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HANDBOOK
OF
PHARMACEUTICAL
GENERIC DEVELOPMENT
S E M I
S OLIDS
VOLUME III - Part One
Generic Development Topical Dosage Forms
HANDBOOK OF PHARMACEUTICAL
GENERIC DEVELOPMENT
Handbook of Pharmaceutical
Generic Development 24 Volume Series
Handbook of Pharmaceutical
handbooks@locumusa.com
http://www.l o c u m u s a . c o m
Generic Development
SEMISOLID
Handbook of Pharmaceutical
Generic Development Series
Compiled by :
J. D. BLOCK
BSc. MPS. D/PHARM.
Research Director Generic & Innovative Drug Development Division, Locum International Group.
Science Editor - International Journal of Generic Drugs & International Journal of Drug Development
School of Pharmacy University of the Witwatersrand and Witwatersrand Technikon
Johannesburg RSA.
Edited:
IAGIM Scientific Committee
Review Process :
Generic & Innovative Drug Development Division
Research Center
Locum International Research
Vol. 1 - Tablets
Vol. 2 - Capsules
Vol. 3 - Semisolids
Vol. 4 - Liquids
Vol. 5 - SG Capsules
Vol. 7 - Suspensions
Vol. 11 -Capsules ER
Vol. 19 - SOPs/PAI-Checklist
p
p
ppp
Handbook of Pharmaceutical
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Generic Development
SEMISOLID
Vol. 1 - Tablets
Vol. 2 - Capsules
Vol. 3 - Semisolids
Vol. 4 - Liquids
Vol. 5 - SG Capsules
Vol. 7 - Suspensions
Vol. 11 -Capsules ER
Vol. 12 - Semisolids
Vol. 13 - Analytical
p
p
ppp
Handbook of Pharmaceutical
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Generic Development
SEMISOLID
HANDBOOK OF
PHARMACEUTICAL
GENERIC DEVELOPMENT
Semisolid
Part ONE
DOSAGE
F O R M
Jeremy D. Block
B.Sc. MPS. D/Pharm.
Handbook of Pharmaceutical
handbooks@locumusa.com
http://www.l o c u m u s a . c o m
Generic Development
SEMISOLID
Handbook of
Pharmaceutical
G e n e r i c
Development
Innovative Series
Part
One
Semi
s olids
DRUG Development
Publishers
Handbook of Pharmaceutical
L o c u m
H o u s e
handbooks@locumusa.com
http://www.l o c u m u s a . c o m
P u b l i c a t i o n
Generic Development
SEMISOLID
Handbook of Pharmaceutical
PRINTED IN USA
PRINTED IN ISRAEL
PRINTED IN IRELAND
PRINTED IN REPUBLIC OF SOUTH AFRICA
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Generic Development
SEMISOLID
EDITORIAL PREFACE
his handbook represents the third International Edition for Europe of the ongoing
24 volume series of Generic Drug Development and appears under the
cumulative title of the Handbook series of Generic Drug Development. The ongoing
series is updated annually at the end of each year. This is an ongoing process as
new data, specifications and process techniques are added on a continual and
expanding basis. This handbook is fact, never fully complete, as each new annual
edition brings an enlarged and extended profile in the drug development process, as
well as new agency rules, guidelines and guidance to industry which continue to be
added year by year as the global product data base expands. Currently over 150
scientific publications and drug development conferences are annually referenced in
the 24 volume Handbook series of Generic Drug Development.
This mammoth task presents a continual ongoing commitment by the scientific
review committee to the improvement of the technical databases and the product
specific drug development requirements and know-how technology accessed
through the world wide IAGIM joint ventures and know-how projects currently active
in over 15 countries.
The Handbook is available in electronic format (Online and CD ROM) and the eformat is up-dated annually to association members of IAGIM.
This third international edition of the Handbook has been redesigned and updated
to meet the January 1999 Guidance for Industry - Organization of an Abbreviated
New Drug Application and an Abbreviated Antibiotic Application as well as all current
approved and draft FDA guideline requirements of the Center of Drug Evaluation
and Research (CDER) up to June 2000.
Editor-in-Chief.
An on-going series
Additional Volumes in Preparation
0793 7407
International Print Edition
ppp
LOCUM
ppp
Handbook of Pharmaceutical
handbooks@locumusa.com
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Generic Development
SEMISOLID
Acknowledgments
I.A.G.I.M. (R&D) Foundation.
To Doribelle
for her years of support and help
to Sean for his expert knowledge on computerization
to David and Ari for running the project's computers
and lastly to Pat for his inestimable
contribution.
L O C U M
P U B L I S H I N G
Handbook of Pharmaceutical
H O U S E
handbooks@locumusa.com
http://www.l o c u m u s a . c o m
Generic Development
CONTENTS.
Contents
PHARMACEUTICAL
DEVELOPMENT
Table of Contents
Acronyms - Abbreviations
Introduction
Preface
Forward
Chapter
VIII
XIII
XVI
XV
XVI
Regulatory
- Pre-formulation checklist
Documentation
- SOP Control checklist
Development Notebooks
- Development Notebooks checklist
- SOP Control and Development Notebooks SOPs
Chapter
Chapter
1.1
1.2
1.3
1.4
1.5
1.6
1.7
2.1
2.2
2.3
2.4
2.5
2.7
2.12
2.19
Active Ingredients
-Dos and Donts
-Active checklist - Approved suppliers
-Active checklist timeline
-Standard Operating Procedures, actives
-Active Ingredients - Approved suppliers SOP
3.1
3.2
3.4
3.5
3.6
3.7
CONTENTS.
Contents
Chapter
Chapter
Chapter
6.1
6.2
6.5
6.9
6.16
6.21
6.25
Chapter
5.1
5.2
5.5
5.8
Manufacturing Instructions
Chapter
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.11
4.14
7.1
7.2
7.4
7.5
8.1
8.3
8.4
8.7
24 Volume Drug Development Series
handbooks@locumeuro.com
CONTENTS.
Contents
Chapter
Process Optimization
Qualification of Antioxidant and Preservatives
Qualification of finished Product Specification
Qualification of antioxidant and chelating Agent Limits
Optimization - Stability Studies
Chapter
10
Scale-up procedures
- Re-mixing & Processing Times
- Scale-up procedures; checklist
- Scale-up procedures; SOPs
Chapter
11.1
11.6
11.7
12
Chapter
10.1
10.3
10.4
10.5
11
Cleaning Limits
Chapter
9.1
9.2
9.3
9.5
9.8
12.1
12.21
12.23
12.27
12.31
13
13.1
13.2
13.3
13.4
13.6
13.8
CONTENTS.
Contents
Chapter
14
Pivotal batch
-The Pivotal Batch
-Pivotal batch Checklist
-Pivotal batch SOPs
-Sampling and Testing the Pivotal Batch
-Auditing the Pivotal batch
-Auditing the Pivotal batch Checklist
Chapter
14.1
14.2
14.3
14.5
14.10
14.11
15
15.1
15.2
154.
15.7
15.9
Topical Bioequivalence
Biostudy Graphs (Standard)
Diffusion Testing
SUPAC SS*
Chapter
16
Chapter
17
Chapter
16.1
16.5
16.7
16.10
17.1
17.3
17.4
17.5
17.8
18
Pre--Approval Inspections
Pre--Approval Summary Audit
Pre--Approval Team Set-Up
Pre--Approval Team Audit Activities
18.1
18.8
18.9
18.11
CONTENTS.
Contents
Chapter
19
Chapter
19.1
19.15
19.21
19.24
19.29
19.31
19.39
20
Development SOPs
Index of Pharmaceutical Standard Operating Procedures
Index of Analytical Standard Operating Procedures
Index of Microbiological Standard Operating Procedures
Index of Stability Standard Operating Procedures
20.1
20.5
20.9
20.16
20.21
20.27
An on-going series
Additional Volumes in Preparation
Handbook of Pharmaceutical
Generic Development Series
ISSN 0793 8748 - Electronic Versions
Handbook Development 24 Volume Series
Series ISSN Number 0793 7792 - Electronic Version
CONTENTS.
DRUG DEVELOPMENT
Hand?20@&?00@Books
Drug Development & M anufacture for Pharmaceutical Technology Professions
H P G D
Initiation Date :
Expiration Date :
No of Years
:
Update Period :
January 2000
January 2003
Three (3)
January 2000; to January 2003.
This ANDA Drug Registration program has been updated to January 2000 Office of Generic Drugs
requirements. Handbook clients requiring to continue this annual service need only to become
members of I.A.G.I.M. for the period of the update service required by the firm.
The ANDA Update Program is renewed in December each year as a function of the firms
requirements.
Warning: Copyright 1985 -2000 Locum Publishing House Inc. - All Rights Reserved.
Neither this information nor any part of the data contained therein may be reproduced, copied or transmitted in
any form, modification or merged portion or by any means, electronic or mechanical, including printing
photocopying, microfilming and recording, or by any information storage and retrieval system, without the prior
written permission of the publishers. Trademark - Locum Corporation, Locum International Group
handbooks@locumusa.com
(See web site for IAGIM Membership Benefits / Application Forms and additional details)
handbooks@locumeuro.com
http://www.locumeuro.com
SEMISOLIDS
Introduction
Introduction
T
he purpose of the Handbook Series is to illustrate generic drug development from preformulation to regulatory submission. The Handbook Series on pharmaceutical dosage
forms deals with the US generic drug development process of the ANDA (Abbreviated
New Drug Application). It is equally suitable to the innovative drug development process
for the Chemistry-Manufacturing-Controls (CMC) Section of an New Drug Application (NDA).
Each book is devoted to a specific dosage form e.g. tablets, capsules, liquids, topical semi
solids, suspensions, aerosols and so forth. This is an ongoing series that is reviewed and
updated twice annually, as new agency regulations, guides, guidelines and industry
procedures are adopted or regulated.
The Handbook is a basic hands-on working approach to generic drug development and the
overall developmental process. The book ends with the requirements for manufacturing the
first three commercial product lots for distribution and marketing.
Each Handbook is presented in two volumes referred to as Part One and Part Two. These two
parts are supplementary and should be used and referenced together as they complement
each other. Electronic templates for the full registration process are available for each dosage
form. These approximate +300 templates consist of electronically completed ANDA data where
only the variable facts and figures need to be inserted into the prepared data fields.
Part One covers the development topics from pre-formulation of generic ANDAs to final FDA
filing with the Office of Generic Drugs. Each chapter details key development steps coupled
with a hands-on development checklists that dovetails with a series of SOPs on practical
generic issues that the FDA review chemists and inspectors routinely address during an ANDA
file review and during pre-approval site inspections (PAIs).
Agency site inspections routinely cover the product development unit or R&D departments,
QC and Analytical Research laboratories, as well as the manufacturing facilities and
production warehouses. During a product-specific pre-approval inspection there is a
concentration of effort by the inspectorate to thoroughly review and evaluate the drug
development process from pre-formulation to pivotal batch.
Topics covered are real life examples from A (actives) to V (validation). Procedures are kept
as simple as possible in order that the checklists and SOPs can be understood by all
departmental personnel concerned. Repetition in the checklists and SOP is routinely used to
emphasize essential procedures or requirements and to restate the aims and objective in a
tutorial manner. Thus the checklist becomes a first party audit or self-inspection format for the
Standard Operating Procedures.
Part Two is a complete real-life dosage form specific working model of a US Generic
Application or commonly known as an Abbreviated New Drug Application (ANDA).
Part THREE is a complete real-life dosage form specific working model of a EU Dossier +
Expert Report (the Electronic Handbook exhibits a unique Expert Report Compiler)
3
Handbook of Pharmaceutical
xiv
Generic Development
SEMISOLIDS
Introduction
Preface
getting a generic drug to the market place on time.
etting a generic drug to the market place at the right time is no easy task. The
generic drug product must be approved by the FDA, close to the latest patent
and exclusivity expiration date of the innovator drug, if a firm wants to be the
first generic drug product on the retail shelves.
Getting to this point is a long training and planning operation. That it can be done has
been shown by dedicated and well managed generic innovative and generic
companies. This handbook is designed to show the key highlights of the essential
training and planning along the way.
The length and breath and importance of preparing a successful long life generic
product for the market place requires much attention to detail. Development must stop
if the product fails an essential intermediate, finished product or stability specification
and continue only after the fault has been isolated and corrected - thus the essential
use of checklists and standard operating procedures in this Handbook. The SOPs are
generic in content, they simply highlight important principles and way points and are
suitable for editing and customizing for the firms own in-house needs.
The FDA file contents and review expectations of the drug product must be well
understood and controlled early in the development process in order to avoid problems
with the approval process and later with the quality and customer acceptance of the
marketed product. This Handbook emphasizes first party certification by in-house
auditing and self inspection programs exhibiting a past systematic QC track record that
may help streamline FDAs enforcement of drug Good Manufacturing Practices
(GMPs).
This handbook was designed to produce a rugged generic drug product - to rapidly
facilitate FDA and pre-approval review and reach the market place on time...
Editor
Handbook of Pharmaceutical
xv
Generic Development
Forward
FORWARD
Thirteen Key Directives
on Drug Development.
Directive 1. "Write a clear SOP on drug
development".
The goal of drug
development is to present a quality
rugged drug in the overall shortest
development time. If your firm hasn't
clear, concise drug development
procedures and objectives on file,
backed-up with all the necessary
protocols, from cleaning, to process to
analytical validation - don't start the
project until this is done.
Directive 2.
"Run pilot studies - never uncontrolled
studies" - uncontrolled studies like nonvalidated assays may seem cheaper at
the time but generally give the wrong
guidance. A pilot study to evaluate a
potential bioequivalent product with a
fully
validated
analytical
assay/
metabolite/impurity procedure, prior to
the main study - often works out more
cost effective than plunging into a high
cost study without a pilot evaluation.
Never
do
uncontrolled
studies!
Directive 3.
"Write and Report Facts Faithfully"
A failed result is a positive endpoint as it
may well highlight a wrong development
route. If the result stays 'failed' after a
full investigation, then report its impact
and conclusions on the study or process
faithfully. Never average results in order
to bring an out-of-spec-result into
specification. That's a GLP violation.
Directive 4.
"Remember the 5C's of documentation
Each documentation page of a report,
protocol, method, or submission file
should be like the 5C's of a flawless
diamond (cut, clarity, clear, carat, cost.)
Handbook of Pharmaceutical
xvi
Generic Development
Forward
Directive 8.
"Run a mock PAI against your
Application just before submitting."
The Drug Application will eventually be
judged on the acceptability of the
manufacture,
control
and
testing
facilities as documented in the agency
file and in-house supporting data. Audit
every facet of the development,
manufacture, control and stability
procedures of the drug product. Check
and cross-reference each possible
submission document against the
manufacturing / control and laboratory
files and equipment logs. Build in
routine self-inspection checks during
the development process. Formulate
this quality development routine by
SOPs and department audit checklists.
Directive 11.
"Talk to the regulators regularly."
Allow regulators to review protocols
prior to starting the work. Get their
opinion and express your concerns
openly. Regulators like openness and
honesty - and work well with polite,
respectful and professional personnel.
Directive 9.
"Make your Application really clear,
concise and user friendly "
Well prepared and assembled print or
electronic files and dossiers are a joy to
read, review, and evaluate. Use all the
desk top publishing tools to shape your
firm's reports as attractive, stimulating,
and interesting to read and review.
A document can entice or repel a reader
simply by its construction - it can also be
made a scientific work-of-art.
Directive 12.
"Take a hard look a your cGMP's "
Directive 13.
"Audit everything enthusiastically".
Leave no audit stone unturned.
Establish consistent in-house audit selfinspection programs effective at each
stage of the drug development pathway.
At the end of every development report
submission stage, (refer to the Development
Checklist), audit the department and
relevant steps concerned.
End-of-study auditing is quite ineffective
as early errors or omissions can not be
corrected promptly and on-time
2
Directive 10.
your
key
Handbook of Pharmaceutical
xvii
Generic Development
SEMISOLIDS
D O C U M E N T A T I O N
CHAPTER 1
Regulatory
Sit and review with your regulatory department before you start
eveloping successful generic drugs in the least possible time and without
expensive mistakes, requires significant pre-planning with the regulatory affairs
department. Successful generic project managers can visualize all the key sections
of the ANDA or EC submission file, before pre-formulation work has actually been
initiated.
The regulatory department must insure that the innovators drug or the reference
listed drug ( R L D ) is suitable for generic manufacture and marketing.
This purpose of this Handbook is to allow the reader to visualize the complete
generic development pathway in a concentrated rational picture.
Review the checklist titled Initial Regulatory Check Prior to Pre-formulation in order to obtain
an initial overview of the forensic regulatory elements.
An early decision on all the pack sizes is required from the marketing and sales
department in order to initiate reverse engineering of all the product specifications.
Part Two
Part Two of the Handbook of Pharmaceutical Generic Development Series provides
a full scale model of a current US abbreviated new drug application (ANDA) for the
selected dosage form chosen (e.g. tablets, capsules, semi-solids, liquids etc.)
In the model ANDA, the right hand side pages provides an example of each and
every document required to compile and assemble a complete regulatory file for
submission to the FDAs Office of Generic Drugs (OGD).
The left hand side pages are designed for notes, summaries and explanations on the
submitted data forms and tables. These pages are designed for side-by-side
comparisons and ease of viewing. Essential tips and potential traps are explained
in the notes and summaries as well as the common dos and donts regularly
addressed by the agency review chemists in a ANDA / AADA file submission.
Summary:
Know all the twenty one (21) ANDA sections in the registration file impacting on
the development, formulation, manufacturing procedures, all intermediate and
final product specifications, pivotal batch, stability requirements, as well as key
regulatory ANDA dos and donts.
Complete the pre-formulation regulatory checklist and discuss and review all
the paperwork required to complete this section successfully.
Handbook of Pharmaceutical
Chapter: 1.1
1
Generic Development
SEMISOLIDS
D O C U M E N T A T I O N
CHAPTER 1
SECTION I
Section One of the ANDA file consists of three documents. A drug developer needs
to understand the information required to accurately compile these three documents
as the information impacts upon the development timeline. These three parts are:.
Purpose of Submission
Type of Submission
(Original ANDA / AADA)
(Supplement)
(Re-submission)
(Amendment)
3.
4.
5.
6.
7.
8.
Name of Applicant
Title of Applicant
Signature of Applicant (ink)
Proprietary name (if any)
Generic name of Drug
Number of volumes submitted.
Table of Contents
Table of Contents laid-out to the FDA's CDER Guide to Industry Format, (April 1997
Overall ANDA Guideline Requirements) needs to provide rapid access to the twenty
one (21) sections of the ANDA submission file. A drug developer needs to
understand all 21 sections, in detail, as they contain the overall development,
manufacturing and control data that makes up the entire drug development project.
Careful review of each section and its required contents will aid significantly in the
pre-formulation to final pivotal processes. The overall development report can be
structured on each CMC section highlighting the choices made and work carried out
to fulfill each sectional requirement. The development report is a real-time ongoing
series of procedural reports that culminates in the final collated development report.
SIGNED APPLICATION FORM:
Signed Application Form (Form FDA 356h or 3439) with original ink signature
requires all DMF numbers of materials and containers used in the final product
presentation. Also no test results, analysis, or stability results may be submitted from
a QC / QA or R&D laboratory that has not received a FDA Plant DMF number (Note:
- New Revised Form FDA 356h became official from January 8, 1998).
Obtaining DMF numbers from suppliers on time requires advanced pre-planning (up
to three months or more) and scrupulous care should be taken that no Agency
deficiencies or FDA concerns of a recent or overdue nature are outstanding on the
materials or container components being used in the firm's generic formulation.
Handbook of Pharmaceutical
Chapter: 1.2
2
Generic Development
SEMISOLIDS
D O C U M E N T A T I O N
CHAPTER 1
CHECK LIST
CL # HPGD-03-01YY
qYes qNo
2. Revised Form FDA 356h reviewed (NB: all DMF #s clearly noted.)
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
7. Comparison of your Generic Drug with the chosen Reference Listed qYes qNo
Drug (Select from FDA Orange Book) or original Innovator's product ?
8. Innovators package insert obtained via FOI (insure latest edition)?
qYes qNo
qYes qNo
qYes qNo
11. Proposed draft labeling for carton prepared (main & side panel)
qYes qNo
12. Innovators Insert converted to a generic package insert (remove any qYes qNo
exclusive indications)?
13. Proposed ANDA Package Insert OK (your firm's details added)?
qYes qNo
qYes qNo
15.Repeat check that Innovators Insert is the latest edition and date? qYes qNo
(review FDA Web Site for model insert, check immediately before
ANDA file is submitted to OGD.)
16.Obtain a full set of Jacket Covers (specific colors for file types) from qYes qNo
FDA OGD Offices and review all FDA guidelines for specific dosage
form (i.e. Topical Semisolids)
17.Review and list all DMF #'s required for early vendor implementation
qYes qNo
Footnote : Bold letter in first word indicate that this work must be checked and approved before pre-formulation
work starts.
Handbook of Pharmaceutical
Chapter: 1.3
3
qYes qNo
Generic Development
SEMISOLIDS
D o c u m e n t a t i o n
CHAPTER 1
Do -
Documentation
If there is no documentation its a
rumor;
If its well documented - its a fact.
Do SOP CONTROL
Standard operational procedures for a
generic development unit are the first
essential documentation requirements.
Without a functional set of standard
development
procedures,
developing
generic drugs will follow a haphazard nonreproducible process. SOPs are efficient
and useful instructional and working tools.
Standard Operating Procedures should
meet six basic and functional requirements
Handbook of Pharmaceutical
Dont -
Do
DEVELOPMENT SOPs
A development SOP is a protocol or
summary of the overall generic drug
development process. It acts as a guideline
or road map for the development team to
follow to ensure complete product
development.
Development SOPs are not a CFR
requirement. They are designed for rapid
and complete generic drug development
and are significant aids to agency staff
during pre-approval inspections (PAIs).
DEVELOPMENT NOTEBOOKS
Similar to printed SOPs or better still
electronic SOPs, numbered and bound
printed development notebooks (no
electronic workbooks) are essential tools
for a structured generic or innovative
development program to succeed.
Chapter: 1.4
4
Generic Development
SEMISOLIDS
CHAPTER 1
D o c u m e n t a t i o n
CHECK LIST
CL # HPGD-02-01YY
SOP CONTROL.
failure to follow your SOPs adulterates the product
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
8. Check that no SOP has a date older than two (2) years ?
qYes qNo
qYes qNo
10. Check that all department personnel have signed the Agreement to
Comply with SOPs?
qYes qNo
11. Is the effective date of the SOP about 21 days after the last signature qYes qNo
- to allow for SOP training ?
12. Has the SOP been signed by all authorizing parties within 14-21
days of the first signature?
qYes qNo
13. Are the department SOPs - brief, concise and to the point? (select
and review three examples.)
qYes qNo
14. Are the responsible persons clearly indicated in the SOP's qYes qNo
Responsibility section?
15. Has a product specific Development SOP been prepared for each qYes qNo
dosage form under development (i.e. SOP for Topical Semisolids etc.)?
16. Do these Development SOPs acts as a blue print for the
development team to follow to ensure complete product development?
qYes qNo
qYes qNo
Footnote : Bold letters in checklist indicate that this work must be checked and approved before pre-formulation work starts.
Handbook of Pharmaceutical
Chapter: 1.5
5
Generic Development
SEMISOLIDS
D o c u m e n t a t i o n
DEVELOPMENT
NOTEBOOKS
All
DEVELOPMENT NOTEBOOKS
Pharmaceutical development notebooks are
essential tools for successful generic drug
development. The Development notebooks
are bound, numbered, 100 page, hard cover
notebooks suitable for a development
laboratory environment.
The issue and control of the development
notebooks and the signing procedures after
each work section is complete is an
important control check.
The development notebooks are used to
record all pre-formulation and product
development procedures.
All failed
procedures must be recorded. No product
was ever developed without a number of
reject lots.
Key data recorded in notebooks include :
Development
of pre-formulation and
development lots do not require strict GMP
procedures,
however
good
GMP
development practices enhance the
scientific validity of results obtained.
Non-calibrated
Meticulously
prepared
development
documentation aids in the timely
production of rugged generic products
within the allocated development time
frame.
Good
documentation is a cost-and-time
saver and allows for rapid data review
during pre-approval inspections (PAIs), a
blessing for agency inspectors, as well as a
proven training record for further
successful generic product development.
Handbook of Pharmaceutical
CHAPTER 1
Chapter: 1.6
6
Generic Development
SEMISOLIDS
CHAPTER 1
D o c u m e n t a t i o n
CHECK LIST
CL # HPGD-02-01YY
DEVELOPMENT NOTEBOOKS.
Sign every stage not every page
1. Does the Development Unit have bound & page numbered notebooks ?
qYes qNo
2. Are the printed development notebooks signed on every stage & page ?
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
7. Do the notebooks record successful and failed development product formula ? qYes qNo
qYes qNo
9. Has the Product Development SOP been complied with during the product qYes qNo
development phase ?
10. Is a process of formula, specifications and process optimization evident ?
qYes qNo
qYes qNo
12. Have critical upper and lower range limits been qualified ?
qYes qNo
qYes qNo
14. Are the lot #s, expiration dates and source of each active and non-active qYes qNo
ingredient used during routinely recorded in workbooks ?
15. Does the development notebook appear suitable as a scientific basis for the qYes qNo
generic drug product Product Development Report?
16. The Product Development Report comprises of both pharmaceutical and qYes qNo
analytical development reports.
Footnote : Bold letters in checklist indicate that this work must be checked and approved before pre-formulation work starts.
Handbook of Pharmaceutical
Chapter: 1.7
7
Generic Development
SEMISOLIDS
CHAPTER 1
D o c u m e n t a t i o n
STANDARD OPERATING
PROCEDURE
Page 1 of 1
SOP # HPGD-02-01YY
NOTEBOOKS
The
SOP CONTROL
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# HPGD-02-01YY
# HPGD-02-01YY
# HPGD-02-01YY
# HPGD-02-01YY
# HPGD-02-01YY
# HPGD-02-01YY
DEVELOPMENT NOTEBOOKS
# HPGD-02-01YY
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ED. N0: 01
Replaces NEW
Ed. Status :
Effective Date:
APPROVED:
DD / MM / YY
01
Handbook of Pharmaceutical
Department
R&D
Chapter: 1.8
8
RA
QC / QA
Generic Development
SEMISOLIDS
DEVELOPMENT
CHAPTER 2
AN OVERVIEW
development SOP is a
Thedocument
that contains each stage
Handbook of Pharmaceutical
Chapter: 2.1
1
Generic Development
SEMISOLIDS
DEVELOPMENT
CHAPTER 2
C H E C K L I S T
CL # HBGD-01-01YY
qYes qNo
qYes qNo
3. Are non-soluble active ingredients characterized for particle size for each qYes qNo
approved supplier (special significance in eye preparations)?
4. Are the source and supply of the excipients characterized?
qYes qNo
qYes qNo
6. Does the SOP indicate that non-compendial active material assays requires a qYes qNo
validation and stability indicating assay ?
7. Does the SOP required full analysis of the reference listed drug (RLD), its qYes qNo
impurity profile and stability ?
8. Is an historical listing and summary of all experimental batches manufactured qYes qNo
required ?
9. Are the in-actives qualitatively and quantitatively compatible with the RLD for qYes qNo
topical use (same composition and strength)?
10. Do the manufacturing procedures, process parameters and in-process controls qYes qNo
require optimization and limit challenges ?
11. Is a process of tightening / qualifying the product specifications, (based on qYes qNo
batch analysis) evident as the development process undergoes optimization?
12. Does the development process identify the critical processing steps for the qYes qNo
validation protocol with the potential to affect the product?
13. Has the preservative efficacy of the RLD been evaluated to assess the qYes qNo
suitability of the RLD preservative system?
14. Does the analytical development require a final validated assay and stability qYes qNo
indicating (SI) assay well before running the pivotal batch?
15. Are stability study assays of the PO and PQ batch required to be tested by the qYes qNo
validated assay procedure and SI analysis?
Footnote : Bold numbers in checklist indicate that this work must be checked and approved before formulation work starts.
Handbook of Pharmaceutical
Chapter: 2.2
2
Generic Development
SEMISOLID
Development
CHAPTER 2
Formula Development
research and evaluate the reference listed drug thoroughly'
The
development of a semisolid
dosage requires six key decisions.
Choosing the : reference listed drug (RLD)
Active substance
The active drug substance is chosen
according to standard criteria. Correct
choice of active ingredient is critical
and time consuming. Key selection
parameters include :-
documentation
Active
Material
specifications
remain constant - batch-to-batch
(not a R&D lot or non-commercial
batch)
Chapter: 2.3
3
Generic Development
SEMISOLID
Development
CHAPTER 2
C H E C K L I S T
CL # HBGD-01-01YY
FORMULA DEVELOPMENT
Systematically compare your developing product to the chosen RLD
at all key stages'
1. Has the Reference Listed Drug (RLD) been chosen from the Orange qYes qNo
Guide?
2. Has the RLD been purchased in all the proposed marketing sizes ?
qYes qNo
3. Have different batch numbers (3 lot #s) of the RLD been purchased?
qYes qNo
qYes qNo
5. Conform that at least 10-20 samples of each RLD lot # and pack sizes qYes qNo
are available for physical, chemical (assay/impurities), and stability
testing?
6. Confirm if the RLD has been placed on stability at 40o C for 3 months qYes qNo
for evaluating potential degradation and impurity levels?
7. Confirm if the impurity profile of the RLD has been evaluated?
qYes qNo
qYes qNo
9. Have the chosen inactive and maximum strength been crossed qYes qNo
checked in the IIG? (for unique or unusual excipients)?
10. Are the in-actives qualitatively compatible with the RLD for topical qYes qNo
use (composition and strength)?
11 Have the RLD formula been reviewed in the International Drug qYes qNo
Compendia (Italian, French, Swiss) for formula composition data?
12. Has the FOI system been used to gather data on the Innovative qYes qNo
drug?
13. Has a full analytical profile range been determined from analysis of qYes qNo
the various batch lots of the RLD (at least 3 lots #s for Assay; Content
Uniformity)?
14. Has the chosen RLD undergone stress testing to establish the level qYes qNo
of its degradation products?
15. Has a diffusion profile of several RLD batch lots been evaluated to qYes qNo
assess the consistency of the RLD diffusion parameters?
16. Has the preservative efficacy of the RLD been evaluated to assess qYes qNo
the suitability of the RLD preservative system ?
Footnote : Bold numbers in checklist indicate that this work must be checked and approved before formulation work starts.
Handbook of Pharmaceutical
Chapter: 2.4
4
Generic Development
SEMISOLID
Development
CHAPTER 2
STANDARD OPERATING
PROCEDURES
Page 1 of 1.
SOP # HBGD-01-01YY
FORMULA DEVELOPMENT
The following selected model Standard Operating Procedures are recommended for
a generic development unit : Models of selected SOPs are provided.
DEVELOPMENT SOP
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
DEVELOPMENT FORMULA
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
DEVELOPMENT REPORT
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
NOTE ON DEVELOPMENT
The intent and purpose of the pivotal batch is as a final demonstration that the
formula, process and controls are well developed and tested during development
stages and really need no significant changes or further process qualification.
However scale-up changes can take place within the SUPAC rules after
manufacturing the pivotal batch. These SUPAC rules govern the Scale-Up from
pivotal (10% or more) to commercial (100%) and
changes after registration approval has been given.
Post-Approval Changes
i.e.
[End of Document]
Edition No. 01
Ed. Status :
New
Effective Date
:
DD/MM/YY
Handbook of Pharmaceutical
APPROVED:
APPROVED
___________
Department
____________
RD
Chapter: 2.5
5
____________
RA
_________/_________
QC /
QA
Generic Development
SEMISOLIDS
DEVELOPMENT
CHAPTER 2
Literature search:
The
Patent Evaluation:
The Innovator's overall patent situation
is thoroughly evaluated with special
reference to product and use patents.
Exclusivity and Patent data is reviewed
in the FDA's Orange Book "Approved
Drug
Products
with
Therapeutic
Equivalence Evaluations " Edition 20
Handbook of Pharmaceutical
Chapter: 2.7
7
Generic Development
SEMISOLIDS
DEVELOPMENT
Testing
Sample:
of
Active
Material
CHAPTER 2
Physical
Active:
Characterization
Handbook of Pharmaceutical
of
Chapter: 2.8
8
Generic Development
SEMISOLIDS
DEVELOPMENT
Chemical characterization:
- Viscosity (Rheology)
Optical rotation
Enantiomeric purity (if required)
O.V.I. testing (organic volatiles)
Impurity profile
Evaluation
supplier:
of
raw
- pH
- Emulsion Stability.
material
DMF availability
Compliance with USP monograph
Impurity profile and stability profile
Commitment to maintain written
physical / chemical specifications
Statement of non-patent infringement
DEVELOPMENT LOTS
Developing the formula through a
series of mini experimental trials
involves evaluating the type of mixing
process and the physical properties of
the globules / emulsion formed. Steps
for the choice of a suitable process are:
Evaluation of suitable excipients.
Evaluation of suitable antioxidants /
preservatives.
simple mixing, phase mixing, vacuum
mixing.
Time, Temperature and Vacuum
requirements.
Emulsifying
at
specific
phase
temperatures (low / high shear units.)
Determination of target pH and target
viscosity (re: container orifice.)
Physical properties of semisolid:
- Appearance / Color
Handbook of Pharmaceutical
CHAPTER 2
Assay
Uniformity of Content (three points)
Preservative Efficacy
Microbial Limit Tests.
Active Stability:
Ordering of raw material for Process
Qualification (PQ) and Pivotal Batches.
On accepting the stability profile data
from the active material evaluation,
coupled with the results the from the
development lots, the active supplier is
now approved. Order sufficient material
for the PQ and Pivotal Lot manufacture.
Chapter: 2.9
9
Generic Development
SEMISOLIDS
DEVELOPMENT
It
PROCESS OPTIMIZATION
Process optimization is the process of
fine tuning the manufacturing process
and making minor adjustments to the
formula or process. It should be
performed on a larger batch size so that
the potential problems of scale-up can
be addressed, as they arise with larger
size manufacturing equipment that use
the same operating principle. Fine tune
the effects of mixing and cooling
parameters may include;
mixing speeds (i.e. blade speeds (i.e.
in high speed mixers)
or
phase
Handbook of Pharmaceutical
CHAPTER 2
process
report,
outlining
the
optimization data for final presentation
in the product development report.
PROCESS QUALIFICATION
(The PQ Batch)
The process qualification batch is
manufactured in order to detect any
problems that may arise during the
manufacture of production size batches,
permitting a timely solution before the
manufacture of a pivotal batch.
The process qualification team and
production personnel should discuss
formula and process instructions and
decide on optimum batch size, and then
define critical processing steps and test
parameters to be evaluated.
Master Documentation:
The
Chapter: 2.10
10
Generic Development
SEMISOLIDS
DEVELOPMENT
PIVOTAL LOTS
Based on the PQ batch results and
amended documentation, the pivotal lot is
now prepared. In the manufacture of the
Pivotal Batch, a minimum of 100 000
(net) dosage units are required. Some
firms prepare documentation for 100 000
dosage units gross, ignoring that there
may well be 3% to 5% production losses.
The net batch yield turns out to be 95 000
/ 98 000 dosage units which is below the
100 thousand net required by FDAs
Office of Generic Drugs (OGD).
Semisolids may have a greater
manufacturing loss than solid dosage
forms - thus it is prudent to scale the
pivotal batch for at least 120 000 dosage
units.
Note: the pivotal batch may range from
10% net to 100% (i.e. full size) of the
proposed commercial batch size.
Experienced Generic firms who do not
anticipate any problems with the pivotal
documentation often target the pivotal
quantity to 70-100% of the proposed
commercial lot thus achieving appropriate
scale-up and pivotal in a single batch.
CHAPTER 2
DEVELOPMENT REPORTS
IN-VITRO STUDY
Bioequivalence /Comparison evaluations
The pivotal batch samples are used to
perform a comparison study, if needed.
The FDA guidelines on topical products
are included, and highlight the agency
Handbook of Pharmaceutical
Chapter: 2.11
11
Generic Development
SEMISOLIDS
DEVELOPMENT
Purified
Water
A Key Ingredient
in the Dosage Form
Development.
develop all experimental
batches with Purified Water USP
or Ph. Eur. - similar or identical
to the proposed commercial
production quality.
The
This
Handbook of Pharmaceutical
CHAPTER 2
Changing the
water quality during
product development
may compromise
earlier results
Water quality for product development
should be at least purified water of
Pharmacopeial grade (USP/Pharm Eur)
and used from the very onset of the
development studies.
The research or development water
specifications should not change as the
product develops and as the awareness
grows, that microbial parameters and
pH are significant formula parameters,
to be evaluated in the development
process.
Chapter: 2.12
12
Generic Development
SEMISOLIDS
DEVELOPMENT
Purified
W a t e r
Avoid changing specifications
Changing the water quality half way
through the product development stage
when microbial parameters are being
addressed may well invalidate the early
formula development results, especially
the overall preservative package,
notable the individual preservative
concentrations chosen.
Water-soluble
preservatives,
chelating
Handbook of Pharmaceutical
CHAPTER 2
Development Pointers:
Initiate development with plant quality
water.
Preservative Efficacy Testing conducted
with specific organisms found in
commercial plant - as well.
Chapter: 2.13
13
Generic Development
SEMISOLIDS
DEVELOPMENT
Purified
W a t e r
Eventually the firm may not have a
proper basis for developing a fully
validated and optimized drug product or
for that matter, an appropriate
validation protocol without the need of
repeating
some
of
the
initial
developmental batch lots with the
applicable standardized commercial
water quality.
Similarly the use of a higher water
quality, (during the development stages
i.e. WFI) than the proposed plant
commercial quality available, will result
in a commercial product with distorted
microbial parameters, as well as a
biased stability profile. This, indeed, is
the more serious case.
These products are prone to develop
severe production problems resulting in
greater microbial bioburdens or OOS
chemical pH shifts that frequently fail
the product release specifications or
worse still, fail the annual commercial
stability tests resulting in a drug product
recall.
In such cases the Preservative Efficacy
Test results as well as the Total
Microbial Count (TMC) and the
Microbial Limit Tests (MLT) are
presented optimistically during the enddevelopment stages, which are not
actually seen in the commercially
manufactured lots.
Generic
CHAPTER 2
Chapter: 2.14
14
Overseas or remote
R&D
Development Units
must harmonize
their water qualities
with commercial
production
Generic Development
SEMISOLIDS
DEVELOPMENT
Purified
W a t e r
Remote Units
Generic developers who are based in
remote affiliations or research units
(i.e. overseas development units) that
are far removed from the commercial
plant,
where
the
proposed
manufacturing will be effected, should
obtain a batch-to-batch water quality
analysis report of the previous 6-12
months
manufactured
lots
(consecutive batches) and carefully
evaluate the physical, chemical and
especially
microbial
water
specification profiles.
Worst case scenarios where water
quality has been used in commercial
production when the action and
warning limits were exceeded should
be noted and carefully evaluated in
the PET studies.
Handbook of Pharmaceutical
CHAPTER 2
Chapter: 2.15
15
Generic Development
SEMISOLIDS
DEVELOPMENT
Donts:
Dont assume that the newly
developed generic or innovative
product will not be occasionally
manufactured for commercial use with
a water quality bioburden of 70 to 100
organisms per mL.
Dont
Dont
Absent
development GMP
adulterates
the drug
development pipeline
Dont develop
Handbook of Pharmaceutical
CHAPTER 2
Stagnant residual
rinse water at ambient
temperatures supports
microbial growth
Dont
Chapter: 2.16
16
Generic Development
SEMISOLIDS
DEVELOPMENT
2
CHAPTER
C H E C K L I S T
CL # HBGD-01-029Y
Handbook of Pharmaceutical
Chapter: 2.17
17
Generic Development
SEMISOLIDS
DEVELOPMENT
2
CHAPTER
C H E C K L I S T
CL # HBGD-01-029Y
11. Careful note is taken of the microbial alert and warning levels in qYes qNo
force at the proposed commercial site?
12. The firms water quality alert/action levels are set at NMT 30 qYes qNo
organisms /mL?
13. The firms water quality warning levels are set at NMT 70 organisms qYes qNo
/mL?
14. The firms water quality
organisms /mL?
15. The presence of frequent found organisms at the proposed qYes qNo
manufacturing site are noted and incorporated during product
development testing
16. The indicator microbe pseudomonas statzeri is used during qYes qNo
Preservative Efficacy Studies during the product development stages.
17. 6-12 months of consecutive commercial quality water lots have qYes qNo
been evaluated for upper and lower bioburden parameters at periodic
intervals?
18. The final end-formula when spiked with water quality at the alert or qYes qNo
maximum levels adequately meets the USP Preservative Test?
19. Bulk ingredient purified water is boiled (30-45min) and cooled to the qYes qNo
required temperature immediately before use, when used in open type
manufacturing kettles for semisolid preparations?
20. Water quality when not in immediate use, is maintained at not less qYes qNo
than 80o C and continually circulated in appropriate distribution piping
that has no stagnant sections (slight downward slope)?
21. The company maintains a full batch-to-batch analysis profile (in real qYes qNo
time) of all water quality lots produced for product production use?
22. All Alert / Action and Warning level results from the batch-to-batch qYes qNo
analysis are fully investigated and proper corrective action taken ?
4
Handbook of Pharmaceutical
Chapter: 2.18
18
Generic Development
SEMISOLIDS
DEVELOPMENT
CHAPTER 2
Development Stage
Stage 1
Literature Search
Literature Research
FDA - FOI
On-line
search
Stage 2
Active
Sourcing
Stage
Evaluate
Actives
Stage
Active
Evaluation
Active
Purchasing
Purchase
(Potential) Evaluate at least two potential active material suppliers for
Active Material
approved supplier status
Stage
Active
Testing
Testing
of
Active Chemical testing by the Development analytical lab as per either:
Material sample
a. Pharmacopoeia monograph (if present)
b. Pharmacopoeia Forum (if available)
c. In-house method (based on manufacturer)
d. Supplier's test methods and specifications
Handbook of Pharmaceutical
Chapter: 2.19
19
Generic Development
SEMISOLIDS
DEVELOPMENT
CHAPTER 2
PRE-FORMULATION
Development
Stage
Stage
Innovator's
DRUG PRODUCT
Innovator Samples
Stage
Product Purchasing
Innovator's
Product Testing
Innovator Testing
Innovator Physical
Testing
Physical Testing:
Viscosity; SG; pH, Texture; (grittiness, greasiness, stiffness,
tackiness) Particle / globule size of dispersed phases (microscope)
Evaluation of Topical Review FDA CDER Home page for listing and Bioequivalent
parameters for semisolids (e.g. topical corticosteroids).
Bioequivalent
parameters
Diffusion
profile
Active release
Stage
Bulk
Active Testing
Stressed Analysis
CHARACTERIZATION
Degradants (Expected)
Impurity profile
Optical rotation
Enantiomeric purity
O.V.I. Testing
Handbook of Pharmaceutical
Chapter: 2.20
20
Generic Development
SEMISOLIDS
DEVELOPMENT
CHAPTER 2
DEVELOPMENT BATCHES
Development Stage
Stage
Evaluation of formula
Excipient compatibility using FDA's Active Ingredient Guide (IIG)
with suitable excipients
and stability assessment of proposed formula
Stage
10
Evaluation of suitable
Container-Closure
System
Stage
11
EVALUATION
SUITABLE
MANUFACTURING
PROCESSES
Manufacturing Process
Determination of order of mixing
Aqueous and non aqueous phase mixing - high/low shear mixing
Determination of pre-mixing of separate phases (optimum ToC)
Determination of phase addition amounts & specific
temperatures Determination of mixing times
Determination of torque end-point values
Determination of viscosity parameters / Rheology1
Time-variable rheology testing
Determination of pH limits2
Determination of temperature endpoints (cooling points)
1
(State machine used e.g. Brookfield, Plate&Cone 2Mettler).
Bulk Material
Visual Appearance
Physical Properties of Color Odor (pungent odor or presence of fragrance)
Semisolid bulk
Homogeneous semisolid mixture
Particulate contamination
Physical
Tests
on pH
SG / Density Viscosity/Rheology Color / odor
Semisolid bulk
Homogeneity Particle size in dispersed phases
Microbial Tests on bulk
Final Formula
Established
Stage
12
Active material
Bulk purchase
Handbook of Pharmaceutical
Chapter: 2.21
21
Generic Development
SEMISOLIDS
DEVELOPMENT
CHAPTER 2
Stage
13
Analytical
Semisolid
testing
PROCESS OPTIMIZATION
Development
Stage
14
MIXING
OPTIMIZATION
PROCESS
OPTIMIZATION
PROCESS
OPTIMIZATION
REPORT
Development
Stage
Stage
15
Scale-up
Scale-up Report
Handbook of Pharmaceutical
Chapter: 2.22
22
Generic Development
SEMISOLIDS
DEVELOPMENT
CHAPTER 2
PROCESS QUALIFICATION
Development
Stage
Stage
16
Process Qualification
The process qualification batch is manufactured in order to detect any problems that may arise during
the manufacture of production size batches, allowing a solution prior the manufacture of the pivotal
demonstration batch. Scale-up to the pivotal batch size or 70% of the pivotal batch may be combined
with qualifying the manufacturing process At this stage full manufacturing documentation is prepared
alone standard procedures.
PRODUCTION
FACILITIES
BATCH SIZE
Size of pivotal and marketing batch confirmed (NLT 100 000 net/
packed at target parameters or 10% of proposed market batch).
BATCH
DOCUMENTATION
FINAL REVIEW and Review of proposed formula, manufacturing process and control
AUTHORIZATION
parameters with production personnel and QA Staff with
authorization signatures (RD; QA-QC; RA; and Production)
PROTOCOL
KEY STEPS
OPERATING
CONDITIONS
PROCESS
QUALIFICATION
REPORT
Upon completion prepare P-Q Report. This P-Q report forms part
of the overall Development Report
PIVOTAL BATCH
Development
Stage
17
PRODUCTION
FACILITIES
BATCH
DOCUMENTATION
REVIEW and
AUTHORIZATION
OPERATING
CONDITIONS
PIVOTAL REPORT
Handbook of Pharmaceutical
Chapter: 2.23
23
Report
forms
part
Generic Development
SEMISOLIDS
DEVELOPMENT
CHAPTER 2
PRE-SUBMISSION AUDITING
Development
Stage
Stage
18
Development Report
SOPs
cGMP
Validation Protocol
ANDA SUBMISSION
Development
Stage
Stage
19
ANDA Submission
VALIDATION BATCHES
Development
Stage
Stage
20
Protocol
Execute validation
Report
Similarity
Pivotal-Validation
Similarity
Stage
21
Formula Changes or
Process Changes.
Equipment, Process,
Formula or site change
Handbook of Pharmaceutical
Chapter: 2.24
24
Generic Development
SEMISOLIDS
Development
CHAPTER 3
Active Ingredients
Now think about the active ingredient, its source, its supply
and how to keep its specifications constant.
Active Ingredients
The active ingredient for your firms
generic drug must be cost-effective
and freely available (for at least 8-10
years or even more). The active drug
substance should be a commercial
product batch and not a research or
development lot (as development
specifications are still changing).
Active ingredients for innovative drugs
still on patent with 2 or 3 years to go
are the active ingredients most
interested to generic firms.
Changing specifications
Bulk pharmaceutical chemical firms
(BPCs) synthesizing
these active
substances may not have a fully
validated and optimized active product
and may supply generic firms with
developmental batch lots.
These R&D lots will most certainly
change in their drug substance
specifications, especially particle size
and bulk density as the process is
refined and optimized. The impurity
profile will also change as the active
firm optimizes the key synthesis steps
and purification process.
Generic drug manufactures must
insure
that
the
active
drug
specifications do not change once the
formulation
and
drug
product
development
stage
is
reached.
Process qualification, pivotal and the
Handbook of Pharmaceutical
Generic
However
Chapter: 3.1
1
Generic Development
SEMISOLIDS
Development
CHAPTER 3
Active Ingredients
Remember,
Handbook of Pharmaceutical
Chapter: 3.2
2
Generic Development
SEMISOLIDS
Development
CHAPTER 3
C H E C K L I S T
CL # HBGD-01-0298
qYes qNo.
2. Each analytical test falls within the USP/NF limits as stated in the official
USP monograph?
qYes qNo.
3. If the USP active material monograph is in the BP as well then the active
passes the BP Related Substances monograph test?
qYes qNo.
qYes qNo.
qYes qNo.
6. All spectra are fully labeled and show the active materials lot # ?
qYes qNo.
qYes qNo.
8. The DMF holder (active manufacturer) has included a statement that all
FDA issues / concerns communicated to the DMF holder i.e. deficiencies in
the active DMF have been fully addressed?
qYes qNo.
9. The active material safety data sheet has been provided by the approved
supplier?
qYes qNo.
10.
qYes qNo.
The latest USP supplement has been checked for monograph changes?
Footnote : Checklist applies to non compendial (non USP) active drug substances - where applicable .
Handbook of Pharmaceutical
Chapter: 3.4
4
Generic Development
SEMISOLIDS
Development
CHAPTER 3
Active Ingredients
timeline for active materials from first look
to Approved Supplier
Handbook of Pharmaceutical
Chapter: 3.5
5
Generic Development
SEMISOLIDS
Development
CHAPTER 3
C H E C K L I S T
CL # HBGD-01-02YY
1.
qYes qNo.
2.
qYes qNo.
3.
qYes qNo.
4.
qYes qNo.
5.
qYes qNo.
6.
qYes qNo.
7.
qYes qNo.
8.
qYes qNo.
9.
qYes qNo.
qYes qNo.
11. A full batch-to-batch analysis with three lot #s has been tested? qYes qNo.
12. All abnormal
investigated?
results
from
the
batch-to-batch
13. Are the accelerated stability results of the active drug qYes qNo.
substance alone and in the proposed product formulation
satisfactory?
14. Does the purchasing department have a full set of approved qYes qNo.
specifications for the active drug substance?
15. Has a vendor approval certificate for the approved active qYes qNo.
substance been issued (copy with purchasing department)?
Handbook of Pharmaceutical
Chapter: 3.6
6
Generic Development
SEMISOLIDS
Development
CHAPTER 3
STANDARD OPERATING
Page 1 of 1.
PROCEDURES
SOP # HBGD-01-02YY
ACTIVE INGREDIENTS
P-000-02-01YY
P-000-02-01YY
P-000-02-01YY
P-000-02-01YY
P-000-02-01YY
P-000-02-01YY
P-000-02-01YY
P-000-02-01YY
4
[End of Document]
ED. N0: 01
Replaces NEW
Ed. Status :
Effective Date:
APPROVED:
DD / MM / YY
01
Handbook of Pharmaceutical
Department
R&D
Chapter: 3.7
7
RA
QC / QA
Generic Development
SEMISOLIDS
EXCIPIENTS
CHAPTER 4
'Semi Actives'
Challenge each preservative and anti-oxidant system during development
and then optimize its formula concentration
emi
active
ingredients
are
preservative systems, antioxidants
and chelating excipients. They are
not active ingredients, nor are they
fully inactive ingredients as they
maintain the quality, inhibit impurity /
degradant growth and enhance the
stability profile of the product formula.
CHOOSING SEMIACTIVE INGREDIENTS
Formula Optimization:
A anti-oxidant optimization protocol
(provided in this chapter) will enable
drug developers to fully eliminate
antioxidant
release
and
check
specifications from routine product
release
and
stability
testing
requirements of the pivotal and
subsequent commercial marketed
batches
of
the
type:
Handbook of Pharmaceutical
Semisolid
Chapter: 4.1
1
Generic Development
SEMISOLIDS
EXCIPIENTS
CHAPTER 4
C H E C K L I S T
CL # HBGD-03-01YY
qYes qNo
10. Has the product formula been evaluated at lower, middle and upper qYes qNo
antioxidant percentages and evaluated against active assay values?
11. Has it been clearly established that the inclusion of chelating or an qYes qNo
antioxidant synergist positively enhances the action of the antioxidant?
12. Does the stability testing protocol only evaluate formula specifications qYes qNo
that are directly impacted by the aging process ?
13. Has a complete product development profile of the antioxidant been qYes qNo
evaluated in order to eliminate routine release and stability testing of the
antioxidant agent during commercial manufacture ?
14. Is the stability testing protocol for the pivotal batch a logical qYes qNo
development sequence from the product development work ?
Footnote :
Bold numbers in checklist indicate this work must be qualified and or validated before
manufacturing the Process Qualification Batch, which actually marks the end of the product
development stage.
Handbook of Pharmaceutical
Chapter: 4.2
2
Generic Development
SEMISOLIDS
EXCIPIENTS
CHAPTER 4
Non-active Ingredients
Each excipient must play its role - and all non active ingredients must be
necessary
The
ANDA
Generic
Handbook of Pharmaceutical
percentage
Insoluble / Suspended
ingredients specifications
not
Inactive
Suspended
or
insoluble
inactive
ingredients with unspecified physical size
parameters may require quality control in
physical specifications;
Chapter: 4.3
3
Generic Development
SEMISOLIDS
EXCIPIENTS
CHAPTER 4
HECKLIST
CL # HBGD-03-01YY
qYes qNo
qYes qNo
qYes qNo
qYes qNo
5. Has the particle size of insoluble or suspended non actives been qYes qNo
specified with an appropriate range, to prevent grittiness?
6. Is the in-vitro diffusion profile of the proposed generic formula qYes qNo
similar to the RLD's in-vitro diffusion profile (Hanson Diffusion Cell)?
7. Have Preservative Efficacy Testing (PET) of the Generic and RLD qYes qNo
been performed under normal room temperature testing?
8. Is the uniformity of content spread less than 4.0 - 5.0% with a RSD qYes qNo
of NMT 6.0%?
9. Does the Development Report show that the final formula was qYes qNo
derived from PET studies testing lower and upper [preservatives]
concentration levels?
10. Does the firm regularly review the Pharmacopoeial Forum for qYes qNo
proposed monographs and specifications for non-compendial
excipients ?
11. Has the firm reviewed all the suppliers for potential Approved qYes qNo
Suppliers as listed the Handbook of Pharmaceutical Excipients ?
12. Is Purified Water USP/BP used as an approved ingredient?
qYes qNo
13. Have the excipient specifications been reviewed in USP / NF, qYes qNo
Ph. Eur / BP, and JP and the latest supplements and addenda?
14. For compendial excipients has the latest supplement been qYes qNo
checked ?
15. Does your generic firm have a current Approved Supplier SOP ' qYes qNo
for non active ingredients?
Footnote : The words non active ingredient; inactive ingredient and excipient are all the same meaning and interchangeable in use.
Handbook of Pharmaceutical
Chapter: 4.4
4
Generic Development
SEMISOLIDS
EXCIPIENTS
CHAPTER 4
C H E C K L I S T
CL # HBGD-03-01YY
16. Has the variability of natural, semi-synthetic, synthetic and qYes qNo
especially polymeric material as a function of source been evaluated?
17. Has the variability of natural, semi-synthetic, synthetic and qYes qNo
especially polymeric material from a single source been evaluated?
STANDARD OPERATING
PROCEDURES
Page 1 of 1.
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
4
[End of Document]
Edition No. :
01
Ed. Status : New
Effective Date :
Handbook of Pharmaceutical
APPROVED
______________ _______________
Department
RD
Chapter: 4.5
5
_____________ _______________
RA
QC / Q A
Generic Development
CHAPTER 5
CONTAINER-CLOSURE
SEMI SOLIDS
C ontainer-closure Systems
the container documentation is the key
dot every i and cross every t
Product protection
The degree of product protection must
be equal to the RLDs container and the
container-closure
system
should
prevent
physical,
chemical
or
microbiological changes to the drug
product, on storage and during
customer-consumer use.
Semisolids are packed in coated
aluminum tubes, HDPE / LDPE squeeze
tubes or thermoplastic HDPE / HDPP
bulk containers or jars.
Three principal rules apply to semisolid
container-closure systems: All development stability testing is
performed in the container-closure in
which the drug is to be marketed.
All the manufacturer's container-linerclosure documentation must meet for
current specifications (fully audited).
Container closure specifications
need to be compatible with the
commercial production filling/packaging
equipment where the lots are produced.
Container-liner-closure suppliers that
are approved must be supported by
detailed technical specifications &
testing methodology.
Special emphasis is placed on the type
of
thermoplastic
resin
utilized.
Manufacturers who change the resin
automatically compromise the generic
stability studies performed for ANDA
Handbook of Pharmaceutical
Documentation requirements
The
documentation requirements of a
suitable chosen container system
requires careful auditing and review.
Obtaining the correct documentation is
time consuming and may take several
months
before
all
supplier
documentation is complete, correct and
on file with the proposed manufacturer.
Full specifications, Letters of Access
(LOAs) for components with DMF
numbers, Certificates of Analysis and
21 CFR certification is required.
The principal components in direct
contact with the semisolid are most
critical:
each
component have been itemized in the
attached SOPs with actual model
examples of the full container-linerclosure package in Part II of this
Handbook.
Chapter: 5.1
1
Generic Development
CHAPTER 5
Containers
SEMISOLIDS
CHECKLIST
CL # HBGD-03-0298
Container-liner-closure Systems
check that the suppliers specifications - always refer to the latest USP edition
1.
qYes qNo
2.
qYes qNo
3.
qYes qNo
4.
qYes qNo
5.
qYes qNo
6.
The inner seals in the cap complies with the 21 CFR 176.180 ?
qYes qNo
(where relevant)?
21 CFR 172.280
qYes qNo
(where relevant)
21 CFR 175.300
qYes qNo
7.
qYes qNo
8.
qYes qNo
9.
qYes qNo
qYes qNo
11. Each pack size (e.g. 20, 50, 100 g) has a separate set of qYes qNo
component specifications (for container, resin, liner, cap, colorant etc.)
12. Letters of authorization (LOA) from the DMF holders obtained ?
qYes qNo
13. Certificates of Compliance identifying the materials used in the qYes qNo
component manufacture conform to 21 CFR 172-177 etc.?
14. Certificate of Analysis identifying component meets specific USP qYes qNo
Test Requirements (e.g. moisture permeability test etc.)?
15. GMP Certification statement indicating GMP status of component qYes qNo
manufacturing facility?
Footnote : Bold numbers in checklist indicate that this documentation must be on file with generic drug
developer prior to process qualification or pivotal batch manufacture.
Handbook of Pharmaceutical
Chapter: 5.2
2
Generic Development
CHAPTER 5
Containers
SEMISOLIDS
CHECKLIST
CL # HBGD-03-0298
Container-Liner-Closure Systems
16.
qYes qNo
qYes qNo
No materials specification changes will be made without full notification to all qYes qNo
ANDA holders ?
17. Technical data sheet and component drawings supplied by manufacturer qYes qNo
for each component (container, liner composite, closure, fillers)?
18.
- tube/container?
qYes qNo
19.
- seal/laminate?
qYes qNo
20.
- cap/closure?
qYes qNo
21.
qYes qNo
22.
Generic Developer has a LOA for every DMF File referenced to FDA?
qYes qNo
23.
qYes qNo
24.
qYes qNo
25. Documentation has been audited in-house for current pharmacopoeial qYes qNo
editions, latest Certificate of Analysis and updated component specifications?
Footnote : Insure that vendors and manufacturers have updated all their component specification and
documentation to the current year. Specifications must apply to actual batch lot supplied to developers. A
typical component description: 22mm x 100 mm blind ended metal tube with valspar 3846 (5061) lining
with HDPE cap with #16 neck
Handbook of Pharmaceutical
Chapter: 5.3
3
Generic Development
CHAPTER 5
Containers
SEMISOLIDS
STANDARD OPERATING
PROCEDURES
SOP #
Page 1 of 1.
HBGD-03-0298
Container-Liner-Closure Systems
Semisolid based topical products are marketed in single or multi-unit containers.
Rigid bottles / jars (glass or polypropylene )
collapsible tubes (coated metal or thermoplastic low density polyethylene (LDPE)
Flexible pouches
The tubes are fabricated by rolling and heat-sealing flat stock into a continuous tube
of desired diameter, then trimming to length and attaching the head by injection
molding. The head insert is sometimes made of urea formaldehyde. Typically there
is no cap liner. The inner seal may be plastic or metal which is heat-sealed into
place
or molded with the tube. The former may have a lip for removal by hand. The
alternative is to incorporate a device into the construction of the cap before breaking
the inner seal. The marketed package may include a separate applicator device or
the applicator may be part of the closure.
The following selected model Standard Operating Procedures are recommended SOPs:
CONTAINER-LINER-CLOSURE SYSTEMS
# P-000-01-0298
# P-000-01-0298
# P-000-01-0298
# P-000-01-0298
Effective Date :
DD/MM/YY
Handbook of Pharmaceutical
177. 1520
177. 1520
175.300
177.1520
175.300
177.1380
177.1520
177.1630
176.180, 172.280, 175.300
HDPP
HDPE
APPROVED
___________
Department
___________
RD
Chapter: 5.4
4
____________ __________/___________
RA
QC
/
QA
Generic Development
CHAPTER 5
CONTAINER-CLOSURE
SEMISOLIDS
Total Number
STANDARD OPERATING
SOP # S-115-01-06YY
of Pages: 3.
PROCEDURES
PURPOSE
1.
The
RESPONSIBILITY
2.
FREQUENCY
3.
PROCEDURE
4.
Certificate of Analysis
Edition Number:
01
Ed. Status:
New
Effective Date:
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
_______________ ______________
Department
R &D
Chapter: 5.5
5
C1-05-2.doc
_______________ __________/________
RA
QC / QA
Generic Development
CHAPTER 5
CONTAINER-CLOSURE
SEMISOLIDS
Total Number
STANDARD OPERATING
SOP # S-115-01-06YY
of Pages: 3.
PROCEDURES
Letters of Authorization
-
LoA from resin manufacturer referencing their resin DMF #0000 as used in the
manufacture of the container.
Obtain separate letters for each resin type used in different tubes or plastic containers.
Certificate of Analysis
Letters of Authorization
-
Obtain separate letters for each resin type used in thermoplastic closures.
Liner Specifications (bulk jars and plastic containers):From the cap/liner manufacturers (including) :-
Certificate of Analysis
Letters of Authorization
LoA from manufacturer referencing DMF #000 of seal
Statement of GMP compliance of manufacturer
Edition Number:
01
Ed. Status:
New
Effective Date:
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
_______________ ______________
Department
R &D
Chapter: 5.6
6
C1-05-2.doc
_______________ __________/________
RA
QC / QA
Generic Development
CHAPTER 5
CONTAINER-CLOSURE
SEMISOLIDS
Total Number
STANDARD OPERATING
SOP # S-115-01-06YY
of Pages: 3.
PROCEDURES
Pressure sensitive, tamper resistant, adhesive seals:From the Adhesive seal manufacturers :Adhesive seal Specifications for jars and containers (including);
-
Certificate of Analysis
Letters of Authorization
Certificate of Analysis
Letters of Authorization
-
LoA from resin manufacturer referencing their resin DMF #0000 as used in the
manufacture of the nozzle/applicator.
Obtain separate letters for each resin type used in different nozzle or plastic applicator.
[End of Document]
Edition Number:
01
Ed. Status:
New
Effective Date:
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
_______________ ______________
Department
R &D
Chapter: 5.7
7
C1-05-2.doc
_______________ __________/________
RA
QC / QA
Generic Development
CHAPTER 5
CONTAINER-CLOSURE
SEMI SOLIDS
STANDARD OPERATING
PROCEDURES
SOP # S-115-01-03YY
Total Pages: 2
CLOSURE
DRAWINGS &
SPECIFICATIONS
DRAWINGS &
SPECIFICATIONS
MATERIAL TESTS
(USP)
MATERIAL TESTS
(USP)
Certificate of
Analysis
Certificate of
Analysis
Letter of Access
(from each vendor)
Edition Number:
01
Ed. Status :
New
SEAL
DRAWINGS &
SPECIFICATIONS
MATERIAL TESTS
(USP)
Certificate of
Analysis
Letter of Access
(from each vendor)
Effective Date:
APPROVED
DD/MM/YY
_______________
Department
Handbook of Pharmaceutical
Letter of Access
(from each vendor)
C1-05-3.doc
__________________
R &D
__________________
RA
Chapter: 5.8
8
_______________
QC
________________
QA
Generic Development
SEMISOLIDS
MANUFACTURING
Manufacturing
Instructions
start with the order of addition and
the processing conditions...
End with process optimization and
process validation...
Handbook of Pharmaceutical
CHAPTER 6
Chapter: 6.1
1
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
C H E C K L I S T
CL # HBGD-01-01YY
MANUFACTURING INSTRUCTIONS
write the manufacturing instructions clearly - so they can be simply followed
one step at a time
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
qYes - qNo
Handbook of Pharmaceutical
Chapter: 6.2
2
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
TABLE OF CONTENTS.
This section contains:
Outlines of process and controls
Description of Manufacturing Process
Manufacturing Procedure Flow Chart
Master Production Batch Records for intended production lots
Packaging Records for intended production lots
Formula comparison between pivotal and intended commercial lots
Equipment Comparison pivotal and intended commercial lots
Description of Packaging Operation
Reprocessing Statement(s)
Handbook of Pharmaceutical
Chapter: 6.3
3
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
OUTLINE OF STANDARD OPERATING PROCEDURES FOR :
MANUFACTURING AND PROCESSING
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Handbook of Pharmaceutical
Chapter: 6.4
4
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
OUTLINE OF STANDARD OPERATING PROCEDURES
FOR:
IN-PROCESS CONTROLS
1. At all stages of manufacturing, processing, time limitations and packaging
appropriate control procedures are employed in conformity with current good
manufacturing practice.
2. Appropriate in-process controls include material testing by quality control and
quality assurance personnel. These test cover:
nclosed are the production batch records (master, packaging and labeling) for
Post-Approval production batch.
Handbook of Pharmaceutical
Chapter: 6.5
5
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
IN-PROCESS CONTROLS
DURING SEMISOLID FILLING
In-process testing is conducted independently by both production and
quality control trained personnel. The tests specified in the underlying
tables are performed in accord with the in-process product specifications.
When, a test is not required, according to the written specifications, it will
not be performed.
Production personnel test the physical specifications of random samples
according to the individual product specifications: A minimum sampling frequency is
tabulated for each eight hour (shift) period.
Production In-process
Testing Schedule:
TEST
PERFORMED
Bulk Description
Sample
Size
Frequency
per shift
(min)
(1)
At start.
10
At 30 min.
intervals.
Cap Torque
At 30 min.
intervals.
Acceptance
Criteria (2)
Within written specifications.
NMT 2 Containers from of the 20 tested
may deviate from product spec. No
deviation permitted from Double Limits(3)
specification.
No deviation from product specifications is
permitted.
KEY:
1
The testing frequency is performed twice when the overall filling time is less than four hours.
Deviations from specifications and acceptance criteria, arising during the in-process
controls, shall determine the corrective action to be performed on the filling machinery
during the filling stage.
Handbook of Pharmaceutical
Chapter: 6.6
6
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
Quality Control
In-process Testing Schedule:
TEST
Sample
Frequency
PERFORMED
Size
per shift
(min.)
Material Description
1 (1)
Once
(1)
at start
Individual Fill
20
(1)
6 (1)
60 min
60 min
Weight
CAP TORQUE
Acceptance
Criteria (2)
KEY:
1
Samples are taken, independently by QC personnel for batch release purposes, at least
once per hour throughout the FILL run, producing a total representative sample quantity of 20
- 40 Containers . This representative sample lot is for QC batch release purposes .
2
Deviations from specifications and acceptance criteria, arising during the in-process controls,
shall determine the corrective action to be performed on the filling machinery during the
filling stage.
3
Double Limits for the Individual Fill Weight test are defined as the double value from the
minimum or maximum limit in relation to the nominal Fill value (i.e. target weight value).
Handbook of Pharmaceutical
Chapter: 6.7
7
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
PRODUCTION YIELDS
STANDARD OPERATION PROCEDURE - OUTLINE
alculation of batch yield in the overall manufacturing involves the use of three
different types of calculations.
The first yield calculation is called the
Percentage Yield - Usable Material [% Yield Usable].
The second term Percentage Yield - Overall [% Yield Overall] and the third
calculation is called the Percentage Batch Yield. The three yield calculations are
defined as follows:
USABLE MATERIAL PERCENTAGE YIELD:
This calculation is performed at the end of each step in the manufacturing process
and is recorded on the actual Manufacturing Procedure documents. The intent of
the calculation is to define the usable amount of material available for use in the next
manufacturing step (i.e. compression, packaging, etc.). Because this value is only
determining the available amount of material, it does not take into consideration the
amount of material that may be lost to waste, sampling or rejection during
compression/encapsulation/coating. Logically, this value is calculated for
informational purposes and is not held to specific limits as it is partially dependent
on sampling requirements and equilibration of manufacturing equipment (i.e. tablet
presses, etc.).
PERCENTAGE YIELD OVERALL:
This calculation is performed at the end of each step in the manufacturing process
and is recorded on the attachment entitled Material Balance/Dry Production. The
intent of the calculation is to determine the overall batch yield attained at each step
in the process. Because this value determines the overall yield, it takes into account
not only the usable portion of the batch but also the quantity of material lost to
recoverable waste, sampling and rejection during compression/ encapsulation/
coating. Since this value incorporates all measurable and accountable quantities of
the material, it is used as a means with which to control the manufacturing process.
The limit established for this value is Not less than 98% [in other words not more
than 2% unexplained loss] from the previous manufacturing stage.
In the event that this limit is not achieved during the batch production, report of the
deviation is made in an accompanying Manufacturing Deviation Report.
PERCENTAGE BATCH YIELD:
This
4
Handbook of Pharmaceutical
Chapter: 6.8
8
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
A DETAILED EXAMPLE ON DOCUMENTATION STRUCTURE
IDENTIFICATION OF BATCH PARAMETERS.
Product name:
[Generic] Cream
Batch Number:
AIG0000-00
Batch Size:
Department:
WET UNIT
Precautions:
Sub-lot No:
Caution:
Cat./Formula No:
# AIG-[0YY001]
Based on PQ:
Batch # AIG-PQ[00-00
Semisolid
PIVOTAL
VALIDATION LOT
COMMERCIAL LOT
[000-000] units
1
BATCH
Original
No Change
Change
KEY to:
Precautions:
Wear Mask and Gloves
Wear disposable overalls
Use air stream face visor with AIR filter
Use Mask, Gloves and Safety glasses Material causes extreme irritation to
skin and eyes Do not expose to skin or exposed areas.
Cautions:
Avoid exposure to light / Protect form light
Store in well closed containers and minimize or avoid exposure to
environmental air
Raw material has to be stored at 5C - hold active material at 25o C for one
hour to reach room temperature before weighing, sampling or processing
Potential danger to pregnant women, pregnant women are prohibited in this
area
Do not heat above [00]
C
Maintain Room humidity below 50%
Note:
A detailed structure for documenting the manufacturing process for emulsification
and homogenization is given as an example of how to prepare and write the
manufacturing and processing instructions.
This specific set of manufacturing instructions was chosen as it represents a
complex example and highlights numerous processing principles. The order of each
process step is critical and should follow the order that the ingredients appear in the
master formula.
As actual values and numerical parameters are not significant in the example
provided. The figures are simply reported as [00] for ease of purpose. Further
commercial examples are additionally provided annually with each new edition.
Handbook of Pharmaceutical
Chapter: 6.9
9
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
MANUFACTURING INSTRUCTION
COMMERCIAL PRODUCTION
[Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000
Miconazole Cream USP [20.0] mg/gram
Batch No:
Weighing Date :
Page 1 of 2 pages
Mg
Per
gram
%
Exc
ess
Sign
weigh.
Dept.
per [150] kg
Kg
mg
mL
20.00
30.00
1.50
9.60
10.00
Pegoxol 7 Stearate
[Tefose 63]
Heavy Mineral OIL NF
Benzoic Acid USP
Butylated Hydroxyanizole
27
000
780
300
7
500
31
087
500
3
4
000
500
1
1
225
440
500
10
665
108
247
108
247
150
000
500
500
Handbook of Pharmaceutical
150
000
APPROVED
____________
Department
__________
R &D
Chapter: 6.10
10
_______________
RA
The ORDER
of appearance
of the ingredients
is the same
ORDER of
processing
_________/________
QC / QA
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
MANUFACTURING INSTRUCTION
COMMERCIAL PRODUCTION
[Generic name] SEMISOLID [USP] [000.0] mg/g Lot: 000
Miconazole Cream USP [20.0] mg/gram
Batch No:
Weighing Date :
Page 2 of 2 pages
Mg
Per
gram
%
Exc
ess
Sign
weigh.
Dept.
per [300] kg
Kg
mg
mL
20.00
30.00
1.50
9.60
10.00
Pegoxol 7 Stearate
[Tefose 63]
Heavy Mineral OIL NF
Benzoic Acid USP
Butylated Hydroxyanizole
54
000
560
600
15
62
175
6
9
000
000
2
3
450
880
000
21
330
216
495
216
495
000
300
000
1000.0
300
000
Edition Number:
01
Ed. Status:
New
Effective Date:
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
__________
R &D
Chapter: 6.11
11
_______________
RA
_________/________
QC / QA
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION
Weighing Date:
Page 1 of 4 pages
Machine
MANUFACTURING INSTRUCTIONS
Sign
A+B
Date
NOTE:
The ingredients are written in
the same order as they are
processed and also as they
appear in the 'Master
Formula'
Effective Date:
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
__________
R &D
Chapter: 6.12
12
_______________
RA
_________/________
QC / QA
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION
Page 2 of 4 pages
MANUFACTURING INSTRUCTIONS
Machine
Sign
A+B
Date
[ ] C).
[ ]
[ ] min
NMT [
[
[
[
NOTE
Each action
is
CAPITALIZED
] C
]
]
] min
[ ]
[ ]
[ ] min
Step 9. CHECK that the oil phase after the mixing period is a
homogeneously dispersed oily suspension - if necessary mix for an
additional 20 minutes
Start of Mixing
[ ]
End of Mixing
[ ]
Additional Mixing Time
[ ] min
Ed Number:
01
Ed. Status:
New
Effective Date:
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
__________
R &D
Chapter: 6.13
13
_______________
RA
_________/________
QC / QA
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION
Page 3 of 4 pages
MANUFACTURING INSTRUCTIONS
Machine
Sign
A+B
Date
Effective Date:
Ed. Status:
New
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
__________
R &D
Chapter: 6.14
14
_______________
RA
_________/________
QC / QA
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION
Page 4 of 4 pages
MANUFACTURING INSTRUCTIONS
Machine
Sign
A+B
Date
YIELD CALCULATION
Step 20. Theoretical Weight [00.0] Kg.
Yield ___________ %
(Yield Limits: NLT 95% of Theoretical Weight.) No of Bins ______
Step 21. COLLECT 10 samples, each equivalent to the approximate
weight of 10 g in labeled sample containers. Collect samples from upper,
middle and lower part of the container. Send the samples to the QC
laboratory for Content Uniformity Testing.
The ingredients
are rewritten for
each sub-lot. Up to
three sublots are
common
Effective Date:
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
__________
R &D
Chapter: 6.15
15
_______________
RA
_________/________
QC / QA
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION
FLOW CHART
Chart One
880-920C
MIXER
Water Phase Cooling
0
0
60 -62 C
Water USP
Purified Water
Lipophyllic Emulgent
1st RINSE
2nd RINSE
Nitrogen blanket
3rd RINSE
(microgram Actives )
OIL PHASE
MIXER
(S/S
Inlet temp.
up to 62C
(target 60C)
Mixing vessel)
Oily Solvent
Lipophobic Emulgent
Emulsifier
(Ross
IPQC Testing
pH
Viscosity
Content Uniformity
Microbial limits
mixer)
Viscosity Agent
Cool to 280C
(Specify Type)
at controlled temp - T 0C
DE-AERATOR
Homogeneous
Semisolid
Target Temp.
0
0
50 -52 C
HOLDING TANK
Under Nitrogen
Fill tubes according
to specifications
Ultra-clean FILLING
YIELDS
Overall Production Yields
Handbook of Pharmaceutical
Chapter: 6.16
16
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
MANUFACTURING INSTRUCTION COMMERCIAL
PRODUCTION
ATTACHMENTS:
THE FOLLOWING ATTACHMENTS ARE PLACED HERE:
Process
Attachment # 1
Attachment # 2
In-process
Attachment # 3
pH Print-Outs of Bulk.
Attachment # 4
Final Bulk
Mixing Process.
Attachment # 5
Attachment # 6
Weight Control
Filling Process.
Attachment # 7
NOTE:
Where automatic print-outs are not available, Statistical Data Work Sheets are filled
out, during the filling process. Suitable Semisolid Filling machines are highlighted
below.
Filling process:
Handbook of Pharmaceutical
[ALL-FILL \ KING]
Chapter: 6.17
17
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
IN-PROCESS CONTROL SPECIFICATION
BULK MATERIAL
SUMMARY
Product: [Generic name] SEMISOLID [USP] [000.0] mg / g Lot No: 000
Quantity 000000
Yields
Bulk Yield
MNF Date:
Month DD, YY
NLT 95.0%
____________ g.
NLT 00.000g
- NMT 00.000g
____________ Kg
____________ Kg
Handbook of Pharmaceutical
Chapter: 6.18
18
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
IN-PROCESS CONTROL
SPECIFICATIONS
SUMMARY
PRODUCT: [GENERIC NAME] SEMISOLID [000.0] mg.
Labeled Amount: EACH gram contains [000.0] mg [Active Material]
In-process Specifications
Description
Target 000
pH
(1.0 / 0.5 unit)
Viscosity
Target 0.0
Target 0000
In-Process
Semisolid Content Uniformity
Median 000
Yields
Actual Bulk Weight
NLT 95.0%
Note: Exact Decimal points have been set for each specification
Handbook of Pharmaceutical
Chapter: 6.19
19
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
IN-PROCESS CONTROL SPECIFICATION
SUMMARY
Product: [Generic name] SEMISOLID [USP] [000.0] mg / g
Quantity 000000
MNF Date:
Month DD, YY
Lowest
Mean
Highest
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
000.0
Weight Controls
In-Process Yields
Yield after filling vs. bulk material
Yield after filling to theoretical
Semisolid Yield
00.0 %
00.0 %
NMT 2.0% unexplained loss
from the previous step
Handbook of Pharmaceutical
Chapter: 6.20
20
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
RELEASE SPECIFICATION FOR SEMISOLID [USP]
SUMMARY
Product: [Generic name] Semisolid [000.0] mg / g
Labeled Amount: Each gram contains [000.0] mg [Active Material]
Description
Identification A:
Identification B:
Target 000
pH
(0.5 / 1.0 unit)
Viscosity
Target 0.0
Target 0000
NMT 100
NMT 100
Objectionable Organisms
Impurities /Degradation
Products determination
- Each Individual:
- Any other Individual:
- Total:
Assay (Preservative)
(Where Appropriate)
Assay (Active)
Handbook of Pharmaceutical
CFU / g
CFU / g
Chapter: 6.21
21
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
RELEASE SPECIFICATION FOR SEMISOLID [USP]
OUTLINE of
IN-HOUSE ANALYTICAL SOP
Content Uniformity
The requirements for content Uniformity are met if the amount of the active ingredient in
each of the 10 samples, as determined from the Content Uniformity Analytical Method, lies
within the range of 90.0 - 110.0% of the labeled amount and the Relative Standard
Deviation is less than or equal to 6.0%.
If 1 sample is outside the range of 90.0 - 110.0% of labeled amount and no sample is
outside the range of 80.0 - 120.0% of labeled amount, or if the Relative Standard Deviation
is greater than 6.0%, or if both conditions prevail, test 20 additional samples.
The requirements are met if not more than 1 sample of the 30 is outside the range of 90.0 110.0% of labeled amount and no sample is outside the range of 80.0 - 120.0% of labeled
amount, the Relative Standard Deviation of the 30 samples does not exceed 7.8%.
Preservative Efficacy
Preservative Efficacy Testing (USP) is omitted as a routine QC test when fully qualified with
justification during the formulation development, process qualification AND pivotal batch lot
testing.
Preservative Efficacy Test USP are evaluated on stability testing at time of manufacture, 12;
24; and 36 months for PQ, Pivotal and validation batches only.
Handbook of Pharmaceutical
Chapter: 6.22
22
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
COMPARISON OF PIVOTAL AND PRODUCTION FORMULAE
Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000
INGREDIENT
Amount per
Executed
Production
[0] mL
Batch
Batch
(mg)
0000
0000
(Kg)
(Kg)
Miconazole USP
00.00
00.00
00.00
Micronized
00.00
00.00
00.00
00.00
00.00
00.00
63]
00.00
00.00
00.00
00.00
00.00
00.00
00.00
00.00
00.00
Butylated Hydroxyanizole
00.00
00.00
00.00
Peglico 5 Oleate
00.00
00.00
00.00
00.00
00.00
00.00
00.00
00.00
00.00
000.000
000.000
Total
000.000
Adjust where applicable (i.e. if moisture content of active is greater than 0.5-1.0%):
Handbook of Pharmaceutical
Chapter: 6.23
23
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
COMPARISON OF EQUIPMENT AND MANUFACTURING CONDITIONS
BETWEEN PIVOTAL AND COMMERCIAL BATCHES
Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000
Equipment and
Manufacturing Conditions
Executed
Batch
000 Kg
Production
Batch
000 Kg
PROCESSING KETTLE
Production
Production
MIXER I
Production
Production
MIXER II
Production
Production
Production
Production
Production
Production
Production
Production
Production
Production
Production
Production
Equipment Variation
NONE
NONE
Manufacturing Area
Production
Production
Staff
Production
Production
SOP
Production
Production
Handbook of Pharmaceutical
Chapter: 6.24
24
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
PACKAGING OPERATION DESCRIPTION
Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000
Stage One.
PACKAGING COMPONENTS:
1. Bulk Product
2. HDPE / Aluminum / Glass Containers
3. Package Outsert (Product Leaflets)
4. Container Label
5. Master Cartons
6. Carton Shipping Labels
Stage Two
PACKAGING PROCEDURE:
HDPE Containers & Bulk Feed
Capping
(Tube/Jar)
Container Label
and Outsert Attachment
Handbook of Pharmaceutical
Chapter: 6.25
25
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
PACKAGING OPERATION - EQUIPMENT LISTING:
Product: [Generic name] q [Semisolid] [000.0] mg per g. Lot: S-000
Machine
Operation
Manufacturer
Type
Serial #
Supplier
1
Schenck
HDPE Bottle
Schenck Process
1000-S
or Amber
GMBH Darmstadt
AccuRate
No:
Output
CONTAINERS
per min2
50 Low
543123
100 High
Glass
Feeding
2
King
Air Cleaning
Cream
ALLFILL
KING
FILLER(1)
Filling
4
6.
7.
Capper
Torque
Groninger
Prestek
Capping
Torque
KING CAPPER
H.G.Kalish Inc.,
Canada
Groninger & Co
DFVK
KarlsHeim,
Germany
3000
Labelling &
Prestek Ltd
Printing
Science Park
SmartDate
Intelligent
Thermal
Transfer
Printer
Outserter
Nottingham UK
(1)
(2)
CAP 80
MK-
50 Low
2994
100 High
L-333
Count
L-334
50
50*
100
100*
2232-
50 Low
2234
100 High
2234-
50 Low
9987
100 High
5664
50 Low
100 High
53342
50 Low
100 High
Average figures for containers per minute output for Slow and High Speed.
All indicated machine outputs are adjusted to the Filling rate.
Handbook of Pharmaceutical
Chapter: 7.26
26
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
BATCH RECORDS FOR EXECUTED BATCH
TYPE OF SEMISOLID
Lot No
Enclosed are the batch records of the executed batch
labeling).
Note:
Translation Policy - (Foreign Manufacturing Plants):
All documents provided are authenticated photocopies of the executed batch
document.
The documents are written in (local language) with parts of the data and information
presented in English.
Where information is provided in the (local language), a verified English translation
is provided together with the original document in the local language. Where, only
English is used in a document, the original copy document is provided.
Executed batch of [Generic Name] SEMISOLID was manufactured on production
equipment under actual production conditions.
ACTIVE MATERIAL
The active material is manufactured by [BPC] Pharmaceutical and Chemical
Manufacturing Company - [Address].
Handbook of Pharmaceutical
Chapter: 7.27
27
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
REPROCESSING STATEMENT
(Delete statement where appropriate)
---------------------------------------
Date
Plant Manager
Pharmaceutical Manufacturing Division
----------------------------------------
Date
----------------------------------Date
Handbook of Pharmaceutical
Chapter: 7.28
28
Generic Development
SEMISOLIDS
MANUFACTURING
CHAPTER 6
Manufacturing Instructions
REPROCESSING STATEMENT
(Delete statement where appropriate)
The following manufacturing stages have been reworked during the full size process
Qualification batch (essentially similar to the pivotal batch shown) and the finished
product specifications were evaluated.
At time of manufacture (Time zero):
No detectable change was recorded for the following test studies
pH
Viscosity
Content Uniformity
At 3 months stability station (40o C / 75% RH):
The above parameters showed no detectable changes. The full re-work study is
presented in the Product Development Report and a Summary outline is given in
Section XXI.
Conclusion:
It is concluded that an additional 20 minute mixing (last stage) may be repeated
once as shown, without affecting or impacting on the products physical parameters
as shown in the in-process, release or stability (check) specifications.
[Signature of Responsible Person]
------------------------------------------------
--------------------------------------
Date
Plant Manager
Pharmaceutical Manufacturing Division
-------------------------------------
Date
Handbook of Pharmaceutical
Chapter: 7.29
29
Generic Development
SEMISOLIDS
IN-PROCESS CONTROLS
CHAPTER 7
In-process
Quality Controls
A critical stage of the overall development validation choosing process and product in-process controls
In-process
Diffusion
Diffusion profile, is not a compendial
requirement, may be omitted. It is an
useful test for demonstrating similarity
between
the
pivotal
and
three
commercial validation batches. It is an
official requirement for scale-up and
post approval changes (SUPAC-SS)
Manufacturing In-process Controls
n controls are those routine tests
performed on each lot that are
intended to ensure the completion of a
given manufacturing step or the
suitability of the intermediate material for
subsequent steps. The tests used and
subsequent parameters and in-process
controls set in order to produce
consistent batch-to-batch
Chapter: 7.1
1
Generic Development
IN-PROCESS CONTROLS
SEMISOLIDS
CHAPTER 7
C H E C K L I S T
CL # P-000-03-01YY
1. All dry powders are screened (state mesh size) prior to processing?
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
8. Mixing times are identified and recorded by start and stop entries?
qYes qNo
qYes qNo
0
qYes qNo
qYes qNo
11. The bulk pH value is tested by a sample portion and evaluated via a
calibrated pH electrode?
qYes qNo
12. Homogenization (rpm) sieve size (mm) and orifice settings are
identified ?
qYes qNo
13. Warning and Action limits have been established for microbial limit
testing?
qYes qNo
Footnote : The procedure for selecting approved suppliers for non active ingredients will minimize
inter-batch excipient variation significantly. This variation, if present, may impact upon the in-process
controls.
The absence of
adequate GMP (cleaning procedures) may adversely affect the microbial
bioburden of the bulk material during the manufacture and the filling process.
Handbook of Pharmaceutical
Chapter: 7.2
2
Generic Development
IN-PROCESS CONTROLS
SEMI SOLIDS
CHAPTER 7
C H E C K L I S T
CL # P-000-03-01YY
Routine in-process quality controls on the Final Product consists of testing the bulk
semisolid and the in-process fill weights during the tube filling stage: The following
parameters should be evaluated in the at the in-process and finished product stage:
14. Maximum processing times are stipulated for key stages and the
overall manufacturing time is controlled and documented ?
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
20. Qualification - Range limits (e.g. pH) have been suitably qualified by
manufacturing the product at the lower and upper limit of the Finished
Product Release Specification during the product development stage?
qYes qNo
21. In-process limits are set marginally tighter than the product
release specifications?
qYes qNo
22. Maximum time period between sanitation of filling line and filling
operation is clearly stated in documentation?
qYes qNo
23. Target fill weight for the filling procedure, is established during the
product development stage and then qualified as a filling parameter ?
qYes qNo
Handbook of Pharmaceutical
Chapter: 7.3
3
Generic Development
IN-PROCESS CONTROLS
SEMI SOLIDS
CHAPTER 7
C H E C K L I S T
CL # HBGD-03-01YY
qYes qNo
(After homogenization)
qYes qNo
(After homogenization)
qYes qNo
Viscosity
qYes qNo
Content Uniformity
qYes qNo
Individual Weight
qYes qNo
Average Weight
qYes qNo
qYes qNo
(Prior to packaging)
qYes qNo
(Prior to packaging)
qYes qNo
Notes:Setting the limits may be achieved by manufacturing at the extreme ends of the viscosity range (lowest and
highest values) and measuring the resulting values. The range may be skewed to the right, if necessary. As
an example viscosity - is set a range of say 5000 [lower] - 6000 [target] - 8000 cP [upper], especially if there is
a possibility of a significant variation in raw materials producing a more viscous semisolid. The range
specification may be reviewed in the forthcoming annual report after several batches have been produced
commercially. pH ranges are 0.5 units for acidic or basic target values and 1.0 units for near neutral
preparations. E.g. 4.0 - 4.5 -5.0 (acidic) and 5.5 - 6.5 -7.5 (around neutral pH)
Handbook of Pharmaceutical
Chapter: 7.4
4
Generic Development
IN-PROCESS CONTROLS
SEMI SOLIDS
CHAPTER 7
STANDARD OPERATING
PROCEDURES
SOP #
Page 1 of 1.
HBGD-03-01YY
P-000-02-01YY
P-000-02-01YY
P-000-02-01YY
P-000-02-01YY
Reserved.
----------------
4
[End of Document]
Edition No.:02
Effective Date :
Ed. Status : 01
Handbook of Pharmaceutical
APPROVED
___________ ____________
Department
RD
Chapter: 7.5
5
____________
RA
__________/___________
QC
/
QA
Generic Development
CHAPTER 8
SEMISOLIDS
90.0 - 110.0%
Handbook of Pharmaceutical
in-process
release
finished product
stability
[bulk]
[ T0 ]
[overall]
[shelf life]
Chapter: 8.1
1
Generic Development
CHAPTER 8
SEMISOLIDS
C H E C K L I S T
SOP # P-000-03-01YY
1. The Finished Product Specifications have both release and a stability qYes qNo
check specifications that allows for appropriate product aging
throughout the allocated shelf life ?
2. All the stability specifications are shown to be - stability indicating ?
qYes qNo
3. The Description allows the minor changes in color from release to qYes qNo
end of shelf life (i.e. - smooth white to off-white homogeneous
cream?)
4. Release specifications have narrower limits than the stability check qYes qNo
specifications, allowing an appropriate margin of safety as the product
ages?
qYes qNo
5. The assay release specifications are set at 95.0 - 105.0% ?
qYes qNo
6. The assay check specifications are set at 90.0 - 110.0%
7. The firm performs specified critical in-process controls to insure that
the finished product testing is always in specification (e.g. content
uniformity testing or with older environments, Microbial Limit Tests)?
8. Uniformity of Content is tested at the end of bulk manufacture ?
9. Batches released at <97.0% are investigated and monitored for
stability, (if development studies show that the active loss is >7% for
the claimed shelf-life)?
10. Development and qualification lots show content uniformity does not
change after the filling process (i.e. cracking, breaking or splitting).
11. Viscosity is tested in-process (bulk) prior to filling?
12. Total Microbial Count and Limit tests are performed after filling ?
13. Total Fungal Count is performed after filling ?
14. Preservative Efficacy Test USP was tested in the development and
qualification batches and demonstrated for regulatory purposes in the
pivotal and if deemed necessary, validation lots?
15. If Q14 answered yes then preservative assay monitoring is
unnecessary for routine commercial lots?
16.The microbial limits test includes pathogens specific to the local
environment and water contaminants ?
Handbook of Pharmaceutical
Chapter: 8.2
2
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
Generic Development
CHAPTER 8
SEMISOLIDS
C H E C K L I S T
SOP # P-000-03-01YY
17. Viscosity testing is not performed as a finished product release test qYes qNo
as this test is routinely addressed during the in-process controls?
18. Content uniformity (U of C) is not evaluated as a check specification, qYes qNo
if development studies shows no changes in U of C with aging studies
(see globule size studies)?
19. Stability Studies show an absence of weeping, bleeding, cracking, qYes qNo
(splitting) or granular effects in the semisolid matrix ?
20. Antioxidant Optimization (either with or without a chelating agent, qYes qNo
where deemed necessary) was performed to establish that the Finished
Product Specification (Stability Check) Assay and Impurities remained
within the specification range?
21. The Preservative Efficacy Test (PET) and final Antioxidant qYes qNo
concentration was evaluated in the development and qualification
batches and demonstrated to produce consistent results in the pivotal
and three full size commercial validation lots?
22. If yes to #13, then PET and Antioxidant monitoring is unnecessary for qYes qNo
routine commercial lots, if neither a USP compendial monograph
requirement?
23. The Description allows for possible minor changes in appearance qYes qNo
from product release to end of shelf-life (i.e. off-white to creamish color)?
24. Where Test failures occur in parameters that have been optimized or qYes qNo
qualified, re-qualification studies must be investigated?
Footnote: Where the product batch history shows test failures due to environmental or raw material
variations is a clear indication that both these parameters should be further investigated and
addressed
Handbook of Pharmaceutical
Chapter: 8.3
3
Generic Development
SEMISOLIDS
CHAPTER 8
GLOSSARY OF TERMS
Approved Target Composition: The components and amount of each
ingredient for a drug product used in an approved pivotal clinical study or
bioequivalence study.
Batch: A specific quantity of a drug or other material produced according to a
single manufacturing order during the same cycle of manufacture and intended to
have uniform character and quality, within specified limits. (21 CFR 210.3(b)(2)).
Contiguous Campus: Contiguous or unbroken site or a set of buildings in
adjacent city blocks.
Creams/Lotions: Semisolid emulsions that contain fully dissolved or suspended
drug substances for external application. Lotions are generally of lower viscosity.
Diluent: A vehicle in a pharmaceutical formulation commonly used for making up
volume and/or weight (e.g., water, paraffin base).
Drug Product: A drug product is a finished dosage form (e.g., cream, gel, or
ointment) in its marketed package. It also can be a finished dosage form (e.g., tablet,
capsule, or solution) that contains a drug substance, generally, but not necessarily,
in association with one or more other ingredients (21 CFR 314.3(b)).
Drug Release: The disassociation of a drug from its formulation thereby allowing
the drug to be distributed into the skin or be absorbed into the body where it may
exert its pharmacological
effect.
Drug Substance: An active ingredient that is intended to furnish pharmacological
activity or other direct effect in the diagnosis, cure, mitigation, treatment, or
prevention of a disease, or to affect the structure or any function of the human body,
but does not include intermediates used in the synthesis of such ingredient (21 CFR
314.3(b)).
Emulsion: Emulsions are two phase systems in which an immiscible liquid
(dispersed phase) is dispersed throughout another liquid (continuous phase or
external phase) as small droplets. Where oil is the dispersed phase and an aqueous
solution is the continuous phase, the system is designated as an oil-in-water
emulsion. Conversely, where water or an aqueous solution is the dispersed phase
and oil or oleaginous material is the continuous phase, the system is designated as
a water-in-oil emulsion.
Emulsions are stabilized by emulsifying agents that prevent coalescence, the
merging of small droplets into larger droplets and, ultimately, into a single separated
phase (bleeding and cracking). Emulsifying agents (surfactants) do this by
concentration in the interface between the droplet and external phase and by
providing a physical barrier around the particle to coalesce.
Surfactants also reduce the interfacial tension between the phases, thus increasing
the ease of emulsification upon mixing. Emulsifying agents substantially prevent or
delay the time needed for emulsion droplets to coalesce. Emulsification is the act of
forming an emulsion. Emulsification can involve the incorporation of a liquid within
another liquid to form an emulsion or a gas in a liquid to form a foam.
Handbook of Pharmaceutical
Chapter: 8.4
4
Generic Development
SEMISOLIDS
CHAPTER 8
GLOSSARY OF TERMS
Formulation: A listing of the ingredients and quantitative composition of the
dosage form.
Gel: A semisolid system in which a liquid phase is constrained within a three
dimensional, cross-linked matrix. The drug substance may be either dissolved or
suspended within the liquid phase.
Homogenization: A method of atomization and thereby emulsification of one
liquid in another in which the liquids are pressed between a finely ground valve and
seat under high pressure (e.g., up to 5,000 psi).
Internal phase: The internal phase or the dispersed phase of an emulsion
comprises the droplets that are found in the emulsion.
In Vitro Release Rate: Rate of release of the active drug from its formulation,
generally expressed as amount/unit area/time . 0.5
Lot: A specific quantity of a drug or other material produced according to a single
manufacturing order during the same cycle of manufacture and intended to have
uniform character and quality.
A Lot may comprise of several sublots, - each sub-lot representing the quantity of
material of the smallest manufacturing unit's capacity in the overall manufacturing
process.
Ointment: An unctuous semisolid for topical application. Typical ointments are
based on petrolatum. An ointment does not contain sufficient water to separate into
a second phase at room temperature. Water soluble ointments may be formulated
with polyethylene glycol.
Pilot Scale Batch: The manufacture of drug product by a procedure fully
representative of and simulating that intended to be used for full manufacturing
scale.
Preservative: An agent that prevents or inhibits microbial growth in a formulation
to which it has been added.
Process: A series of operations, actions and controls used to manufacture a drug
product.
Scale-up: The process of increasing the batch size.
Scale-down: The process of decreasing the batch size.
Shear: A strain resulting from applied forces that cause or tend to cause contiguous
parts of a body to slide relative to one another in direction parallel to their plane of
contact.
In emulsification and suspensions, the strain produced upon passing a system
through a homogenizer or other milling device.
Low shear: Processing in which the strain produced through mixing and/or
emulsifying shear is modest.
High shear: Forceful processes which, at point of mixing or emulsification place
a great strain on the product.
Handbook of Pharmaceutical
Chapter: 8.5
5
Generic Development
SEMISOLIDS
CHAPTER 8
GLOSSARY OF TERMS
Homogenization, by its very nature, is a high shear process which leads to a small
and relatively uniform emulsion droplet size. Depending on their operation, mills and
mixers are categorized as either high shear or low shear devices.
Significant Body of Information: A significant body of information on the
stability of the product is likely to exist after five years of commercial experience for
new molecular entities, or three years of commercial experience for new dosage
forms.
Structure Forming Excipient: An excipient which participates in the formation
of the structural matrix which gives an ointment, cream or gel etc., its specific
semisolid character. Examples are gel forming polymers,
petrolatum,
certain colloidal inorganic solids (e.g., bentonite),
waxy solids (e.g., cetyl alcohol, stearic acid)
emulsifiers used in creams.
Strength: Strength is the concentration of the drug substance (for example,
weight/weight, weight/volume, or unit dose/volume basis), and/or the potency, that is,
the therapeutic activity of the drug product as indicated by appropriate laboratory
tests or by adequately developed and controlled clinical data (expressed, for
example, in terms of units by reference to a standard) (21 CFR 210.3(b)(16)).
For semisolid dosage forms the strength is usually stated as a weight / weight (w/w)
or weight / volume (w/v) percentage.
Suspending agent: An excipient added to a suspension to control the rate of
sedimentation of the active ingredients.
Technical grade: Technical grades of excipients differ in their specifications
and intended use. Technical grades may differ in:
(1) specifications and/or functionality,
(2) impurities
(3) impurity profiles.
Validation: A procedure to establish documented evidence that provides a high
degree of assurance that a specific process or test will consistently produce a
product or test outcome meeting its predetermined specifications and quality
attributes. A validated manufacturing process or test is one that has been proven to
do what it purports or is represented to do.
The proof of process validation is obtained through collection and evaluation of data,
preferably beginning with the process development phase and continuing through
the production phase. Process validation necessarily includes:
process qualification
the qualification of materials,
equipment
systems
building
personnel,
but it also includes the control of the entire processes for repeated batches or runs.
Handbook of Pharmaceutical
Chapter: 8.6
6
Generic Development
CHAPTER 8
SEMISOLIDS
STANDARD OPERATING
PROCEDURES
Page 1 of 1.
SOP # HBGD-03-01YY
P-000-02-01YY
P-000-02-01YY
P-000-02-01YY
# P-000-02-01YY
REFERENCES
1. Shah, V. P., J. Elkins, J. Hanus, C. Noorizadeh, and J. P. Skelly,"In Vitro Release of Hydrocortisone from
Topical Preparations and Automated Procedure," Pharmaceutical Research, 8:55-59, 1991.
2. Shah, V. P., J. S. Elkins, and R. L. Williams, "In Vitro Drug Release Measurement of Topical Glucocorticoid
Creams," Pharmacopeial Forum, 19, 5048-5059, 1993.
3. Corbo, M., T. W. Schultz, G. K. Wong, and G. A. Van Buskirk, "Development and Validation of In Vitro
Release Testing Methods for Semisolid Formulations," Pharmaceutical Technology 17(9):112-128, 1993.
4. Li, J. B. and P. C. Rahn, "Automated Dissolution Testing of Topical Drug Formulations Using Franz Cells and
HPLC Analysis," Pharmaceutical Technology 17(7):44-52, 1993.
5. Shah, V. P. and J. S. Elkins, "In Vitro Release from Corticosteroid Ointments," Journal of Pharmaceutical
Sciences, 84:1139-1140, 1995.
6. Zatz, J.L., "Drug Release from Semisolids: Effect of Membrane Permeability on Sensitivity to Product
Parameters," Pharmaceutical Research 2:787-789, 1995.
4
[End of Document]
Edition No. 03
Effective Date :
Ed. Status :
Supersedes - 02
Handbook of Pharmaceutical
APPROVED
_____________ __________________ _____________
Department
RD
RA
Chapter: 8.7
7
_______________
QC / Q A
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
CHAPTER 9
Process
Optimization
choosing the right formula and process specifications
prior to qualification'
Qualification of Limits
Formula and Process Optimization are
utilised in establishing formula &
processing target values pertaining to
the manufacturing procedure finally
adopted as well as establishing correct
specification limits for key mfg stages.
Semisolid Key Formula parameters are:
Antioxidant concentration
use of a chelating agent (synergism)
preservative(s) and concentration
target pH (and range) - unbuffered
Semisolid Key Process parameters are:
target
heating
and
cooling
temperatures of oil, aqueous, and
the combined phases.
optimum
PHASE
mixing
or
emulsifying TEMPERATURES.
Fine tuning the formulation involves
selecting the correct antioxidant and
where
necessary,
a
synergistic
chelating agent (EDTA) or establishing
the optimum antioxidant concentration
or synergistic combination and then
evaluating the overall formula and
process capability in maintaining assay
and impurity/degradant limits.
Choosing
the
most
effective
preservative is a basic formula development but evaluating its' most effective
concentration in the formula in order to
effectively withstand a challenged by
the Preservative Efficacy Test falls into
process qualification frame, as the
whole overall process is involved.
.
Handbook of Pharmaceutical
Optimization Batches:
Batch 06 - BHA Study + Preservative
Batch 07 - BHA Study + Preservative
Batch 08 - EDTA Study + Preservative
Batch 09 - EDTA Study + Preservative
Batch 10 - Control
All
four
batches
re-evaluated
increasing concentrations of the
preservative while Lot P-10 acted as a
control batch.
Chapter: 9.1
1
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
The
Preservative Qualification
(PO)
Antioxidant
(PO)
Chelating agent
Content Uniformity
Preservative Efficacy
Process Optimization
Qualification (PQ) -
Formula
CONTAINERS
Containers do not have to be sterile just ultra clean (i.e. with low microbial
contamination
levels.)
Microbial
sampling containers should always be
sterile, as not to bias the testing.
NOTE: The preservative may inhibit or
possibly (with time after ~30 days),
chemically sterilize the semisolid
preparation in the tube. It can be
demonstrated in Preservative Efficacy
Testing, that after 28 days incubation,
many or all of the spiked organisms
introduced in the test are not detected
for growth (i.e. chemically sterilized).
PRESERVATIVES-pH
(PO)
(PQ)
(PQ)
& Process
Differences.
Handbook of Pharmaceutical
CHAPTER 9
ANTIOXIDANTS-CHELATES
Antioxidant(s) and chelating agents are
generally synergistic and are qualified
together.
AQUEOUS-OIL PHASE
Oil phase and the aqueous phase ratios
and phase-mixing temperature affects
the diffusion test results (Hanson), Fix
O/W ratios during early development.
ACTIVE SOLUBILITY
The active may be soluble in one of the
phases, but if insoluble, it is suspended
and homogenised as a 'semisolid
suspension'.
(Note:pastes
are
semisolid suspensions with a relatively
high suspended solids i.e. viscosity).
Chapter: 9.2
2
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
CHAPTER 9
C H E C K L I S T
SOP # HPGD-03-02YY
Handbook of Pharmaceutical
Chapter: 9.3
3
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
qYes qNo
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
CHAPTER 9
Formulae Ingredients
Batch No.
P-07
EDTA STUDY
P-09
P-08
P-10
BHA STUDY
180.0
180.0
180.0
180.0
180.0
25.0
25.0
25.0
25.0
25.0
1.0
1.5
2.0
2.0
0.0
Butylated Hydroxyanisole NF
(BHA).
0.05
0.15
0.05
0.05
0.0
Low
High
Low
Mixing
20.0
20.0
20.0
20.0
20.0
Peglico 5 Oleate
[LABRAFIL M 1944]
30.0
30.0
30.0
30.0
30.0
1.5
0.5
1.5
1.0
0.0
High
Low
20.0
20.0
Intermediate
20.0
20.0
20.0
722.85
721.45
721.95
725.0
1000.0
1000.0
1000.0
1000.0
pH
5.0
Viscosity
4000.0
Total
4.5
4000.0
0.0
FORMULA
FOR
OPTIMISING
ANTIOXIDANT
AGENT
Handbook of Pharmaceutical
0.0
4.0
4.0
4000.0
4000.0
0.0
0.0
6.8
3800.0
0.0
FORMULA
FOR
OPTIMISING
CHELATING
RANGE
Chapter: 9.4
4
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
CHAPTER 9
P-06
P-07
P-08
P-09
P-10
Results:
Description / Color / Odor
Conforms
Conforms
Conforms
Conforms
Conforms
Fails
Just Fails
PASS
PASS
Fails
Elegant
Elegant
Elegant
Elegant
Secondary
Analysis
Percentage (micron size)
Solid Particles
Microscopic Method
or Coulter Counter
<10
<20
10
11
<30
20
17
20
17
18
<40
18
16
18
15
15
<50
10
12
10
16
16
<60
22
22
21
22
20
>60
Semisolid
Physical Parameters
Weeping
MILD
Absent
Absent
Absent
Present
Bleeding
MILD
MILD
Absent
Absent
MILD
Splitting
Absent
Absent
Absent
Absent
MILD
Granular Appearance
Absent
Absent
Absent
Absent
MILD
Samples examined
after maximum
holding time
in bulk stage
Physical
Parameters
evaluated
Handbook of Pharmaceutical
Chapter: 9.5
5
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
CHAPTER 9
:
:
Storage conditions
BHA
%
HPLC
ANY TOTAL
Assay Impurity Impurity Impurity ANY TOTAL Impurity
Impurity Impurity
Impurity TLC
I
II
II
III
TI
H
II
TLC
TLC
HPLC
TLC
NMT
Specs. Off White to 50- 90.0 Cream
110 110.0
NMT
1.0
NMT
0.5
NMT
0.5
NMT
0.1
NMT
3.0
NMT
0.5
NMT
0.1
NMT
1.0
Conforms
90
102.2
<0.1
<0.1
<0.1
<0.1
0.3
<0.02
<0.02
<0.02
Conforms
60
99.7
<0.1
<0.1
<0.1
<0.1
0.3
<0.02
<0.02
<0.02
Conforms
65
101.3
0.1
<0.1
<0.1
<0.1
0.4
0.1
0.05
0.15
Conforms
55
100.8
0.3
<0.1
<0.1
<0.1
0.4
0.1
0.05
0.2
Table No. 13
Parameters
Storage
(months)
HPLC
Appear
ance
BHA
%
Conforms
98
103.2
<0.1
<0.1
<0.1
<0.1
<0.1
<0.01
<0.01
<0.01
Conforms
92
101.6
<0.1
<0.1
<0.1
<0.1
<0.1
<0.01
<0.01
<0.01
Conforms
85
101.0
<0.1
<0.1
<0.1
<0.1
<0.2
<0.01
<0.01
<0.02
Conforms
70
102.2
0.3
0.1
0.4
0.1
0.9
0.15
0.05
0.2
Specs
Key:
Assay % of Label Claim of Active.
BHA
Butylated Hydroxyanisole NF (GRAS)
Impurity I ; II ; III - Known impurities (by TLC)
ANY T = Any other impurities (by TLC)
TOTAL TLC = Total impurities (by TLC)
Impurity spot III separated by horizontal TLC development of impurity spot II using new edition TLC method.
Impurity II HPLC - Known impurities (by HPLC)
ANY II = Any other impurities (by HPLC)
TOTAL H = Total impurities (by HPLC)
Handbook of Pharmaceutical
Chapter: 9.6
6
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
CHAPTER 9
:
:
Storage conditions
BHA
%
HPLC
ANY TOTAL
Assay Impurity Impurity Impurity ANY TOTAL Impurity
Impurity Impurity
Impurity TLC
I
II
II
III
TI
H
II
TLC
TLC
HPLC
TLC
NMT
Specs. Off White to 50- 90.0 Cream
110 110.0
NMT
1.0
NMT
0.5
NMT
0.5
NMT
0.1
NMT
3.0
NMT
0.5
NMT
0.1
NMT
1.0
Conforms
96
100.2
<0.1
<0.1
<0.1
<0.1
0.3
<0.02
<0.02
<0.02
Conforms
85
99.9
<0.1
<0.1
<0.1
<0.1
0.3
<0.02
<0.02
<0.02
Conforms
78
101.5
0.1
<0.1
<0.1
<0.1
0.4
0.1
0.05
0.15
Conforms
69
101.4
0.3
<0.1
<0.1
<0.1
0.4
0.1
0.05
0.2
Table No. 15
Parameters
Storage
(months)
HPLC
Appear
ance
BHA
%
Conforms
90
103.2
<0.1
<0.1
<0.1
<0.1
<0.1
<0.01
<0.01
<0.01
Conforms
75
100.6
<0.1
<0.1
<0.1
<0.1
<0.1
<0.01
<0.01
<0.01
Conforms
65
99.0
0.2
<0.1
<0.1
<0.1
<0.3
<0.01
<0.01
<0.02
Conforms
53
97.2
0.4
<0.1
0.1
<0.1
0.5
0.2
0.05
0.3
Specs
NOTE:
P-08
P-09
BHA Assay higher than P-09 ; Impurities marginally lower than P-09
BHA Assay lower than P-08 ; Impurities marginally higher than P-08
BHA is greater irritant and/or toxicant than EDTA - therefore presents a greater safety
factor.
Handbook of Pharmaceutical
Chapter: 9.7
7
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
CHAPTER 9
Storage
in
(%)
P-06
Batch
months P-06
Specs.
Appearance
of
Semisolid
P-08
Off-white to
Cream color
smooth appearance
non gritty feel
Conforms
Conforms
Conforms
Conforms
Conforms
Conforms
Conforms
Assay
Top
P-08
Middle Crimp
Top
Middle
Crimp
CONTENT
UNIFORMITY
CONTENT
UNIFORMITY
(RSD)
(RSD)
103.5
102.1
102.5
101.9
100.1
(1.9)
(0.9)
100.5
101.8
99.9
101.5
101.0
101.9
102.4
97.8
101.5
(1.0)
Conforms
97..5
98..5
100.5
(2.1)
(2.3)
Range fully
within
specification
CONTENT
UNIFORMITY
in Specification
Handbook of Pharmaceutical
99..5
Chapter: 9.8
8
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
CHAPTER 10
SCALE-UP
P rocedures
Scale-up is a development procedure pivotal and validation lots are demonstration procedures
S C A L E - U P
O F
D E V E L O P M E N T
Handbook of Pharmaceutical
L O T S
time/temperature/vacuum
requirements
requirements of time / temperatures
Processing times;
in-process
prior to filling
total manufacturing time
sampling procedures / protocol
Scale-up procedures
Net ingredient weight
The addition of bulk liquids or
semisolids to large processing vessels
may require pumping or hand /
mechanical transfer. The recording of
the net ingredient weight from each
drum or container requires specific
documentation and signatures. Drum
transfer require individual gross, net
and tare weights to be recorded.
Chapter: 10.1
1
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
SCALE-UP
Procedures
Where indirect measurements using
specific gravity and temperature
measurements are used to calculate
mass transfer - check signatures are
required for each calculation.
Significant decimal points recorded with
respect to the calibrated measuring
instruments must be relevant to each
recording.
Bulk transfers
Drums and containers may require
preheating to liquefy contents prior to
transfer. Record preheating steps in
batch manufacturing instructions.
Rinsing procedures
Potent active or semi active ingredients
may be transferred directly into the
processing vessel or may require to
undergo a rinsing procedure to remove
trace
amounts.
Processing
documentation must indicate the
quantity of rinse solvent reserved and
the exact number of rinse procedures.
A two rinse procedure is essential and
an efficient practice. Note that the
rinsing fluid is recorded in the master
formula as 1st Rinsing Fluid and 2nd
Rinsing Fluid. Where micrograms of
active material are present an
additional 3rd Rinsing stage is
performed.
CHAPTER 10
End-point temperatures
Temperature end-points for heating or
cooling are documented in the format of
a range, i.e. cool to 250 C ( 20 C) or
heat to 700 C ( 10 C).
It is not necessary to qualify such
narrow operating temperature limits (as
there is no significant impact on the
process).
Chapter: 10.2
2
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
PROCESSING TIMES
SCALE-UP
Procedures
Re-mixing a step
Repeating a mixing step is acceptable,
if the re-mixing procedure has been
qualified
during
the
product
development phase.
To qualify a re-mixing step manufacture the batch with the initial
mixing step.
Sample the bulk at the different
sampling levels and positions. Do not
composite any samples for content
uniformity tests.
With the same batch immediately
repeat the exact mixing step and resample exactly as before. (sampling
procedures and sampling positions
must be recorded). The content
uniformity, viscosity etc. should not
differ in both sampling sets.
Revalidation
Infrequent re-mixing should only occur
in incidences of mechanical breakdown
or due to excipient variation. Where the
re-mixing process becomes more
frequent - revalidate the manufacturing
process to optimize the mixing steps
and review raw material ingredient
specifications.
Do not composite any samples for
content uniformity tests.
Sampling Procedures:-
Handbook of Pharmaceutical
CHAPTER 10
Line Cleaning
[Manufacturing
and
filling
lines
including pumps and transfers lines ]
Product manufacture
[Time from weighing and dispensing to
final in-process bulk control]
W here bulk creams are held for several
weeks or longer prior to filling - stability
and microbial limit tests of the bulk
material must be qualified and
documented during its holding storage
in the bulk containers.
Product filling
[Continuous filling without stoppages or
over week-end breaks]
Manufacturing
&
Processing
documentation controls include:
Maximum
time period to
complete
a
critical
manufacturing step
The
Chapter: 10.3
3
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
CHAPTER 10
C H E C K L I S T
CL # HBGD-03-02YY
SC AL E
UP P ROCEDURES
1.
qYes qNo
2.
The process qualification batch is manufactured under normal production qYes qNo
facilities ?
3. The process qualification batch documentation is similar or identical to the qYes qNo
pivotal lot documentation, which is identical to the commercial lots?.
4.
Where two commercial batch sizes are manufactured, the equipment used qYes qNo
differs only in capacity or size?
5.
qYes qNo
6.
qYes qNo
7.
qYes qNo
8.
Speed, temperature and time control charts attached to manufacturing qYes qNo
instructions clearly identify batch, vessel, and processing step #?
9.
qYes qNo
10. Special instructions exist to prevent product contamination during normal qYes qNo
processing breaks and temporary work stoppages?
11.
qYes qNo
12.
qYes qNo
13.
qYes qNo
14.
Line screen covers protect open containers from aerial particle settling?
qYes qNo
Handbook of Pharmaceutical
Chapter: 10.4
4
Generic Development
SEMISOLIDS
P R O C E S S - O P T I M I Z A T I O N
CHAPTER 10
C H E C K L I S T
CL # HBGD-03-02YY
S CA LE
U P P ROCEDURES
Scale-up Procedures
SOPs
P-000-01-02YY
P-000-01-02YY
P-000-01-02YY
P-000-01-02YY
Processing Times:
The following pre-processing and processing controls have SOP documentation:
the maximum period allowed between end of processing and start of the filling
operation.
4
[End of Document]
Edition No. 01
Effective Date :
Handbook of Pharmaceutical
APPROVED
______________ __________ ______________ ________________
Department
RD
RA
QC / Q A
Chapter: 10.5
5
Generic Development
SEMISOLIDS
CL
L E A N I N G
L I M I T S
CHAPTER 11
CLEANING
LIMITS
Check the baby not the bath rinse water
Check the pot not the dish water
Validation Protocol
Handbook of Pharmaceutical
Solubility factors
Non
Adulteration
Zero adulteration for penicillin's has
been
regulated.
Steroids
(e.g.
hydrocortisone and estrogen) as well
as sulfa drugs require extremely low
levels of active residues remaining in
the equipment after cleaning.
Written procedures
Written cleaning procedures (SOPs)
are required detailing the cleaning
process for each piece of equipment
used in the manufacturing and filling
process.
Chapter: 11.1
1
Generic Development
SEMISOLIDS
CL
L E A N I N G
L I M I T S
Clean to remove
extraneous peaks
to below their LQ
in the next batch, if
they affect your assay
Parameters evaluated
Written procedures detail the cleaning
procedures are required:
non-water
residues.
soluble
product
The
specific
procedure.
written
cleaning
Sampling procedures.
Analytical
methodology
(and
Acceptance
criteria
and
establishment of residual limits after
cleaning.
A revalidation period.
The final validation cleaning report.
cleaning procedures in a
development / production department
need to assure that the residual levels
of the active drug substance, after the
cleaning process does not introduce
extraneous HPLC peaks in the next
development / production batch (for
non-serial product lots).
Handbook of Pharmaceutical
sensitivity.)
Routine
CHAPTER 11
Chapter: 11.2
2
Generic Development
SEMISOLIDS
CL
L E A N I N G
Contaminating
materials
in
a
pharmaceutical Master Cleaning Plan
fall into two to three main types for
evaluation and limit testing. These are:
the active material
the cleaning detergent
colored and/or insoluble excipients
Strongly
colored
or
insoluble
excipients should be removed by
cleaning to a pre-set limit value for
active
materials
and
cleaning
detergents.
If excipients are not remove to a zero
visible level a further residue limit
should be set for the problematic
ingredient. Generally water soluble and
easy-to-clean excipients do not require
analytical limit testing to a pre-set limit
value.
Establish acceptance
criteria
and residual limits
for the cleaning
process
Maximum cleaning limits
The maximum residual limits of
active
material A is acceptable when it is
present at a 1 in 1000 part in product B
and when expressed as a function of
the therapeutic ratio (TR) of product B.
What is the TR of a product ?
The therapeutic ratio is the lowest
marketing dose (LMD) divided by the
maximum daily dose for the intended
purpose (i.e. LMD / MDD). The LMD is
in fact for all purposes the lowest
therapeutic dose of the active drug
substance, for the intended clinical
indications.
Steroid
hormones
such
as
betamethazone are available for widely
varying clinical indications. Both 25 mg
per gram and 100mg / g are available.
Handbook of Pharmaceutical
L I M I T S
CHAPTER 11
Clean to leave
1 in 1000
active residuals in
the next dosage unit
Cleaning levels per next unit dose may
readily be achieved down to 0.5-1
microgram contamination limits or
better.
Firms cleaning to a maximum residual
limits of 1/2000 would be well within the
pharmaceutical industry standard while
residual limits of 1/10000 could be
considered a possible cleaning over-kill
and a costly sanitation procedure for
standard routine drug manufacturing
processes.
Set detergent
residual limits to
1 in 1000 of its
lowest toxic dose
This implies that the cleaning methods
used are effective in removing all
product and cleaning residues that are
in direct contact with the equipment
surface areas during the manufacturing
process.
Chapter: 11.3
3
Generic Development
SEMISOLIDS
CL
L E A N I N G
LLSA x
1000
TR
L I M I T S
CHAPTER 11
Residual limits
are always based
on the lowest
therapeutic dose
It
The
Calculations-
The calculation to
determine the limit of residuals in the
next known product for dosage forms is
given below:
Chapter: 11.4
4
Generic Development
SEMISOLIDS
CL
L E A N I N G
Clean Limits
(in mcg / dose)
= LLSA
1000
x
LSB
x MDD
Where:
CL
LLSA
LSB
(mg)
1000
MDD
A
B
Clean Limits
(in mcg/dose)
= LLSA x
1000
x
LSN
MDD
Where:
CL
LLSA
(mg)
LSN
1000
MDD
A
N
LMD
Firms
Handbook of Pharmaceutical
L I M I T S
CHAPTER 11
Clean Limits
(in mcg/dose)
LLS(A)
8000
The
Chapter: 11.5
5
Generic Development
SEMISOLIDS
CL
L E A N I N G
L I M I T S
CHAPTER 11
C H E C K L I S T
CL # HBGD-03-02YY
qYes qNo
qYes qNo
qYes qNo
14. A standardized surface area (approx. 0.1 - 0.2 m2 ) is wiped in a qYes qNo
unidirectional manner with the swab?
15. Cleaning procedure manuals or SOPs highlight hard to clean areas qYes qNo
such as valves, threads, seals, shafts and mixer blades - where product
may accumulate and remain static after cleaning? These hard to clean
areas are evaluated during the cleaning validation procedure ?
Handbook of Pharmaceutical
Chapter: 11.6
6
Generic Development
SEMISOLIDS
CL
L E A N I N G
L I M I T S
CHAPTER 11
C H E C K L I S T
CL # P-000-03-02YY
16. The 1/1000 of the lowest marketing dose (LMD) are the acceptable
active material residue limits ?
qYes qNo
17.The 1/1000 of the LD50 are the acceptable detergent residue limits?
qYes qNo
18. Wiping-solvents for cleaning swabs are specifically pre-determined qYes qNo
for each active material - depending on whether it is water soluble or
insoluble ?
19. Purified Water USP is the wiping solvent for most detergents?
qYes qNo
20. Rapid assessment of equipment cleanliness after manual procedures qYes qNo
is achieved by simple analytical test methods ?
21. High pressure hot water jets and steam jets are available in the qYes qNo
cleaning area?
qYes qNo
22. The final rinse water is Purified Water USP ?
23. Maximum time limits prior to cleaning have been established ?
qYes qNo
24. Maximum time limits between equipment cleaning and sampling have qYes qNo
been established to avoid post-cleaning sampling errors ?
25. Maximum time limits between equipment cleaning and next batch qYes qNo
production have been established?
Handbook of Pharmaceutical
Chapter: 11.7
7
Generic Development
SEMISOLIDS
CL
L E A N I N G
L I M I T S
CHAPTER 11
STANDARD OPERATING
PROCEDURES
Page 1 of 1.
SOP #HBGD-03-02YY
CLEANING VALIDATION
Cleaning Validation Requirements
The following Standard Operating Procedures are recommended for a generic
development unit :
Time limits before and after cleaning must be laid down
in writing
P-000-01-02YY
P-000-01-02YY
P-000-01-02YY
P-000-01-02YY
4
[End of Document]
Edition No. :
01
Ed. Status : New
Effective Date :
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Handbook of Pharmaceutical
APPROVED
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Department
RD
RA
QC / Q A
Chapter: 11.8
8
Generic Development
SEMISOLIDS
ANALYTICAL
Analytical
However
Validation
Analytical Validation - a working
validation protocol for HPLC system.
Official USP
Analytical method
for well known
actives are not
generally stabilityindicating test
methods as well
What to validate?
Assays
Stability Assays
Impurity Package
Dissolution
when in-house
These
CHAPTER 12
In-house
Validation
Chapter: 12.1
1
Generic Development
SEMISOLIDS
ANALYTICAL
Analytical
A spects
Method Validation
Non-compendial method validation
usually follows the USP direction for
parameters needed for the validation
of test methods.
Typical parameters for validating
assays and other non-compendial
analytical methods designed for
providing quantitative reproducible
results include:
Accuracy
Recovery
Precision
(Repeatability, Reproducibility and
Intermediate precision (ruggedness)
Specificity
Linearity
Range
Frequent revalidation
of analytical assay
methods is an
Handbook of Pharmaceutical
CHAPTER 12
essential procedure
Chapter: 12.2
2
Generic Development
SEMISOLIDS
ANALYTICAL
Analytical
A spects
The Precision of the System
Is defined as the degree of
agreement among the individual
assay results when the assay step
is applied to replicates of the
standard (volumetric) preparation
(i.e. the variation due to sampling is
eliminated) - this sampling variation
may be significant in tablet
granulation material or semi-solid
dosage forms.
Method precision
includes
sampling error
The precision of a method is
challenged
by
including
the
sampling error in an homogeneous
sample or composite of samples.
No granulate material is perfectly
homogeneous thus the precision of
the method is detecting both the
minor variations in the homogeneity
of the sample and the precision of
the HPLC system, due to minor
detector, pump, mechanical and
electronic fluctuations.
Precision of a method is defined as
the degree of agreement between
individual HPLC test assay results
when
the
analytical
method
procedure is applied repeatedly to
multiple samplings of a homogeneous sample of composite.
A frequent error cited by the agency
inspectors deals with linearity and
range. Laboratory HPLC analysts
inject amounts that are outside the
range for which the linearity of the
test
method
has
Handbook of Pharmaceutical
CHAPTER 12
Peaks must be
homogeneous.
Not
a mixture of
co-eluting peaks
Peak
Homogeneity
is
a
chromatographic term. A peak is
homogeneous if it corresponds to a
single chemical entity i.e. it is not a
mixture of co-eluting peaks possibly
derived from impurities or the
placebo excipients.
Placebo Analysis.
A mixture of non-actives (placebo)
is prepared and subjected to HPLC
analysis.
Normally no interfering peaks are
observed in the graph of the
placebo chromatogram.
Chapter: 12.3
3
Generic Development
SEMISOLIDS
Where
interfering
peaks
are
observed, their position should be
noted as well as checked that no
reinforcement of the active peak is
present - resulting in biased or
skewed assay results.
Standard Solution - Stability. - Take
care to evaluate the stability of the
Standard solution. It is assessed by
re-injection of the standard solution
again after the said period of days
the standard will be used and
------------------------------------------
Oxidation Stress
[H2O2] plus length of standing time.
Base Hydrolysis
Acid Hydrolysis
[HCl] plus length of standing time.
Heat Stress I
@ T1 oC - abnormal production.
Heat Stress II
@ T2 oC - active breakdown.
Edition Number:
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CHAPTER 12
ANALYTICAL
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Chapter: 12.4
4
______________
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SEMISOLIDS
Analytical
Identify known
degradants, and label
and tag unknown
degradants and
impurities
A spects
Specificity and Suitability
Resolution and Tailing Factors.
W hen
a satisfactory separations of
all the degradation peaks have been
achieved
through
the
forced
degradation reactions, a Resolution
Factor (according to the USP
requirements) between the main
active peak and the nearest
degradant peak is calculated using
the USP formula.
Stressing
the placebo is often
ignored when searching
for extraneous HPLC
peaks in stability
indicating methods
A Tailing Factor (according to the
USP formula) is also calculated for
the main active substance peak.
Both the resolution and tailing factors
are standard procedures and should
be presented in a standard format in
every method validation protocol and
report.
Relative Retention Time of Main and
Additional peaks:
In each stressed analysis routinely
indicate the percentage by which the
Main peak Is decreased as well as
the relative retention time (RRT) for
any other Additional peaks.
Edition Number:
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CHAPTER 12
ANALYTICAL
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
Analytical
Aspects I
Accuracy
Recovery
Precision ( System reproducibility, Method reproducibility )
Specificity
Linearity
Range
Ruggedness (different analysts / days /different equipment models / columns)
Edition Number:
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Chapter: 12.6
6
______________
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
Storage conditions
Difference. relative
to freshly prepared
standard
[Active] 100%
4C
<2%
[Impurity] 100%
4C
<2%
Standard Solutions are stored at controlled temperatures and light conditions as per
labeling.
[d]. Stability Indicating Procedures.
For the Stability Indicating Method, the product sample usually includes forced
degradation by stressed analysis. Conditions of concentration and reaction time
may vary depending on the active drug substance and drug product - e.g:
Oxidation
Base Hydrolysis
Acid Hydrolysis
Sun light
Heat
Temp.
o
( C)
Time
(hr)
Raw Material;
Remaining
Substance.
(%)
Peak Purity,
(Figure)
Tablets
Remaining
Substance
(%)
Peak
Purity,
(Figure)
Solution heating
90
12
100.2
pure
98
pure
Solid heating
160
101.3
pure
92
pure
40
14
101.1
pure
84.8
pure
70
10
99.8
pure
100.2
pure
10%Hydrogen Peroxide
37
77.5
pure
90.5
pure
5% Hydrochloric Acid
Room
20
79.7
pure
78.6
pure
Edition Number:
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___________
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Chapter: 12.7
7
______________
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_________/________
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
2.65 = 0.31
8.45
W0.05
9
=
= 1.1
2f
4.2
The values depict the specificity of the method for resolution between the main peak
and impurity peak. (values shown for demonstrations purposes).
Peak Purity
The photo diode-array is used for the evaluation of the stability indicating nature of
the assay method number SI-1000 for [000]mg and [000] mg tablets using a Waters
996 Unit, controlled by the chromatography manager Millennium 2010.
Peak purity and match results are reported as:
Purity Angle is a measure of spectral non-homogeneity across a peak - i.e. the
weighed average of all Spectral Contrast Angles calculated by comparing all spectra
in the integrated peak against the peak apex spectrum.
Purity Threshold is the sum of Noise Angle and Solvent Angle. It is the limit of
detection of shape differences between two spectra.
Match Angle is a comparison of the spectrum at the peak apex against a library
spectrum.
Match Threshold is the sum of the Match Noise Angle and Match Solvent Angle.
Noise Angle is a measure of spectral non-homogeneity caused by system noise.
Edition Number:
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8
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CHAPTER 12
ANALYTICAL
Specificity
Edition Number:
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Chapter: 12.9
9
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
Analytical
Aspects II
Introduction
2. System Repeatability
Precision
Method
and Edition #
used.
Batch # of samples tested (test
the lowest and the highest label
strength.
Type
Stress
Precision - Table 1.
System Repeatability
[Also called intra-assay precision]
SYSTEM
REPEATABILITY
SAMPLE No.
PEAK AREAS
1
2
3
4
5
6
7
8
9
10
Repeatability shows
precision
under the same operating
conditions over a short
interval of time - same day
same morning
=
=
=
0.5 - 1.0
W here
Edition Number:
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Chapter: 12.10
10
______________
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
REPRODUCIBILITY
SAMPLE No
ASSAY %
Batch No:
1
2
3
4
5
6
7
8
9
10
Method
Reproducibility
monitors the sample-tosampling variation of the
same drug product by
evaluating
the
full
analytical
method over
and over again.
(same operator - same
equipment)
Average Assay %
Standard Deviation
Relative
Standard
Deviation.
=
=
= 1.5 - 3.0
[4] Accuracy
The
Edition Number:
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11
______________
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_________/________
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Generic Development
SEMISOLIDS
CHAPTER 12
ANALYTICAL
ACCURACY
INJECTION
No
PEAK
AREA
CALCULATED
CONC.
%
ACCURACY
1
2
3
4
5
6
7
8
9
10
Mean (% Accuracy) =
Standard Deviation =
% Coef. of Variation =
the SAME
sample solution may
be averaged
DIFFERENT
sample solution
may not be
Edition Number:
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averaged
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Chapter: 12.12
12
______________
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
[5] Recovery
RECOVERY - EXTRACTION
TIME IN MINUTES
Batch No:
% ASSAY
0.5 T
Run at between
3 and 5
extraction times
to
demonstrate
recovery
0.75 T
T
1.25 T
1.5 T
[6] Recovery
(of spiked placebo samples)
Five
RECOVERY
TESTING
ALSO
DEMONSTRATES
DETECTOR
LINEARITY
are tabulated.
Edition Number:
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Chapter: 12.13
13
______________
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
R E C O V E R Y
Standard solution mg/100mL
Peak Area =
CONC.
Theoretical
(mg/100ml)
PEAK AREA
FOUND
CONC.
FOUND
(mg/100ml)
PERCENTAGE
RECOVERY
50
75
100
125
150
Mean (% Recovery) =
Standard Deviation =
% Coef. of Variation =
Display values
The Linear Regression value, Slope and Y-Intercept are shown in the GRAPH. The
placebo chromatogram (vehicle only) is shown to highlight the absence of Additional
Peaks
The
Edition Number:
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14
______________
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
LINEARITY
AND
CONC.
Batch No:
RANGE
PEAK AREAS
50 %
75 %
100 %
125 %
150 %
Linear Regression
Y-Intercept
Slope
=
=
=
The results are shown graphically (peak area Vs range conc. (mg/100 mL).
GRAPH OF LINEARITY
120000
P
e 100000
a
80000
k
60000
A
40000
r
e 20000
a
0
0
25
50
75
100 125
150
Conc. mg/100mL
Edition Number:
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15
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
[8] Robustness.
Internal
Different laboratories
Different analysts
Different instruments
Different reagent lots
Different analysis days
Different elapsed assay times
Different assay temperatures "
Ruggedness
is a USP
Requirement
Robustness
is not.
The
Robustness of an analytical
procedure is a measure of its capacity
to remain unaffected by small but
deliberate
variations
in
method
parameters thus providing an indication
of its reliability under normal usage.
The method may be evaluated for
specificity using two different columns.
No differences in specificity, selectivity
or column performance should be
observed.
Robustness
determinations
are
essential when transferring analytical
methods
from
the
development
laboratory to the commercial quality
control laboratory. There may usually
be a difference in columns or HPLC
machine models used.
Ruggedness
Measures External
Robustness
Internal Variations.
Ruggedness measures the lack of
external influence on the test results
whereas robustness measures the
lack of internal influences on the test
results.
Robustness is defined by both the USP and the ICH Tripartite guidelines as "a
measure of its capacity to remain unaffected by small but deliberate variations in
method parameters and provides an indication of its reliability during normal use "
Robustness is defined both in the USP and ICH, but is not required.
Robustness variations.
Deliberate variations according to the following table were made to the critical
parameters of the method such as column, flow rate and concentration of [organic
acid] in the mobile phase. Using the System Suitability solution and LOQ (also QL)
solution as the Test Solutions the performance of the method was evaluated.
Edition Number:
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16
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
Flow Rate
mL/min
RESULTS
Buffer
Conc. (%)
RRT
Tf
RSD
RSD
bet. LOQ of bet. LOQ of
[Active]
[Impurity]
1
2
1
1
2.5
2.2
0.1
0.1
0.3
0.3
1.1
1.1
<10
<10
<10
<10
3
4
5
1
1
2
2.8
2.5
2.5
0.1
0.15
0.1
0.3
0.3
0.3
1.1
1.1
1.1
<10
<10
<10
<10
<10
<10
RUGGEDNESS
ANALYST
No 1
%
ASSAY
Column I
ANALYST
No 2
%
ASSAY
Column 2
1
2
3
4
5
6
7
8
9
10
Mean (% Accuracy) =
Standard Deviation =
% Coef of Variation =
Notes on different terms frequently used:
The analytical variation expressed between laboratories on different days; with
different equipment; or different analysts is known as - intermediate precision. This
intra-laboratory precision or the precision between laboratories is known as
reproducibility or more specifically - intra-laboratory reproducibility. Both the above
are ruggedness - and a USP requirement.
Edition Number:
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17
______________
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
STABILITY OF
THE STANDARD SOLUTION
mg/100mL
Initial Analysis
(Date)
mg/100mL
Repeat Analysis
2nd (Date)
1 injection
2 injection
3 injection
4 injection
5 injection
6 injection
7 injection
8 injection
9 injection
10 injection
1 injection
2 injection
3 injection
4 injection
5 injection
6 injection
7 injection
8 injection
9 injection
10 injection
Mean
Standard Deviation
Relative Standard Dev.
Edition Number:
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Effective Date:
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Handbook of Pharmaceutical
=
=
= NMT 2.0 %
APPROVED
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Chapter: 12.18
18
______________
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SEMISOLIDS
CHAPTER 12
ANALYTICAL
System Suitability
Standard Solution
Drug Product
placebo
When Representative Chromatograms are displayed - all peaks are LABELED with
the peak name and RRT.
Representative chromatogram
Drug Product
[11]Conclusion.
It
(Closing Statement)
An appropriate conclusion should be
given stating clearly that:
The method # 005 Ed. No 00 is shown
to be accurate and precise for carrying
out assay analysis as part of the Assay
and Stability Studies for the Drug
Product conforming to the formula as
shown in Appendix 1 .
[12] References & Appendixes.
Where
there is a formulation or
excipient change as well or a new
processing
principle
of
the
manufacturing procedure, the analytical
validation package should be amended
to account for appropriate changes.
Frequently this involves a full
revalidation of the overall methodology.
Edition Number:
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Effective Date:
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19
______________
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Generic Development
SEMISOLIDS
Revalidation
An entire validation procedure should
Validation Checklist
1. Are all in-house methods validated?
2. Is the dissolution method for
development, release and stability
validated.
3. Are the different validation editions
comparable with the previous
edition?
4. Was the stability assay and
dissolution method validated at the
time of process optimization
5. Was the stability assay and
dissolution method validated at the
time of process qualification
6. Is the validated stability assay,
impurity profile and dissolution
method used in the pivotal essential
similar to the commercial validation
lots so that data is comparable.
7. When a new edition is not
comparable to the previous edition is a new method number allocated?
8. Has the lab an historical track record
of all assay dissolution etc. methods
used from early development to
commercial validation?
All
Accuracy
Specificity
Recovery
Precision (interday & intraday)
Linearity (of standard curves)
Sensitivity
Stability (Storage & handling)
Bioequivalence studies
Linearity and range at the extreme
lower ends of the active analyte or
metabolite(s) in sera are important
parameters in assaying blood serum
concentrations.
Range studies MUST be linear at the
lower and upper limits as found in the
serum samples or those used for
calibration curves, a point sometimes
frequently overlooked by analytical
method
developers
in
clinical
environments when dealing with very,
very dilute concentrations.
References:
1. "Validation of compendial methods" USP 23
<1225> USPC Rockville Maryland USA
1994.
2. USP/NF XXIII USPC Rockville Maryland
USA 1994.
3. Scale up and Post approval Changes
Manufacturing and Controls In vitro
Dissolution and In Vivo Bioequivalence
Documentation CDER 1995 (SUPAC)
4. International Conference on Harmonization
"Guidelines on validation of Analytical
Procedures: Definitions and Terminology;
Federal Register (March 1, 1995.)
5. ASTM Standard Guide For Conducting
Ruggedness Tests E1169 American Society
for testing Materials Philadelphia 1989.
6. G. Kateman and L. Buydens, The
Ruggedness Test Quality Control in the
Analytical chemistry John Wiley and Sons
NY 2nd Edition 1993, pp118 125.
All
Edition Number:
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Supersedes 02
CHAPTER 12
ANALYTICAL
Effective Date:
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20
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SEMISOLIDS
ANALYTICAL DEVELOPMENT
CHAPTER 12
OUT-OF-SPECIFICATION
TEST RESULTS
Investigate all Out-of-Specification Results routinely and immediately,
the findings may well be in the firms commercial interests...
Out Of Specification
(OOS) Retesting and
Product failures based
on the 1993 Judgment
Handbook of Pharmaceutical
Drug
An Out of Specification
(OOS) Result
may or may not
be a product failure
Out-of-Specification
Where is my data
invalidating
an Out-of-Specification
(OOS) Result?
Out-of-Specification
results
must
not
become
un-investigated
failures. The maxim we investigated but
didnt write it down is often heard and
carries little weight with an agency official.
Sect: 12.21
12.21
Generic Development
SEMISOLIDS
Retest procedures
must follow
pre-written rules
Where
An
Handbook of Pharmaceutical
Investigate according
to a set procedure
and then retest if the
error is conclusive?
Inconclusive errors
CHAPTER 12
ANALYTICAL DEVELOPMENT
An overview of Out-of-Specification
Results procedures is provided by the
decision tree. Re-sampling the material for
a new representative sample should take
place only when the original procedure
was found to be clearly non-representative
of the whole.
Sect: 12.22
12.22
Generic Development
SEMISOLIDS
CHAPTER 12
ANALYTICAL DEVELOPMENT
Dos
Donts
&
Retest procedures
must follow
pre-written rules.
The Donts
Dont
- use the outlier test for a
dissolution test or profile.
Dont
- use the outlier test for an
Assay or a Content Uniformity test.
reporting,
classifying and
Dont
- use the outlier test frequently
to reject non-chemical test results.
investigating jointly.
sample
Dont
- use the outlier test outside
the USP specifications prescribed.
Dont
- retest before an investigation
is completed and closed.
Do retest
on
the
same
collected.
from the same sample as the first.
Dont
- retest before reporting to
your supervisor and conducting an
informal investigation - together.
Dont
- ignore ever the rules for
governing a single or multiple OOS result.
Dont
- re-sample unless the sample
procedure was proved to be faulty.
Dont
- re-sample
without
your
supervisor permission obtained only after
an informal investigation.
Failure Report or an
Investigation Report log.
Handbook of Pharmaceutical
Sect: 12.23
12.23
Generic Development
SEMISOLIDS
CHAPTER 12
ANALYTICAL DEVELOPMENT
C H E C K L I S T
CL # P-HGD-03-069Y
OUT-of-SPECIFICATION RESULTS
Averaging passing and OOS Test Results together
is not permitted as it conceals the full analytical picture
3. Are the previous (or related) batches associated with the failed batch qYes qNo
specification reviewed and the overall impact (on quality) evaluated?
4. Are written investigations undertaken and then follow-up procedures qYes qNo
recommended in writing?
5. Are the investigations performed in a timely manner and follow a qYes qNo
defensible scientific logic (see attached Decision Tree)?
6. Does the companies 'Investigation SOP' include the three key tenants qYes qNo
i.e. TO INVESTIGATE - TO CONCLUDE - TO FOLLOW-UP?
7. Have the laboratory analysts been instructed to keep the original qYes qNo
'suspect test solutions' for possible reanalysis (Ref. Decision Tree)?
8. When an OOS has been detected does the initial review, before the qYes qNo
investigation, check for instrument or system suitability malfunction,
faulty reagents, calculation, documentation or transcribing errors?
9. If no clear analytical errors are detected in a 'suspect result' does a qYes qNo
comprehensive 'failure investigation' ALWAYS follow?
10. Where malfunctions are identified and detected are all prior 'suspect qYes qNo
data' evaluated and reviewed for a possible related (or similar) errors?
11. Are analytical failures tracked back to their original point of failure?
qYes qNo
12. When a faulty lab procedure is detected, is the analytical test qYes qNo
procedure immediately terminated (as a matter of routine)?
13. Have the analysts been trained to immediately report to their qYes qNo
supervisors an obvious error or an analytical fault?
14. Are obvious errors (spilling, incorrect dilution, injection volume etc.) qYes qNo
documented in the lab book and a brand new test restarted?
Handbook of Pharmaceutical
Sect: 12.24
12.24
Generic Development
SEMISOLIDS
CHAPTER 12
ANALYTICAL DEVELOPMENT
C H E C K L I S T
CL # P-HGD-03-069Y
OUT-of-SPECIFICATION RESULTS
failure investigations are conducted to determine
what caused the unexpected OOS result
qYes qNo
qYes qNo
6. Does the firm's own QC Unit perform the 'full scale failure qYes qNo
investigation'?
7. Does the general review include a list of related batches - impacted?
qYes qNo
8. Does the full scale failure investigation include the production side qYes qNo
and the laboratory side?
9. Does the laboratory protocol include the two key steps - retesting the qYes qNo
original sample and testing a new sample from the batch lot?
10.Retesting the original sample with a new analyst, is generally the first qYes qNo
step after the 'initial assessment' is completed?
11.Are the number of retests (usually duplicates) specified and not qYes qNo
exceeded?
Averaging 'original suspect' and retest results is
forbidden.
12. When improperly prepared samples are proved, then the original qYes qNo
results may be immediately invalidated?
13. The firm may re-sample when the investigation highlights that the qYes qNo
original sample was unrepresentative?
14. Where the investigation concludes that the sampling method is in qYes qNo
error a new sampling method must be developed and qualified ?
15. To prove the original aliquot is faulty, the analyst prepare two qYes qNo
additional aliquots and compares the three sets of results?
Handbook of Pharmaceutical
Sect: 12.25
12.25
Generic Development
SEMISOLIDS
CHAPTER 12
ANALYTICAL DEVELOPMENT
C H E C K L I S T
CL #
P-HGD-03-069Y
OUT-of-SPECIFICATION RESULTS
Batches must be formulated with the intent to provide 100%
of the labeled amount'
qYes qNo
qYes qNo
qYes qNo
5. When the intent is to highlight variability within the product then qYes qNo
averaging is not acceptable, but RSD (CV) values are generally
reported to show statistical significance.
6. Replicate peak responses whether test or standard should be qYes qNo
averages as one result.
7. Are analysts trained, not to average passing and OOS results together qYes qNo
in order to hide the failing results?
8. Composite assays, require only one assay result and are in fact qYes qNo
average assay values, as opposed to individual content uniformity
values.
Handbook of Pharmaceutical
Sect: 12.26
12.26
Generic Development
ANALYTICAL
SEMISOLIDS
CHAPTER 12
ASSAY VALIDATION
Ruggedness
and
Robustness
Ruggedness
is a USP
Requirement
Robustness is not.
Ruggedness and Robustness.
The USP defines ruggedness as "the degree
of reproducibility of test results obtained by
the analysis of the same samples under a
variety of normal test conditions such as:
Different laboratories
Different analysts
Different instruments
Different reagent lots
Different analysis days
Different elapsed assay times
Handbook of Pharmaceutical
But
Chapter: 12.27
27
Generic Development
ANALYTICAL
SEMISOLIDS
Comparison Table.
Attribute.
Ruggedness. Robustness.
USP Validation
Requirement
ICH Validation
Requirement
CHAPTER 12
Internal change
Table 1.
External change
Method
Variations
Environmental
Variations
No
B C D
ASSAY
TEST
RESULT
+ + +
+ + +
99.3
101.5
97.9
The
Handbook of Pharmaceutical
External / Internal
Changes / Variations
Test
+ +
+ +
+
+
+
+ +
3
4
5
+
+
99.0
97.9
100.9
100.4
98.5
Table 2.
8 RUN DESIGN
1.8
-1.35
-0.76
G - Reagents I & II
-0.35
E - Week I & II
+0.35
C - Column I & II
+0.76
D - HPLC No I & No II
+1.35
Chapter: 12.28
28
Generic Development
ANALYTICAL
SEMISOLIDS
100.4
assigning
99.0
+
a positive or
97.9
+
negative value
obtained from
100.9
the 8 run
-7.2
design
/4
-1.8
For D
99.3
101.5
100.4
97.9
98.5
99.0
97.9
100.9
0
0
Table 3.
+
+
+
10
11 +
12
1
2
3
4
5
6
7
8
9
Figure 2.
+
+
+
/4
Perform this
addition for
each of the eight
variables and
divide the
sum by 4
(half the number
of runs)
Results.
A linear-linear scale is used. Plotting the
Ranked Effect on the X-axis vs. the M
values on the Y-axis produce a normal
probability plot of effects. If a value lies
outside this straight line one can conclude
that the method is not rugged / or robust, as
classified, for that particular variable (e.g.
[say] flow rate).
12 Run Designs.
A template for 12 run design is used (Tables
3 & 4), when more than seven factors are
present. This design will give 11 factors for
analysis. The M values are constant for any
given design and are actually the means of
the order statistics (3) for a sample size of
eleven. As they always remain the same, the
template can be used for any ruggedness /
Robustness validation method protocol. Use
a Eight Run for evaluating say, ruggedness
only, and a Twelve Run design for both
Handbook of Pharmaceutical
CHAPTER 12
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
ASSAY
TEST
J K
+
+
+
+
+
+
+
+
+
+
RESULT
+
+
+
+
+
99.3
101.5
100.4
97.9
98.5
99.0
98.8
99.9
100.6
98.9
97.9
100.9
Table 4.
-1.59
-1.06
-0.73
-0.46
-0.22
+0.00
+0.22
+0.46
+0.73
+1.06
+1.59
Chapter: 12.29
29
Generic Development
ANALYTICAL
SEMISOLIDS
Method Procedure.
1. Choose the number of variables required
and select a run design template.
2. Assigning the minus (-) or plus (+) values:
These are arbitrary designations. As a
standard rule assign a 'minus' (-) to I or a
lower limit and a 'plus' (+) to II or a upper
limit. Evaluate a range limit by assign (-)
value for lower and (+) value for higher (i.e.
Flow rate 1.2 mL/min assign (-) and 1.8
mL/min assign (+)). Likewise Day I assign () and Day II assign (+) and so on
3. Perform the HPLC assays in a random
order.
4. Tabulate the assay results in the template.
5. Calculate the Effects (Figures 1 and 2).
6. Rank the Effects from smallest to largest.
7. Plot the Effects against the M values.
8. Evaluate the plot.
Conclusion.
The results from the plot form a near
straight line. It can be concluded that the
analytical method is (a) rugged for the
external factors over the tested range and
(b) robust for the internal factors over the
tested range in the 12 run design.
Figure 3.
*
*
*
*
*
-1.5
-8
Ranked Effects
Handbook of Pharmaceutical
+7
CHAPTER 12
Chapter: 12.30
30
Generic Development
SEMISOLIDS
PROCESS QUALIFICATION
CHAPTER 13
Process
QUALIFICATION
The process qualification batch is a simulation of the forthcoming pivotal
lot
proving in-house, that the process really works
Process qualification
Getting to the end point in the generic
development program is the manufacture of
the process qualification batch. All generic
development,
product
and
control
specifications are challenged in this batch.
Simulation of Pivotal
It is a full simulation of the pivotal
process
with
completed
process
documentation and fully validated analytical
methods, including stability indicating assay
analysis.
Development of the formula and
manufacturing process terminates at this
point, as all specifications and parameters
have now been qualified and optimized.
Complete Documentation
Full manufacturing instructions and
specific SOPs and all supporting analytical
documentation is complete and audited and
signed off.
Qualification of Process
The intention is to challenge every aspect
of the formula, process instructions and all
product specifications, which include full
accelerated stability tests.
Commercial conditions
The PQ batch is manufactured in the
plants commercial facilities where the
marketing lots will be produced, using
standard production raw materials and
personnel, as well as routine QA
procedures.
Production Equipment
The equipment used are the same
models as planned for the marketing lots
and the cleaning procedures and operation
routine production SOPs.
Handbook of Pharmaceutical
An Exhibition Batch
The Plant Production Director needs to
fully comprehend the importance of the
firms in-house Process Qualification batch
and the MA Pivotal production batch.
Although not for commercial sale both
exhibition batches are manufactured under
standard commercial conditions.
Documentation fine-tuning
The final PQ documentation and
specifications are the data basis from which
the Pivotal Batch
manufacturing
instructions and specifications evolve.
Chapter: 13.1
1
Generic Development
SEMISOLIDS
PROCESS QUALIFICATION
CHAPTER 13
C H E C K L I S T
CL # HBGD-03-01YY
PROCESS QUALIFICATION
well developed process qualification batch with good in-process controls
and excellent documentation will ensure a failure-free pivotal lot
1.
The Process Qualification batch is equal to the 70% or more of the pivotal qYes qNo
batch or the smallest commercial batch size that will be validated?
2.
qYes qNo
3.
All non actives are routine production excipients or have been approved?
qYes qNo
4.
qYes qNo
5.
qYes qNo
6.
The Master Manufacturing Batch Instructions has all authorization qYes qNo
signatures?
7.
The manufacturing flow chart (identifying all equipment and process qYes qNo
parameters) is final with all authorization signatures?
8.
qYes qNo
9.
qYes qNo
10.
qYes qNo
11.
qYes qNo
12.
qYes qNo
13.
qYes qNo
14.
qYes qNo
15.
qYes qNo
16.
The
Content
Uniformity
Protocol
evaluation during PQ batch manufacture.
17.
The Preservative Efficacy Test protocol will be evaluated during the PQ qYes qNo
batch manufacture?
is
prepared
Handbook of Pharmaceutical
Chapter: 13.2
2
Generic Development
SEMISOLIDS
PROCESS QUALIFICATION
CHAPTER 13
STANDARD OPERATING
PROCEDURES
Page 1 of 1.
CL # HBGD-03-01YY
PROCESS QUALIFICATION
The following Standard Operating Procedures are recommended for a generic
development unit:
P-000-02-01YY
P-000-01-01YY
P-000-01-01YY
4
[End of Document]
Edition No. 01
Effective Date :
Handbook of Pharmaceutical
APPROVED
______________ ________________ ___________ ________________
Department
RD
RA
QC / Q A
Chapter: 13.3
3
Generic Development
SEMISOLIDS
PROCESS QUALIFICATION
CHAPTER 13
Process
Qualification
these are the product specifications
indicating the product quality throughout the shelf life
Sampling Bias
CONTENT UNIFORMITY
SAMPLING
BULK
Handbook of Pharmaceutical
Different Sampling
thieves or dies may give
varying results with the
same bulk material
S ampling
Chapter: 13.4
4
Generic Development
SEMISOLIDS
PROCESS QUALIFICATION
Sampling Bias
Different
sampling
techniques
with
the
same
thief
can
profoundly impact on sampling
errors in solids and suspensions,
with somewhat lesser effects in
semisolids, producing non representative results, with respect
to the true content uniformity
value.
Bulk
depth
Sampling motion
Sampling Angle
Sampling Orientation
may bias results
the sample in different ways are:-
Handbook of Pharmaceutical
Bulk
Content
Final
CHAPTER 13
References
1. Current Good manufacturing Practice of Certain
Requirements for the Finished Pharmaceuticals;
Proposed Rules May 3 1996 (61 FR 20103).
2. United States of America vs. Barr Laboratories
Inc., civil action for the district of N.J., Feb 1993.
3. J.T. Carstensen and M.V. Dali "Blending
Validation and Content Uniformity of low content
powder blends " Drug development and Industrial
Pharmacy Vol. 22 Issue 4 pp. 285-290 (1996).
4.J Berman, A Schoeneman and JT Shelton, Unit
Dose Sampling - a tale of two thieves" Drug
development and Industrial Pharmacy Vol. 22 Issue
11 pp.1211-1132 (1996).
5. J Berman, and J.A. Planchard "Blend Uniformity
and Unit Dose Sampling" Drug development and
Industrial Pharmacy Vol. 21 Issue 11 pp.1257-1283
(1995).
6.J.T. Carstensen and C.T. Rhodes " Sampling in
Blending Validations" Drug development and
Industrial Pharmacy Vol. 19 Issue 20 pp.2699-2708
(1993).
Chapter: 13.5
5
Generic Development
SEMISOLIDS
PROCESS QUALIFICATION
CHAPTER 13
q Semisolids
q Liquid Filling
Machine
No:
LOW
Weight
HIGH
Weight
No of Units
SAMPLED
LEFT
RIGHT
Time
Signature
SPEED - RPM
q
q
q
q
q
q
q
q
LOW SPEED
- RPM
q
q
q
q
q
q
q
q
HIGHSPEED
- RPM
q
q
q
q
q
q
q
q
TARGET
Sample
No:
TOP
o
o
o
o
Edition Number:
04
Ed. Status:
Spds:
03
Effective Date:
DD/MM/YY
Handbook of Pharmaceutical
o
o
o
o
END
Quantity
Sampled
in Grams.
Time:
Signature:
o
o
o
o
APPROVED
______________
Department
_____________
R &D
Chapter: 13.6
6
______________
RA
______/__________
QC / QA
Generic Development
SEMI SOLIDS
PROCESS QUALIFICATION
Material Sampling
In-process controls
Do remember that the variation in the
of
active material as narrow as possible Use
micronized
material
where
appropriate. Do not exceed 50 microns
Do use the same sampling thief type
for all development, scale-up, and
validation sampling operations.
Do formulate with appropriate
viscosity agents to allow for similar,
rheological properties resulting in
representative samples & assays.
SOPs
Do
SAMPLERS
Do take into account that all samplers
sample dissimilarly, due to different
construction geometry.
Do
Do
Do
Handbook of Pharmaceutical
CHAPTER 13
Sampling
Do
Don't use different sample thief types choose a suitable unit and use it
consistently, in a standardized manner.
Chapter: 13.7
7
Generic Development
SEMISOLIDS
PROCESS QUALIFICATION
CHAPTER 13
STANDARD OPERATING
SOP # D-000-03-03YY
PROCEDURES
1.
PURPOSE
2.
RESPONSIBILITY
3.
FREQUENCY
4.
PROCEDURE
Sampling
Points
Edition Number:
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Ed. Status:
Supercedes: 02
Effective Date
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
______________
__________
______
Department ------------------R &D-----------------RA--------------------- QC / QA---------------------------
Chapter: 13.8
8
Generic Development
SEMISOLIDS
PROCESS QUALIFICATION
CHAPTER 13
STANDARD OPERATING
SOP # D-000-03-03YY
PROCEDURES
5.0
ACCEPTANCE CRITERIA
5.1 All parameters tested will be within the upper and lower control limits of the
control chart.
5.2 These limits for the in-process and finished product test shall be within the
defined specification limits for the in-process and finished product.
5.3 The overall process shall be evaluated for capability and shall be within the
process capability index for the finished product.
Special Note:
In-process specifications for the Bulk Assay Content.
For In-process Bulk Content Testing (Content Uniformity):
6.2 The Upper control limit (UCL) is defined as the mean + 3 x Standard Deviation
6.3 The Lower control limit (LCL) is defined as the mean - 3 x Standard Deviation
7.0
DOCUMENTATION
7.1 A Qualification Report (QR-) including tabulation of results, statistical
evaluation, process capability evaluation, report conclusions and recommendations
will be submitted to QA Unit, Production and Development Unit Managers.
3
[End of Document]
Edition Number:
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Ed. Status:
Supercedes: 02
Effective Date
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
______________
__________
______
Department ------------------R &D-----------------RA--------------------- QC / QA---------------------------
Chapter: 13.9
9
Generic Development
SEMISOLIDS
PIVOTAL BATCH
PIVOTAL
CHAPTER 14
BATCH
Handbook of Pharmaceutical
Chapter: 14.1
1
Generic Development
CHAPTER 14
PIVOTAL BATCH
SEMI SOLIDS
C H E C K L I S T
CL # HBGD-03-01YY
1.The product formula for the pivotal is the final marketing formula?
qYes qNo
qYes qNo
6.The pivotal batch size is 10% or greater of the largest proposed qYes qNo
commercial lot?
7.The complete pivotal batch must be 100 % filled and packaged in the qYes qNo
marketing container-closures (no part-packaging permitted)?
8.All production equipment has been physically checked for appropriate qYes qNo
recorders and control units as written in the pivotal documentation ?
9.The validation protocol for the first three full scale lots is drawn up?
qYes qNo
10.The validation protocol addresses all key processing parameters, that qYes qNo
if changed, will significantly impact on product quality ?
11.All microbiological methodology has been audited and signed-off ?
qYes qNo
12.Assays and test methods based on the pharmacopoeia, with in- qYes qNo
house modifications has been validated?
13.The actives assay has been validated and is a stability indicating qYes qNo
test?
14.The stability
specifications ?
protocol
addresses
the
key
stability
qYes qNo
Footnote :
The Pivotal Batch is sometimes referred to as the; the Bioequivalent Batch,
the Exhibition Batch, the Demonstration Batch, the Clinical Batch, the Regulatory Batch,
or the PIVOTAL Batch. The names have all the same meaning.
Handbook of Pharmaceutical
Chapter: 14.2
2
Generic Development
CHAPTER 14
PIVOTAL BATCH
SEMI SOLIDS
STANDARD OPERATING
PROCEDURES
Page 1 of 1.
CL # HBGD-01-01YY
P-000-01--01YY
P-000-01--01YY
P-000-01--01YY
P-000-01--01YY
Note:
Revised FDA COMPLIANCE POLICY GUIDE NUMBER 7157.02 (1996).
The FDA has been sensitive to the need for industry to protect information
generated by internal in-house GMP auditing programs. It is the agencies intention
not to review the internal audit results, except under circumstances of litigation or a
judicial search warrant.
A firm requires to have a written quality assurance program in place at the regulated
site in order for the FDA not to review or copy the firms records and reports that
resulted from audits of a written quality assurance in-house program.
A written Certificate of Audit notifying management that such audits and inspections
have been implemented, performed and documented and that all corrective action
necessary has been taken is required.
The intent of the FDA policy is to encourage firms to conduct in-house quality
assurance program audits and self-inspections that are both candid and meaningful.
4
[End of Document]
Edition No. 01
Ed. Status : New
Effective Date :
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
______________ ______________ _____________ ________________
Department
RD
RA
QC / Q A
Chapter: 14.3
3
Generic Development
SEMI SOLIDS
PIVOTAL BATCH
CHAPTER 14
NOTES
Handbook of Pharmaceutical
Chapter: 14.4
4
Generic Development
SEMI SOLIDS
PIVOTAL
SOP #HBGD-04-03YY
STANDARD
BATCH
CHAPTER 14
OPERATING
PROCEDURES
1.
PURPOSE1
The purpose of this Standard Operating Procedure is to describe the production inprocess sampling procedure and the testing to be performed on the pivotal batch.
2.
RESPONSIBILITY
3.
FREQUENCY
The procedure is performed with each pivotal batch. The procedure may be used for
the Process Qualification Batch.
4. PROCEDURE
4.1 In-Process Control - Sampling and Testing
Bulk material - (prior to filling).
Physical Testing - Sampling Protocol
A total of nine samples (about 50g per sample) is collected from the bulk containers,
representing the top, middle and the end of the BULK material.
Three 50g samples are used for testing and the balance of the samples reserved for
further testing, if so required.
Chemical Testing - Sampling Protocol
Ten (10) samples, each sample equivalent to the approximate weight of one (to
three) dose application are collected from the bulk processor. Sampling techniques
are outlined in the written product protocol and the Batch Manufacturing Instructions
(BMI).
1
This sampling plan is structured upon the PDA Technical Report, April 30 97 & FDA's "Guidance on the Packaging of Test
Batches", of February 8, 1995 Number 41-95".
Edition Number:
04
Ed. Status:
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Effective Date:
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Handbook of Pharmaceutical
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______________
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_____________
R &D
Chapter: 14.5
5
_______________
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______/__________
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Generic Development
SEMI SOLIDS
PIVOTAL
SOP #HBGD-04-03YY
STANDARD
BATCH
CHAPTER 14
OPERATING
PROCEDURES
and Limitations)
10 samples (of 50g) will be collected
and stored as retention samples for
additional testing, if required.
Sampling procedure:
The samples are collected via an appropriate Sampling Thief equipped with the
necessary die - unless otherwise instructed in the written protocol. Samples
container shall be sterile.
Edition Number:
04
Ed. Status:
Spds: 03
Effective Date:
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______________
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_____________
R &D
Chapter: 14.6
6
_______________
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______/__________
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Generic Development
SEMI SOLIDS
PIVOTAL
SOP #HBGD-04-03YY
STANDARD
BATCH
CHAPTER 14
OPERATING
PROCEDURES
Page 3 of 5.
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______________
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_____________
R &D
Chapter: 14.7
7
_______________
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Generic Development
SEMI SOLIDS
PIVOTAL
SOP #HBGD-04-03YY
STANDARD
BATCH
CHAPTER 14
OPERATING
PROCEDURES
Edition Number:
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Ed. Status:
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_____________
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Chapter: 14.8
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Generic Development
SEMI SOLIDS
PIVOTAL
SOP #HBGD-04-03YY
STANDARD
BATCH
CHAPTER 14
OPERATING
PROCEDURES
8.0
9.
CORRECTIVE ACTION
Out-of-specification test results (OOS) are handled according to the firms current
Out-of-Specification SOP.
10.
DOCUMENTATION
3
[End of Document]
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Ed. Status:
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______________
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_____________
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Chapter: 14.9
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_______________
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Generic Development
SEMI SOLIDS
PIVOTAL BATCH
Auditing the
Pivotal Batch
CHAPTER 14
Error-Free Pivotal
documentation saves
time and money
Thus the need to get it right, at the very
first attempt at the production level
(pivotal lot) is paramount. Careless
omissions in the batch documentation
will eventually result in an agency
deficiency letter and thereby delaying
approval for an additional few months costing both time and valuable
development and lost sales dollars.
Experienced Pharmaceutical Firms
know the high costs of undetected
documentation omissions or data fields,
and have set up efficient development
quality assurance units that closely
examine, inspect, audit and review
every
aspect
of
the
batch
documentation
for
submission.
Handbook of Pharmaceutical
Divide
audit
checklist
into
representative sections portraying each
operation, manufacturing and control
procedure.
Add new check points to the list,
when a new error or omission arises.
Test the checklist, by evaluating
routine production batches, to get a
sense of possible omission categories.
Break multiple check points into
individual audit items on the checklist.
Carefully cross-reference handwritten dates and times on the
production forms against machine printouts that have immediately follow the
operational step.
Remember - weighing, pH, HPLC
and temperature print-outs and charts
normally give the date and the exact
time of the operation or test procedure.
Evaluate production yields and
adherence to time-limitation against
actual weighing & recording print-outs. 2
Chapter: 14.10
10
Generic Development
SEMISOLIDS
PIVOTAL BATCH
14
SOP # HBGD-02-02YY
CHAPTER
STANDARD OPERATING
PROCEDURES
Dosage Strength;
Batch No.
Date of Audit:
mg
/
/YY
Page 1 of 3.
Yes
No
q
q
q
q
Are the batch documents equivalent to the Master documents and available for the
audit?
Is the batch size equal or greater than 110,000 units?
Are the batch document pages numbered correctly?
Evaluate whether some of the pages could be replaced or rewritten?
Is there any evidence of erasures or white-outs?
Are cross-outs legible and correctly signed and dated ?
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Edition Number:
02
Ed. Status:
Supwecedes - 01
Effective Date
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
______________
Department
__________
R &D
_______________
RA
Chapter: 14.11
11
______/__________
QC / QA
Generic Development
SEMISOLIDS
PIVOTAL BATCH
14
SOP # HBGD-02-02YY
CHAPTER
STANDARD OPERATING
PROCEDURES
Dosage Strength;
Batch No.
Date of Audit:
mg
/
/200Y
Page 2 of 3.
Edition Number:
02
Ed. Status:
Supwecedes - 01
Effective Date
DD/MM/YY
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APPROVED
______________
Department
__________
R &D
_______________
RA
Chapter: 14.12
12
______/__________
QC / QA
Generic Development
SEMISOLIDS
PIVOTAL BATCH
14
SOP # HBGD-02-02YY
CHAPTER
STANDARD OPERATING
PROCEDURES
Dosage Strength;
Batch No.
Date of Audit:
mg
/
/200Y
Page 3 of 3.
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Edition Number:
02
Ed. Status:
Supwecedes - 01
Effective Date
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
______________
Department
__________
R &D
_______________
RA
Chapter: 14.13
13
______/__________
QC / QA
Generic Development
SEMISOLIDS
BIOEQUIVALENCE
CHAPTER 15
Topical
Bioequivalence
vs. Reference Listed Drug
Evaluating
whether
your
firms
corticosteriods drug will pass the
vasoconstrictor bioassay at the first
time
is
a
key
requirement.
Vasoconstrictor bioassays are relatively
costly clinical evaluations.
The primary goal is to ensure that the
generic topical drug is similar to the
reference drug. Knowing the reference
drugs overall diffusion profile and
ageing parameters are critical input
data requirements to make this
decision.
Handbook of Pharmaceutical
This
chapter
combines
the
developments in diffusion testing and
the May 1997 data correlation of
SUPAC-SS to produce a working model
on accessing similarity between your
drug and the reference listed drug (i.e.
RLD.)
Two essential steps the topical
development unit can do to achieve this
goal?
Drug Classification:
Classify the drug product whether it is a
corticosteroid or non-corticosteroid
product. This classification will furnish
two useful aspects;
1. The type of diffusion studies
considered necessary to fully evaluate
your formulated drug against the RLD
that has been selected (Reference.
Graph 1 & Graph 2 demonstrate
comparison diffusion studies.
2. Whether it is possible to establish an
IVIVC (in-vitro, in-vivo correlation)
between your drug and the intended
vasoconstrictor
bioassay
/
bioequivalence study necessary for
corticosteriods applications to the FDA.
Chapter: 15.1
1
Generic Development
SEMISOLIDS
BIOEQUIVALENCE
Topical
LABORATORY WORK:
Bioequivalence
several (CDfP) using multipoint profiles
with multiple (i.e. 3) batches, hopefully
with different manufacturing dates and
thus assessing miscellaneous product
ages.
Diffusion method requirements are
highlighted in summary given.
Handbook of Pharmaceutical
CHAPTER 15
It
The
The
Chapter: 15.2
2
Generic Development
SEMISOLIDS
BIOEQUIVALENCE
CHAPTER 15
Topical Bioequivalence
DIFFUSION CONDITIONS
Used for Comparative Diffusion Profiles (CDP)
DIFFUSION CONDITIONS
(Semisolids)
System:
System Orifice:
15mm
Temperature:
320 C (0.50 C)
Membrane (creams):
Polysulfone (Tuffryne)
Diameter 25mm saturated with
Isopropylmyristate/Ethomeen
Membrane (ointments):
Polysulfone (Tuffryne)
Diameter 25mm saturated with
Isopropylmyristate (IPM)
Receptor Phase:
Ethanol-Water Mixture
Sampling Time:
0.5; 1; 2; 4; 6 - hours
Analysis:
Water/Acetonitrile
IPM/Water/Ethanol 10:85:5
Release Rate:
Cautions:
Note Difference in membrane treatment and receptor phases for creams and
ointments. Semisolids age > one month (ideally between 3-6 months.)
Handbook of Pharmaceutical
Chapter: 15.3
3
Generic Development
SEMISOLIDS
BIOEQUIVALENCE
CHAPTER 15
Topical Bioequivalence
COMPARATIVE DIFFUSION PROFILE
FOR CORTICOSTEROID DRUG PRODUCT LOTS
USED IN TOPICAL BIOEQUIVALENCE STUDIES:
[Generic name] [Topical Preparation] [00.0] mg/gram.
Lot No:[000]
200
150
S-12345
RLD AA0000
100
50
0
0 0.5
1.0
1.5
2.0
2.5
3.0
References:
1. SUPAC SS Statistics Committee Maryland USA 1997.
2. Donald J Schuirmann - QMR/OEB/CDER Maryland USA
3. Robert Dillard Ph.D. (PhRMA) USA
4. David Pearce PH.D (NAPM & GPIA) USA
5. US Department of Health and Hunam Sciences FDA CDER May 1997
6. Gordon L Flynn Ph.D. SUPAC-SS Working Group University of Michigan USA
7. USP XXIII USPC USA
8. Richard J Davis FDA Mid Atlantic Division USA
9. Jerome Elkins Dallas District Laboratory FDA USA 1997.
10.International Journal of Generic Drugs, Vol..1 No 1-8, 1997.
Handbook of Pharmaceutical
Chapter: 15.4
4
Generic Development
SEMISOLIDS
BIOEQUIVALENCE
CHAPTER 15
Topical Bioequivalence
COMPARATIVE DIFFUSION PROFILE
IN-VITRO RELEASE
THREE DRUG PRODUCT LOTS SHOWING SAMENESS PRIOR TO
BIOEQUIVALENCE STUDIES:
[Generic name] [Topical Preparation] [00.0] mg/gram.
(g.cm )
S-115
60
S-116
40
20
0
( Time)
CERTIFICATES OF ANALYSIS REPRESENTING THE DRUG PRODUCTS USED IN
BIOEQUIVALENCY STUDY
Lot: 1234
Lot: AA000
The analytical results of the Certificates of Analysis for [Generic Company Name Inc. / Ltd.] and
[RLD Company Name Inc. / Ltd.] Drug Product lots were tested the Analytical Research Laboratories
of [Generic Company Name Inc. / Ltd. & Address].
Handbook of Pharmaceutical
Chapter: 15.5
5
Generic Development
SEMISOLIDS
BIOEQUIVALENCE
CHAPTER 15
Topical Bioequivalence
COMPARATIVE DIFFUSION PROFILE
IN-VITRO RELEASE
FIVE DRUG PRODUCT LOTS SHOWING EQUIVALENT PROFILES
[Generic name] [Miconazole Nitrate] [20.0] mg/gram.
Lot No:1234
Test
Product
200
Innovator
2
(g.cm )
150
Product A
100
Product B
50
Product C
0
0 2 4 6 8 10 12 14 16 18 20
( Time)
Hours
Lot: 1234
Lot: AA00
Lot: S3420
Lot: EX230
Lot: C369
The analytical results of the Certificates of Analysis for [Generic Company Name Inc. / Ltd.] and
[RLD Company Name Inc. / Ltd.] Drug Product lots were tested the Analytical Research Laboratories
of [Generic Company Name Inc. / Ltd. & Address].
Handbook of Pharmaceutical
Chapter: 15.6
6
Generic Development
I.
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
II.
GENERAL BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
A.
Critical Manufacturing Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
B.
General Stability Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
C.
The Role of In Vitro Release Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
III.
IV.
MANUFACTURING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
A.
Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
B.
Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
V.
14
14
15
16
VI.
MANUFACTURING SITE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A.
Level 1 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B.
Level 2 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
C.
Level 3 Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
17
17
18
VII.
I.
INTRODUCTION
The guidance provides recommendations on application documentation for the following multiple
This guidance has been prepared by the Scale-Up and Post Approval Change Semisolids (SUPAC-SS)
Working Group operating under the direction of the Chemistry Manufacturing Controls Coordinating Committee (CMC
CC) and the Biopharmaceutics Coordinating Committee (BCC) in the Center for Drug Evaluation and Research
(CDER) at the Food and Drug Administration. This guidance document represents the Agencys current thinking on
semisolid dosage forms scale-up and postapproval changes. It does not create or confer any rights for or on any person
and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the
requirement of the applicable statute, regulations, or both.
changes, provided appropriate test and filing documents are submitted (1) multiple level 1 changes
with level 1 test and filing documentation; (2) multiple level 1 changes; one level 2 change with
level 2 test and filing documentation; (3) multiple level 2 changes with level 2 test documentation
and a prior approval supplement (PAS) and (4) level 3 manufacturing site change and any other
level 1 change with level 3 manufacturing site change test and filing documentation. The
documentation to support the changes varies depending on the type and the complexity of the
semisolid dosage form. For those changes filed in a Changes Being Effected (CBE) Supplement
(21 CFR 314.70(c)), the FDA may review the supplemental information and decide that the
changes are not approvable. Sponsors should contact the appropriate CDER review division and
staff for information about tests and application documentation for changes not addressed in this
guidance, or for successive level 2 or 3 changes submitted over a short period.
The regulations provide that applicants may make changes to an approved application in
accordance with a guidance, notice, or regulation published in the Federal Register that provides
for a less burdensome notification of the change (e.g., by notification at the time a supplement is
submitted or in the next annual report) (21 CFR 314.70(a)). This guidance permits less
burdensome notice of certain postapproval changes within the meaning of
314.70(a).
II.
GENERAL BACKGROUND
In general, semisolid dosage forms are complex formulations having complex structural elements.
Often they are composed of two phases (oil and water), one of which is a continuous (external)
phase, and the other of which is a dispersed (internal) phase. The active ingredient is often
dissolved in one phase, although occasionally the drug is not fully soluble in the system and is
dispersed in one or both phases, thus creating a three-phase system. The physical properties of
the dosage form depend upon various factors, including the size of the dispersed particles, the
interfacial tension between the phases, the partition coefficient of the active ingredient between
the phases, and the product rheology. These factors combine to determine the release
characteristics of the drug, as well as other characteristics, such as viscosity.
A.
For a true solution, the order in which solutes are added to the solvent is usually
unimportant. The same cannot be said for dispersed formulations, however, because
dispersed matter can distribute differently depending on to which phase a particulate
substance is added. In a typical manufacturing process, the critical points are generally the
initial separation of a one-phase system into two phases and the point at which the active
ingredient is added. Because the solubility of each added ingredient is important for
determining whether a mixture is visually a single homogeneous phase, such data, possibly
supported by optical microscopy, should usually be available for review. This
The effect that SUPAC changes may have on the stability of the drug product should be
evaluated. For general guidance on conducting stability studies, see the FDA Guideline
for Submitting Documentation for the Stability of Human Drugs and Biologics. For
SUPAC submissions, the following points should also be considered:
1.
In most cases, except those involving scale-up, stability data from pilot
scale batches will be acceptable to support the proposed change.
2.
Where stability data show a trend towards potency loss or degradant
increase under accelerated conditions, it is recommended that historical accelerated
stability data from a representative prechange batch be submitted for comparison.
It is also recommended that under these circumstances, all available long-term data
on test batches from ongoing studies be provided in the supplement. Submission
of historical accelerated and available long-term data would facilitate review and
approval of the supplement.
3.
A commitment should be included to conduct long-term stability studies
through the expiration dating period, according to the approved protocol, on either
the first or first three (see section III-VI for details) production batches, and to
report the results in subsequent annual reports.
C.
The key parameter for any drug product is its efficacy as demonstrated in controlled
clinical trials. The time and expense associated with such trials make them unsuitable as
routine quality control methods. Therefore, in vitro surrogate tests are often used to
assure that product quality and performance are maintained over time and in the presence
of change. A variety of physical and chemical tests commonly performed on semisolid
products and their components (e.g., solubility, particle size and crystalline form of the
active component, viscosity, and homogeneity of the product) have historically provided
reasonable evidence of consistent performance. More recently, in vitro release testing has
shown promise as a means to comprehensively assure consistent delivery of the active
3
III.
This section of the guidance focuses on changes in excipients in the drug product. Qualitative
changes in excipients should include only those excipients which are present in approved drug
products for the specific route of administration. Quantitative changes in excipients should not
exceed the amount previously approved in products with the same specific route of
administration.2 The chronology of changes in components and composition should be provided.
Changes in components or composition that have the effect of adding a new excipient or deleting
an existing excipient are defined as level 3 changes (see section III.C below), except as described
below. These changes generally result in the need to change the labeling.
FDA, CDER, Inactive Ingredient Guide, 1996, Division of Drug Information Resources.
4
Compositional changes in preservatives are considered separately and are not included as part of
the total additive effect under sections III.A, B and C.
A.
Level 1 Change
1.
Definition of Level
Level 1 changes are those that are unlikely to have any detectable impact on
formulation quality and performance.
Examples:
!
2.
Test Documentation
a.
Chemistry Documentation
None.
c.
None.
5
3.
Filing Documentation
Level 2 Change
1.
Definition of Level
Level 2 changes are those that could have a significant impact on formulation
quality and performance.
Examples:
!
2.
Test Documentation
a.
Chemistry Documentation
None.
3.
Filing Documentation
Level 3 Change
1.
Definition of Level
Level 3 changes are those that are likely to have a significant impact on
formulation quality and performance.
Examples:
!
2.
Test Documentation
a.
Chemistry Documentation
Filing Documentation
Preservative
For semisolid products, any change in the preservative may affect the quality of the
product. If any quantitative or qualitative changes are made in the formulation, additional
testing should be performed. No in vitro release documentation or in vivo bioequivalence
documentation is needed for preservative changes.
1.
Level 1 Change
a.
Definition of Level
Test Documentation
c.
Filing Documentation
8
Annual report
2.
Level 2 Change
a.
Definition of Level
Test Documentation
c.
Filing Documentation
Level 3 change
a.
Definition of Level
Test Documentation
Filing Documentation
IV.
MANUFACTURING
Manufacturing changes may affect both equipment used in the manufacturing process and the
process itself.
A.
Equipment
1.
Level 1 Change
a.
Definition of Level
Test Documentation
i.
Chemistry Documentation
None.
iii.
None.
c.
Filing Documentation
10
Level 2 Change
a.
Definition of Level
Test Documentation
i.
Chemistry Documentation
The in vitro release rate of a lot of the dosage form prepared in new
equipment should be compared with the release rate of a recent lot
of comparable age of the product prepared using original
equipment. The median in vitro release rates (as estimated by the
estimated slope from each cell, see section VII) of the two
formulations should be demonstrated to be within acceptable limits,
using the testing procedure described in section VII (IN VITRO
RELEASE TEST) below.
iii.
None.
c.
Filing Documentation
11
Level 3 Change
Process
1.
Level 1 Change
a.
Definition of Level
Test Documentation
i.
Chemistry Documentation
None.
iii.
None.
c.
Filing Documentation
Annual report.
2.
Level 2 Change
a.
Definition of Level
Test Documentation
i.
Chemistry Documentation
The in vitro release rate of a lot of the dosage form prepared by the
new/modified process should be compared with the in vitro release
rate of a recent lot of comparable age of the dosage form prepared
by the prechange process. The median in vitro release rates (as
estimated by the estimated slope from each cell, see VII) of the lots
prepared by the two processes should be demonstrated to be within
acceptable limits, using the testing procedure described in section
VII (IN VITRO RELEASE TEST) below.
iii.
None.
c.
Filing Documentation
Level 3 Change
13
V.
This guidance recommends that the minimum batch size for the NDA pivotal clinical trial batch or
the ANDA/AADA biobatch be at least 100 kg or 10% of a production batch, whichever is larger.
Deviations from this recommendation should be discussed with the appropriate agency review
division. All scale changes should be properly validated and may be inspected by appropriate
agency personnel.
A.
Level 1 Change
1.
Definition of Level
Change in batch size, up to and including a factor of ten times the size of the
pivotal clinical trial/biobatch, where: (1) the equipment used to produce the test
batch(es) are of the same design and operating principles; (2) the batch(es) is
manufactured in full compliance with cGMPs; and (3) the same standard operating
procedures (SOPs) and controls, as well as the same formulation and
manufacturing procedures, are used on the test batch(es) and on the full-scale
production batch(es).
2.
Test Documentation
a.
Chemistry Documentation
None.
c.
None.
3.
Filing Documentation
B.
Level 2 Change
14
1.
Definition of Level
Changes in batch size from beyond a factor of ten times the size of the pivotal
clinical trial/biobatch, where: (1) the equipment used to produce the test batch(es)
are of the same design and operating principles; (2) the batch(es) is manufactured
in full compliance with cGMPs; and (3) the same standard operating procedures
(SOPs) and controls, as well as the same formulation and manufacturing
procedures, are used on the test batch(es) and on the full-scale production
batch(es).
2.
Test Documentation
a.
Chemistry Documentation
The in vitro release rate of a lot of the scaled-up batch should be compared
with the in vitro release rate of a recent lot, of comparable age, of the
prechange scale. The median in vitro release rates (as estimated by the
estimated slope from each cell, see section VII) of the lots of the two scales
should be demonstrated to be within acceptable limits, using the testing
procedure described in section VII (IN VITRO RELEASE TEST) below.
c.
None.
3.
Filing Documentation
Level 3 Change
15
VI.
MANUFACTURING SITE
16
A.
Level 1 Change
1.
Definition of Level
Level 1 changes consist of site changes within a single facility where the same
equipment, standard operating procedures (SOPs), environmental conditions (e.g.,
temperature and humidity) and controls, and personnel common to both
manufacturing sites are used, and where no changes are made to the manufacturing
batch records, except for administrative information and the location of the facility.
Common is defined as employees already working on the campus who have
suitable experience with the manufacturing process.
2.
Test Documentation
a.
Chemistry Documentation
None.
c.
None.
3.
Filing Documentation
Annual report.
B.
Level 2 Change
1.
Definition of Level
Test Documentation
17
a.
Chemistry Documentation
Location of new site and updated executed batch records. None beyond
application/compendial product release requirements.
Stability testing: First production batch on long-term stability reported in
annual report.
b.
None.
c.
None.
3.
Filing Documentation
Level 3 Change
1.
Definition of Level
Test Documentation
a.
Chemistry Documentation
18
The in vitro release rate of a lot of the dosage form from the new
manufacturing site should be compared with the in vitro release rate of a
recent lot of comparable age of the dosage form manufactured at the prior
site. The median in vitro release rates (as estimated by the estimated slope
from each cell, see section VII) of the lots from the two
sites should be
demonstrated
to be within
acceptable
limits, using
the testing
procedure
described in
section VII
(IN VITRO
RELEASE
TEST) below.
c.
None.
3.
Filing Documentation
VII.
In vitro release is one of several standard methods which can be used to characterize performance
characteristics of a finished topical dosage form, i.e., semisolids such as creams, gels, and
19
A diffusion cell system with a standard open cap ground glass surface with 15 mm
diameter orifice and total diameter of 25 mm.
Synthetic Membrane:
!
Receptor Medium:
!
Appropriate receptor medium such as aqueous buffer for water soluble drugs or a hydroalcoholic medium for sparingly water soluble drugs or another medium with proper
justification.
Number of Samples:
20
Multiple replicates (six samples are recommended) to determine the release rate (profile)
of the topical dermatological product.
Sample Applications:
!
About 300 mg of the semisolid preparation is placed uniformly on the membrane and kept
occluded to prevent solvent evaporation and compositional changes. This corresponds to
an infinite dose condition.
Sampling Time:
!
Multiple sampling times (at least 5 times) over an appropriate time period to generate an
adequate release profile and to determine the drug release rate (a 6-hour study period with
not less than five samples, i.e., at 30 minutes, 1, 2, 4 and 6 hours) are suggested. The
sampling times may have to be varied depending on the formulation. An aliquot of the
receptor phase is removed at each sampling interval and replaced with fresh aliquot, so
that the lower surface of the membrane remains in contact with the receptor phase over
the experimental time period.
Sample Analysis:
!
Appropriate validated specific and sensitive analytical procedure should be used to analyze
the samples and to determine the drug concentration and the amount of drug released.
A plot of the amount of drug released per unit membrane area (mcg/cm2) versus square
root of time should yield a straight line. The slope of the line (regression) represents the
release rate of the product. An X intercept typically corresponding to a small fraction of
an hour is a normal characteristic of such plots.
The typical in vitro release testing apparatus has six cells. For each run of the apparatus,
the two products being compared should be assigned to the six cells as follows:
or
21
where T represents the Postchange Lot (Test product) and R represents the Prechange
Lot (Reference product). This approach of including both products in each run of the in
vitro apparatus will help ensure an unbiased comparison in the event of a systematic
difference between runs.
!
The choice of the assignment of products to cells (i.e., whether the prechange lot or the
postchange lot is assigned to the upper left corner cell of the apparatus) may either be
made systematically (i.e., alternate the pattern for each successive run) or randomly (i.e.,
flip a coin or use some other random mechanism).
For the case of a nonstandard apparatus, with other than six cells, the principle of
including both the prechange lot and the postchange lot in the same run should still be
used. If the apparatus has only a single cell, the runs on the prechange and postchange
lots should be intermixed, rather than obtaining all observations on one product followed
by all observations on the other product.
22
Because outliers are expected to occur on occasion with this testing (for example, due to
an air bubble between the product sample and the membrane), a nonparametric
Prechange
Lot (R)
1.1331
1.3496
1.1842
1.4946
1.0824
1.4668
1.3049
1.1911
1.0410
1.2210
1.2419
The first step in the computation of the confidence interval is to form the 36 (= 6 x 6)
individual T/R ratios. This is illustrated in the following table, where the prechange lot
slopes (R) are listed across the top of the table, the postchange lot slopes (T) are listed
down the left margin of the table, and the individual T/R ratios are the entries in the body
of the table:
1.1331
1.1842
1.0824
1.3049
1.0410
1.2419
1.3390
1.1817
1.1307
1.2371
1.0261
1.2863
1.0782
1.3496
1.1911
1.1397
1.2469
1.0343
1.2964
1.0867
1.4946
1.3190
1.2621
1.3808
1.1454
1.4357
1.2035
1.4668
1.2945
1.2386
1.3551
1.1241
1.4090
1.1811
1.1911
1.0512
1.0058
1.1004
0.9128
1.1442
0.9591
1.2210
1.0776
1.0311
1.1280
0.9357
1.1729
0.9832
The second step in the computation of the confidence interval is to order these 36
individual T/R ratios from lowest to highest:
0.9128 0.9357 0.9591 0.9832 1.0058 1.0261 1.0311 1.0343 . . . 1.2863 1.2945
23
The statistical test described above is based on a standard confidence interval procedure
related to the Wilcoxon Rank Sum/Mann-Whitney rank test, applied to the log slopes.
References to this confidence interval procedure include:
Conover, W.J., Practical Nonparametric Statistics (Second Edition), John Wiley & Sons,
page 223ff, 1980.
Hollander, M. and D.A.Wolfe, Nonparametric Statistical Methods, John Wiley & Sons,
page 78ff, 1973.
However, as was seen in the example, it is not necessary to actually compute logs in order
to carry out the test.
The example illustrates the case of full data, i.e., where there are 6 slopes per lot at the
24
first stage and, if the second stage is necessary, 18 slopes per lot at the second stage. If
slopes are missing, the computations will need to be modified. For example, if a single
slope were missing from one of the lots (it does not matter if it is the prechange lot or the
postchange lot) at the first stage, there would only be 30 (= 5 x 6) individual T/R ratios,
and the limits of the 90% confidence interval would no longer be the eighth and twentyninth ordered individual T/R ratio, but rather would be the sixth and twenty-fifth ordered
individual T/R ratio. If data are missing at either stage of the test, the correct computation
should be determined either by reference to a statistical text or consultant, or by
consultation with CDER staff.
!
The statistical procedure as described above does not take the block structure of the test
(i.e., the fact that data are obtained in runs of six slopes at a time, rather than all at once)
into account. This is justified by the following:
1. In vitro release data available to the Center at this time show no evidence of an
important run-to-run effect.
2. The proposed experimental design, in which both products are included in each
run, will help to ensure unbiasedness if a run-to-run effect should occur.
25
GLOSSARY OF TERMS3
Approved Target Composition: The components and amount of each ingredient for a drug
product used in an approved pivotal clinical study or bioequivalence study.
Batch: A specific quantity of a drug or other material produced according to a single
manufacturing order during the same cycle of manufacture and intended to have uniform character
and quality, within specified limits. (21 CFR 210.3(b)(2)).
Contiguous Campus: Contiguous or unbroken site or a set of buildings in adjacent city blocks.
Creams/Lotions: Semisolid emulsions that contain fully dissolved or suspended drug substances
for external application. Lotions are generally of lower viscosity.
Diluent: A vehicle in a pharmaceutical formulation commonly used for making up volume and/or
weight (e.g., water, paraffin base).
Drug Product: A drug product is a finished dosage form (e.g., cream, gel, or ointment) in its
marketed package. It also can be a finished dosage form (e.g., tablet, capsule, or solution) that
contains a drug substance, generally, but not necessarily, in association with one or more other
ingredients (21 CFR 314.3(b)).
Drug Release: The disassociation of a drug from its formulation thereby allowing the drug to be
distributed into the skin or be absorbed into the body where it may exert its pharmacological
effect.
Drug Substance: An active ingredient that is intended to furnish pharmacological activity or
other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to
affect the structure or any function of the human body, but does not include intermediates used in
the synthesis of such ingredient (21 CFR 314.3(b)).
Emulsion: Emulsions are two phase systems in which an immiscible liquid (dispersed phase) is
dispersed throughout another liquid (continuous phase or external phase) as small droplets.
Where oil is the dispersed phase and an aqueous solution is the continuous phase, the system is
designated as an oil-in-water emulsion. Conversely, where water or an aqueous solution is the
dispersed phase and oil or oleaginous material is the continuous phase, the system is designated as
a water-in-oil emulsion. Emulsions are stabilized by emulsifying agents that prevent coalescence,
the merging of small droplets into larger droplets and, ultimately, into a single separated phase.
Emulsifying agents (surfactants) do this by concentration in the interface between the droplet and
external phase and by providing a physical barrier around the particle to coalesce. Surfactants
also reduce the interfacial tension between the phases, thus increasing the ease of emulsification
upon mixing. Emulsifying agents substantially prevent or delay the time needed for emulsion
See Workshop Report: Scale-up of liquid and semi-solids disperse systems. G. A. Van Buskirk, V. P. Shah, D.
Adair, et al. Pharmaceutical Research, 11, 1216-1220, 1994,
26
droplets to coalesce. Emulsification is the act of forming an emulsion. Emulsification can involve
the incorporation of a liquid within another liquid to form an emulsion or a gas in a liquid to form
a foam.
Formulation: A listing of the ingredients and quantitative composition of the dosage form.
Gel: A semisolid system in which a liquid phase is constrained within a three dimensional, crosslinked matrix. The drug substance may be either dissolved or suspended within the liquid phase.
Homogenization: A method of atomization and thereby emulsification of one liquid in another in
which the liquids are pressed between a finely ground valve and seat under high pressure (e.g., up
to 5,000 psi).
Internal phase: The internal phase or the dispersed phase of an emulsion comprises the droplets
that are found in the emulsion.
In Vitro Release Rate: Rate of release of the active drug from its formulation, generally
expressed as amount/unit area/time0.5.
Ointment: An unctuous semisolid for topical application. Typical ointments are based on
petrolatum. An ointment does not contain sufficient water to separate into a second phase at
room temperature. Water soluble ointments may be formulated with polyethylene glycol.
Pilot Scale Batch: The manufacture of drug product by a procedure fully representative of and
simulating that intended to be used for full manufacturing scale.
Preservative: An agent that prevents or inhibits microbial growth in a formulation to which it
has been added.
Process: A series of operations, actions and controls used to manufacture a drug product.
Scale-up: The process of increasing the batch size.
Scale-down: The process of decreasing the batch size.
Shear: A strain resulting from applied forces that cause or tend to cause contiguous parts of a
body to slide relative to one another in direction parallel to their plane of contact. In
emulsification and suspensions, the strain produced upon passing a system through a homogenizer
or other milling device.
!
Low shear: Processing in which the strain produced through mixing and/or emulsifying
shear is modest.
27
High shear: Forceful processes which, at point of mixing or emulsification place a great
strain on the product. Homogenization, by its very nature, is a high shear process which
leads to a small and relatively uniform emulsion droplet size. Depending on their
operation, mills and mixers are categorized as either high shear or low shear devices.
28
REFERENCES
1.
2.
Shah, V. P., J. S. Elkins, and R. L. Williams, "In Vitro Drug Release Measurement of
Topical Glucocorticoid Creams," Pharmacopeial Forum, 19, 5048-5059, 1993.
3.
4.
5.
6.
29
Change
Test Documentation
Application/compendial product
release requirements
Application/compendial product
release requirements
30
Filing Documentation
C
Change
C
Test Documentation
C
Application/compendial product
release requirements
Stability:
Significant body of information
available: One batch with three
months accelerated stability data and
first three production batches on longterm stability.
Significant body of information not
available: Three batches with three
months accelerated stability data and
first three production batches on longterm stability
31
Filing Documentation
C
Change
C
Test Documentation
C
32
Filing Documentation
C
Annual report
Change
C
Nonautomated or nonmechanical
equipment to automated or
mechanical equipment to transfer
ingredients
Test Documentation
C
Application/compendial product
release requirements
Application/compendial product
release requirements
Stability:
Significant body of information
available: One batch with three months
accelerated stability data and first
production batch on long-term
stability.
Significant body of information not
available: Three batches with three
months accelerated stability data and
first three production batches on longterm stability.
33
Filing Documentation
C
Change
Test Documentation
Filing Documentation
Annual report
Stability:
Significant body of information
available: One batch with three months
accelerated stability data and first
production batch on long-term stability.
Significant body of information not
available: Three batches with three
months accelerated stability data and
first three production batches on longterm stability.
34
Change
C
Test Documentation
C
C
Note: See text for additional information.
35
Filing Documentation
C
Change
Test Documentation
Filing Documentation
Annual report
C
C
Stability
Different campus
Contract manufacturer
36
SEMISOLIDS
TECHNICAL TRANSFER
CHAPTER 16
TTD
Technical Transfer
Documentation-Pharmaceutical
TTDs should be
comprehensive
and well
structured
Moving
the
Technical
Transfer
Documentation from the development or
researched-based unit to manufacture will
enable production and quality control
personnel to get to know the ins and outs
of the newly developed drug product.
Such dossiers are referred to as the
TTDs and consist of :
procedures
and
This
section
deals
with
the
Pharmaceutical TTD content. Data reports
and results that are in the domain of the
Pharmaceutical development department.
The Pharmaceutical TTD file contains all
necessary process methods, process
qualification,
product
specifications,
technical data, reports, tabulations and
summaries based on the Pharmaceutical
development work regarding the generic
drug development from the preformulation to process qualification stage.
This data is required for manufacturing
and control of the pivotal submission
batch and the initial three full size
validation batches produced at the
commercial manufacturing site facility.
Really g o o d
TTDs will
get your product
to the market
sooner
TTD programs of excellence are more
than just transferring data. They include
an evaluation of the product development
documentation (Development Report),
the proposed manufacturing process, the
in-process specifications, and the quality
systems used to control the product.
A guideline SOP is given.
W ell managed TTD programs are
essential to firms engaged in the
development of new products which
require regulatory approval. A structured
on-time program will improve efficiency
and effectiveness in moving the product
from development to product launch. 3
Chapter: 16.1
1
Generic Development
SEMI SOLIDS
T E C H N I C A L
T R A N S F E R
CHAPTER 16
TTD
Technical Transfer
Documentation
the time has come the researcher said to speak of many things
- of pivotal and protocols and to validated cleanings...
Which Data?
The data is obtained from two preexisting sources:- the audited ANDA
Chemistry, Manufacturing and Control
section (CMC) and the Product
Development Report.
The efficient transfer of technology
from the development environment to
the
full
scale
commercial
manufacturing plant is a complex
process. The TTD documents support
this overall manufacturing and control
process. The entire spectrum initiating
from the purchasing of raw materials
from approved suppliers to the final full
size validation protocol should be
covered
by
the
transfer
documentation.
Rationale
Product development reports and
technology transfer documentation
provide final CMC technology and the
rationale of the component and
process choices made during the
product development.
Handbook of Pharmaceutical
Sect: 16.2
16.2
Structure
The technical information should be
structured in a well developed and
organized dossier containing all the
product
and
process
specific
documentation and final specifications.
The documentation should be written
in an easily understood manner and
similarly to SOPs contain a read and
understood paragraph or certification
section.
Production and
control personnel
need to know
the new process
Technical Personnel
Production and control personnel at
the selected manufacturing site will
ensure that the technical data has
been clearly absorbed and understood
prior to commencement of full scale
commercial
or
validation
lot
manufacture.
From the inspection point of view, the
TTD file is the basic documentation
that will be needed to support the
pending PAI agency program. Since
the FDA requires that the firm be
prepared for the PAI program
(inspection-audit) at the time of file
submission to agency headquarters,
Generic Development
SEMI SOLIDS
T E C H N I C A L
The Development
Report is
part of the
Transfer Process
Handbook of Pharmaceutical
Sect: 16.3
16.3
T R A N S F E R
CHAPTER 16
Production Know-how
The pivotal batch ends with the Pivotal
Batch Report and this report finalizes
the Technical Transfer Documentation
process. There should be no further
scale-up processing after the pivotal
lot has been manufacture other than
possible fine-tuning adjustments to the
scaled-up process. No new process or
product
specification
may
be
introduced into the documentation
after the demonstration of the pivotal
batch. In generic drug development
the pivotal batch is usually the batch
on which the bioequivalence study
against a selected reference drug
(RLD) is performed.
It is this batch that is filed in the ANDA
submission. When a biostudy has
been performed, the pivotal batch may
also be referred to as the Biobatch.
Development
Pharmaceutical
and
Analytical
Data
is Transferred
to the factory
floor
Generic Development
SEMI SOLIDS
T E C H N I C A L
TTD Contents
Specifications
for
purchasing
department
(Active
material
Approved
Suppliers
detailed
specifications).
Manufacturing, engineering and
quality control procedures and
specifications of the generic drug
product and process.
All analytical methodology and
results including stability protocol
and results.
All microbiological methodology and
results.
The Development Report and ANDA
File and development notes and
graphs.
T R A N S F E R
CHAPTER 16
[Master
Formula;
Instructions;
IPQC,
Product Specifications]
Process
Finished
Engineering Units
[Cleaning validation ; Process
validation; Metrology (calibrationstandards) HVAC System, Air
System; Nitrogen System; Purified
Water System, Water For Injection
System;
Washing
Tunnels;
Autoclave Systems; Oven System;
Freeze Drier Systems; Sanitation
Systems. (Where appropriate).
Microbiology Laboratory
[Validated
microbial
methods;
microbiological specifications.]
Stability Unit
Operational Departments
Quality Assurance
Regulatory Affairs
[Active
material;
excipients;
container-closures
purchasing
specifications to the 'Approved Raw
Material Suppliers' ].
Manufacturing
Controls
Process
Handbook of Pharmaceutical
and
Sect: 16.4
16.4
Archives
[ANDA copy; Development Report;
Process Optimization Report ;
Process Qualification Report; TTD
Reports; Development Notebooks,
Pharmaceutical, Analytical, and
microbiological
Notebooks and
Logs; Analytical HPLC IR UV etc.
graphs and charts].
Generic Development
SEMI SOLIDS
T E C H N I C A L
T R A N S F E R
CHAPTER 16
C H E C K L I S T
CL # HBGD-03-01YY
1. The buying department has purchasing specifications for the qYes qNo
procurement of approved actives, excipients and container-closure
systems ?
2. Printing specification and QA approved artwork for product labels, qYes qNo
cartons, package inserts and advertising claims are approved ?
3. The manufacturing formula and master processing instructions for each qYes qNo
commercial batch sizes are approved ?
4. Cleaning validation protocol specific to the active material is complete ?
qYes qNo
5. The validation protocol for the first three consecutive batches is qYes qNo
approved?
6. All new manufacturing equipment has been fully qualified (IQOQ)?
qYes qNo
7. The metrology department has calibrated all equipment recording qYes qNo
units?
8. Plant QC laboratory has evaluated the transferred analytical methods qYes qNo
for system suitability and robustness (ruggedness) ?
qYes qNo
lab
has
all
container-closure
methods
11. All product specific SOPs have been distributed and signed as read qYes qNo
and understood by the production operators and supervisors?
12. Stability unit has the ANDA commitment stability protocol (real-time qYes qNo
study) and the validation stability protocol for three validation batches?
13. All vendor DMF deficiencies (and GMP concerns) have been qYes qNo
corrected?
14. The CMC file is compiled in full and signed-off ?
qYes qNo
qYes qNo
Handbook of Pharmaceutical
Sect: 16.5
16.5
Generic Development
SEMI SOLIDS
T E C H N I C A L
T R A N S F E R
CHAPTER 16
STANDARD OPERATING
PROCEDURES
Page 1 of 1.
CL # HBGD-03-01YY
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
Footnote : In-house training must be given to all QC oratory staff, production and
QA sections on specific manufacturing and control aspects of the newly developed
drug as well as SOP training pertaining to the commercial aspects of the generic drug
manufacture
4
[End of Document]
Edition No. :
01
Ed. Status : New
Effective Date :
Handbook of Pharmaceutical
APPROVED
______________ ________________ _____________ _______________
Department
RD
RA
QC / Q A
Sect: 16.6
16.6
Generic Development
SEMI SOLIDS
T E C H N I C A L
T R A N S F E R
CHAPTER 16
STANDARD OPERATING
PROCEDURES
SOP # HBGD-02-03YY
PROCEDURE or SCOPE
[4.1]. The responsible personnel for the product development will prepare the
pharmaceutical section of the technical transfer file (TTD) for process and data
information transfer to the commercial manufacturing site facility.
[4.2]. The Pharmaceutical TTD file will contain all necessary pharmaceutical master
formula, manufacturing methods, validation criteria, product specifications, technical
data, reports, tabulations and summaries based on the pharmaceutical development
work pertaining to all strengths of the generic drug development from the preformulation to process qualification stage.
This data is required for the manufacture and control the pivotal submission batch and
the three initial full size validation batches produced at the commercial manufacturing
site facility.
[4.3]. Each section of the TTD File is presented in a modular form for ease of
updating. Sections are numbered [A] to [K]. The outline of the TTD requirements is
presented in a standard operating procedure format.
[4.4]. The requirements of the Pharmaceutical Technical Transfer documentation will
be part of the Product Development SOP for the specific dosage form. This
documents is based on formulation development for semisolid dosage forms.
[4.5]. An pharmaceutical TTD SOP will be prepared for each separate generic dosage
form under product development. 3
Edition No. : 01
Ed. Status :
New
Effective Date :
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
_____________
R &D
Chapter: 16.7
7
_____________
QC Lab
_______________
QA
Generic Development
SEMI SOLIDS
T E C H N I C A L
T R A N S F E R
CHAPTER 16
STANDARD OPERATING
PROCEDURES
SOP # HBGD-02-03YY
Edition No. : 01
Ed. Status :
New
Effective Date :
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
_____________
R &D
Chapter: 16.8
8
_____________
QC Lab
_______________
QA
Generic Development
SEMI SOLIDS
T E C H N I C A L
T R A N S F E R
CHAPTER 16
STANDARD OPERATING
PROCEDURES
SOP # HBGD-02-03YY
Master Formula and quantities (in mg per gram and per 100 000 units)
Master Formula and quantities for each DOSAGE strength.
SOP Index and Checklists (read and understood - signed and dated)
Manufacturing and Control Audit Checklists (signed and dated)
Pharmaceutical Development Completion Form. (signed and dated).
Edition No. : 01
Ed. Status :
New
Effective Date :
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
_____________
R &D
Chapter: 16.9
9
_____________
QC Lab
_______________
QA
Generic Development
SEMI SOLIDS
T E C H N I C A L
SOP #HBGD-03-01YY
T R A N S F E R
CHAPTER 16
STANDARD OPERATING
PROCEDURES
PURPOSE
he purpose of this Standard Operating Procedure is to establish the overall
table of contents for the preparation of the analytical part or section of the
technical transfer file for product information transfer to the selected commercial
manufacturing site facility. This SOP is specific for ANDA preparations of semisolid
dosage forms.
T
2.
RESPONSIBILITY
The Head of Analytical Development together with the Responsible Researcher for
the Generic Drug Development Project.
3.
FREQUENCY
Each ANDA product formula under development intended for the US market.
4.
PROCEDURE or SCOPE
[4.1]. The responsible personnel for the product development will prepare the
analytical section of the technical transfer file (TTD) for method and data information
transfer to the commercial manufacturing site facility.
[4.2]. The Analytical TTD file will contain all necessary analytical methods, method
validations, product specifications, technical data, reports, tabulations and
summaries based on the analytical development work pertaining to the generic drug
development from the pre-formulation to process qualification stage. May include
pivotal and scale-up date when available.
This data is required for testing and analyzing the pivotal submission batch and the
three initial full size validation batches produced at the commercial manufacturing
site facility.
[4.3]. Each section of the TTD File is presented in a modular form for ease of
updating. Sections are numbered [A] to [G]. The outline of the TTD requirements is
presented in the standard operating procedure format.
[4.4]. The requirements of the Analytical Technical Transfer documentation will be
part of the Product Development SOP for the specific dosage form. This document
is based on a Q & Q formulation development for semisolid dosage forms.
[4.5]. An analytical TTD SOP will be prepared for each separate generic dosage form
under product development.
4
Edition No. 02
Ed. Status : 03
Effective Date :
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
_____________ ______________
R &D
QC Lab
Chapter: 16.10
10
______________
QA
Generic Development
SEMI SOLIDS
T E C H N I C A L
SOP #HBGD-03-01YY
T R A N S F E R
CHAPTER 16
STANDARD OPERATING
PROCEDURES
1.1
1.2
1.3
1.4
1.5
Edition No. 02
Ed. Status : 03
Effective Date :
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
_____________ ______________
R &D
QC Lab
Chapter: 16.11
11
______________
QA
Generic Development
SEMI SOLIDS
T E C H N I C A L
SOP #HBGD-03-01YY
T R A N S F E R
CHAPTER 16
STANDARD OPERATING
PROCEDURES
Vendor Compliance Audit - Approved Active Supplier/s (On-site, Mail or Fax Audit).
SOP Index and Checklists (read and understood - signed and dated)
Audit Checklists (signed and dated)
Project Completion Form. (signed and dated) 3
Edition No. 02
Ed. Status : 03
Effective Date :
DD/MM/YY
Handbook of Pharmaceutical
APPROVED
____________
Department
_____________ ______________
R &D
QC Lab
Chapter: 16.12
12
______________
QA
Generic Development
SEMISOLIDS
P R O C E S S
V A L I D A T I O N
CHAPTER 17
Process Validation
process validation(PV) needs to show that the data from the first
three commercial lots of each batch size are essentially similar and
compare well with product data of the biobatch
Validation
Parameters evaluated
Consistency
The
validation
process
must
demonstrate
that
the
overall
manufacturing
process
performs
consistently, as expected, and that the
generic drug product consistently meets
its predetermined filed specifications
(i.e. in-process and finished product
specifications).
Validation Timing
The generic drug process must be validated
before the product is distributed and
shipped, i.e. usually the time between
approval and first marketing.
Experienced companies may well validate
the process prior to approval, if the risk is
considered minimal and it is thought the
review process will not challenge the
process or product specifications.
Cleaning Validation
Approved cleaning validation must be
performed immediately after the pivotal and
after each of the first three commercial
batches.
Cleaning validation specifications are
essentially part of the generic product
development program and are in place
before the validation process.
Validation Parameters
The following parameters generally impact
on the consistency of the bulk and finished
product and are part of the overall
development
validation
plan
from
development to process optimization to
process qualification to commercial
validation.
Handbook of Pharmaceutical
[a][c]
[a][c]
[a][d]
[d]
[a]
[e]
Content
Uniformity:
[a][d][e]
Top, Middle, Bottom sampling [a][d][e]
Dead-spot position sampling
[d][e]
Container weight testing
[a][d][e]
Re-mixing step(s)?
[a][d]
Sample plan / sample tests [a][d][e]
Content Uniformity Qualification [d]
Antioxidant/Chelate Qualification [d]
PV Assay results cf. pivotal lot [e]
PV test results cf. pivotal lot results [e]
pH/viscosity/rheology
[a][b]
Individual tube fill-weight
[b][e]
Average tube fill-weight
[b][e]
Processing time limitations.
[b][e]
[a] - during product development
[b] - during product development and
QC tested in commercial validation
[c] - during process optimization
[d] - during process qualification
[e] - during initial 3 validation lots
Chapter: 17.1
1
Generic Development
SEMISOLIDS
P R O C E S S
V A L I D A T I O N
CHAPTER 17
C H E C K L I S T
CL # HPGD-03-01YY
1
The manufacturing product and processing controls of the commercial lots qYes qNo
are substantially the same (equivalent) as those listed in the MA filing?
2.
Before the validation process and validation batches are run, the firm has qYes qNo
conducted a thorough and comprehensive on-site review and audit of all
development and analytical raw data?
3.
The firm has performed a side-by-side evaluation of the validation protocol qYes qNo
and the submitted MA dossier to ensure that the product and process
specification and control points are common in both documents?
4.
QC conducts routine particle size analysis on the active material(s) qYes qNo
suspended (insoluble) in the drug product (a particle size range is provided)?
5.
Particle size (/bulk density) QC specifications have been established for the qYes qNo
active material(s) present in the final product formula?
6.
During the product development the finished product has been evaluated at qYes qNo
both ends of a two unit pH range (pH 5 1 unit) for suitability in complying with
the finished product specification?
7.
Process controls on mixers (time, rpm settings) are documented in the full qYes qNo
scale commercial process instructions?
8.
Uniformity of Content is a critical processing parameter for the bulk qYes qNo
material after the mixing/homogenization process and prior to tube filing?
9.
Bulk samples taken during sampling operations - for the assay qYes qNo
determination are equivalent to one application (3-5 grams)?
10. In the event that it is not possible to obtain the equivalent of one qYes qNo
application, the closest approximation should be sampled (a function of sampling
thief used)?
11. A tapered sampling thief may during sampling operations be unsatisfactory qYes qNo
for sampling the equivalent of one application unit uniformly (use uniform
diameter thieves)? This effect is maximum in solid dosage forms and minimum in
semisolid preparations.
12.
qYes qNo
13. Manufacturing instructions clearly indicate corrective action taken where qYes qNo
older mixers (pony / ribbon) display dead spots - where no direct mixing action
can occur (around shaft / bearing area or discharge valves) ?
Handbook of Pharmaceutical
Chapter: 17.2
2
Generic Development
SEMISOLIDS
P R O C E S S
V A L I D A T I O N
CHAPTER 17
C H E C K L I S T
CL # HPGD-03-01YY
14. Dedicated tubing is used for drug products containing colored or qYes qNo
fragrant/pungent/odorous active drug substances?
15. All critical process parameter temperature and time controls qYes qNo
incorporate automatic recording equipment?.
16. The product batch number and date is routinely entered on the qYes qNo
automatically recording temperature and time control graphs?
17. Diffusion profiles are performed on 6 units for each of the three qYes qNo
validation lots. Note: Used to determine 'sameness' statistically.
18. Where validation batches are used for sale then routine Finished qYes qNo
Product Testing must be performed on composite sample representative
of the overall production run.
19 This sampling procedure is a routine procedure and independent qYes qNo
and separate to the validation sampling requirements?
20. Assay, Content Uniformity and microbial limit tests, are critical qYes qNo
parameters and results are compared side-by-side to the bioequivalent /
pivotal batch for equivalency?
21. Equivalency of the bioequivalent / pivotal batch with the validation qYes qNo
batch lots implies a variation < 5% from the filed Biobatch?
22. All results, including failing results (if any) have been fully qYes qNo
discussed and explained in the validation report?
23. The basis for concluding that the validation process is satisfactory, qYes qNo
particularly those batch lots with failing results has been fully evaluated
in the validation report?
24. Any out-of-specification product or process result during validation qYes qNo
will be fully investigated and an Investigation Report will be completed
and signed-off within 30 days ?
25. A separate Validation Concluding Statement is included in the qYes qNo
validation report? (Place on the approval page).
26. The validation concluding statement indicates that the three qYes qNo
production lots are equivalent in all aspects to the filed MA batch?
Handbook of Pharmaceutical
Chapter: 17.3
3
Generic Development
SEMISOLIDS
P R O C E S S
V A L I D A T I O N
CHAPTER 17
STANDARD OPERATING
PROCEDURES
Page 1 of 1.
CL # HPGD-03-01YY
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
P-000-01-01YY
Footnote:
During the pre-approval inspection the proposed commercial manufacturing
documentation (each batch size) is subject to inspection. These processing
instructions will be compared to the pivotal batch (MA) documentation and
examined
for
substantial
similarity
(comparability).
The
marketing
authorities require that the plant be ready for a PAI inspection when the
firm files the application.
4
[End of Document]
Edition No. :
01
Ed. Status : New
Effective Date :
Handbook of Pharmaceutical
APPROVED
______________ ________________ ______________ ______________
Department
RD
RA
QC / Q A
Chapter: 17.4
4
Generic Development
SEMISOLIDS
PROCESS VALIDATION
PROCESS VALIDATION
CHAPTER 17
M A S T E R PLAN.
FORMULATION
Drug Development Phase
INTRA-BATCH VARIABILITY
(Reproducibility of the
Three Validation Lots)
via:
Assay
Content Uniformity
Parameters within LCL-UCL Range
INTER-BATCH EQUIVALENCY
(Equivalency of the three Validation Lots
and the Topical Biostudy Batch)
Assay + U of C
Microbial Limit Test
Appearance + pH + Viscosity
O P T I M I Z A T I O N
SCALE-UP
PROCESS QUALIFICATION
The
Documentation
PIVOTAL BATCH
VALIDATION - PROTOCOL
CRITICAL STAGES
1. Controlled Mixing Time/Temp.
2. Phase Mixing Temperature
3. Homogenization
4. Filling Process
SAMPLING PLAN
VALIDATION
TESTING PLAN
VALIDATION REPORT
MARKETED PRODUCT
CONTROL LIMITS
Upper Control Limits
Lower Control Limits
PROCESS CAPABILITY
CP 1
Handbook of Pharmaceutical
MAJOR
CHANGE
Chapter: 17.5
5
RE-VALIDATION
of Commercial Product after;
[1] New Process Equipment Introduced
[2] Major Process Change.
Generic Development
SEMI-SOLIDS
PROCESS VALIDATION
PROCESS VALIDATION
CHAPTER 17
M A S T E R PLAN.
THE DOCUMENTATION
VALIDATION PROTOCOL
PURPOSE of STUDY
RESPONSIBILITIES of PERSONNEL
FREQUENCY
PROCESS - CRITICAL STEPS - DEFINED
CRITICAL PARAMETERS - SPECIFIED
SAMPLING PLAN
TESTING PLAN
SAMPLING PLAN - Topical Semisolids
ACCEPTANCE CRITERIA
BULK - Physical and Microbial Tests Only
HOMOGENISED BULK - Content Uniformity
FILLING Process - Fill Weights (3-4 Intervals)
TUBES - Monograph Testing.
STEP
ONE
TWO
TESTING PLAN
CREAMS
OINTMENTS
Description
Description
Bleeding/weeping/splitting/cracking
pH
Viscosity
Viscosity/Rheology
Assay
Assay
Content Uniformity
Content Uniformity
Microbial Limit Test (MLT)
(MLT - only if necessary)
THREE
VALIDATION REPORT
Handbook of Pharmaceutical
Chapter: 17.6
6
FOUR
Generic Development
SEMI-SOLIDS
Process Validation
PROCESS OPTIMIZATION
CHAPTER 17
VALIDATION M A S T E R PLAN.
Choice of
FORMULA
PROCESS
OPTIMIZATION
FORMULATION
Drug Development Phase
QUALIFICATION STUDIES
1. ANTIOXIDANT
2. PET QUALIFICATION
(VIA WRITTEN PROTOCOLS)
SCALE-UP
Choice of
PROCESS QUALIFICATION
PROCESS
The
Documentation
PROCESS OPTIMIZATION
PIVOTAL BATCH
VALIDATION - PROTOCOL
SAMPLING PLAN
VALIDATION
TESTING PLAN
VALIDATION REPORT
MARKETED PRODUCT
MAJOR
CHANGE
Handbook of Pharmaceutical
Chapter: 17.7
7
RE-VALIDATION
of Commercial Product after;
[1] New Process Equipment Introduced
[2] Major Process Change.
Generic Development
SEMI-SOLIDS
P R E - A P P R O V A L S
CHAPTER 18
Pre-Approval
Inspections
'Did you do what you wrote - can you do what you said'
Handbook of Pharmaceutical
Failures
Chapter: 18.1
1
Generic Development
SEMI-SOLIDS
P R E - A P P R O V A L S
Follow-up
Handbook of Pharmaceutical
Build an
CHAPTER 18
Effective
Interdisciplinary
Team for PAI
Success
Management responsible for the
operation needs to involve all
departments associated directly and
indirectly (technical services and
maintenance) with the generic or
innovative drug development - from the
pre-formulation scientists to the night
shift cleaning squads. The cardinal
need
to
build
an
effective
interdisciplinary team is a vital factor to
PAI success.
pharmaceutical
companies
conducting
drug
research
and
development must eventually face a
PAI review. The consequences of a
failed PAI may well impact on existing
products, especially if the deficiency is
a
major
GMP
concern.
Chapter: 18.2
2
Generic Development
SEMI-SOLIDS
P R E - A P P R O V A L S
A crash
Complete
integration of product
manufacturing,
Quality
Assurance,
Quality Control and technical Services
(engineering,
maintenance
&
metrology) is essential, to assure that a
facility is consistently capable of
commercial
manufacture
of
the
proposed product batches. Process
validation should be performed after
the PAI (in the EU) and before the PAI
in non-EU manufacturing plant to
prevent any extra delays
What do agencies
expect during a
PAI?
During the PAI, the agencies expect to
find that the firm complies fully with
cGMPs. No firm will pass a Preapproval Inspection if GMP is sorely
deficient or documentation is absent.
Confirmation that the firm has used
appropriate scientific data to justify
Handbook of Pharmaceutical
CHAPTER 18
All
process
change
Chapter: 18.3
3
Generic Development
SEMI-SOLIDS
P R E - A P P R O V A L S
Audit
Using Technology
Transfer (TTD) for
Process Improvements
and PAI success
Manufacturing equipment and scale-up
procedures require dove-tailing with
both facilities. Analytical and microbial
laboratory test methods are needed to
be rugged and operational in both
facilities. Great care needs to be taken
to insure and demonstrate the
ruggedness of these laboratory tests.
Testing procedure methods should be
chosen in close cooperation with the
production laboratory facilities to insure
a smooth transfer of technical
documentation
Handbook of Pharmaceutical
CHAPTER 18
Effective Development
& Production
Documentation
speeds up the PAI
immensely
Thorough
Chapter: 18.4
4
Generic Development
SEMI-SOLIDS
P R E - A P P R O V A L S
CHAPTER 18
The
Stock
Finished Product
Inventory Cards
(PICs)
are essential for
complete product trails.
In
Handbook of Pharmaceutical
The
Self Inspection
Audits
are an Essential
Pre-approval
Requirement
AUDITING YOUR FIRM
BEFORE THE PAI.
Development
and
production
documentation for the newly developed
dosage form should describe the
purpose and the principles generally
needed to meet the scientific,
regulatory and GMP objectives of a well
run development and production unit.
During the PAI inspection the product is
tracked from pre-formulation to Pivotal
batch.
Chapter: 18.5
5
Generic Development
SEMI-SOLIDS
P R E - A P P R O V A L S
The
Identify deficiencies
well before
the actual investigation
Carefully conducted departmental inhouse pre-PAI audits may save
research based firms and generic
developers significant review time and
thousands
of
much
needed
development funds.
The pre-PAI audit team should start
reviewing
the
generic
drug
development
departments,
namely
pharmaceutical,
analytical,
microbiological and stability units and
end with the manufacturing, packaging /
disposition of the pivotal lot.
Handbook of Pharmaceutical
CHAPTER 18
labeled strength.
Do You Have
Cleaning Validation
firmly in place ?
Remote Development
Generic
Development
of
pharmaceutical drugs may take place in
a non-EU development laboratory
facility i.e. an oversees facility. Where
product development occurs in a
remote development unit (i.e. not
attached to the proposed manufacturing
site - special SOPs dovetailing the
procedures at the remote and
manufacturing site are necessary for
such a situation.
Preparing Foreign
drug firm sites for
Pre-approval
Inspection
Emphasis
Chapter: 18.6
6
Generic Development
SEMI-SOLIDS
P R E - A P P R O V A L S
Where
Conduct an Intensive
mock In-house
Inspection
Challenge
and
dissect
the
manufacturing and controls necessary
to support approval of a new or
reformulated drug whether it be a new
active or a generic.
Asking awkward questions, before the
inspector does, may save months of
work and your companies reputation such as;
Formula development
CHAPTER 18
Method development
The
Master Specifications
active
Raw Materials
In-process
Finished Process
Cleaning
Check /Stability
Handbook of Pharmaceutical
Chapter: 18.7
7
Generic Development
SEMI-SOLIDS
P R E - A P P R O V A L S
CHAPTER 18
PAI SUMMARY:
Pharmaceutical Development
Notebooks containing All the
experimental data
Handbook of Pharmaceutical
Chapter: 18.8
8
Generic Development
SEMISOLIDS
P R E - A P P R O V A L S
CHAPTER 18
C H E C K L I S T
CL # HPGD-03-01YY
qYes. qNo.
2. The PAI Team has outlined its charter and team responsibilities ?
qYes. qNo.
3. The Quality Assurance Head has approved and signed the charter ?
qYes. qNo.
4. The PAI team has issued a SOP detailing regulatory procedures and qYes. qNo.
protocols to be followed during inspection procedures ?
5. The PAI team leader is the Head of Quality Assurance or his designate?
qYes. qNo.
qYes. qNo.
7. A suitably equipped room has been dedicated for use during the PAI?
qYes. qNo.
8. A working list of documents, MA dossiers, Pharmacopoeia, raw data lab qYes. qNo.
books etc. is available on-site in the PAI audit room, during the course
of the inspection ?
9. The PAI team has reviewed all product-specific files and appropriate qYes. qNo.
documentation for accuracy, clarity, and consistency - noting logical
dates, and signatures ?
10.The PAI team has focused on the pivotal batch dossier and the qYes. qNo.
proposed commercial manufacturing documentation
evaluations of actual filed manufacturing facilities?
with
on-site
11.The PAI team has, examined the product development report, together qYes. qNo.
with the project leader, and evaluated the explanations and scientific
rationale for changes that occurred during the process development right
up to the pivotal lot manufacture?
12.The PAI team has evaluated the product(s) cleaning validation, residual qYes. qNo.
limits, acceptance criteria and actual cleaning validation results?
13.The PAI team has evaluated the product(s) process validation protocol?
qYes. qNo.
14.The PAI team is geared to provide assistance in the preparation of qYes. qNo.
written responses to the investigators concerning adverse finding - during
the actual PAI review?
15.The PAI team has established and coached a core of key personnel able qYes. qNo.
to properly respond to questions asked by investigators during the PAI
review?
333
Handbook of Pharmaceutical
Sect: 18.
18 9
Generic Development
SEMISOLIDS
P R E - A P P R O V A L S
CHAPTER 18
C H E C K L I S T
CL # HPGD-03-01YY
Handbook of Pharmaceutical
Sect: 18.
18 10
Generic Development
SEMISOLIDS
P R E - A P P R O V A L S
CHAPTER 18
C H E C K L I S T
CL # HPGD-03-01YY
PIVOTAL BATCH
1. Review list of manufacturing and packaging equipment used in qYes. qNo.
pivotal lot.
2. Examine machine cards and cleaning verification cards or tags.
qYes. qNo.
qYes. qNo.
4. Examine all pivotal manufacturing, packaging and labeling records qYes. qNo.
(review date order, signatures present manufacturing deviations,
yield accountability vs. SOPs, sampling plan / retention samples) ?
5. Review the plan/protocol for sampling and testing the pivotal lot.
qYes. qNo.
qYes. qNo.
Handbook of Pharmaceutical
Sect: 18.
18 11
Generic Development
SEMISOLIDS
P R E - A P P R O V A L S
CHAPTER 18
C H E C K L I S T
Pre-approval Inspection Teams Audit Activities
Pre-approval inspection preparation is a team work affair
All departments must pull their weight equally
its not a QC or RA one man show '
SCALE-UP TO COMMERCIAL
qYes qNo
15. Review scale-up documentation and ensure all changes are within SUPAC rules ?
16. Review ANDA formula and manufacturing variations are within SUPAC limits?
17. Review side-by-side comparison of pivotal vs. commercial process, facilities and equip.?
18. Review SOPs relating to issue and review of batch records, receipt, handling and processing
of raw materials, packaging components and labeling, cleaning procedures, maintenance,
HVAC, calibration and equipment use, change control and manufacture.
19. Review site (manufacturing and labs) personnel training procedures and training records
qYes
qYes
qYes
qYes
qNo
qNo
qNo
qNo
PROCESS VALIDATION
qYes qNo
qYes qNo
20. Validation protocol for first three consecutive commercial lots on-site ?
21. Review the side-by-side comparison between pivotal and validation equipment /facilities ?
22. Review the protocol for sampling and testing the validation lots (part of validation protocol)
qYes qNo
qYes qNo
qYes qNo
ANALYTICAL
qYes
qYes
qYes
qYes
23. Perform a thorough check on the lab notebook referencing all pivotal tests ?
24. Review method validation for in-house assays, impurities and dissolution test?
25. Review stability-indicating assay and the impact of any placebo effect ?
26. Review all out-of-specification results (log) on analytical or product failures?
qNo
qNo
qNo
qNo
STABILITY
27. Does pivotal batch remains in check specifications after 3 months accelerated (40oC) testing
?
qYes qNo
28. Have samples been placed on stability within 30 days of manufacturing release CoA ?
qYes qNo
qYes qNo
30. Statement on proposed expiration period in accordance with obtained test results ?
qYes qNo
31. Review all stability data, in-out dates, exposure times, temperatures and humidity (RH)
including control of environmental parameters (recording devices, graphs and any OOS
conditions) ?
qYes qNo
32. Review Stability SOPs and equipment; Are chambers, probes and monitors calibrated ?
qYes qNo
MICROBIOLOGICAL
33. Microbial parameters in compendial excipients are retested every 12 months ?
qYes qNo
qYes qNo
35. Appropriate use of validated in-house methods with proper method controls ?
qYes qNo
36. Review of microbial testing facilities, test methods, calibration and laboratory SOPs?
qYes qNo
CONTRACT FACILITIES
qYes qNo
qYes qNo
38. Review of analytical testing facilities methods, validation and laboratory SOPs ?
qYes qNo
39. All facilities listed in file submission are fully capable of performing designated tasks ?
qYes qNo
40. Review of packaging and labeling procedures, in-process controls and SOPs ?
qYes qNo
333
Handbook of Pharmaceutical
Sect: 18.
18 12
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
The
l Temperature
l Humidity
l Light.
Stability
testing
permits
the
establishment of recommended storage
conditions, retest periods, and shelf
lives. [ICH Q1A]
This guidance provides recommendations regarding the design, conduct
and use of stability studies that should
be performed to support all the following
categories:-
Investigational
New
Drug
Applications (INDs) (21CFR 312.23(a)(7))
Where
Handbook of Pharmaceutical
Chapter: 19.1
1
Generic Development
DRUG DEVELOPMENT
The
Continuing
Handbook of Pharmaceutical
CHAPTER 19
The
Chapter: 19.2
2
Generic Development
DRUG DEVELOPMENT
Handbook of Pharmaceutical
CHAPTER 19
Simple
Dosage
Forms
the
package is
Chapter: 19.3
3
Generic Development
DRUG DEVELOPMENT
be considered
general ANDA
such as
modified-release products, transdermal
patches, metered-dose inhalers.
Drug products without a significant
body of information.
New dosage forms submitted through
the ANDA suitability petition process
(Q1C applications).
Other exceptions may exist and
should be discussed with the Office of
Generic Drugs.
An ANDA in one of the above categories
should contain a modified ICH Q1A
stability data package, including:
3-month accelerated stability studies.
Long-term stability studies (available
data at the time of original filing and
subsequent amendments).
The expiration dating period for complex
dosage forms will be determined based
on available long-term stability data
submitted in the application.
Handbook of Pharmaceutical
CHAPTER 19
Chapter: 19.4
4
DRUG DEVELOPMENT
If
In Modified Release
Solid Dosage Forms
the PQ batch can be
the third stability batch
Data
CHAPTER 19
ANDA STABILITY
COMMITMENT on THREE
commercial lots until long
term testing is complete
ANDAs withdrawn prior to publication of
this guidance should not normally have
to include stability data in conformance
with the guidance upon resubmission if
the original application was withdrawn
due to non-stability related issues.
However, if new stability studies are
conducted to support the submission,
such studies should be conducted as
recommended in the guidance.
SIMPLE ANDAs
One batch of 100 000 (net) for 1, 2, &
3 months at 40oC 2oC / 75% RH 5%.
Extension
Handbook of Pharmaceutical
COMPLEX ANDAs
TWO batches of 100 000 net for 1, 2,
& 3 months at 40oC 2oC / 75% RH
5% PLUS Small scale (e.g. PQ) lot.
Chapter: 19.5
5
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
TABLE OF CONTENTS
The following example highlights the Overall ANDA Guideline Requirements for the
Stability Section of an application. Only two out of the required EIGHT stability
tabulations (stability profiles) are shown. A separate profile is required for each
strength, pack size and challenge temperature and humidity. The stability section is
divided into seven essential parts, as follows:
17.1
17.2
17.3
Stability Protocol for Post Approval Production Batches (This is the ANDA
stability commitment on what will be done after agency approval of the file)
17.4
Individual Stability Reports (stability profiles) indicating results obtained from
the Pivotal lot after [3] months accelerated and [X] months controlled room temperature
/ humidity studies.
17.5
Package Configuration and sizes (largest and smallest) used in stability
studies.
17.6
Stability Protocol used for Pivotal Batch lot consisting of one PIVOTAL Lot
for the marketed strength.
17.7
Stability Data Summary Report (plus graphical presentations, graphs of assay
values vs. time ).
Handbook of Pharmaceutical
Chapter: 19.6
6
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
Overview
Stability testing is performed on each strength of three batches in the largest and
smallest container-closure systems proposed for marketing; i.e. in each material type,
(HDPE / HDPP) containers, collapsible tubes or glass jars.
When more than one closure for the same container material type (e.g. HDPE
container) is used in the proposed marketing containers, the largest and smallest
container-closure configuration is tested, - for both accelerated and long term studies.
In cases where plastic bottles of the same size range and shape are manufactured
from different thermoplastic resins, they exhibition different storage characteristics and
thus are considered as completely separate container-closure systems.
The number of stability tests conducted can be quite large in such cases. The example
below for the following packaging configuration highlights the number of stability tests
needed. Tests can be significantly reduced using a matrix stability protocol.
1.
HDPP (smallest) container with plastic HDPE cap / nozzle
2.
HDPP (largest) container with plastic HDPE cap / nozzle
When testing ONE strengths with 4 container-closure configuration1 at accelerated and
long term testing (2), the stability Program will produce 8 separate stability protocols
as calculated below.
CALCULATING THE NUMBER OF STUDIES REQUIRED:
Calculation is for 1 pivotal batch lot per strength (1 strengths manufactured.)
i.e. (2 container / sizes x [1 lots] x 2 closures x 1 strength x [25C + 40C] = 8 studies).
1
Handbook of Pharmaceutical
Chapter: 19.7
7
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
ll stability data support the proposed expiration period of 2 years when the product
is stored at room temperatures.
Stability commitment
Long term commercial stability studied in accordance with the approved stability
protocol shall be carried out by [Generic Company Name Inc. / Ltd.] The stability
results of these studies shall be submitted in the annual ANDA Reports filed on the
anniversary date of the submitted product.
[Generic Company Name Inc. / Ltd.] commits to remove any batch promptly from the
market place any material falling outside the products check specifications.
Extensions to the expiration date will be made via the annual ANDA Reports as
acceptable long term stability data is obtained,
Rework procedures may be submitted for batches that fail to meet established specifications. Prior
to implementation, these procedures will be submitted in a supplement in accord with: 21 CFR
314.70 (b)(2)(x) on a lot by lot basis.
-----------------------------------------
Date
Handbook of Pharmaceutical
Chapter: 19.8
8
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
TEST METHOD
& ED. NUMBER
SI-5-000-01
SPECIFICATION
- Each Individual
- Any other Individual
- Total:
Microbial Limit Test
SI-5-000-01
SI-5-000-01
SI-5-000-01
SI-5-000-01
Preservative Efficacy
SI-5-000-01
Report Format:
Results will be tabulated in the format of the Stability Report Form:
1) Product Name, and Strength
2) Batch Number and Batch size
3) Storage Conditions and Intervals
4) Container/Closure Systems - Description
5) Inventory Control Number of (4)
6) Fill Size and No of units on stability
7) Batch Manufacturing Date
8) Batch Packaging Date
Handbook of Pharmaceutical
9)
10)
11)
12)
13)
14)
15)
16)
Chapter: 19.9
9
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
The data indicate that the formulation is stable, with no observed degradation peaks,
under test conditions. There were no significant changes in either the physical
chemical, or microbiological specifications in any samples evaluated after the exposed
storage test conditions.
The attached tables and graphs are summaries of the results for the parameters used
to establish the stability profile of [Generic name] SEMISOLID [USP] [000.0] mg/5g for
the pivotal batch per dosage strength, where applicable.
Included, are assay chromatogram spectra of the stability tests for zero time (T0) and
the three (3) months accelerated test conditions.
[Generic name] SEMISOLID [USP] [000.0] mg/5g were stored at accelerated
conditions (40o 2 o C / 75% RH 5%) and at room temperature (25 2C/ 60% RH
5%) in the proposed market container/closure system. All stability data supports the
proposed expiration period of 2 years when the product is stored at room
temperatures.
Handbook of Pharmaceutical
Chapter: 19.10
10
Generic Development
CHAPTER 19
DRUG DEVELOPMENT
25C 60%RH
40C 75%RH
Smallest
Largest
Smallest
Largest
000 mL
000 mL
Bulk Packaging
[1]
[0]
Number of resins used in the HDPE containers = one resin from same supplier.
1
Typical Assembly : HDPE / ALUMINUM container with HDPE SCREW CAP and inner LINER.
Typical Assembly : HDPE TUBE / PLASTIC SCREW CAP and inner LINER
Handbook of Pharmaceutical
Chapter: 19.11
11
Generic Development
CHAPTER 19
DRUG DEVELOPMENT
11
12
13
14
15
16
17
18
19
40 degrees C / 75% RH
Period
Date of
Analysis
Appearance
and ID
ASSAY
%
HPLC/TLC
Impurity
Profile
90.0 % 110.0%
Impurities
I
Impurities
II
Impurities
III
Total
< 3.0
White to
Creamish
Month
Method #
S-I-000 -01
S-I-000 -02
SEMISOLIDS
n Description
n Appearance / Color / Odor
n Absence of GRITTINESS/WEEPING/SEPARATION
n Appearance of inner tube surface
MLT
PET
Viscosity
pH
Assay:
1/6/Y
conforms
100.3
conforms
Pass /Fail
Pass /Fail
00.0
00.0
00.0
5/9/Y
conforms
99.8
conforms
SKIP
SKIP
00.0
00.0
00.0
9/12/Y
conforms
101.3
conforms
Pass /Fail
Pass /Fail
00.0
00.0
00.0
15/3/Y
conforms
101.4
conforms
SKIP
SKIP
00.0
00.0
00.0
STABILITY
PARAMETERS
Handbook of Pharmaceutical
Chapter: 19.12
12
Generic Development
CHAPTER 19
DRUG DEVELOPMENT
11
12
13
14
15
16
17
18
19
25 degrees C / 60% RH
Period
Month
Date of
Analysis
Lab book
Ref. No
Method #
1/6/Y
Appearance
and ID
ASSAY
%
White to
Creamish
90.0 % 110.0%
S-I-000 -01
S-I-000 -02
HPLC/TLC
Impurity
Profile
Impurities
I
Impurities
II
Impurities
III
Total
< 3.0
S-I 000 -03
5/9/Y
SEMISOLIDS
n Description
n Appearance / Color / Odor
n Absence of GRITTINESS/WEEPING/SEPARATION
n Appearance of inner tube surface
conforms
101.3
conforms
MLT
Pass or
Fail
PET
Pass or
Fail
Viscosity
00.0
pH
0.0
Assay:
000.0
conforms
99.6
conforms
SKIP
SKIP
00.0
0.0
000.0
conforms
102.6
conforms
SKIP
SKIP
00.0
0.0
000.0
conforms
100.0
conforms
SKIP
SKIP
00.0
0.0
000.0
conforms
102.1
conforms
Pass or
Fail
Pass or
Fail
00.0
0.0
000.0
L/Book
N0: Page
L/Book
N0: Page
9/12/Y
L/Book
N0: Page
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15/6/Y
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STABILITY
PARAMETERS
Handbook of Pharmaceutical
Chapter: 19.13
13
Generic Development
CHAPTER 19
DRUG DEVELOPMENT
PACKAGE CHARACTERISTICS
[Generic name] SEMISOLID [000.0] mg/5g [Batch No: 000]
[Generic name] SEMISOLID [USP] [000.0] mg per g.
TYPE 1
TYPE 2
TYPE 3
TYPE 4
Container
manufacturer
Container size
00 / 000cc round,
HDPE JAR
00 / 000cc round,
HDPE JAR
00 / 000cc HDPE/
00 / 000cc HDPE/
COLLAPSIBLE TUBE
COLLAPSIBLE TUBE
(coated metal)
(coated metal)
Resin Type
Cap
Manufacturer
11087 PE
White Master
batch
Cap / Nozzle
Type
Cap Size
Closure Liner
Foam seal Mfg
Inner liner
composition
CONTAINER
CONTAINER
CAP
Nozzle / Applicator
LINER
SEAL
HDPE
Quantum LR-734043
U.S. CAN
(Penn-Wheeling
Closure Corp.)
White Ampacet
11078 Polyethylene
HDPE
Quantum LR-734043
U.S. CAN
(Penn-Wheeling
Closure Corp.)
White Ampacet
11078 Polyethylene
HDPE
Quantum LR-734043
U.S. CAN
(Penn-Wheeling
Closure Corp.)
White Ampacet
11078 Polyethylene
HDPE
Quantum LR-734043
U.S. CAN
(Penn-Wheeling
Closure Corp.)
White Ampacet
11078 Polyethylene
HDPE
LDPE
HDPE
LDPE
HDPE
LDPE
HDPE
LDPE
00 / 00 mm
00 / 00 mm
00 / 00 mm
00 / 00 mm
Tekni-Plex Inc.
Foamseal PS 22
Tekni-Plex Inc.
Foamseal PS 22
TEKNISEAL RVT
+ LF
TEKNISEAL X-14
(polyethylene/Kraft
Paper laminate)
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
-
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
-
CoA #00000
CoA #00000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
CoA #0000
Lot #00000
Chapter: 19.14
14
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
For
Handbook of Pharmaceutical
Chapter: 19.15
15
Pilot-scale
or Pilot Plant Scale
means100 000 units
or 10% of full size
production batch
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
The
For
All
Section
Handbook of Pharmaceutical
DRUG PRODUCTS
The
Chapter: 19.16
16
Generic Development
DRUG DEVELOPMENT
Handbook of Pharmaceutical
CHAPTER 19
Full-term
The
If
Other
meet
Chapter: 19.17
17
Generic Development
DRUG DEVELOPMENT
Where
Handbook of Pharmaceutical
CHAPTER 19
Additional
SPECIFICATIONS
AND
TEST
METHODOLOGY INFORMATION
Physical,
chemical,
and
microbiological regulatory specifications
and attributes/limits (or specific references
to ANDA or USP).
Chapter: 19.18
18
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
A Sampling Protocol
identifying sampling
points is necessary
STABILITY DATA/INFORMATION
Batch number (research, pilot,
production)
and
associated
manufacturing date.
For antibiotic drug products, the age
of the bulk active drug substance(s)
used in manufacturing the batch.
Analytical data, source of each data
point, and date of analysis (e.g., batch,
container composite, etc.) Pooled
estimates may be submitted if individual
data
points
are
provided.
Handbook of Pharmaceutical
DATA ANALYSIS
The following data analysis of
quantitative parameters should be
provided:
Evaluation of data, plots, graphics.
Documentation
of
appropriate
statistical methods and formulas used.
Results of statistical analysis and
estimated expiration dating period.
Results of statistical tests used in
arriving at microbiological potency
estimates.
CONCLUSIONS
Proposed expiration dating period
and its justification.
Regulatory specifications set.
(Note: Establishment of acceptable minimum
potency at the time of initial release for full
expiration dating period to be fully justified).
Chapter: 19.19
19
Generic Development
DRUG DEVELOPMENT
ANDA
CHAPTER 19
STABILITY
DRUG PRODUCT
SIMPLE DOSAGE FORMS
IR
Formulation for Simple Dosage Forms
Immediate Release Solids & Liquids
FLOWCHART
COMPLEX DOSAGE FORMS
CR/MR/ER/DR/MDIs
Formulation for Complex Dosage Forms
Modified Release Solids & MDIs
Sampling Protocol
(Liquids & Suspensions)
Sampling Points
Sampling Protocol
&
Sampling Points
Stability Protocol
Bracketing &
Matrixing Permitted
Stability Protocol
Bracketing &
Matrixing Permitted
ACCELERATED CONDITIONS
1, 2, & 3 months @ 40 oC 75% RH
plus Real Time @ 25 oC
ACCELERATED CONDITIONS
1, 2, & 3 months @ 40 oC 75% RH
A Problematic Rule
Handbook of Pharmaceutical
5% potency
Rule
Chapter: 19.20
20
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
Comprehensive
US Draft Guidance
partly harmonizes
US, EU & Japan
Stability Requirements
The New Draft Guidance to industry is
extremely comprehensive and detailed.
It is intended to replace the aging,
twelve year old, 1987 guidelines,
thereby
in
one
step
partially
harmonising the requirements for US,
EU and Japan while not deviating too
much
from
the
current
ANDA
requirements.
The
EU
stability
requirements are adequately met with
additional
existing
US
ANDA
requirements. The 110 page document
contain detailed recommendations on
all current aspects of stability testing,
Handbook of Pharmaceutical
Significant Change
clause simple means:
START a 30oC / 60%RH
one year study
from DAY ONE of the
Stability Program
Just-in-Case it's Needed
Chapter: 19.21
21
Generic Development
DRUG DEVELOPMENT
Where
Any
Alternatively,
Where
Significant Change
may occur during the
30oC / 60%RH
Failure
Handbook of Pharmaceutical
Should
CHAPTER 19
intermediate study
- as well
In
Qualifying
higher
criteria for a degradant
acceptance
Chapter: 19.22
22
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
ADDITIONAL DATA
The
250C
Test for 0, 1, 2, 3
months
[4] Dissolution
exceeding
the
specification limits for 12 dosage units
[5] Failure to meet specifications for
appearance and physical properties, for
example.
Tablets:Color, hardness
Suspensions:- Color, phase separation
Re-suspendibility, and
caking
Semisolids:- Color, phase separation
Liquids:Color,
Aerosols:Delivery per actuation
phase separation.
Handbook of Pharmaceutical
[ICH-Q1A]
Chapter: 19.23
23
400C
300C
Full Monograph
testing required
Continue
until
either
400C
or
any
300C
study
FAILS
then
STOP
all Test
FAIL
PASS
0, 2, 4, 6, 12 months
sampling periods
If
significant
change
occurs
again
Re-formulate
Re-qualify
Re-view
alternative
approaches
All
400C
tests
pass for
Three
months
Product
OK
Generic Development
CHAPTER 19
DRUG DEVELOPMENT
When Applicable
1
Initial To
Assay decreases
> 5% during
1, 2, or 3 months
of 30/40o C Study
Initial assay must be
'close to 100% rule'
Specification
Limit of any
drug product
degradant is
exceeded during
o
30/40 C Study
4 +5
Drug Product
exceeds it pH
limits during
o
the 30 or 40 C
Study
SIGNIFICANT CHANGE
Dissolution
exceeds 12
dosage unit
specification
or
Appearance
or
Physical
properties
IMPACT ON TESTING
Three Study Temperatures in stability protocol
Evaluate stability profile in PQ batch to access and eliminate significant change
Qualify and document check specifications precisely accounting for relevant
aging (e.g. white to gray-white, or cream/light yellow/light gray colored etc.)
Critical Parameter Qualification Protocol for PQ or Pivotal Batch Lot
pH range Qualification Protocol for liquids, suspensions and semisolids
Rugged Assays with low RSD values for intermediate precision (day-to-day)
SOP to define 5% change as meaning net value change (i.e. 5% RSD1)
More detailed Investigation procedures to evaluate, if >5% change is not due to
an analytical procedure or technician error.
RSD1 values for actual full assay method's intermediate precision calculated on
different days, with different lab technicians and equipment, under routine
conditions.
IMPACT ON DRUG DEVELOPMENT
Longer times required for overall stability study evaluation - more costly studies.
Handbook of Pharmaceutical
Chapter: 19.24
24
Generic Development
DRUG DEVELOPMENT
SOP # S-435-01-089Y
CHAPTER 19
STANDARD OPERATING
PROCEDURES
Total Pages 4.
RESPONSIBILITY
After
FREQUENCY
Applies to laboratory analysis where a questionable stability result or a significant
change in a previous test result has been obtained.
Adjusted Significant Change that includes analytical variance value. Relative Standard Deviation
(RSD) values for test assay method's intermediate precision. Calculated from assays performed on
different days, with different lab technicians and equipment, under routine testing conditions.
ED. N0: 01
Replaces NEW
Ed. Status :
Effective Date :
APPROVED:
DD/MM/YY
01
Handbook of Pharmaceutical
Department
R&D
Chapter: 19.25
25
RA
QC / QA
Generic Development
DRUG DEVELOPMENT
SOP # S-435-01-089Y
CHAPTER 19
STANDARD OPERATING
PROCEDURES
Total Pages 4.
If the sample passes the retest, then the result may be released and accepted.
In cases of retest failure, proceed as per paragraph [9].
[6]. Where the cause is due to faulty analytical methodology, a new edition
methodology revision shall be prepared.
[7]. Where the laboratory investigation is INCONCLUSIVE, and the cause cannot
definitely be ascribed to laboratory error, proceed as follows:
[8]. If the relevant pharmacopoeia specifies acceptance criteria guidelines for the
particular type of test involved (Viscosity, microbial limits etc.), the analyst shall
proceed with the testing according to the official method. If the retest passes, it is
reported according to the pharmacopoeial requirements. If the compendial retest
fails, the Quality Assurance Unit inform for further investigation, where appropriate.
[9]. Where, the relevant pharmacopoeia does not specify retesting procedures for
the particular type of test involved, TWO re-tests will be performed by TWO analysts
(that is, the sample shall be tested in duplicate).
The final result is calculate as the average of the THREE analysis (e.g. 6 results
which include the results from two re-tests and the original test result). No individual
analysis of the retest results shall fail the specifications.
ED. N0: 01
Replaces NEW
Ed. Status :
Effective Date :
APPROVED:
DD/MM/YY
01
Handbook of Pharmaceutical
Department
R&D
Chapter: 19.26
26
RA
QC / QA
Generic Development
SOP # S-435-01-089Y
CHAPTER 19
DRUG DEVELOPMENT
STANDARD OPERATING
PROCEDURES
Total Pages 4.
[10]. In cases that the results are within the specified limits, the results are accepted.
[11]. If the retest result still remains questionable, the supervisor will inform the
Quality Assurance Unit for further investigation, if so required.
[12]. The Quality Assurance Unit shall fully review the data and decide if the test
results should be reported as is, or additional action is required.
CORRECTIVE ACTION
Retesting is performed on the same sample container originally used, (obtaining
new samples, new sample stock or performing new sampling procedures from bulk
material or stability stock is prohibited.)
DOCUMENTATION
Laboratory investigations shall be fully documented, and the conclusions signed and
dated by the Laboratory Manager.
In case where the investigation is passed on to the Quality Assurance Unit Manager,
an Investigation Report shall be prepared.
All analytical re-testing of stability tests is to be reported and documented in the
Significant Change Log. The Log book is held under the responsibility of the
Analytical Laboratory Manager and the Stability Unit Manager.
A Checklist For Laboratory Investigation Reports is filed in all cases of
questionable or significant change results following a laboratory investigation.
The Investigation Report Number is recorded in the Significant Change Log.
ED. N0: 01
Replaces NEW
Ed. Status :
Effective Date :
APPROVED:
DD/MM/YY
01
Handbook of Pharmaceutical
Department
R&D
Chapter: 19.27
27
RA
QC / QA
Generic Development
CHAPTER 19
DRUG DEVELOPMENT
STANDARD OPERATING
PROCEDURES
SOP # S-435-01-089Y
Total Pages 4.
LABORATORY INVESTIGATION
FINDINGS in LOGBOOK
NON CONCLUSIVE
RESULTS
LABORATORY ERROR
Invalidate original results
and RETEST on the SAME
sample in duplicate.
Specific Pharmacopoeial
Retest Procedures allowed
Retesting
Not Specified
PASS
Retest TWICE (duplicates) on
Same Sample - TWO analysts
FAIL
PASS
FAIL
PASS
FAIL
LOG
RESULT
LOG
RESULT
QA INVESTIGATION
ED. N0: 01
Replaces NEW
Ed. Status :
Effective Date :
APPROVED:
DD/MM/YY
01
Handbook of Pharmaceutical
Department
R&D
Chapter: 19.28
28
RA
QC / QA
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
TEMPERATURE/HUMIDITY
STABILITY GUIDELINES
LONG TERM, INTERMEDIATE &
CONTAINER-CLOSURE SYSTEMS
Solutions
Handbook of Pharmaceutical
ACCELERATED CONDITIONS
The
Development Stability
Studies Include
versus inverted/on-the-side
stability studies should be performed
during the pre-approval and postapproval verification stages of the
stability program.
Once it has been demonstrated that the
product in maximum contact with the
primary pack does not have a
significantly greater impact on drug
product quality than the upright
orientation, stability studies may be
continued only in the most stressful
orientation, which is generally the
inverted or on-the-side position.
Chapter: 19.29
29
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
Container-Closure
CONDITIONS
TIME at File
Storage Orientation
25oC 2oC
o
25 C 2 C
25oC 2oC
25oC 2oC
Optional
60% RH 5%
12+
3+
[60%RH 5%]
[60%RH 5%]
12
12+
12+
NDA
3+
3+
3+
ANDA
6
6
6
NDA
3
3
3
3
ANDA
6+
6+
6+
6+
6+
6+
6+
6+
6+
6+
6+
6+
40% RH 5%
Optional
Accelerated Stability
Solid Dosage Forms
Glass Containers (solid oral)
Glass Containers (liquids)
Semi Permeable Containers
40oC 2oC
40oC 2oC
40oC 2oC
40oC 2oC
75% RH 5%
[75%RH 5%]
[75%RH 5%]
15% RH 5%
Optional
Intermediate Stability
Solid Dosage Forms
Glass Containers (solid oral)
Glass Containers (liquids)
Semi Permeable (SP)
Ophthalmics + Otics (SP)
Nasal Sprays (SP)
30oC 2oC
30oC 2oC
30oC 2oC
30oC 2oC
30oC 2oC
30oC 2oC
Submission
NDA
ANDA
60% RH 5%
[60%RH 5%]
[60%RH 5%]
40% RH 5%
40% RH 5%
40% RH 5%
Stability
DOSAGE FORM
Container-Closure
Long Term Stability - Refrigerator
5oC 5oC
TIME
At Submission
No Control
60% RH 5%
No Control
Handbook of Pharmaceutical
Chapter: 19.30
30
Ambient RH
NDA
ANDA
12+
NDA
3+
ANDA
6
NDA
3
ANDA
12+
NDA
3+
ANDA
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
Setting-up
a Functional
Stability Unit
Handbook of Pharmaceutical
Chapter: 19.31
31
Generic Development
DRUG DEVELOPMENT
Stability Facilities
Adequate stability facilities
are
required. The number of stability tests
increase every year. Thus facilities are
required to be sufficiently large in order
to accommodate the annual growth.
Firms need to invest adequately in the
stability department facilities and
equipment.
The stability data on development,
regulatory, or production lots constitute
critical review data during ANDA file
review and Pre-approval Inspections
(PAIs.)
The minimum stability facilities required
are:
controlled
temperature
77
The Minimum
Set-up
Requirements
The Computer system
A stability computer (Pentium) with a
validated stability software program.
A computer back-up system (e.g.
Handbook of Pharmaceutical
CHAPTER 19
for Managing
Stability
Departments.
Formal SOP monitoring
Do - insure that Stability SOPs
are
or bi-
Chapter: 19.32
32
Generic Development
DRUG DEVELOPMENT
Do
ALWAYS KEEP
DEPT. SOPs
ON SITE
(Electronically
If possible)
Do -
Do
CHAPTER 19
room to be
used as a stability office, where
personnel are continually entering and
leaving the controlled facility.
Dont - allow an air-conditioned 22o 25oC stability office to function as a
25oC climatic room.
Dont - store the 25oC long term
stability samples in an office.
(In terms of GMP compliance such a
facility
is
inadequate
and
the
environment cannot be controlled).
Dont - install unreadable chart
temperature recorders due to the
smallness of the rotating chart.
(Out-of-specifications temperatures are
not adequately shown on these charts,
as the range divisions on the chart are
cramped and often too small. Narrow
chart sensitivity scales are generally
unsuitable and unreadable. The
compliance value of such a temperature
recording system is of minimal value
and open to agency challenge).
Do - insist that current recording
devices are fitted with larger chart
recorder so that the daily temperatures
and OOS values can be read with
accuracy and precision.
Do - insure there is a system for 60%
RH control (environmental humidity).
Do - insure the stability room has
sufficient temperature probes at the
upper and lower levels of the room
where the stability samples are being
stored.
Do - construct a dedicated stability
room with controlled environmental
facilities that maintain the temperature
at 25o C ( 2o C) and the relative
humidity at 60% RH ( 5%).
Do - install the 30o and 40o C climatic
chamber units inside the controlled
stability areas or rooms.
Dont - allow stability samples for
ANDA/NDA and OTC (development, or
Chapter: 19.33
33
Generic Development
DRUG DEVELOPMENT
Handbook of Pharmaceutical
CHAPTER 19
Review Recording
Charts for OOS
Values - Daily
Do
Have emergency
procedures in place
Do
Chapter: 19.34
34
Generic Development
DRUG DEVELOPMENT
Do
Handbook of Pharmaceutical
CHAPTER 19
Do
Investigate OOS
Results
- Daily
Do
Chapter: 19.35
35
Generic Development
DRUG DEVELOPMENT
Do
Handbook of Pharmaceutical
CHAPTER 19
the
Chapter: 19.36
36
Generic Development
DRUG DEVELOPMENT
Do
PAI
OBSERVATIONS
on
Stability
Traceability
of retested stability
samples difficult and inconsistent.
Corrected
Use
Annual
Insure
all
C of A's
are
in-date
SOPs
Avoid
any
White-0uts
Stability
Do
Do -
CHAPTER 19
Handbook of Pharmaceutical
Chapter: 19.37
37
Generic Development
DRUG DEVELOPMENT
No
Stability
storage
recording
temperature procedures not in cGMP
compliance.
Stability
CHAPTER 19
Single-probe
recorders are
suitable for temperature control.
not
No
Inadequate
temperature validation
studies performed in stability room.
Uneven
No
Upper
room
been
Overall
Absent
Sample
No
Original
LIMS
(Laboratory
Information
management System) data not
accurately reported.
LIMS
Out-of-Specifications
LIMS stability
results not reported after a full
investigation performed.
Laboratory
Rewriting
Stability
Missing
QA
Inadequate
Director.
Handbook of Pharmaceutical
Chapter: 19.38
38
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
Stability
SOP
Development
operating a functional stability unit
This
Handbook of Pharmaceutical
Handling
4
S-005-02-06YY Indexing
procedure for Stability Studies.
The purpose of this standard operating
procedure is to establish an index and
an annual supplementary index for
stability
study
SOPs.
The
supplementary index allows for new
SOPs, or updated existing SOPs, to be
indexed in the supplement and
distributed in real time.
4
S-010-02-06YY Index for
Stability Studies.
The purpose of this standard operating
procedure is to index the Stability SOPs
as shown above. 4
Chapter: 19.39
39
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
S-015-02-06YY Initiating a
Stability Study.
The purpose of this standard operating
procedure is to define the stages and
documentation required in order to start
or initiate a development, pivotal, or
commercial stability study.
4
S-020-02-06YY Contents of a
Stability Protocol.
The purpose of this standard operating
procedure is to define the parameters
needed in the stability protocol that
meet the specific FDA regulatory
requirements.
4
S-025-02-06YY Setting limits for
check specifications in a
Stability Study.
The purpose of this standard operating
procedure
is
to
establish
the
development procedures for setting
upper and lower specification limits for
the release and stability (check)
specifications for a Stability Study.
4
S-030-02-06YY Number and size
of batches for stability testing.
The purpose of this standard operating
procedure is to establish the procedure
for determining the number and sizes of
batches commonly required from
development to commercial batch,
stability study purposes.
4
S-035-02-06YY Number of
samples required for performing
stability tests.
The purpose of this standard operating
procedure is to establish the number of
samples required for performing the
analytical tests in a Stability Study. This
SOP is specific for each dosage form
under evaluation.
4
S-040-02-06YY Storage
configuration of samples in a
stability environment.
The purpose of this standard operating
procedure is to determine the storage
configuration of the stability samples in
the climatic controlled rooms or
chambers during the course of the
stability study.
4
S-045-02-06YY Stress testing
the bulk drug substance for
stability analysis.
The purpose of this standard operating
procedure is to determine the stress
testing procedures and parameters for
an approved supplier of the active drug
substance. The data is used for
impurity
evaluation
and
method
validation.
4
S-050-02-06YY Intervals and
climatic and storage conditions
for a US development Stability
Study.
The purpose of this standard operating
procedure is to define the intervals and
storage conditions for conducting
formulation stability studies intended for
ANDA/OTC
formulations
for
US
approval in accordance with the FDAEU-Japan ICH Guidelines.
4
S-055-02-06YY Intervals and
climatic conditions for a US
Pivotal /Bioequivalence Stability
Study.
The purpose of this standard operating
procedure is to define the intervals and
storage conditions for conducting,
Pivotal and commercial stability studies
intended
for
ANDA
and
OTC
formulations for US approval in
accordance with the FDA-EU-Japan
ICH Guidelines.
Handbook of Pharmaceutical
Chapter: 19.40
40
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
4
S-065-02-06YY - Placing the
Reference Listed Drug (RLB) on
Stability.
The purpose of this standard operating
procedure is to establish the procedure
for placing batch lots of the reference
listed drug on stability in order to
evaluate
the
RLDs
analytical
parameters, aging and impurity profile
at different time intervals and different
RLB manufacturing dates in order to
produce an overview of the reference
drugs
stability
parameters
(e.g.
especially dissolution and impurities)
(produces a set of mean curves over a
year).
4
Handbook of Pharmaceutical
4
S-085-02-06YY - Packaging
procedures on Formulation lots
for a stability study.
The purpose of this standard operating
procedure is to determine the
packaging procedures and quality
control functions on development
formulation lots for a Stability Study.
The number of units packed and the
sampling protocol is clearly established.
4
S-090-02-06YY - Packaging
procedures on the Process
Qualification Batch for a
stability study.
The purpose of this standard operating
procedure is to determine the
packaging procedures and quality
control functions on the final process
qualification lots for a Stability Study.
The number of units packed and the
sample protocol is clearly established.
4
S-095-02-06YY - Representative
sampling procedures during
batch packaging of stability
samples.
The purpose of this standard operating
procedure is to define the sampling
protocol
used
during
packaging
procedures in order to accomplish a
Chapter: 19.41
41
Generic Development
DRUG DEVELOPMENT
CHAPTER 19
4
S-100-02-06YY - ContainerLiner-Closure systems for a
Stability Study.
4
S-105-02-06YY - Certification of
a Container -Liner-Closure
system.
The purpose of this standard operating
procedure is to establish the vendor
and
in-house
documentation
requirements in order to meet the FDA
documentation filing requirements for
container-liner-closure systems. The
contents of each document is briefly
described.
4
S-000-02-06YY Labeling of
Stability Study Samples.
The purpose of this standard operating
procedure is to specify the procedure
and exact label data requirements for
labeling stability study samples.
4
S-115-02-06YY Storing the
stability study samples under
controlled conditions prior to
analysis.
The purpose of this standard operating
procedure is to establish the storage
conditions
under
which
stability
samples are kept during the interim
period between the sample due date
and the time
prior to laboratory
analysis to prevent sample spoilage.
Handbook of Pharmaceutical
4
S-130-02-06YY The control of
Analytical methods #s and
Edition #s in stability
documentation.
The purpose of this standard operating
procedure is to ensure that the correct
analytical methods numbers and edition
numbers are used in the analytical and
microbiological testing laboratory, and
are
specified
in
the
stability
documentation during the course of a
Stability Study. This SOP insures that
method changes are updated in the
stability documentation.
4
S-135-02-06YY Crossreferencing laboratory
notebooks with computerized
stability documentation.
The purpose of this standard operating
procedure
is
to
cross-reference
laboratory
analytical
and
microbiological notebooks containing
the raw data at each specific test
interval with the computerized stability
documentation.
4
Chapter: 19.42
42
Generic Development
DRUG DEVELOPMENT
4
S-150-02-06YY Recording
stability study climatic
conditions
The purpose of this standard operating
procedure is to ensure the correct
recording procedures, of temperature
and humidity control charts for the
climatic
chambers
or
controlled
environment
rooms.
Breakdown
procedures of chart recorders and
corrective action are documented.
4
S-155-02-06YY Review and
control of temperature and
humidity recording charts.
The purpose of this standard operating
procedure is to ensure the correct
review, audit and record keeping of
temperature and humidity control charts
for a climatic chambers or controlled
environment rooms.
4
S-160-02-06YY Periodic
revalidation of climatic rooms
and chambers.
The purpose of this standard operating
procedure is to ensure the periodic
revalidation of the climatic rooms and
chambers
to
secure
that
the
temperature and humidity is within limits
at all points where samples are stored
in the controlled area.
4
S-170-02-06YY Sanitation and
house-keeping requirements of
climatic
chambers.
Handbook of Pharmaceutical
CHAPTER 19
4
S-175-02-06YY Fault correcting
procedures (after breakdowns)
during a Stability Study.
The purpose of this standard operating
procedure is to determine the
procedures to follow after a breakdown
or failure of the equipment or power
supply during an ongoing stability
study. The use of hand thermometers
and recording logbooks
and the
corrective
action
procedure
is
documented.
4
S-180-02-06YY - Emergency
procedures during a Stability
Study.
The purpose of this standard operating
procedure is to is to determine the
procedures to follow after a permanent
breakdown or failure of the climatic
chambers
equipment
(motor
burnout/probe
failure)
during
an
ongoing stability study. Corrective
action procedures are documented.
4
S-185-02-06YY Reserved.
The purpose of this standard operating
procedure is to identify specific inhouse SOPs due to unique conditions,
methods or equipment operating within
the companies development operational
procedure.
4
S-190-02-06YY Conditions for
stopping a Stability Study.
The purpose of this standard operating
procedure is to define the precise
conditions subject to which an ongoing
stability study will be terminated.
Chapter: 19.43
43
Generic Development
DRUG DEVELOPMENT
4
S-210-02-06YY- Self inspection
procedures in a stability
department.
The purpose of this standard operating
procedure is to provide for self
inspection procedures according to the
written in-house compliance program
specific for the stability department.
4
4
S-225-02-06YY - The Dos and
Donts of a Stability Study - a
departmental training tool.
The purpose of this standard operating
procedure is to document a check list
for departmental training purposes of
common practice to follow and to avoid
when performing stability studies.
4
S-230-02-06YY - Stability
department compliance staff
training
The purpose of this standard operating
procedure is to provide a written
Compliance and stability procedure,
Handbook of Pharmaceutical
CHAPTER 19
4
S-235-02-06YY - Documentation
requirements for a Stability
Study - contents of a Stability
Dossier
The purpose of this standard operating
procedure is to provide a check list and
explanation of all the documentation
and data forms required to make up the
complete contents of a Stability Study
Dossier.
4
S-240-02-06YY - Job description
of stability department
personnel
The purpose of this standard operating
procedure is to document and provide
appropriate job descriptions (and a
training outline) for the personnel in the
stability department or personnel
involved in the performance of stability
related functions.
4
S-245-02-06YY - Review and
auditing stability study
documentation.
The purpose of this standard operating
procedure is to review and audit and
review each stability study performed in
order to ensure that all documentation
from
laboratory
Notebooks
to
computerized stability reports are
accurate and complete.
4
S-250-02-06YY- Accepting and
Signing-off a Completed
Stability Study.
The purpose of this standard operating
procedure is to specify the acceptance
and signing-off procedure by the
Quality Assurance Unit for a completed
stability study to ensure that the study
is in fact complete.
4
Chapter: 19.44
44
Generic Development
SEMISOLIDS
S O P s
CHAPTER 20
Development
SOPs
the essential internal standard system of a
successful drug development unit'
tandard
Operating
Procedures
(SOPs) for drug development
applies to individuals or groups
responsible for the management and
operation of the innovative/generic drug
development unit. It is equally valuable
for the operation and control of the
CMC (chemistry, manufacturing and
control) section of a NDA researchedbased unit.
All
pharmaceutical
companies
conducting
drug
research
and
development
must
have
understandable SOPs. The primary
purpose of the SOP is to translate the
various regulations and guidelines,
which are open to interpretation, into
clear and concise sets of instructions.
Don't Do
Without
Development
SOPs
The
Essentially
Handbook of Pharmaceutical
Distribute
e-SOPs
electronically
Sect: 20.
20 1
SEMISOLIDS
S O P s
Testing
Regulatory Audit
SOPs are
an Essential
Pre-submission
Requirement
Regulatory
Sect: 20.
20 2
CHAPTER 20
Generic
Development
of
pharmaceutical drugs may take place in
a Non-US development laboratory
facility.
W here product development occurs in
a remote development unit (i.e. not
attached to the proposed manufacturing
site - special SOPs dovetailing the
procedures at the remote and
manufacturing site are necessary for
such a separated situation.
Emphasis has been placed in certain
SOPs on external development (outside
the
US)
while
commercial
manufacturing is targeted at a US
commercial site. In the majority of the
SOP examples the regulatory Pivotal
batch for regulatory inclusion into the
NDA/ANDA submission file, is targeted
for manufacture at the US commercial
manufacturing site.
Oversees developers who have FDA
inspected / approved commercial
manufacturing facilities may produce
the pivotal batch at a non-US small or
large scale manufacturing facility. The
manufacturing and testing facility must
be in full GMP compliance, as if it were
a US based operation.
Non-GMP R&D or drug development
facilities are not suitable for clinical or
pivotal drug manufacturing. Full cGMP
pilot plants or to use the more
appropriate terminology small scale
manufacturing facilities are the correct
venue for manufacturing clinical
batches.
Although this procedure may be within
the OGD framework of regulations, it is
not a recommended route, if the object
is to routinely manufacture at an
approved US commercial production
site.
Pivotal batches for regulatory
submission to the authorities should
always be manufactured at the US
commercial site - if the intended generic
market is the USA.
3
Generic Development