an API would be affected (i.e., must
prepare and submit a PMN) is when the manufacturer imports the new chemical
substance or makes it in the plant in quantities greater than 1,000 kg per year as a
reactant in the chemical synthesis of either an intermediate or the active drug sub-
stance itself.
The API manufacturer must complete on a specified PMN form all avail-
able data on the chemical identity, amounts to be produced, by-products and
impurities, intended use, environmental release potential, disposal particles
to the environment, human exposure potential, and available data on toxic-
ity and safety. Under the TSCA, the EPA is required to protect from disclosure
all confidential business information (CBI) submitted on properly identified
documents.
The EPA will send a letter by return mail and include a PMN number as-
signed to the submission and the expiration date of the PMN review period.
The present fee structure for PMN filings is as follows:
• Small business exceptions: $100.

• Intermediate substance: $1,000.
• Multiple (more than two) related intermediate substances: $2,500.
Almost 90 percent of the PMNs submitted complete the EPA review

process without being restricted or regulated in any way. Information
about the PMN program may be obtained by contacting Environmental As-
sistance Division (TS-799), Office of Toxic Substances, U.S. EPA, Washing-
ton, DC, 20460 or from the EPA Web site at http:/ /www.epa.gov/
internet/appts.
THE VALIDATION OF APis

According to the FDA's Guidelines on General Principles of Process Validation, the
term process validation, whether for APis or drug products, is defined as "estab-
lishing documented evidence, which provides a high degree of assurance, that
a specific process (i.e., the manufacture of a API) will consistently produce a
product meeting its predetermined specifications and quality attributes." The
process for making an API consists of a series (flow diagram in logically de-
fined steps) of unit operations (modules) that result in the manufacture of the
finished API.
There is much confusion as to what process validation is and what con-
stitutes validation documentation. We use the term validation generically to
cover the entire spectrum of cGMP concerns, most of which are essentially fa-
cility, equipment_ component, methods, and process qualification. The spe-
cific term process validation should be reserved for the final stages of the
development and product scale-up sequence.
The end of the development and scale-up data generation sequence that
should be assigned to the formal, protocol-driven, three-batch process valida-
tion derives from the fact that the specific exercise of process validation
should never be designed to fail. Failure in carrying out the formal process
validation assignment is often the result of incomplete or faulty understand-
ing of process capability, in other words, what a given process can and cannot
do under a given set of operational requirements. The formalized, final three-
batch validation sequence is used to provide the necessary process validation
documentation required by the FDA to show API reproducibility and a manu-
facturing process in a state of control.
PROCESS VALIDATION OPTIONS

The FDA Guidelines on the General Principles of Process Validation mention three
options: prospective validation (also called premarket validation), retrospective
validation, and revalidation. In actuality, there are four, if concurrent validation
is included.
Process validation is carried out prior to the distribution of either a new
API or an existing API made under a revised manufacturing process, where
such revisions affect product specifications and/or quality characteristics. The
prospective approach features critical step analysis in which the unit operations
(i.e., reaction step, crystallization, sublimation, distillation, filtration, cen-
trifugation, fermentation, sterilization, extraction, drying, milling, etc.) are
challenged during the process qualification stage to determine, using either
"worst-case" analysis or a fractional factorial design, those critical process vari-
ables that may affect overall process performance. During the formal, three-
batch process validation that follows, critical process variables should be set
within their operating ranges and should not exceed their upper and lower
control limits during process operation. Output responses should be well
within finished API specifications.
PROCESS DESCRIPTION
There are four primary options used in the manufacture of APis. They are
chemical synthesis, fermentation, extraction from natural products, and purifica-
tion from crude materials. A flow diagram and a description of the chemistry
involved are used in defining the manufacturing process.
I have chosen Dow's process (Midland, Mich) for the manufacture of as-
pirin and salicylic acid to illustrate a typical API flow diagram (Figure 20.1).
The GMP-designed aspirin plant, which is capable of producing 12 million
lb/yr, is state of the art with advanced process control systems, stainless steel
tanks, glass-lined reactors, metal detection, and fully automated and comput-
erized to provide for production flexibility and process control.
According to the flow diagram logic, five reagents are used (i.e., liquid
phenol, sodium hydroxide, carbon dioxide under pressure, hydrochloric acid,
and acetic anhydride). Two forms of aspirin are produced. They are aspirin
USP crystals (not less than 99.5 percent pure and containing not more than
0.1 percent salicylic acid).and aspirin with starch granulation for tableting ap-
plications. The process also yields salicylic acid USP crystals (melting point
158-161 oc and purity not less than 99.5 percent) as a by-product of the basic
aspirin process.
The chemistry is relatively simple and consists of four reaction steps:
1. Phenol + sodium hydroxide -? sodium phenate + water

2. Sodium phenate + C02 -? sodium salicylate
Figure 20.1 Flow Diagram of Dow's Process for the Manufacture of Aspirin and
Salicylic Acid
Intermediate
L-------~r=========~------~~P~a~ck~a~g~in~g API&
Intermediate
Acetic Acetic Acid By-Product
Anhydride
A Pis
Source: Chemical Processing July, 1988

3. Sodium salicylate + HCl ~ salicylic acid + salt

4. Salicylic acid + acetic anhydride ~ aspirin + acetic acid
Side products of sodium salicylate, sodium chloride, and acetic acid are JlOt
exploited commercially. The primary equipment consists of reactors, pressure
vessels, precipitators, evaporators, centrifuges, dryers, granulators, and mills.
No solvents, other than water, are used or produced in the overall
process, thus simplifying environmental and plant safety concerns.
Packaging areas are not completely enclosed and segregated, and a posi-
tive, low humidity, airflow is maintained throughout critical areas of the
plant to ensure a contamination-free environment and to maintain aspirin
stability.
The diagrams for a synthetic chemical, single reaction step process (Fig-
ure 20.2) and a typical single product fermentation (Figure 20.3) are taken
from Wintner's excellent article (1993). Both flow diagrams feature about the
same number of unit operations and start with raw material weighing proce-
dures. The essential difference between the two (Figures 20.2 and 20.3) is that
the fermentation process features sterilization, inactivation, and preservation
unit operations.
The critical unit operations that should be monitored and/or optimized
are the reaction and fermentation steps for the purpose of increasing API yield
and reducing the residual impurity profile. Other critical unit operations that are
especially important to the end user (pharmaceutical dosage form operations)
include precipitation or crystallization, milling, sizing, and purification oper-
ations, which may affect the physical properties (particle size and shape and
bulk powder flow, blend uniformity, and compressibility) of the API.
Theoretically, every unit operation conducted in the plant comes under
the cGMP umbrella, and is, therefore, subject to validation documentation re-
quirements. This includes not only the final API but also the manufacture of
the final intermediate(s) (or main reactants), key intermediates that are used to
prepare the final intermediate(s), all the way back to commercial starting ma-
terial that enters the plant, as well as the pivotal intermediates thereafter.
The level of control and validation documentation required (i.e.,
through increased testing and tighter specifications) increases as one moves
closer, in a multistep, in-plant process, to the final outcomes [i.e., final inter-
mediate(s) and the API itself]. Naturally, when key and final intermediates are
sourced from outside, they must enter with appropriate certificates of analysis
(CofAs), plus thorough inspections of off-site facilities by quality assurance
personnel.
Those unit operations, especially the reaction step(s) that are considered
critical, are determined through an analysis of process variables or parameters
and their respective measured responses or outcomes (see Table 20.3). The
most favorable operating conditions to run the reaction are usually worked
out in the laboratory (1 x stage) and refined and/or optimized in the pilot
Figure20.2 API Process
j
.
Weighed
.. Premix
Reaction Precipitation
Filtration/
Ingredients
. Blender Centrifugation
)::.
Additional Ingredients Organic Solvent ::2
_t_ I (bi
3:s·
Milling and
Blender ""-
Dryer 0
Sizing
~
tll
;::,
Q.
~
C')
~
To Warehouse
~ Labeling
_.. Packaging
§
Qj
.....
Source: Pharm. Engineering 13(4), 1993 g·
en
....en
en
m
Figure 20.3 Typical Fermentation API Process
~
Organic Solvent or Water-----, ~
~
o·
::::s
Weighed 0.....,
Ingredients Sterilization Fermentation Cell Separation Inactivation ~
Q.
~-
Organic Solvent··················+ Organic Solvent----, ~

Q)
§
Q)
- Final Product
Purification -- Product
Purification Product Recovery ~I Solvent Extraction 2t:
I -~2
OrganJSolvent ~
Q..
~-
~ Bulk Preparation Preservation --
To Warehouse
or
Source: Pharm. Engineering 13(4), 1993

Table 20.3 Important Parameters to Be Evaluated in the Reaction Step

Parameter (X) Outcome (Y)
Temperature Yield & Purity

Time Yield & Purity
Oxygen Pressure Yield & Purity
C0 2 Pressure Yield & Purity
Medium or Solvents Used Yield & Purity
Type, Purity, & Amount of Catalyst Used Yield & Purity
Type & Speed of Agitators Particle Size Distribution
Reagent Ratios Particle Shape & Stereospecificity
Reagent Purity Catalyst Performance
Reagent Order & Addition Rate Yield, Purity, & Morphology
plant (lOx stage), with a view toward increasing yield and reducing residual
impurities. Fractional factorial designs, constraint, and "worst-case" analysis
are used to establish control of the manufacturing process.
IMPURITY PROFILE
The USP permits up to 2 percent of ordinary nontoxic impurities in the API.
Individual impurities greater than 0.1 percent should be fully characterized
and quantified by validated analytical methods. Impurities include residual
intermediates, reagents, by-products, degradation products, catalysts, heavy
metals, electrolytes, filtering aids, and residual solvents.
Known toxic impurities, however, should be held to a tighter standard
below 0.1 percent. One of the objectives of the prospective validation pro-
gram for APis is to maintain control over the impurity profile and to hold
contaminants and impurities to an achievable minimum standard.
RETROSPECTIVE VALIDATION
Retrospective validation of APis consists of a review and analysis, using statis-
tical process control methods, the physical process parameters, and analytical
test data for immediate past batches (at least the last 10-30 consecutive lots),
and should include numerical data for starting materials, key intermediates,
and the finished API. Impurity profiles are an important part of such historic
data. The purpose of retrospective validation is to show, through supporting

documentation, process control and reproducibility for both in-process mate-
rials and the finished API itself.
If the data for retrospective validation are faulty or insufficient, the FDA
will expect the manufacturer to conduct appropriate prospective or concurrent
validation studies in accordance with a preestablished, adequate testing plan
or protocol. Such a plan or protocol should identify process equipment, critical
process parameters and their operating ranges, critical characteristics of the
API, the sampling plan, and test data to be collected for at least three consecu-
tive designated batches to demonstrate consistency of the overall manufactur-
ing process of the API. In addition, the plan or protocol should define what
constitutes acceptable validation results.
REVALIDATION
The revalidation of an API process may be initiated at periodic intervals (an-
nually) or whenever significant changes are made to equipment, systems, or
processes. The revalidation effort will depend on the nature and extent of the
changes made. The evaluation and decisions regarding the need for revalida-
tion should be documented.
Any indication of failure (more than 10 percent of the batches) should
result in an investigation to identify the cause and to take necessary corrective
action, and an assessment should be made regarding the need for additional
formal process validation. In the absence of changes or process failure, peri-
odic review of data covering manufactured lots should be made to assess the
need for more formal revalidation.
CHANGE CONTROL
Process validation of an API should include a Standard Operating Procedure
(SOP) to reassess a process whenever there are significant changes in process,
equipment, facilities, reactants, process materials, systems, etc., that may af-
fect the critical quality attributes and specifications of the API. Such changes
should be documented and approved in accordance with the scope of the
change control SOP. The change control SOP should consist of the following
elements:
• Documentation that describes the procedure, review, approval, and

basis for formal revalidation studies
• Identification of the change and assessment of its likely implication
• Requirements for monitoring change and testing needs

• Assessment of information and justification of the change
• Review and formal approval to proceed
• Identification of changes made to the physical and chemical com-
position of API
• Possible regulatory action and customer notification
BULK ACTIVES POSTAPPROVAL CHANGES
The FDA recently instituted a new program to speed the procedure of approv-
ing changes for both APis and drug products. With respect to APis, it is called
bulk actives post/approval changes, or BACPAC. The types of changes being con-
sidered under the BACPAC area are as follows:
• Site, scale, and equipment changes

• Specification changes
• Manufacturing process changes
• Multiple changes
The procedure for acceptance consists of three levels of approval. They

are as follows:
• Level one-the change is made and then reported in the company's

Annual Report (AR) to the FDA.
• Level two-the change is handled by submitting a change being ef-
fected supplement (CBE) to the FDA and then waiting 30 days be-
fore making the change if there is no response from the Agency.
• Level three-the change is handled by filing a supplement to the
approved NDA for the drug product, which also covers the An
then waiting for formal approval called a prior approval supple-
ment (PAS) before the change is made.
Such changes must be supported by data that clearly reconfirm a validated

API and its process for manufacture. At the present time, BACPAC I changes
have been recommended for key intermediates. In the future BACPAC II
changes will apply to the active moeity or API.
Site changes within a single facility where the synthetic pathway remains
unchanged and cGMPs procedures are followed need not be filed with the
FDA. They are considered level one changes. If the site change involves the
final intermediate, it is considered to be a level two change. If the new site is

under new ownership, which is not listed in the approved NDA, it constitutes
a level two change.
Scale changes either increase or decrease in batch size and are considered
to be level one changes, as long as the data output is comparable with the orig-
inal batch size.
Specific changes related to a new analytical method that provides equal or
greater assurances of quality is considered to be a level one change.
Manufacturing process changes encompass a wide range of process-related
changes from the use of different equipment to changes in synthetic compo-
nents and procedures. Such changes are considered to be level two changes.
Multiple changes in site; scale and manufacturing processes are consid-
ered to be level three changes, which require prior approval from the FDA.
More detailed information is provided in the current FDA guidance doc-
uments (see References).
REPROCESSING
One of the major areas of difference between APis and drug products is repro-
cessing. The reprocessing of an API is done primarily to increase yield, to ob-
tain a purer material, or to bring important parameters (i.e., particle shape,
size distribution, etc.) into conformity with their specification limits. In con-
trast, reprocessing of a drug product rarely results in improved drug purity.
The use, for example, of recrystallization procedures and secondary re-
covery from mother liquors is not contrary to the spirit and intent of the
cGMPs. Reprocessing of APis, if carried out by procedures already used to
manufacture the original batch, in other words, recycling through one or more
consecutive unit operations, is an acceptable practice as long as
• there is no blend-off of high and/or low rejected material with re-

spect to potency, impurities, and certain physical properties in or-
der to salvage rejected batches; and
• the recycling or reprocessing procedure is essentially physical in na-
ture rather than chemical.
It is important to establish written Change Control procedures to cover re-

processing and/or recycling unit operations. Such information should also be
incorporated in the DMF. Unit operations, such as crystallization, evapora-
tion, distillation, hydration, acetylation, hydrogenation, salt formation, and
pH adjustment are especially sensitive to the need for effective reprocessing
procedures.
VALIDATION MASTER PLAN

The creation of a master plan enables one to develop an overview of the vali-
dation effort. It lays out in a logical sequence the activities and/or key ele-
ments to be performed versus the approximate time schedule in a Gantt chart
(Figure 20.4) or PERT chart format. Once generated and maintained, the mas-
ter plan establishes the critical path against which progress can be monitored.
The validation program starts with the design and development of
raw materials and components; followed by the installation qualification/
operational qualification (IQ/OQ) of facilities, equipment, and systems;
performance and process qualification stages; and terminates in the protocol-
driven, three-batch, formal process validation program. Many of the activities,
shown in Figure 20.4, move forward in series. However, by combining activi-
ties and elements in groups and moving on parallel tracks where possible with
respect to API development program; analytical methods development; facili-
ties, equipment, and the support system; and the manufacturing process de-
velopment for the drug product itself, a great deal of time can be saved
before the individual elements or groups of activities come together prior to
the formal process validation program of the finished pharmaceutical dosage
forms.
This requires effective communication and flexibility on the part of API
operations, analytical methods development, and drug product development
with respect to integrating their areas of responsibility. In my opinion, such
effective relationships among API operations, analytical methods develop-
ment, and drug product development is the key to prospective process valida-
tion and producing a quality drug product in the shortest possible time.
CLEANING VALIDATION
According to section 211.67 of the CFR, equipment cleaning and mainte-
nance of the cGMP regulations,
... (3) equipment and utensils shall be cleaned, maintained,

and sanitized at appropriate intervals to prevent malfunction
or contamination that would alter the safety, identity,
strength, quality, or purity of the drug.... Written procedures
shall be established and followed for cleaning and mainte-
nance of equipment .... These procedures shall include, but
are not limited to, the following:
• assignment of responsibility for cleaning and maintain-
ing equipment.
• maintenance and cleaning schedules and sanitizing
schedules where appropriate.
Figure 20.4 Validation Process Gantt Chart
PHARMACEUTICAL DISCOVERY
DRUG
API PRODUCT
CHEMICAL PROCESS PREFORMULATION

RESEARCH DEVELOPMENT
CLINICAL API CLINICAL PRODUCT

MANUFACTURE MANUFACTURE
DRUG PRODUCT
API MANUFACTURE
MANUFACTURE
Courtesy of Austin Chemical Company
• description in sufficient detail of methods, equipment,

and material used in cleaning and maintenance opera-
tions, and the methods of disassembling and reassem-
bling equipment as necessary to assure proper cleaning
and maintenance.
• removal or obliteration of previous batch identification.

• protection of clean equipment from contamination prior
to use.
• inspection of equipment for cleanliness immediately be-
fore use.
Records shall be kept of maintenance, cleaning, sanitizing,
and inspection.
The objective of cleaning validation of equipment and utensils is to provide
the necessary documentation that the cleaning procedures can reproducibly
reduce the residues of a given product below established limits so that such
residues of the previous product do not affect the quality and safety of the
subsequent product to be manufactured in the same equipment and facility.
Cleaning validation requirements not only apply to drug products
and their manufacturing facilities and equipment but also to APis and their
environment as well. The focus of cleaning validation for APis is to establish
procedures and residue limits that are practical, achievable, verifiable, and as-
sure safety.
Since the "equipment train" in most API plants consists of reactors,
tanks, piping, pumps, valves, centrifuges, dryers, mills, and blenders, with the
exception of piping, pumps, and valves, the rest of the equipment is either
glass-lined or stainless steel, open, easily accessible, and relatively easy to
clean. With the exception of milling equipment that can be isolated, the en-
vironment of API plants is relatively dust free. It is true that the smell of sol-
vents permeates and characterizes such plants, but quality exhaust and
ventilating systems can keep such vapor problems under control and well be-
low critical fire and explosion limits (see the discussion of Explosion Suppres-
sion Validation below).
With respect to cleaning validation, the train should be disassembled
and cleaning of individual pieces of equipment should be handled separately
and should be tied to a Prewash and Inspection Program. In most cases, the
cleaning procedures should feature thorough cleaning with detergent solu-
tions, chelants, or solvents, alone or in combination and ultimately followed
with rinsing with the ideal placebo, purified water. The final purified water
rinse can then be tested for pH, total organic carbon, and conductivity in con-
formance with a USP standard of acceptance.
The most difficult part of a cleaning validation program for APis is the
cleaning of piping, in-line pumps, valves, elbows, and such. Rinsing proce-
dures should be supplemented with high-pressure, filtered, air pushing, lint-
free, fabric tampons through the lines. Final inspection with modular
borescopes (Lenox Instruments Co., Trevose, Penn.) should follow such clean-
ing procedures.
EXPLOSION SUPPRESSION VALIDATION

Explosion suppression is a concern in the operation of API manufacturing
plants. A recent explosion and fire (April1995) at an API plant was traced to a
clog in the pipeline supplying benzaldehyde to a vacuum tumble dryer (an
example of faulty or no cleaning validation procedures). In an attempt to un-
clog the line, water was introduced (unauthorized procedure) into the reactor,
which already contained sodium hydrosulfite and powdered aluminum. The
rapid heat of reaction build-up from the interaction among the three reac-
tants lead to the explosion and fire.
Some approaches to explosion suppression should include the following:
• Design equipment "train" so that the reactors, pumps, piping, and
so on can withstand the force of a potential explosion.
• Install instrumented heat. sensors and pressure devices with warn-
ing alarms at key locations in the equipment "train."
• Establish key locations in the "train" for pressure build-up venting
and blow-off to occur.
• Perform laboratory testing, using small-scale equipment to estab-
lish the explosion potential of the manufacturing process. Include
in your laboratory studies "what if?" analysis.
• Practice explosion prevention through dust control, facility and
equipment cleaning validation, solvent handling and control pro-
cedures, and control of ignition sources.
• Finally, qualify and validate all aspects (people, facilities, materials,
equipment, procedures) of the program and provide program re-
view and approved documentation.
VALIDATION DOCUMENTATION
Plans, protocols, and reports with respect to validation documentation of
APis are covered by most of the following elements. The formatting, content,
and specifics are left to the discretion of the reader.
• Introduction: Purpose, scope, corporate quality policy, organiza-
tional structure, and responsibilities
• Process Description: Flow diagram; chemistry; manufacturing in-
structions; equipment IQ OQ, and performance qualification (PQ);
facilities and equipment maintenance; process conditions; critical
process variables and specifications; in-process checks; mother
liquors; blend analysis; yield; impurity profile and residual limits;

reprocessing options; utility support systems; automation and com-
puter systems validation; water systems testing; and maintenance
• Testing and Control: Raw materials, in-process and finished API
testing and release specifications, analytical methods validation,
stability report, process development report, formal validation re-
ports, and summaries of lot and batch production data
• General Considerations: Materials handling, storage, packaging

and preservation, personnel training, change control system, reval-
idation option, solvent recovery and tank farm maintenance,
cleaning validation, sterilization versus sanitation, product label-
ing, documentation preparation, external and internal auditing
In addition, two other outlines are presented in Tables 20.4 and 20.5
on formatting validation documentation for APis. A summary of the essen-
tials of the FDA's Guide to the Inspection of API Manufacturing is presented in
Table 20.6.
Table 20.4 Validation Master Plan: Protocol and Reporting Format

1. Purpose: for the validation of system or process
2. Scope: validation limits and boundaries of system or process
3. Corporate Policy: develop basic operational SOP documentation with respect to validation poli-
cies and procedures
4. Organizational and Responsibilities: develop basic operational SOP documentation
5_ Prequalification Documentation: provide functional requirements, systems definitions, pro-

posed specifications, supplier's and vendor's information
6. Basis of Design: develop qualification requirements, definitions, and specifications, for pro-
posed system or process
7. IQ/OQ/PQ Documentation: develop appropriate protocols, procedures, documentation, and

reports
8. Specifics of Validation Program: review existing procedures and specifications of system or

process and develop new procedures and specifications including hard data to support Valida-
tion Program
9. Environmental Program: provide SOP documentation and procedures for personnel training,
system or process security, and environmental concerns including cleaning validation and main-
tenance of equipment and facilities
10. Change Control and Revalidation: establish the basis for initiating
Table 20.5. Qualification/Validation of Active Pharmaceutical Ingredients

Process Definition
Options: synthesis/fermentation/extraction/purification
Facilities and equipment (unit operations)
IQ (design)
OQ (operating ranges)
PQ (attributes/specs)
Cleaning Validation Program
Manufacturing SOP and control parameters
Process flowchart and description of chemistry
Personnel training and safety considerations
Quality Attributes
Assay and yield
Impurity profile (qualitative and quantitative)
Contaminant profile (qualitative and quantitative)
Physical characteristics of active API (aspect, thermal analysis, particle size, optical activity,
moisture, LOD (limit of detection), microbial content, etc.)
Analytical methods validation
Critical Operating Parameters
Reactant ratios, reaction time, temperature, pressure, 0 2 /C0 2 ratios, pH, impurity concentration,
etc.
Ranges for Critical Operating Parameters
Worst-case challenges during pilot laboratory scale-up for yield, stability, and impurities
Control of Process Components
Raw materials, solvents, catalysts, gases, processing aids, processing water, steam, packaging
materials and bioburden
Process Validation Protocol
Sampling and testing strategy
What constitutes acceptable in-process and final product
Formal Process Validation
At least three batches for reproducibility
Change Control Procedures and Conditions for Revalidation, Reprocessing, and Recovery Validation
Documentation
Include all pertinent data and reports from design, qualification, and validation stages
Table 20.6 Summary of the FDA Guide to Inspection of API Manufacturing, Re-
vised March 1998
1. Prevent contamination/cross-contamination (need separate air handling system)
2. Water systems/air quality (potable water acceptable for nonsterile operations)
3. Aseptic/sterile processing (EtO is acceptable)
4. Multipurpose equipment/cleaning/closed systems-acceptable for outdoors
5. Protect environment against waste
6. Cleaning of product contact surfaces (cleaning procedure/sampling plan; analytical method)
Limits: practical, achievable, and verifiable
7. Raw materials (storage inside and outside is acceptable)
8. Containers, closures, and packaging components
9. Mother liquors (secondary recovery is acceptable)
10. In-process blending/mixing (blending off out-of-spec material is not acceptable)
11. Reprocessing (investigation and reason for failure)
12. Validation (variations that affect chemical/physical/microbial characteristics-establish rei·
evance and reproducibility)
13. Process change control system in place
14. Control productjprocess impurities
15. In-process testing
16. Packaging and labeling
17. Expiry dating and stability data
18. Laboratory controls and analytical methods validation
RECOMMENDED READING
Anisfeld, M. H., and F. Shaviv. 1997 Implementation of U.S. GMPs in the manufactur-
ing of active ingredients. Phann. Techno!. 21 (4):40-54.
Armstrong, M., E. Duckworth, J. Linder, A. Meisch, and D. Yoakam. 1994. API pilot
plants-bridges to the future. Phann. Engineering 14 (4):8-14.
Barr, D. B., and W. C. Crabbs, and D. Cooper. 1993. FDA regulation of API production.
Phann. Techno[. 17 (9):54-70.
Baseline phannaceutical engineering guide, Vol. 1, APis. 1995. Tampa, Fla., USAISPE.
Brocklenbank, M.P. 1992. Multi-purpose pharmaceutical plants-Solutions to key de-

sign problems. Phann. Engineering 12 (6):17-31.
Demmer, F., N. C. Franklin, S. Geussenhainer, H. Hausler, R. Kirrstetter, C. Rufer, E.
Walter, and F. Zimmermann. 1994. FDA regulation of APis-An industrial com-
mentary: Part I. Phann. Technol. 18 (10):80-90.
Demmer, F., N. C. Franklin, S. Geussenhainer, H. Hausler, R. Kirrstetter, C. Rufer, E.

Walter, and F. Zimmermann. 1994. FDA regulation of APis-An industrial com-
mentary: Part II. Phann. Techno/. 18 (12):36-43.
GMPs for excipient APis. 1995. Wayne, N.J., USA: International Pharmaceutical Excipi-
ent Council.
Gold, D. H. 1992. GMP issues in API manufacturing. Phann. Techno!. 16 (4):74-84.
Guidelines for API manufacturers. 1994. Geneva, Switzerland: European Chemical Indus-
try Council.
Hanson, R. W. 1980. Controlling the quality of APis. Phann. Techno/. 4 (10):26-30.
Lazar, M.S. 1995-1996. PhRMA Guidelines for the production, packing, repacking, or
holding of drug substances. Phann Techno/. 19 (12):20-25 and 20 (1):50-63.
Lazar, M.S. 1995. Sterile APis-A PhRMA position paper. Phann. Techno!. 19 (8):38-42.
Mercill, A. 1995. Good manufacturing practice guide for bulk pharmaceutical excipi-
ents. Phann. Techno/. 19 (12):34-40.
Moore, R. E. 1992. FDA's guideline for APis-A consultant's interpretation. Phann.
Techno!. 16 (9):89-100.
Rivera-Martinez, E. 1994. FDA perspective on API GMPs, control and validation.
Phann. Engineering 14 (3):8-14.
Sawyer, C.]., and R. W. Stotz. 1992. Validation requirements for API facilities. Phann.
Engineering 12 (5):44-52.
Thompson, A. G., and J. G. O'Hara. 1994. Quality assurance program for validation
and facility design of a API plant. Phann. Engineering 14 (3):66-72.
REFERENCES
APhA. 1994. Handbook of phannaceutical excipients, 2nd ed. Washington D.C.: Ameri-
can Pharmaceutical Association, and London: Pharmaceutical Press.
APhA. 2000. Handbook ofphannaceutical excipients, 3rd ed. Washington D.C.: American
Pharmaceutical Association, and London: Pharmaceutical Press.
FDA. 1998. Guidance for industry, manufacturing, processing, or holding active phar-
maceutical ingredients. Rockville, Md., USA: Food and Drug Administration.
FDA. 1998. Guidance for industry, BACPAC 1: Intermediates in drug substances syn-
thesis, chemistry, manufacturing, and controls documentation. Rockville, Md.,
Fry, E. M. 1984. An FDA perspective on APis. Phann. Techno/. 8 (2):49-52.
PIC. 1999. Recommendations on validation master plans, IQ/OQ, non-sterile process
validation, cleaning validation. Geneva Switzerland: Pharmaceutical Inspection
Convention.
PIC. 1997. Internationally Harmonised Guide for APis, GMPs. Geneva Switzerland;
Pharmaceutical Inspection Convention.
Tuthill, S.M. 1979. APis: GMP. Pharm. Techno!. 3 (2):48-52.
Wintner, B. 1993. Environment emissions control in the pharmaceutical industry.
Pharm. Engineering 13 (4):8-22.
Index
AADAs (Abbreviated Antibiotic Drug adulteration. See also deviations; impurities;

Applications), 3 misbranding
AAPS (American Association of by cGMP noncompliance, 15-16, 57,
Pharmaceutical Scientists), 330 65-66
Abbott Laboratories, 77, 418 FD&C protecting against, 14
Abbott Laboratories v. Celebreeze, 77 and import/export, 39-40
Abbott Laboratories v. Gardner, 77 other forms of, 19-20, 79
Abbreviated Antibiotic Drug Applications process validation against, 16-19
(AADAs), 3 and quality assurance, 385
Abbreviated New Animal Drug Application aerobic microorganism, 511
(ANADA), 14 agents, 344
Abbreviated New Drug Applications. See airborne particulate cleanliness class, 511.
AND As See also room classifications
acceptable daily intake (ADI), 418-419 airflow
acetaminophen, 283 laminar, 513
Action Letters, 88 in microbiological control, 494, 497-499
active ingredients, 12. See also APls and pressure differentials, 435-437
characteristics of, 548-549 in room classification, 434
chiral, 550-551 separate, for certain drugs, 400
DMFs for, 42-44 system overview, 442-444
versus dosage form manufacturing, alcohol, 547
263-264,401,543 alkaloids, 400
FDA introduction of, 1, 2 American Association of Pharmaceutical
import/export authority over, 22, 37-42 Scientists (AAPS), 330
misbranding, 20 American Pharmaceutical Association
pharmacy compounded, 46 (APhA), 546
regulatory status, 12-14 American Society for Quality (ASQ), 390,
tools against, 32-3 7 523,528
when chemicals become, 12-13, 487 ANADA (Abbreviated New Animal Drug
active pharmaceutical ingredients. See active Application), 14
ingredients; APis anaerobic microorganism, 511
active sampling, 498 analgesic drugs, 551
ADI (acceptable daily intake), 418-419 analysis of variance (ANOVA), 528
573
ANDAs (Abbreviated New Drug control; postapproval manufacturing

Applications) changes; process change
DMF supporting, 42, 545 (see also DMFs) bacteriostasis and fungistasis (B/F)
for new drug, 3, 14 testing, 502
PAl policy, 5 (see also PAl) bacteriostatic, 5 11
postapproval changes, 332-333, 337 barriers, 494, 511
in quality assurance, 373 Baseline Pharmaceutical Engineering
reporting impurities in, 279-280, 281 Guides, 163
Animal Health Institute, 330 batches
Annual Product Quality Reviews versus continuous processing, 524
(APQRs), 139 documenting, 123, 150-152
ANOVA (analysis of variance), 528 number of, in validation, 72, 116, 118
antibiotic drug certification, 46, 56 release procedure, 136, 530
Antibiotic Forms 6 and 7, 545 validation case study records, 167,
anticancer drugs, 551 168, 191
anti-infective drugs, 551 batch process, 524, 541
anti-inflammatory drugs, 551 batch production records (BPRs), 123
APhA (American Pharmaceutical benzyl alcohol, 547
Association), 546 BET testing, 483-484, 550
APis (active pharmaceutical ingredients), B/F (bacteriostasis and fungistasis)
345, 511, 541, 544. See also active testing, 502
ingredients bioburden, 484-486, 511. See also
APQRs (Annual Product Quality ' microbiological control
Reviews), 139 bioburden approach to sterilization,
aseptic process validation. See sterility 490-491
validation Biological Indicators (Bis), 489-491, 511
aspect analysis, 549 Biologics Licensing Application (BLA), 458,
aspirin, 554-556 463-464
ASQ (American Society for Quality), 390, Biotechnology Industries Organization, 330
523,528 Bls (Biological Indicators), 489-491, 511
assay testing, 79-80, 358 BLA (Biologics Licensing Application), 458,
asymmetric dihydroxylation, 551 463-464
asymmetric epoxidation, 551 blend state testing, 71, 72, 80
audits. See site inspections Boyce Motor Lines, Inc. v. United States, 62
BP (British Pharmacopoeia), 479
BACPAC I (Bulk Active Chemicals Postap- BPCs (bulk pharmaceutical chemicals), 12,
proval Changes). See also BPCs; 164,345
change control; postapproval manu- as excipients, 6-7, 25-26, 45
facturing changes; process change versus finished drug products, 106, 398
on change assessment, 333-335, 522 introduction of, 544
in deviation investigations, 296 postapproval changes to (see BACPAC I;
on DMF documentation, 52, 95 BACPAC II)
filing mechanism, 332-333 when chemicals become, 1-2
history, 330-331 BPEs (bulk pharmaceutical excipients), 520,
on impurities, 287-289 541. See also excipients
objectives, 329-330 BPRs (batch production records), 123
overview,46-47,561-562 British Pharmacopoeia (BP), 479
on processing changes, 336-337, 520, bubble point test, 487, 511
521,539 Bulk Active Chemicals Postapproval
scope, 331-332 Changes. See BACPAC 1; BACPAC II
site, scale, and equipment changes, bulk drug substances, 51. See also BACPAC I;
335-336 BACPAC II; BPCs
specification changes, 336 bulk pharmaceutical chemicals. See BPCs
in vendor qualification, 351
BACPAC II (Bulk Active Chemicals calibration
Postapproval Changes), 46, 288, 331, in deviation investigation, 299
337-339. See also BPCs; change and site inspections, 148-149
Index 575
in validation case study, 181 international noncompliance, 101-105

in vendor qualification, 361, 364 judicial analysis of, 61-63, 77
capillary zone electrophoresis, 410, 412 open-endedness of, 63-65
carbamazapine, 285-287 preventing adulteration, 273
carbon beds, 536 and quality assurance, 376
carboxymethylcellulose, 54 7 regulations before, 55-56, 76-77
cardiovascular drugs, 551 SOPs, 478
catalysts, 536 validation as part of, 16-19
Category A Vendor, 352 change control. See also process change
Category B Vendor, 352 cleaning process, 425
Category C Vendor, 352 DMF information, 43-44, 52, 95
CBE (changes being effected) supplement, guidelines, 138-139, 560-561
288-289 in PAl inspections, 5
CBER (Center for Biologics Evaluation and postapproval (see BACPAC I; BACPAC II;
Research), 98, 99, 458 postapproval manufacturing changes)
CDER (Center for Drug Evaluation and in processing procedure, 537-540
Research) in QA system, 386, 388-389
on airflow and pressure differentials, 437 site changes, 531, 534, 561-562
on BPC/API guidelines, 98, 99, 100, 330 sterility validation, 449
on DMFs, 90, 93 technology (see technology transfer)
quality assurance role, 382-383 in validation process, 266-267, 466-469
CD-ROMs (compact disk, read only in vendor qualification, 350-351,
memory), 388, 389, 390. See also 356,365
computers changes being effected (CBE) supplement,
CEFIC (European Chemical Industry 288-289
Council), 99, 111, 114 chemical control regulations, 551-553
cellulose acetate phthalate, 547 Chemical Manufacturers Association
Center for Biologics Evaluation and Research Responsible Care code, 523
(CBER), 98, 99, 458 chemistry, manufacturing, and controls
Center for Drug Evaluation and Research. (CMC), 83, 95. See also DMFs (Drug
See CDER Master Files)
Center for Veterinary Medicine, 98, 330 chiral APls, 550-551
central nervous system drugs, 551 chromatography. See GC; HPLC; ion
cephalosporins, 400 chromatography; TLC
certificates of analysis. See CofA CIBA Corp. v. Weinberger, 78
certification, 345. See also vendor CIP (clean-in-place), 323, 406, 408, 422
certification CIS (continuous improvement systems),
CFU (colony forming unit), 481, 511 371,373
cGMPs (current Good Manufacturing citric acid, 547
Practices). See also GMPs cleaning agents, 404, 405, 426
airflow patterns, 43 7 cleaning process. See also sterility validation
amendments to, 164, 261-262 analytical methods, 409-414, 423
applying to API processes, 106-107, Barr Laboratories validation of, 73-74
398,475 dedicated versus multiple use equipment,
challenges to, 59 399-401
change control, 521 documentation, 406, 420-425
cleaning validation, 563-565 equipmen~ 145-148,444-445,456-457
compliance guidelines, 15 FDA regulations, 18-19, 118-119
drug products versus APis, 66-67, and impurities, 283
398,543 international noncompliance, 104
equipment, 299 limits and acceptance criteria, 414-420,
failure to comply with, 65-66, 363-365 423-424
FDA analysis of, 59-61 in microbiological control, 489
Food and Drug Amendments of 1962, multiple levels approach, 402-403
56-59 nature of contaminants, 404-405
history, 98, 429 and raw materials storage, 142-143
lCH guidance, 46 regulatory requirements, 397-399
sampling in, 407-409 contact plate sampling, 499-SOO, 501. See

techniques, 406-407 a/soRODAC™
in technology transfer, 323 containment, 493-494, 512
trends in, 42S-426 contaminants, 404-405. See also
unique nature of APis, 401 adulteration; impurities
validation, 148, 167, 407, 454-456, contamination, 512. See also adulteration;
563-56S impurities
validation case study, 176-179, 233-241 continuous improvement systems (CIS),
in vendor qualification, 358, 364 371, 373
worst case selection, 400-401, 405- continuous processing, S24, 541
406,456 controlled areas, 512
clean-in-place (CIP), 323, 406, 408, 422 control limit values, 464-466
clean-out-of-place (COP), 406-407 fohn D. Copanos eta/. v. Food and Drug
closed barrier, 494 Administration eta/., 80
closed isolator, 494 COP (clean-out-of-place), 406-407
CMC (chemistry, manufacturing, and cough and cold drugs, 551
controls), 83, 95. See also DMFs (Drug Covey, Stephen, 378-379
Master Files) criminal prosecution, 35-3 7
Co fA (certificates of analysis) critical areas, 495-496, 512
and microbiological control, 485-486, critical operating parameters, 524-525, 541.
507, 509 See also process validation
in monitoring vendors, 352, 353 critical process parameters, 321-322, 324
on outsourced intermediates, 556 crystallization stage testing, 550
in site inspections, ISS current Good Manufacturing Practices.
in vendor qualification, 349 See cGMPs
colloidal silicon dioxide, 54 7
colony forming unit (CFU), 481, 511 DCS (distributed control system), 179
commodity chemicals, 538 dead legs, 483
common carrier authority, 30 decision tree, 531, 532-533
compact disk, read only memory (CD-ROMs), degradation products, 278-280, 281
388, 389, 390. See also computers Deming, W. Edwards, 371, 377, 387, 523
compendia! requirements, 512 departures from approved conditions or
compendia! standards, 549-SSO procedures. See deviations
computers design qualification (DQ), 143, 144, 453
compliance information via, 388-389 development reports, 5, 6, 160, 167
in determining significant change, 528 deviations, 294. See also adulteration
in labeling, 149 common audit findings, 136-137
validating, 172, 297 examples, 304-308
validation case study, 179-181, 197 quality problems causing, 302-304
in warehouse management, 141 regulatory considerations, 29S-296
concomitant components, 27S scope of investigating, 297-304
concurrent validation, 116-117, 269 dextrose, 507-508, 546
after initial validation, 182 diastereoisomers, 551
in Barr Laboratories decision, 71 dibasic caldum phosphate, 547
case study, 172-176, 182-184 differential pressure, 512. See also pressure
cleaning process, 233-241 differentials
of computer systems, 179-180 differential scanning calorimetry (DSC), S49
controlled environment, 220-226 dioctyl phthalate (DOP) testing, 498, 512
guidelines, 163-164, 187, 560 discipline review letters, 88
in' master plan schedule, 168, 169 dissolution testing, 80
micronization, 242-2S1 distill and, 512
protocol, 199 distillation, 512
supreme process, 227-232 distributed control system (DCS), 179
condemnation, 34-35 distributors, 344. See also vendors
conductivity, 410, 411 DMFs (Drug Master Files), 3, 83, 541, 545
Consumer Healthcare Products approval, 89
Association, 330 basic requirements, 545
Index 577
compliance, 5, 382 DSC (differential scanning calorimetry), 549

Guideline for Drug Master Files, 42-43, 84 Due Process Clause (Fifth Amendment), 61
handling process, 85-86 D value, 489, 512
holder and applicant relationship, 84-85
holder obligations, 43-44 EC (European Community), 29-30, 47, 435
in impurity detection, 127 economic adulteration, 19
intermediates and starting materials, 93 edetate, 547
and manufacturing changes, 95, 520, EEA, member countries, 51
521,537 EEC (European Economic Community), 373
multisite, 91-92 EFPIA (European Federation of
regulatory basis, 84 Pharmaceutical Industries'
reviewing, 87-89, 93-95 Association), 99, 111, 114, 128
status as record, 44, 545 EFTA (European Free Trade Association), 373
types of, 42-43, 51-52, 89-91 EIRs (Establishment Inspection Report),
USP monograph as, 272 48,348
in vendor qualification, 360, 364 ELISA (enzyme-linked immunosorbent
documentation. See also labeling; SOPs assay), 410, 412
BACPAC filing, 332-333 EMS (eosinophilia-myalgia syndrome), 125
Barr Laboratories decision, 75-76 enantiomeric impurities, 276
of batches, 123, 150-152, 167, 168, 191 enantiomers, 285, 550-551
CBE supplement, 288-289 endotoxins, 512
change control, 43-44, 52, 466 limits, 506-510
cleaning validation, 406, 420-425 testing for, 413, 440, 503-506
developmental reports, 5, 6, 160 endotoxin unit (EU), 505, 512
deviations, 136-137, 302 Environmental Protection Agency. See EPA
Drug Master Files (see DMFs) environment monitoring. See also
equipment, 145, 149 microbiological control; sterility
failure investigation reports, 136-13 7 validation
Guideline for Submitting Supporting air, 497-499 (see also airflow)
Documentation in Drug Applications for concurrent validation, 220-226
the Manufacture of Drug Substances, critical areas, 495-496
108, 126 need for, 494-495
international noncompliance, 104 nonsterile areas, 496
ISO 9000 requirements, 537 operators, 495, 501
master plan (see Master Plan; validation surfaces, 499-501
master plan) technology transfer, 318
master production and control, 150-151 testing sites and frequency, 496-497
new drug applications (see ANDAs; NDAs) trending data, 501
raw data, 156 enzyme-linked immunosorbent assay
validation development, 264-265 (ELISA), 410, 412
validation protocols (see validation eosinophilia-myalgia syndrome (EMS), 125
protocols) EPA (U.S. Environmental Protection Agency)
validation requirements guide, 566-569 on calculating limits, 418
validation summary report, 175-176, Premanufacturing Notices, 551-553
252-259,463 on water systems, 440, 479
in vendor audits, 354-355, 357, 359 equipment
DOP (dioctyl phthalate) testing, 498, 512 calibration, 148-149, 361, 364
dosage form manufacturing, 263-264, 401. changes to, 335-336, 534-537 (see also
See also finished drug products change control)
Dow manufacturing process, 554-556 cleaning (see cleaning process)
DQ (design qualification), 143, 144, 453 in deviation investigations, 299
drug listing, 3 in microbiological control, 488-493
Drug Master Files. See DMFs multiple use versus dedicated, 399-401
drug product, 520, 541, 543 qualification, 143-145, 157-158, 453-454
drugs, APis as, 13-14. See also new drugs in technology transfer, 320-321, 322-323
drug substances, 520, 541. See also active in vendor audits, 361
ingredients; APis; BPCs; BPEs Escherichia coli, 469, 485
Establishment Inspection Report (EIRs), Federal Records Center, 85

48,348 on filter validation, 446
ethyl cellulose, 54 7 focus on APis, 1
EU (endotoxin unit), 505, 512 Foreign Inspection Working Group, 28
EU (European Union), 51, 108 forms (see under Form FDA)
European Chemical Industry Council GMP regulations (see GMPs)
(CEFIC), 99, 111, 114 on harmonization, 127, 128
European Community (EC), 29-30, 47, 435 import/export authority, 22, 37-42
European Economic Community (EEC), 373 on impurity testing, 6, 124-127
European Federation of Pharmaceutical increasing validation regulations, 55,
Industries' Association (EFPIA), 99, 188,261-262,345
111, 114, 128 inspection criteria (see site inspections)
European Free Trade Association (EFTA), 373 on microbiological contamination, 476
European Pharmaceutical Excipient Council, Modernization Act (see FDAMA)
546--547 on-line services, 389
European PIC (Pharmaceutical Inspection PAl policy, 5
Conference), 2. See also PIC on process change, 519-522, 524, 525,
European Union (EU), 51, 108 528, 529, 537, 538
excipients. See also BPEs process steps and parameters, 113-116
BPCs as, 6-7, 25-26, 45 on process validation, 17-19, 519-520
functions of, 546 purpose, 83
and impurities, 278-279 QA evolution, 373, 374 (see also QA)
inspecting, 25-26, 45 on reprocessing/reworking, 123-124
manufacturing changes (see change risk policies, 415
control; process change) on site changes, 531
testing methods, 549-550 (see also specific on starting material, 107-110
method) SUPAC, 329, 520
excursions from approved conditions or validation guideline of 1987, 69-70
procedures. See deviations on water quality, 120-123, 481
expiration dates, 159 FDA guidelines
explosion suppression validation, 566 Aseptic Processing Guideline, 503
exports, 40-42, 51 Biotechnology Inspection Guide, 399
BPC Guide, 16, 18, 24-25
failure investigations, 136--13 7, 356--35 7, Bulk Active Chemical Postapproval
364. See also deviations Changes (see BACPAC I; BACPAC II)
Fair Packaging and Labeling Act, 28. See also Bulk GMPs for Drug Substances-
labeling Position Paper on GMP Control and
FDA (U.S. Food and Drug Administration) Validation, I l l
accepting retrospective validation, Bulk Pharmaceutical Chemical Guide,
163-164, 560 293,296
on APis as drugs, 13-14, 544 Changes to an Approved NDA or ANDA,
Bacterial Endotoxins Test, 505 95,520
Center for Drug Evaluation and Research Compliance Policy Guide on
(see CDER) International MOU, 28
Central Documents Room, 85 Compliance Program Guidance Manual for
cGMP regulations (see cGMPs) APis, 544
on change control, 310 Current Good Manufacturing Practices
on chemicals becoming APis, 12-13 Regulations for Finished
chiral drug marketing guidelines, 550 Pharmaceuticals, 68
on cleaning validation, 404, 407 Current Good Manufacturing Practices
compliance profiles, 348 Regulations for Medical Devices, 68
contact information, 84 Draft Guidance for Industry on Exports and
disciplinary actions, 88, 349, 359 (see also Imports Under the FDA Export Reform
recalls; warning letters) and Enhancement Act of 1996, 42
DMF regulations (see DMFs) The Gold Sheet, 520
on equipment changes, 535 Good Guidance Practices, 100
on equipment cleaning and validation, Guidance for Industry: ANDAs: Impurities in
118-119 Drug Substances, 47, 127
Index 579
Guidance for Industry: Content and Format history, 188, 372, 429
of Investigational New Drug Applications on imports, 40
(INDs) for Phase I Studies of Drugs, In- judicial analysis, 61, 77
cluding Well-Characterized, Therapeutic, Kefauver-Harris amendment to, 372
Biotechnology-Derived Products, 95 site inspections, 4-7, 23
Guidance for Industry: Manufacturing, Pro- violation punishment, 51
cessing, or Holding Active Pharmaceuti- fermentation, 551, 558
callngredients, 98-101, 105, 114, 115, FIFO (first-in/first-out), 142
116-117, 118-119, 120, 124, 127, 137, filters
293,294,296,476,521,544 in airflow patterns, 437, 442
Guideline for Drug Master Files, 42-43, 84 blinding of, 535-536
Guideline for Submitting Supporting documentation, 440
Documentation in Drug Applications for in microbiological control, 487-488,
the Manufacture of Drug Substances, 84, 492-493,502,504
108, 126 validating, 439
Guideline for Validation of the Limulus filtration systems, 445-446, 448, 479. See
Amebocyte Lysate Test as an End Product also water systems
Endotoxin Test for Human and Animal final intermediates, 556
Parenteral Drugs, Biological Products and finished drug products, 106. See also dosage
Medical Devices, 505, 506, 507, 510 form manufacturing
Guideline on Sterile Drug Products Produced first-in/first-out (FIFO), 142
by Aseptic Processing, 431, 496 Food and Drug Administration. See FDA
Guidelines on General Principles of Process Food and Drug Amendments of 1962, 55,
Validation, 431, 521, 553, 554 56-59
Guide to Inspection of API Manufacturing, Food, Drug, and Cosmetic Act. See FD&C Act
544,567,569 foreign API facilities. See also international
Guide to Inspection of Bulk Pharmaceutical manufacturing
Chemicals, l, 2, 17, 98, 106, 113, 376, agents for, 344
380,398 FDA guidance affecting, 100-101
Guide to Inspection of Validation of inspections, 26-30, 37, 101-105, 345-346
Cleaning Processes, 6 vendor qualification considerations, 349
Guide to Inspections of High Purity Water foreign substances. See impurities
Systems, 439 Form FDA 483
Guide to Inspections of Sterile Drug on cleaning process, 104, 406
Substance Manufacturers, 493 legal effect of, 51
Kinetic LAL Testing: Interim Guidance for as part of EIR, 48
Human Veterinary Drug Products and responding to, 32
Biologicals, 505, 507, 510 on SOPs, 134
"Manufacture, Processing or Holding of Form FDA 712, 37-38
Active Pharmaceutical Ingredients," Form FDA 717, 38
70, 79 Form FDA 718, 38
The Manufacturing, Packaging, and Form FDA 766, 38
Holding of Active Pharmaceutical Form FDA 772, 38
Ingredients, 398 Fourier transform infrared (FTIR), 410
Sterilization Process Validation, 43 9 F0 value, 489, 512
FDAMA (FDA Modernization Act) fractional crystallization, 551
amendments, 46 fractional factorial design, 554, 559
on foreign manufacturing, 27, 28 Fry, Edmund M., 21
on OTC drugs, 47 FTIR (Fourier transform infrared), 410
in vendor qualification, 351 fungistasis, 512. See also B/F (bacteriostasis
FD&C (Federal Food, Drug, and and fungistasis) testing
Cosmetic) Act
adulteration protection, 14, 15 galenic validation, 263-264, 267
applying to bulk and finished drugs, 67, Gantt chart, 563, 564
385,388,543 Gardner v. Toilet Goods Ass'n, 77
enforcement tools, 34-37 (see also GC (gas chromatography), 265, 274, 549
Warning Letters) generic drug scandal, 21, 24, 374
and foreign manufacturers, 28 Generic Pharmaceutical Association, 330
Generic Pharmaceutical Industry on process validation, 265

Association, 330 Q2A document, 282
Generic Products Industrial Association, 99 Q2B document, 282
German Association of Research Based Q3A document, 47, 275, 331, 332, 334
Pharmaceutical Companies, 99 Q3B document, 275
Ciaccia v. Pennsylvania, 61 Q6A document, 277-278, 285-287
glycerine, 539-540 Q7 A document, 2, 46, 97, 128
GMP Compliance Program, 4 Import Alerts, 38-40, 51
GMPs (Good Manufacturing Practices). See imports, 22, 37-40
also cGMPs impurities. See also adulteration
awareness training, 153-154 BACPAC guidelines, 287-289, 333,
concepts, 2-3 334-335
for excipient BPCs, 7, 524 enantiomers as, 285
history, 188 FDA guidelines, 6, 47, 124-127
judicial analysis of, 63, 66 guidance for APis, 282-284
microbiological control, 484 ICH documents on, 275-280, 281
quality assurance, 372 nature of contaminants, 404-405
quality reviews (APQRs), 139 polymorphs as, 285-287
site inspections checking, 4 process validation, 267-268, 280, 282
Good Manufacturing Practices. See GMPs sample USP monograph, 272-273
Gram-negative bacteria, 503-504, 509 USP descriptions of, 273-275
grand jury subpoenas, 31-32 impurity profiles, 462-463, 541
gravimetric analysis, 410 evaluating changes in, 522, 529
guaifenesin, 403 in PAl policy, 5
USP guidelines, 559
harmonization, 27-30, 127-129, 381, 398. inactive ingredient, 543. See also excipients
See also ICH IND (Investigational New Drug), 83, 467, 545
Health Protection Branch (HPB), 127, 128 indirect visualization, 412, 426
heat exchangers, 447 Information Request, 88
HEPA (high efficiency particulate air) filters, infrared spectroscopy, 280, 326, 549
437, 442, 498, 513 injunctions, 35
high performance liquid chromatography. inorganic impurities, 275
See HPLC in-process material, 543
Homeopathic Pharmacopeia of the United input variables. See operational parameters
States, 13, 19-20, 543 In re Grand Jury Subpoenas, 31
hormonal drugs, 551 In re Medtronic, Inc., 31
HPB (Health Protection Branch), 127, 128 in rem legal action, 35
HPLC (high performance liquid inspections. See site inspections
chromatography) Installation Qualification. See IQ
chiral versus achiral assay, 285 insulin, 507
in cleaning validation, 410, 412 intercompany technology transfer, 319
compendia! standards, 549 intermediates, 93, 556
for ordinary impurities, 273 International Conference on Harmonisation.
in purification phase, 265 See ICH
in technology transfer, 325 international manufacturing. See also EC
humidity conditions, 437 (European Community); foreign API
hydrochloric acid, 547 facilities
hydroxpropylmethyl cellulose, 547 cGMP noncompliance, 101-105
hydroxyethyl cellulose, 547 in developing QA, 386
FDA guidance affecting, 381
ICH (International Conference on and regulatory inconsistency, 382
Harmonisation). See also International Organization for
harmonization Standardization. See ISO
on API manufacture, 99, 398 International Pharmaceutical Excipients
and generic drug industry, 374 Council. See IPEC
on impurities, 127, 275-280, 281 International Society for Pharmaceutical
on master/batch records, 151 Engineering (ISPE), 114, 128, 163
Index 581
Internet, 389. See also computers laboratory operations, 154-160

intracompany technology transfer, 318-319 lactose, 54 7
Investigational New Drug (IND), 83, 467, 545 LAL (Limulus Amebocyte Lysate) test, 440,
ion chromatography, 410 504,505,506,513
IPEC (International Pharmaceutical laminar airflow, 498, 513
Excipients Council) LCL (lower control limit), 525-526
on equipment changes, 535 Letters of Authorization (LOAs), 85, 91,
GMP guideline, 6-7 92, 93
Good Manufacturing Practices Guide for limit of detection (LOD), 282
Bulk Pharmaceutical Excipients, 114, limit of quantitation (LOQ), 282
521,522 LIMS (laboratory information management
harmonization monographs, 546-547 systems), 157
levels of change, 529-530 Limulus Amebocyte Lysate (LAL) test, 440,
on processing changes, 538, 539 504,505,506,513
on significant process change, 525, lipase immobilized hollow-fiber
528-531, 532-533 membranes, 551
on site changes, 531 LOAs (Letters of Authorization), 85, 91,
as vendor qualification resource, 366 92,93
IQ (Installation Qualification), 541 LOD (limit of detection), 282
equipment, 453-454, 455, 535 LOQ (limit of quantitation), 282
microbiological control, 482 lower control limit (LCL), 525-526
site changes, 531 Lowry protein analysis, 410, 412
site inspections, 143, 144-145, 158 !-tryptophan, 125, 261
validating sterile APis, 430, 445
validation case study, 172-173, 180, MACO (maximum allowable carryover),
192-197 418-419
validation master plan, 563 macroappearance, 549
ISO (International Organization for magnesium stearate, 547
Standardization), 373 main reactants, 556
ISO 9000 standard, 373, 379, 385, 537 manual cleaning, 407
isolators, 513 manufacturers, 344. See also vendors
isolator systems, 493-494, 502-503 manufacturing
ISPE (International Society for API process, 520, 554-559
Pharmaceutical Engineering), 114, changes (see change control)
128, 163 chemistry, manufacturing, and controls,
83, 95
Japanese Pharmaceutical Excipient Council, dosage form, 263-264, 401
546-547 foreign (see foreign API facilities;
Japanese Pharmacopoeia OP), 479 international manufacturing)
JIT (just in time), 371 postapproval changes (see BACPAC I;
JP Oapanese Pharmacopoeia), 479 BACPAC II)
Juran, Joseph M., 371, 523 marketing department, in technology
just in time OIT), 371 transfer, 310-311
master/batch record system, 150-151, 357.
key intermediates, 556 See also batches
Master Plan, 420, 421, 452. See also
labeling validation master plan
changes in, 523 material flow, 317-318, 439
controls, 149 Material Safety Data Sheets (MSDS), 313, 418
Fair Packaging and Labeling Act, 28 maximum allowable carryover (MACO),
in misbranding, 20 418-419
of production equipment, 145, 149 maximum valid dilution (MVD) factor, 505
and storage guidelines, 326 media fills, 492
in vendor qualification, 362, 364-365 meso-compounds, 551
of warehouse stock, 141 method validation, 157
laboratory information management methylparaben, 547
systems (LIMS), 157 microbial testing, 413, 440, 550
microbiological control. See also sterility New Chemical Entities (NCEs), 24, 312,
validation 375,406
affecting processing, 486-488 New Drug Applications. See NDAs
bioburden, 484-486 new drugs, 14
endotoxin testing, S03-S06, S06-S10 applying cGMP to, 64-6S
environmental monitoring, 494-501 exporting, 40-42
facilities and equipment, 488-493 preapproval inspections, 23-24
as governed by GMPs, 47S-478 NF (National Formulary), 13, 19, S43
isolator systems, 493-494 NIR (near infrared), 410
and process change, S29 NOEL (no observed effect level), 418-419
SOPs, 478-479 Nonprescription Drug Manufacturer's
sterility testing, S02-S03 Association (NDMA), 390
water quality, 479-484 no observed effect level (NOEL), 418-419
microcrystalline cellulose, S47
micronization, 242-2S 1 objectionable microorganism, S13
microscopy, 410 Office of Generic Drugs, 93
misbranding Office of New Drug Chemistry, 93
and exporting, 40 Office of Regulatory Affairs (ORA), 98, 99
FD&C protecting against, 14, IS, 20 Office of the General Council, 98
and importing, 39 on stability programs, 1S9
mobile phases, labeling of, 1S8 on starting material, 108
Motise, Paul, 47S OOS (out-of-specification) results
MSDS (Material Safety Data Sheets), batch release procedure, 136
313,418 CofA validation, ISS
MVD (maximum valid dilution) factor, SOS guidelines for handling, 1S8, 296
microbiological control, 484
NADA (New Animal Drug Application), 14. versus process deviations, 294
See also new animal drugs vendor audits, 356-357
National Association of Pharmaceutical open isolator, 494
Manufacturers (NAPM), 99, 330 operational parameters, 459, 460-461,
National Association of Pharmaceutical S24-S2S
Manufacturers ("NAPM") v. Department Operational Qualification. See OQ
of Health and Human Services, 64, 78 optical isomers, 27S. See also enantiomers
National Association of Pharmaceutical optical microscopy, S49
Manufacturers ("NAPM") v. FDA, 61 OQ (Operational Qualification), S41
National Center for Drugs and Biologics, 21 equipment, 453, 4S4, 456, 535
National Drug Manufacturers microbiological control, 482
Association, 330 site changes, S31
National Formulary (NF), 13, 19, S43 site inspections, 143, 145, 158
National Nutritional Foods Ass'n v. validating sterile APis, 430, 445
Weinberger, 77 validation case study, 172-173, 180,
National Pharmaceutical Alliance, 99, 330 192-197,200
NCEs (New Chemical Entities), 24, 312, validation master plan, 563
37S,406 ORA (Office of Regulatory Affairs), 98, 99
NDAs (New Drug Applications) oral administration, 485
DMF supporting, 42, S4S (see also DMFs) organic impurities, 27S,.276
and drug listings, 3 organic nonelectrolytes, 548
interstate commerce requirement, 14 organic volatile impurities (OVIs), 274
PAl policy, S (see also PAl) OTC (over-the-counter) drugs, 47, 101, 390
postapproval changes, 332-333, 337, S34 out-of-specification results. See OOS
in quality assurance, 373 output variables. See performance
using Process Development Report, 311 parameters
versus USP monograph, 272 over-the-counter (OTC) drugs, 47, 101, 390
NDMA (Nonprescription Drug OVIs (organic volatile impurities), 274
Manufacturer's Association), 390
near infrared (NIR), 410 packaging, 28, 326, S23. See also labeling
New Animal Drug Application (NADA), 14 PAl (preapproval inspection) policy
new animal drugs, 14, 23-24, 40 developmental reports for, 6
Index 583
in DMF process, 92 on postapproval changes, 330

FDA authority, 23-25 Quality Control Bulk Pharmaceutical
history, 5, 379 GMP Task Force, 535
laboratory operations, 154 physical properties, 522, 541
quality assurance role, 382-383, 385, PIA (Pharmaceutical Industries Association),
391-392 372-373
Parenteral Drug Association. See PDA PIC (Pharmaceutical Inspection
partial barrier, 494 Convention), 99, 127, 128, 373. See
particle morphology, 549 also European PIC
particle size distribution, 549 PIC/S (Pharmaceutical Inspection
particulates, 513 Cooperation Scheme), 99, 127, 128
passive sampling, 498 P&IDs (piping and instrumentation
PDA (Parenteral Drug Association) diagrams), 167, 168, 180
on GMP guidance document, 99 pilot plant, 319-320
on postapproval changes, 330 pilot unit testing, 530
Technical Report #13: Fundamentals of a piping and instrumentation diagrams
Microbiological Environmental (P&IDs), 167, 168, 180
Monitoring Program, 495-496 pivotal intermediates, 556
Validation of Computer-Related Systems, 116 Plan-Do-Study-Act (PDSA) cycle, 377, 378,
PDSA (Plan-Do-Study-Act) cycle, 377, 378, 388-393,395
388-393,395 planned deviations, 137
penicillin, 400, 493 plasmid stability testing, 461
performance parameters, 460, 461-462 PM (preventative maintenance), 299. See also
Performance Qualification. See PQ equipment
personnel flow, 437-438 PMA (Pharmaceutical Manufacturers
Personnel Training Program, 4. See also Association). See also PhRMA
training Concepts for the Process Validation of Bulk
PERT chart, 563 Pharmaceutical Chemicals, 110-111
Peters, Tom, 388 on GMP guidance document, 98
petrolatum, 547 using "BPC," 544
PFDs (process flow diagrams) on validation, 114-115
in technology transfer, 313-314, 315 PMN (Premanufacturing Notice), 551-553
in validation case study, 167, 168, 180 polyethylene glycol, 54 7
Pharmaceutical Industries Association (PIA), polymorphs
372-373 as impurities, 275, 276, 285-287
Pharmaceutical Inspection Convention and preapproval inspection, 5, 6
(PIC), 99, 127, 128, 373. See also in technology transfer, 326
European PIC polysorbate 80, 547
Pharmaceutical Inspection Cooperation postapproval manufacturing changes. See
Scheme (PIC/S), 99, 127, 128 also BACPAC I; BACPAC II; change
Pharmaceutical Manufacturers Association. control; process change
SeePMA FDA guideline, 46-4.7
Pharmaceutical Press, 546 process validation, 18, 336-337
Pharmaceutical Research and Manufacturers potato dextrose agar, 498
of America. See PhRMA PQ (performance qualification), 453,
Pharmaceutical Technology, 111 454,482
pharmacy compounded drug products, 46 PQ (process qualification)
pH method, 410, 411, 525-529, 550 validation case study, 172, 173, 174,
PhRMA (Pharmaceutical Research and Man- 227-232
ufacturers of America). See also PMA vendor qualification, 143, 144
air monitoring survey, 499 preapproval inspection (PAl) policy, 5, 23-25
on BPC validation, 429 Premanufacturing Notice (PMN), 551-553
on dosage versus APis, 263-264 premarket validation. See prospective
on GMP guidance document, 98, 99 validation
on harmonization, 128 pressure differentials, 435-437, 497. See also
PhRMA Guidelines for the Production, differential pressure
Packing, Repacking, or Holding of Drug pressure hold test, 487
Substances, 105, 544 pretreatment, 513
preventative maintenance (PM), 299. See also case study, 168, 169, 172-176, 182-184
equipment cleaning process, 233-241
process capability study, 526-527, 528, 529 computer systems, 197
process change, 519, 541. See also BACPAC I; guidelines, 161, 163, 187, 554
BACPAC II; change control; micronization, 242-251
postapproval manufacturing changes process equipment, 195-196, 210-219
equipment, 534-537 protocol, 199, 560
facility, 531, 534 support systems, 192-194
identifying significant, 522, 524-531, supreme process, 227-232
532-533 providone, 54 7
regulations, 519-524 pseudoephedrine, 402-403
technology (see technology transfer) Pseudomonas aeruginosa, 485
Process Development Report, 311, 313-316 Public Health Service Act, 28, 51
process flow diagrams. See PFDs Pure Food and Drugs Act of 1906, 56,
processing, 519, 541 164, 188
process pool stability testing, 461 purification. See impurities
process qualification. See PQ purification stage testing, 550
process status table, 316 purity profiles, 536, 539-540
process transfer document, 313-316 pyrogens, 503, 504-506, 513
process validation
activity timing, 458-459 "Q" documents. See under ICH
analytical methods, 409 QA (quality assurance)
Barr Laboratories decision, 70-76 annual reviews, 139
case study, 166-185, 187-259 batch release procedure, 136
change control, 266-267, 466-468 change control system, 138-139
cleaning (see cleaning process) compliance inspections, 381-383
critical parameters in, 115_-116, 161, deviation and failure investigations,
165,422,460 136-137, 296
critical steps in, 112-115, 161-162, emphasizing GMPs in, 380-381
267,554 evolution of, 369-375
definition, 16, 69, 164, 430, 553 installing system of, 383-38 7
documenting (see documentation) management philosophy, 375-380
dosage form versus APis, 263-264 in Master Plan, 452
explosive suppression, 566 Medical Products Quality Assurance Staff,
goal of, 457 23-24
guideline application for APis, 110-113 in microbiological control, 484
history, 67-68, 164 PDSA cycle, 388-393, 395
impurity testing (see impurities; impurity quality system diagram, 394
profiles) reworking and reprocessing, 137-138
master planning, 452 standard operating procedures, 134-136
microbiological control, 477, 482- structure, 133-134
484,495 technology transfer, 318
modular approach to, 165-166 validation case study, 167-168
monitoring, 464-466 in vendor qualification, 350, 355,
as part of GMP, 2-3 364,365
protocols (see validation protocols) QC (quality control)
revalidation, 467, 468-469 definition of quality, 272
sterility (see sterility validation) laboratory operations, 154-160
technology transfer, 266, 323-324 in Master Plan, 452
types of, 71, 72, 116-118, 268-269 quality control unit, 133, 295, 386
of unit operations, 554 technology transfer, 318
variables, 459-462 in vendor qualification, 350
in vendor audits, 357 QFD (quality function deployment), 387
prodrugs, 549 QP (Qualified Person), 134, 136
production equipment, 145-146 QS 9000 standard, 379
product validation, 430 Qualified Person (QP), 134, 136
prospective validation, 117, 269 quality assurance. See QA
in Barr Laboratories decision, 71 quality control. See QC
Index 585
quality function deployment (QFD), 387 room classifications, 434-435, 497, 499. See
Quality System Program, 4 also airborne particulate cleanliness
quarantine control, 141, 143 class
quaternary compounds, 548 RTDs (resistance thermal devices), 489
rabbit pyrogen test, 504, 506 Sabouraud dextrose agar (SDA), 498
racemates, 550-551 safety factor (SF), 418
raw data handling, 156 safety programs, 318, 360
raw materials, 513. See also starting salicylic acid, 554-556
materials Salmonella, 485
changes in, 522,523,531,534,538 sampling. See also swab sampling
handling, 140-143,347 air, 498-499
in technology transfer, 314, 316, 320 Barr Laboratories decision, 72
R&D (research and development), 160- cleaning validation, 178, 407-409,
161,318 423,456
rDNA technology, 12 facility for, 142
reaction stage testing, 550, 559 before import, 37-38
reagents, labeling of, 158 RODAC™, 438, 499
recalls, 34, 349, 359 stability programs, 159-160
recombinant DNA technology, 513 surface, 499-501
rectal administration, 485 trending data from, 501
refractive index, 326 vendor qualification, 349, 350
replicate organism detection and counting scale changes, 562
(RODAC™) samples, 438, 499. See also Scale-Up and Postapproval Changes
contact plate sampling (SUPAC), 329, 520
reprocessing scale-up process. See technology transfer
in APis versus drug products, 562 scanning electron microscopy, 549
in deviation investigation, 301 SCD (soybean casein digest) medium,
in FDA BPC guidelines, 296 498,500
and preapproval inspections, 5 SDA (Sabouraud dextrose agar), 498
versus reworking, 123-124, 137-138 SDS-PAGE (sodium dodecyl sulfate-
in vendor qualification, 357, 363-364 polyacrylamide gel electrophoresis)
research and development (R&D), 160- analysis, 410, 412
161,318 search warrants, 22, 31
residue limits. See also cleaning process seizure action, 34-35, 57
calculating, 414-420 SF (safety factor), 418
regulatory requirements, 398, 399 signal impurities, 27 4
residue on ignition testing, 550 significant new use rule (SNUR), 552
resistance thermal devices (RTDs), 489 significant process change, 522, 524-531,
retrospective validation, 117, 118, 268 541,560
in Barr Laboratories decision, 71, 72 significant process steps, 113. See also
case study, 168, 169-171, 179-180, 198, process validation
201-209 site changes, 531, 534, 561-562. See also
FDA accepting, 163-164 change control; technology transfer
guidelines, 162, 554, 559-560 site inspections
revalidation, 468-469, 554, 560. See also common carrier authority, 30
change control; process change EIRs, 48
reverse osmosis, 4 79, 513 equipment and facility qualification,
reworking 143-146, 361
in deviation investigation, 301 equipment calibration, 148-149, 361
in FDA BPC guidelines, 296 equipment cleaning, 146-148, 358, 400
versus reprocessing, 123-124, 137-138 FDA guidelines, 4-7, 22-23
in vendor qualification, 357, 363-364 foreign, 26-30, 37, 101-105, 345-346
rinse sampling, 407, 408, 411, 419 grand jury subpoenas, 31-32
risk, 415-416, 529-530 history, 21-22
RODAC™ (replicate organism detection and labeling controls, 149, 362, 365
counting) samples, 438, 499. See also for OTC drugs, 47
contact plate sampling priorities, 25-26
process validation, 161-162 starting materials, 93, 107-110, 332. See also
QC laboratory operations, 154-160 raw materials
and quality assurance, 133-139, 379 State Pharmaceutical Administration
raw materials handling and controls, (China), 128
140-143 statistical process control. See SPC
record keeping, 150-152 steam cleaning, 444-445
recovering solvents, 149-150 stearic acid, 54 7
research and development, 160-161 sterile, definition, 513
scope of authority, 23-25 sterile bulk antibiotics, 544
. and search warrants, 22, 31 sterility validation. See also cleaning process;
training, 153-154 environment monitoring;
in vendor qualification, 350, 353-366 microbiological control
site registration, 3 facilities, 432, 434-439, 456-457
smallest therapeutic dose method, maintenance, 449
416-417 manufacturing process, 432, 433,
SNUR (significant new use rule), 552 447-449
sodium chloride, 547 microbiological control, 489-493
sodium dodecyl sulfate-polyacrylamide gel protocol format, 431-432
electrophoresis (SDS-PAGE) analysis, regulatory documents, 431
410,412 support systems, 439-447
sodium hydroxide, 547 sterilization, definition, 513
sodium saccharin, 547 sterilizing filter, 514. See also filters
sodium starch glycolate, 547 steroids, 400, 493
solvents. See also cleaning process sucrose, 547
as impurities, 274, 275, 276 sulfanilamide, 3 72
recovery of, 5, 149-150 SUPAC (Scale-Up and Postapproval
rinse sampling, 407, 408 Changes), 329, 520
SOPs (Standard Operating Procedures). See suppliers, 344. See also vendors
also documentation swab sampling. See also sampling
change control, 467, 468, 560-561 analytical methods, 409
compliance, 4 FDA preference for, 407-408
endotoxin testing, 5 10 limit calculation, 419-420
equipment cleaning, 146 microbiological monitoring, 499, 500
FDA guidelines, 134-136 versus visual examination, 411
microbiological control, 478-479, Swiss Intercantonal Office for the Control of
482-483 Medicines, 128
operational parameters in, 459
in validation case study, 167-168, talc, 547
189-190 Taylor, Frederick, 3 70
vendor audits, 355, 362 technology transfer. See also change control;
vendor qualification, 346, 347, 352, 353 site changes
warehouse operations, 140-143 API container/closure, 326
soybean casein digest (SCD) medium, categories, 312-313
498,500 marketing role, 310-311
SPC (statistical process control), 541 organization, 317-319
in determining significant change, in PAl compliance, 392
525-526 process definition, 311
in improving manufacturing process, 523 Process Development Report, 313-316
in processing changes, 538, 539 regulations, 327
stability, 5, 326, 327, 461 scale-up process, 319-326
stability programs stability, 327
in facility audits, 159-160 validating, 266
and impurities, 284 technology transfer team, 317-318
in vendor qualification, 358, 364 temperature conditions, 437
Standard Operating Procedures. See SOPs testing methods, 549-550. See also specific
standard solutions, labeling, 158 method
Staphylococcus aureus, 485 TGA (Therapeutic Goods Administration),
starch, 547 127, 128
Index 587
thalidomide, 125, 372 United States v. Calandra, 31

Therapeutic Goods Administration (TGA), United States v. Consolidated Midland
127, 128 Corp., 78
thermal analysis, 549 United States v. Dianovin Pharmaceuticals,
thermocouples, 489 Inc., 79
thin layer chromatography (TLC), 265, 273, United States v. Dotterweich, 77
410,549 United States v. Jamieson-McKames
thiophosphate ester, 540 Pharmaceuticals, Inc., 31
threshold pyrogenic dose, 514 United States v. Kendall Co., 78
titanium dioxide, 547 United States v. Lit Drug Company, 79
titration, 410 United States v. Medwick Laboratories, Inc., 65
TLC (thin layer chromatography), 265, 273, United States v. Morton Norwich Products, Inc.,
410, 549 63, 78
TOC (total organic carbon) analysis, 410, United States v. Park, 36-37
411, 413-414 United States v. 789 Cases, 58, 79
biotechnology cleaning validation, 412, United States v. Undetermined Quantities ...
454,456 Larson Laboratories, Inc., 65-66
microbiological monitoring, 483 United States v. Undetermined Quantities of
trend toward, 426 Various Articles, 79
Toilet Goods Ass'n v. Gardner, 78 United States v. Westem Serum Co., Inc., 77
topical administration, 485 unlicensed biologicals, exporting, 40--42
total organic carbon. See TOC upper control limit (UCL), 525-526
total process management (TPM), 371 urethral administration, 485
total quality management. See TQM U.S. Army Medical Bioengineering Research
toxicity method, 417-420 and Development Laboratory, 418
toxic substances. See impurities U.S. Environmental Protection Agency.
Toxic Substances Control Act (TSCA), 552 See EPA
TPM (total process management), 371 U.S. National Institute of Standards and
TQM (total quality management). See also QA Technology, 181
components, 386-387, 391 USP (United States Pharmacopeia)
evolution of, 371, 378 on adulteration, 19
terminology, 383-384 on API and drug recognition, 13, 543
training Bacterial Endotoxins Test, 504, 505
cleaning processes, 423 in Barr Laboratories decision, 73
departure from SOP, 137 on endotoxin limits, 506
deviations relating to, 299-300 on impurities, 125-126, 271, 273-275
FDA guidelines, 153-154 on method validation, 157
microbiological control, 495 on microbiological control, 476, 485,
Personnel Training Program, 4 495,499,501
vendor qualification, 356, 363, 365 Pyrogen Test, 504, 506
transfer hoses, 146 requirements changes, 520
TSCA (Toxic Substances Control Act), 552 Sterility Test, 479, 492, 502, 503
t-test of the means, 527-528 as vendor qualification resource, 366
on water quality, 121, 440, 479, 481, 483
UCL (upper control limit), 525-526
ultrafiltration, 514 vacuum systems, 447
ultraviolet spectroscopy, 326, 549 vaginal administration, 485
United States Pharmacopeia. See USP validation, 514. See also specific types of
United States v. An article of drug... George N. validation
Bell Manufacturing Chemists, 57, 62, validation life-cycle approach, 188
63,78 validation master plan. See also Master Plan
United States v. Articles of Drug... Colchicine, 78 case study, 168, 174-175, 199
United States v. Barr Laboratories, 70-76, 294, format, 563, 564, 567
380--381,399,404 validation protocols. See also process
United States v. Bel-Mar Laboratories, Inc., 58, validation
63, 65, 78 case study, 175
United States v. Bronx Drug Co .... Isaac cleaning process, 421-425
Zonana, 79 in master planning, 452
recombinant protocol requirements, 463 water systems. See also filtration systems; WFI
sample, 471-474 in cleaning process, 426
validation summary report, 175-176, deficiencies, 104
252-259, 463 FDA guidelines, 120--123
vendor certification impurities, 283
ISO 9000, 3 73 microbiological control, 479-484
procedure overview, 346-347 site changes, 531
purpose, 345-346 sterility validation, 439-442
system, 351-352 validation case study, 172, 173, 17 6,
vendor qualification 178-179
definition of terms, 344-345 weak acids and their salts, 548-549
in microbiological control, 485--486 weak bases and their salts, 548-549
monitoring program, 352-353 Weinberger v. Bentex Pharmaceuticals, Inc., 77
procedure overview, 346-347 Weinberger v. Hynson, Westcott & Dunning,
purpose, 345-346 Inc., 78
site inspections, 353-366 WFI (Water for Injection). See also water
steps, 347-351 systems
vendors, 344, 352 FDA guidelines, 122
Veterinary Master Files (VMFs), 51 in microbiological control, 480, 481,
visual examination 483,508
of cleaning samples, 410, 411-412, in steam cleaning, 444, 445
422-423, 426 system diagram, 441
in determining significant change, 527 WHO (World Health Organization), 128, 373
VMFs (Veterinary Master Files), 51 worst-case approach ·
cleaning validation, 400--401, 405-
warehouse operations, 140-143 406,456
Warning Letters, 32-34 limit calculation, 417
on cleaning process, 406 process qualification, 554, 559
deficiencies sited in, 48-51, 363-365
excerpts from, 295-296 x-ray diffraction, 549
for foreign firms, 27
on process validation, 18 zvalue, 489, 514
Water for Injection. See WFI

API 原料药的验证 PDF

Caricato da

Informazioni sul documento

Titolo originale

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

API 原料药的验证 PDF

Caricato da

Copyright:

Formati disponibili

Validation of Active

No claim to original U.S. Government works

International Standard Book Number-13: 978-1-4200-2597-2 (eBook - PDF)

PREFACE 2001 xvii

AUTHOR BIOGRAPHIES xix

2. THE LEGAL FRAMEWORK FOR THE REGULATION

3. THE LEGAL BASIS FOR VALIDATION 55

4. DRUG MASTER FILES 83

5. THE FDA's PERSPECTIVES ON ACTIVE PHARMACEUTICAL

6. DOMESTIC AND FOREIGN API MANUFACTURING

Reworking and Reprocessing 137

7. VALIDATION OF APis: A CASE STUDY 163

Executive Summary-Concurrent/Prospective Validations 180

8. ACTIVE PHARMACEUTICAL INGREDIENT VALIDATION:

Prospective Validation 269

9. IMPURITIES IN DRUG SUBSTANCES AND DRUG PRODUCTS 271

10. INVESTIGATING PROCESS DEVIATIONS 293

Examination of Data Available 298

11. TECHNOLOGY TRANSFER:

Ancillary Issues 326

12. POSTAPPROVAL CHANGES TO BULK DRUG SUBSTANCES 329

13. VENDOR QUALIFICATION AND CERTIFICATION 343

Reprocessing and Rework 357

14. QUALITY ASSURANCE SYSTEMS 369

15. CLEANING FOR ACTIVE PHARMACEUTICAL

Level 4 Cleaning 403

16. VALIDATION OF STERILE APis 429

17. VALIDATION OF BIOTECHNOLOGY ACTIVE

18. MICROBIOLOGICAL ATTRIBUTES OF ACTIVE

Microbiological Monitoring of Air 497

19. EXCIPIENTS: FACILITY, EQUIPMENT, AND

20. API TERMINOLOGY AND DOCUMENTATION 543

Validation Master Plan 563

experience, he consults for approximately 250 companies worldwide since

several retrospective reviews and concurrent and prospective validations

Edwin Rivera Martinez

validation of APis. He is a technical expert on the ICH Q7 A Expert Working

Karen Zink McCullough

University of Colorado Medical School, and a PhD in biochemistry from Col-

University. Prior to joining Catalytica Pharmaceuticals, he was department

• When there is no recognized nondrug commercial use for the

tion," defines and expands on these terms.

FDA SITE INSPECTIONS

Domestic and foreign manufacturers of drug substances and drug products

• A commitment to quality by the entire organization, including top

The GMP regulations require manufacturers to establish written operat-

Process validation is another area of concern to the investigator (Barr et

chemistry of the API. Max Lazar's chapter, "Active Pharmaceutical Ingredient

FR. 1996. Current good manufacturing practice: Amendment of certain requirements

THE LEGAL FRAMEWORK

legal requirements imposed on APis and their manufacturers, as well as the

THE REGULATORY STATUS OF APis

APis and BPCs

1. When there is no recognized non-drug commercial use for the

• Recognized in the official United States Pharmacopeia [USP], offi-

APis as "New Drugs" or "New Animal Drugs"

proper validation specifically). However, API manufacturers should be aware

There are also guidelines being developed by trade associations repre-

Validation as Part of cGMPs

Process validation requirements for the manufacture of [APis]

Many [API] manufacturers have recently initiated validation

Based on recent emphasis by FDA, the industry has begun to

A. The [API] firm has not established or is not following an