Strategies To Write Effective Validation Protocol

Testing / Sampling -- Drug Product
Manufacturing Process Validation
STRATEGIES TO WRITE EFFECTIVE

VALIDATION PROTOCOLS
Paul L. Pluta, PhD

Journal of Validation Technology
Journal of GXP Compliance
University of Illinois College of Pharmacy
Chicago, IL USA
OUTLINE
Protocols General
PV Guidance requirements
Process Validation Protocols
Equipment Qualification Protocols
Protocol Templates Key sections
and
d content
Protocol Problems
2
1
OBJECTIVES and APPROACH

Review FDA Process Validation Guidance (draft)
Specific FDA requirements
Consider FDA Guidance requirements in protocol
p p
preparation
Consider Corporate requirements / templates
Review PQ document group
Requirements of PV stages
Stage 1, Stage 2, Stage 3
Application to Qualification documents

Approval of validation documents
Templates for PQ documents provided
Protocol problems
Participation needed!
3
TERMINOLOGY: PROCESS VALIDATION
Process Validation Process Qualification
Qualification Qualification
E i
Equipment t #1 HVAC
Utilities
Equipment #2 Facilities
Computers
Equipment #3
Analytical methods validation

Cleaning process validation
Packaging process validation
Application to other process validation
2
FDA PROCESS VALIDATION GUIDANCE (DRAFT)
Definition: Collection and evaluation of data, from the

process design stage throughout production, which
establishes scientific evidence that a process is capable
of consistently delivering quality products.
products
Three stages of activities:

Stage 1 Process Design Development and scale-up activities
Stage 2 Process Qualification Reproducible manufacturing
Stage 3 Continued Process Verification Routine production
This document consistent with GHTF medical device process validation.
Before commercial distribution to consumers, a

manufacturer should have gained a high degree of
assurance in the manufacturing process
Manufacturers should:
Understand the sources of variation
Detect the presence and degree of variation
Understand the impact of variation on the process and
product attributes
p
Control the variation in a manner commensurate with
risk to process and product
3
Good project management and good archiving to capture

scientific knowledge.
Enhance accessibility of information later in lifecycle.
Integrated team approach: Process engineering, industrial
pharmacy, analytical chemistry, microbiology, statistics,
manufacturing, and quality assurance.
PROCESS DESIGN
(PROCESS UNDERSTANDING)
Define commercial-scale process
Define unit operations and process parameters
Identify and understand sources of variability
Identify critical process parameters
Studies to understand effects of scale
Establish mechanisms to control variability
Process Analytical Technology
Designed experiments
Lab scale and pilot scale experiments
Reference: McNally, Grace. GMP by the Sea, 8-07, 8-08
4
PROCESS DESIGN (PROCESS UNDERSTANDING)

Objective
API and excipient pharmaceutics
Quality attributes
Risk analysis
Process parameters
Design of experiments
Design space
Normal operating range
In-process controls
Product development key inputs to design stage
Variability by different component lots, production operators,
environmental conditions, and measurement systems
Use risk analysis tools to screen variables
Establish a strategy for process control
9
QUALITY BY DESIGN (QbD)

1. Target product profile
2. Critical quality attributes
3. Critical process parameters
4. Design space
5. Input variable control strategy
6
6. Continuous improvement
Other considerations: PAT, Risk analysis
10
5
PROCESS QUALIFICATION
(VALIDATION PERFORMANCE)
Confirmation at commercial scale of process design information
Qualification of equipment, utilities, facilities
Performance qualification
Conclusion that process consistently produces quality product.
Conformance batches
All support systems, documents, training, personnel, etc. in
place
Target / nominal operating parameters within design space
Additional testing
Decision to release
release process
process for routine commercial manufacturing
Reference: McNally, Grace. GMP by the Sea, 8-07, 8-08
11
PROCESS QUALIFICATION
Conformance Lots
Procedures
Validation plans
Protocols
Sampling
Testing
Results
Plan to maintain validation
alidation
ALL EQUIPMENT AND SUPPORTING SYSTEMS MUST
BE QUALIFIED.
12
6
PERFORMANCE QUALIFICATION APPROACH

Higher level of sampling, testing, and scrutiny of process performance.
Protocol should address:

Operating parameters, processing limits, and raw material inputs
Data to be collected and how evaluated
Test to be performed and acceptance criteria
Sampling plan sampling points, number of samples, frequency
Statistical methods used
Statistical confidence levels
Provisions to address deviations and non-conformances
Facility, utility, and equipment qualification
Personnel training
Status of analytical method validation
Review and approval by appropriate departments and quality unit
NOTE DETAILS FROM PV GUIDANCE

13
PERFORMANCE QUALIFICATION APPROACH

The PQ lots should be manufacturer under normal conditions by
personnel expected to routinely perform each step of each unit
operation in the process. Normal operating conditions should cover
the utility systems (air handling and water purification), material,
personnel environment
environment, and manufacturing procedures.
procedures
PQ report:
Discuss all aspects of protocol
Summarize and analyze data as specified in protocol
Evaluate unexpected observations and additional data
Summarize and discuss nonconformances
Describe
D ib corrective
ti actions
ti or changes
h
Clear conclusions
Approval by appropriate departments and quality unit
NOTE DETAILS FROM PV GUIDANCE

14
7
CONTINUED PROCESS VERIFICATION

(VALIDATION MAINTENANCE)
Activities to assure process remains in validated state

Annual Product Review
T d and
Trend d assess d
data
t
Study OOS and OOT (Out of Trend) data
Timely monitoring of critical operating and performance
parameters.
Monitor product characteristics, personnel training, materials,
facilities, equipment, and SOP changes
Establish process history based on ongoing process
performance
Improve process
Improve control to detect and reduce variability
Change control; evaluate impact of change and test as necessary
Reference: McNally, Grace. GMP by the Sea, 8-29-07
15

Monitoring
Statistical process control
Trend analysis
Change control
Continuous improvement
Revalidation
Management review
STATISTICIAN RECOMMENDED BY FDA
16
8

ITEMS TO BE REVIEWED
Product and process data
Relevant process trends
Quality of incoming materials or components
In-process material
Finished products
Defect complaints
OOS findings
Deviations
Yield variations
Batch records
Incomingg raw material records
Adverse event reports
Production operator feedback
Operator errors also to measure quality of the training program
Above should help identify possible product / process improvements

17
EFFECTIVE PROTOCOLS
PROCESS VALIDATION
Stage 1: Product Design

Development information
Identification of CQA and CPP
Identification of sources of variation
Variation control plan
Stage 2: Process Qualification
Equipment qualification
Analytical method validation
Stage 3: Continued Process Verification
Post PQ plan
APR
Change control
18
9
PRODUCT DESIGN INFORMATION

Technical reports from R&D
Pharmaceutics reports
Development reports (CQA, CPP impact protocols)
Technology transfer / Scale-up reports
Identification of sources of variation
Variation control plans
REPORTS STORED IN VALIDATION AREA OR BE READILY
AVAILABLE (within 30 minutes)
REPORTS SHOULD BE REVIEWED FOR CONSISTENCY

BETWEEN GROUPS
REPORTS SHOULD BE REFERENCED IN VALIDATION SPECIFIC

VALIDATION PLAN, PQ, AND RESULTS REPORT
19
PROCESS VALDIATION PROTOCOLS (PQ)

FDA GUIDLINE RECOMMENDATIONS
Higher level of sampling, testing, and scrutiny of process performance.
Protocol should address:

Operating
O ti parameters,
t processing
i limits,
li it andd raw material
t i l iinputs
t
Data to be collected and how evaluated
Test to be performed and acceptance criteria
Sampling plan sampling points, number of samples, frequency
Statistical methods used
Statistical confidence levels
Provisions to address deviations and non-conformances
Facility,
F ilit utility,
tilit and
d equipment
i t qualification
lifi ti
Personnel training
Status of analytical method validation
Review and approval by appropriate departments and quality unit
20
10
VALIDATION PHILOSOPHY
Validation is confirmation.
Acceptable results are expected.
Validation is not
Research
Final stage of development
Optimization
O ti i ti
Fine-tuning
Debugging
21
PROCESS VALDIATION DOCUMENTS

Corporate policy
Corporate templates use and supplement with new requirements
Validation Master Plan (VMP)
--------------------------------------------------
Validation Request
Validation Plan
Validation Protocol(s)
Engineering Study
Other requirements
Validation Results
Validation Report
--------------------------------------------------
22
11
PROCESS VALIDATION DOCUMENTS

Written for the reader US vs. Europe
Objective: Understanding
Clarity much more important than brevity
Stand-alone document
Potential for review in 10+ years
Author / Management not available
Spelling and grammar correct
Need good writers Who writes protocols?
Simple sentences
Simple words
23
VALIDATION REQUEST
Objective of validation
Why needed?
Why acceptable? See Validation Plan
Impact of validation
Risk analysis
Approach to accomplish
Compliance to internal requirements and policies
Regulatory impact
Other systems or product impacted
Procedure changes or other document changes
Notifications to affected groups (internal, external, labs)
Above applicable to equipment and other qualification

24
12
TERMINOLOGY EXAMPLES
Validation request:
Process validation of Product A
S t
System: New
N product
d t validation
lid ti
Change impact: High impact. New product validation
Reason: New product to be manufactured at site
Justification: See Validation Plan
SIMPLE AND CLEAR
25
Validation request:
Qualification of 150 cu. ft. blender
System: New equipment qualification
Change impact: High impact. New equipment and new
size at site
Reason: New equipment to increase manufacturing

efficiency and throughput
SIMPLE AND CLEAR

26
13
Validation request:
Change air supply and return ductwork to coincide with Line 1 floor
space changes
System: HVAC system #3
Change impact: Medium impact. Change to direct product contact
support utility
Reason: Room configuration change to increase manufacturing

efficiency
SIMPLE AND CLEAR
27
VALIDATION PLAN
Introduction
Technical information
Validation strategy and testing
Validation documentation
List of required protocols, reports, procedures, etc.
References
Li t off reports
List t and
d scientific
i tifi references
f
Format development critical need model document
28
14
VALIDATION PLAN -- INTRODUCTION
INTRODUCTION
Overview describing validation / product / process /
equipment / etc.
Requirements to complete validation
Conformance to regulations and internal policy validation will
be completed
Impact of change to maintain the validated state
Impact on regulatory submission
Impact of change on procedures, drawings, other documents
Notifications to other areas internal and external
Notification to test labs and other areas impacted by validation
29
VALIDATION PLAN -- TECHNICAL INFORMATION

TECHNICAL INFORMATION
Basic product / process / equipment description
Formula
Process
Specifications
Include non-technical description information
Technical aspects of validation / qualification
Reference to technical reports from Design Stage or DQ
Total validation approach
Experimental studies
Past data (retrospective data)
V lid i protocols
Validation l
Other work
New procedures
Number of lots related to impact of change and risk
WRITTEN FOR THE READER

30
15
VALIDATION PLAN
VALIDATION STRATEGY AND TESTING
Prospective validation only
IQ / OQ / PQ -- general
Types of testing -- general
Regulatory specifications
Internal controls
Process tests
Tests and rationale general
Address changes based on risk analysis
Sampling and rationale general
Exceed routine QA testing based on impact and risk analysis
Data treatment general
Statistical data treatment
Acceptance criteria general
DETAILS OF ABOVE PROVIDED IN PROTOCOLS

31
VALIDATION PLAN
VALDIATION DOCUMENTATION
Doc # Title Date closed
01 Validation request
02 XXX Dryer Engineering Study
03 XXX Dryer Qualification
04 XXX Process Scale-up Engineering Study
05 XXX Process Validation
06 Update Validation Master Plan Product and

Equipment sections
07 XXX Project Summary Report
32
16
VALIDATION PLAN -- REFERENCES
R&D Reports
Published literature
Scientific and technical support to validation plan

Report copies in validation area
33
VALIDATION PROTOCOL
Objective of validation specific protocol
Validation description -- specific
System description (for equipment)
Validation approach
Testing and rationale -- specific
Sampling and rationale -- specific
Data treatment -- specific
Acceptance criteria specific
All testing must have acceptance criteria
Data sheets specific
Validation is confirmation
34
17
VALIDATION PROTOCOL
TESTING AND SAMPLING
Based on product specifications and testing
Exceed routine Q
QA testing
g based on impact
p and risk
Consider the following:

Product for seizures
Product for hypertension
New product
Change in compressing machine
Increase compressing machine speed
Change in granulation method
Change in batch size
35
VALIDATION PROTOCOL
FDA Powder Blends and Finished Dosage Units

Stratified Sampling and Assessment
Blend sampling.
sampling n = 1010, Indi
Individuals,
id als RSD
Tablets. 20 samples, n = 3-7 per location, mean,
range, RSD.
Application is possible approach for high risk

p
products
Supportive of USP Uniformity of Dosage Units on
composite / stratified samples
Product types: Potency and weight testing
36
18
VALIDATION SAMPLING
What is routine QA sampling?
Impact of change
No impact
Low impact
Medium impact
High impact
Risk analysis
y
High risk
Regular risk
Low risk
37
ENGINEERING STUDY
Conducted in advance of validation
No acceptance criteria
Trial
T i l run
Examples: Manufacturing process without

bulk drug (low dose API)
Process runs with placebo
Categories of Engineering Studies
Conduct Engineering Study concurrently with validation? -
- Not recommended
38
19
DATA SHEETS
Designed sheet with space for expected data

Data treatment specified
Signature and data of person supplying data
Highly recommended for Operators or persons not
familiar with sampling
Prevents missing data in complex protocols

Record sampling and / or testing
39
VALIDATION RESULTS
Data sheets
Data treatment
Results
Discussion
Results pass is not sufficient.
Validation statement:
Results indicate that ___ is validated.
Post-validation monitoring plan
40
20
VALIDATION REPORT
Recommended for complex projects

Recommended for multiple protocol projects
PRIMARY REPORT FOR AUDIT
Cut and Paste exercise from multiple

documents
Best approach to avoid inconsistency
41
VALIDATION REPORT FORMAT

Introduction
Key information from Validation Plan
Supporting information
Protocol #1 results
Protocol #2 results
Protocol #3 results
Protocol #n results
j
Project conclusions ((for Validation Plan))
Validation statement
Results indicate that ______ is validated.
42
21
EQUIPMENT QUALIFICATION
IQ, OQ, PQ
Same approach as with processes
Same philosophy
Same requirements
Same approval
Critical tests only
Non critical tests in FAC
Non-critical FAC, SAC
SAC, etc
etc.
Do as much as possible in commissioning
Difference from PV: Do tests only once
43
EQUIPMENT QUALIFICATION
IQ Installation Qualification
Function: Materials,, structure,, and maintenance
OQ Operational Qualification
Function: Operation
PQ Performance Qualification
Function: Operation with materials and / or
within other system components
44
22
VALIDATION DOCUMENT APPROVAL

Approval group must review documents
with p
perspective
p of an external auditor
Assure compliance with regulations
Assure acceptability of technical validation
and product quality
Assure acceptability of documentation
documentation.
Spelling and grammar
45
VALIDATION DOCUMENT APPROVAL

Technical validation
Scientific and technical principles
Consistent approach
Supports objective of validation
Supports routine manufacturing in type of testing and
sampling
Support routine manufacturing in duration of sampling
and testing
Results and discussion support data
Correct technical conclusions
Equipment testing support entire operating range used in
manufacturing
46
23
PROTOCOL PROBLEMS
No plan
No basic explanation of validation
No statement of strategy and approach
No test rationale
No sampling rationale
How to treat data
No discussion of results
No acceptance criteria rationale
N validation
No lid ti statement
t t t
Poorly written
Written for the reader

47
PROTOCOL PROBLEMS
Protocol requires BME samples for potency.
Acceptance criteria: 95-105%
B = 95%
M = 100%
E = 105%
All results pass
p
Conclusion?
48
24
PROTOCOL PROBLEMS
There is no requirement for 3 lots.
Consider impact of change.

Consider product.
Consider risk.
What is post validation plan?
How many lots should be done?
49
SUPPORTING DOCUMENTS
PROCESS ANALYTICAL TECHNOLOGY (PAT)
Processes verified by PAT are not validated
All associated PAT equipment and analytical methods are

validated
Reference: FDA. PAT -- A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance. September 2004
50
25
SUPPORTING DOCUMENTS
PROCESS ANALYTICAL TECHNOLOGY (PAT)
Process Understanding
All critical sources of variability are identified and explained.
Variabilityy is managed
g by y the pprocess
Product quality attributes can be accurately and reliably
predicted over the design space
Materials used
Process parameters
Manufacturing
Environmental
Other conditions
Reference: FDA. PAT -- A Framework for Innovative Pharmaceutical

Development, Manufacturing, and Quality Assurance. September 2004
WHEN PAT IS IN PLACE, WILL THERE BE ANY MORE VALIDATION?

51
SUMMARY
WHERE WE ARE -- CURRENT PRACTICE
R&D Validation Commercialization
52
26
SUMMARY -- VALIDATION CURRENT PRACTICE
Emphasis on repeatability (3x)

One-time effort
Documentation important
Last step in development
Hope we can pass validation
Required for product release to market
Key regulations:
1987 Process Validation Guidance
1990s Pharma Inspection Guidelines
1997 Medical Device Quality Systems Manual
53
SUMMARY -- WHERE WE ARE GOING

LIFECYCLE APPROACH TO PROCESS VALIDATION
Lifecycle approach:
Validation is never completed
Validation is always ongoing
Objectives:
Scientific and technical process
Demonstrate process works as intended
Process must remain in control
Reference: McNally, Grace E. GMP by the Sea, 8-07, 8-08
54
27
LIFECYCLE APPROACH TO PROCESS VALIDATION

Process Design
Studies to establish process
Identify critical process parameters
Identify sources of variation
Consider range of variation possible in processes
Process understanding g
Process Qualification
Equipment, facilities, and utilities
Confirm commercial process design
Validation performance
Continuous process verification
Monitor, collect information, assess
Maintenance, continuous verification, process improvement
Change control
Validation maintenance
The process of process validation.
Reference: McNally, Grace E. GMP by the Sea, 8-07, 8-08
55
SUMMARY
PROCESS VALIDATION HISTORY
1978
CGMP iincludes
l d V Validation
lid ti
1987
Development -- VALIDATION -- Control
2008
Lifecycle approach
Continuum of understanding validation maintenance
UNDERSTANDING -- VALIDATION -- MAINTENANCE
56
28
SUMMARY
VALIDATION -- FUTURE
Understanding Performance Maintenance
57
SUMMARY EFFECTIVE PROTOCOLS

Protocols consistent with validation guidelines and
expectations
Validation guidelines specify details
Validation is confirmation -- Acceptable results are
expected
Validation is not R&D, optimization, fine-tuning
New requirements
Scientific and technical basis
CQA and CPP
Sources of Variation
Variation Control Plan
Reference and retrieve R&D reports
58
29
SUMMARY
Protocol requirements
Specific guidance requirements
Strategy and approach
Impact of change
Risk analysis
Testing and sampling rationale
Acceptance criteria
Statistical data treatment
Data sheets
Post-validation monitoring plan
59
SUMMARY
Validation Results
Discussion of results
Validation statement
Summary report for multiple protocol
validation or complex products
Most important validation document
Simple sentences, simple words
Written for the reader
60
30
REFERENCES -- GENERAL
FDA. Guidance for industry. Process Validation: General Principles
and Practices. Draft Guidance, November 2008.
FDA. Guideline of General Principles of Process Validation. May,
1987.
FDA. Compliance Policy Guide 7132c.08. Section 490.100. Process
Validation Requirements for Drug Products and Active
Ph
Pharmaceutical
ti l Ingredients
I di t Subject
S bj t tto P
Pre-Market
M k t Approval.
A l
GHTF Study Group 3. Quality Management Systems -- Process
Validation Guidance. Edition 2, January 2004.
PQRI. Process Robustness. Pharmaceutical Engineering, Nov-Dec,
2006.
McNally, Grace E. Lifecycle Approach to Process Validation. DIA
Annual Meeting, 6-29-2005.
McNally, Grace E. Insights on Validation. GMP by the Sea,
Cambridge MD
Cambridge, MD. 8-29-2007
8 29 2007.
McNally, Grace E. Lifecycle Approach Process Validation. GMP by
the Sea, Cambridge, MD 8-26-08.
Famulare, Joseph. Benefits of a Pharmaceutical Quality System. PDA
/ FDA Joint Conference, Bethesda MD, 11-2-2007.
Health Canada. Validation Guidelines for Pharmaceutical Dosage
Forms (GUIDE-0029). 10-1-2004
61
REFERENCES PROCESS UNDERSTANDING
FDA. Guide to Inspections of Oral Solid Dosage Forms. Pre/Post

Approval Issues for Development and Validation. 1-94.
FDA. Guide to Inspections of Topical Drug Products. 7-94.
FDA. Guide to Inspections. Oral Solutions and Suspensions. 8-94
FDA PAT -- A F
FDA. Frameworkk ffor IInnovative
ti PhPharmaceutical
ti l
Development, Manufacturing, and Quality Assurance. 9-04.
ICH Q7. Good Manufacturing Practice Guide for Active Pharmaceutical
Ingredients. 11-10-00.
ICH Q8. Pharmaceutical Development. 11-10-05.
PQRI. Process Robustness. Pharmaceutical Engineering, 11-06.
Pharmaceutical Process Validation, 3rd edition. Drugs and the
Pharmaceutical Sciences, Volume 129. Marcel Dekker, New York,
NY 2003
NY, 2003.
62
31
Product Quality Lifecycle Implementation (PQLI). www.ispe.org

Draft PQLI Summary Report update, 9-14-2007
Conformia. www.conformia.org
Ph
Pharmaceutical
ti l development
d l t Case
C Study:
St d ACE T Tablets,
bl t V 22.0.
0
Conformia CMC-IM Working Group, 3-13-2008.
Am Ende, Dave, et.al. API Quality by Design Example from the
Torcetrapib Manufacturing Process. J. Pharmaceutical Innovation 2,
71-86, 12-2007.
Stryczek, Karel, et.al. Capitalizing on Aggregate Data for Gaining
Process Understanding -- Effect of Raw Material, Environmental
anddP
Process C Conditions
diti on th
the di
dissolution
l ti R Rate
t off a S
Sustained
t i d
Release Product. J. Pharmaceutical Innovation 2, 6-17, 12-2007.
Somma, Russ. Development Knowledge Can Increase Manufacturing
Flexibility and Facilitate Quality by Design. J. Pharmaceutical
Innovation 2, 87-92, 12-2007.
63

MacGregor, John F. et.al. A Framework for the Development of Design and
Control Space. J. Pharmaceutical Innovation 3, 15-22, 3-2008.
Cogdill, Robert P. et.al. Risk-based Quality by Design (QbD): A Taguchi
Perspective on the Assessment of Product Quality, and the Quantitative
Linkage of Drug Process Parameters and Clinical Performance. J.
Pharmaceutical Innovation 3, 23-29,
23 29, 3
3-2008.
2008.
Garcia, Thomas, et. al. PQLI Key Topics Criticality, Design Space, and
Control Strategy. J. Pharmaceutical Innovation 3, 60-68, 6-2008.
Nosal, Roger, et al. PQLI Definition of Criticality. J. Pharmaceutical Innovation
3, 69-78, 6-2008.
Lepore, John, et.al. PQLI Design Space J. Pharmaceutical Innovation 3, 79-
87, 6-2008.
Bolton, Ray, et.al. PQLI Engineering Controls and Automation Strategy. J.
Ph
Pharmaceutical
ti l Innovation
I ti 3,
3 88-94,
88 94 6-2008.
6 2008
Davis, Bruce, et.al. PQLI Control Strategy Models and Concepts. J.
Pharmaceutical Innovation 3, 95-104, 6-2008.
Seibert, Kevin D. et.al. The Use of Routine Process Capability for the
Deteriation of Process Parameter Criticality in Small-molecle SPI Synthesis.
J. Pharmaceutical Innovation 3,105-112, 6-2008.
64
32
REFERENCES VALIDATION PERFORMANCE

FDA. Guideline of General Principles of Process
Validation. 5-87.
FDA. Medical Device Quality Systems Manual. 1-97.
FDA. Guide to Inspections of Oral Solid Dosage Forms.
Pre/Post Approval Issues for Development and
Validation. 1-94.
FDA. Guide to Inspections of Topical Drug Products. July
1994. FDA. Guide to Inspections. Oral Solutions and
Suspensions. 8-94.
GHTF Study Group 3. Quality Management Systems --
Process Validation Guidance, Edition 2. 1-04.
ASTM E 2500-07.
2500 07 Standard Guide for Specification
Specification,
Design, and Verification of Pharmaceutical and
Biopharmaceutical Manufacturing Systems and
Equipment. 6-1-07
65
REFERENCES VALIDATION MAINTENANCE
FDA. Quality Systems Approach to Pharmaceutical CGMP

Regulations. September 9-06.
FDA. Pharmaceutical cGMPs for the 21st Centuryy -- A
Risk-Based Approach. 9-04.
ICH Q10. Pharmaceutical Quality System. 5-9-07.
GHTF Study Group 3. Quality Management Systems --
Process Validation Guidance, Edition 2. 1-04.
Joneckis, Chris, PhD. Implementing Quality Systems.
GMP by the Sea, Cambridge, MD. 8-29-06.
66
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Testing / Sampling -- Drug Product

Manufacturing Process Validation

STRATEGIES TO WRITE EFFECTIVE

Paul L. Pluta, PhD

OBJECTIVES and APPROACH

Application to Qualification documents

TERMINOLOGY: PROCESS VALIDATION

Process Validation Process Qualification

Analytical methods validation

Application to other process validation

FDA PROCESS VALIDATION GUIDANCE (DRAFT)

Definition: Collection and evaluation of data, from the

Three stages of activities:

This document consistent with GHTF medical device process validation.

FDA PROCESS VALIDATION GUIDANCE (DRAFT)

Before commercial distribution to consumers, a

FDA PROCESS VALIDATION GUIDANCE (DRAFT)

Good project management and good archiving to capture

PROCESS DESIGN (PROCESS UNDERSTANDING)

QUALITY BY DESIGN (QbD)

Other considerations: PAT, Risk analysis

Reference: McNally, Grace. GMP by the Sea, 8-07, 8-08

PERFORMANCE QUALIFICATION APPROACH

Protocol should address:

NOTE DETAILS FROM PV GUIDANCE

PERFORMANCE QUALIFICATION APPROACH

NOTE DETAILS FROM PV GUIDANCE

CONTINUED PROCESS VERIFICATION

Activities to assure process remains in validated state

Reference: McNally, Grace. GMP by the Sea, 8-29-07

CONTINUED PROCESS VERIFICATION

STATISTICIAN RECOMMENDED BY FDA

CONTINUED PROCESS VERIFICATION

Above should help identify possible product / process improvements

Stage 1: Product Design

PRODUCT DESIGN INFORMATION

REPORTS SHOULD BE REVIEWED FOR CONSISTENCY

REPORTS SHOULD BE REFERENCED IN VALIDATION SPECIFIC

PROCESS VALDIATION PROTOCOLS (PQ)

Protocol should address:

Review and approval by appropriate departments and quality unit

PROCESS VALDIATION DOCUMENTS

PROCESS VALIDATION DOCUMENTS

Above applicable to equipment and other qualification

Reason: New product to be manufactured at site

Justification: See Validation Plan

SIMPLE AND CLEAR

Reason: New equipment to increase manufacturing

Justification: See Validation Plan

SIMPLE AND CLEAR

Reason: Room configuration change to increase manufacturing

Justification: See Validation Plan

SIMPLE AND CLEAR

Format development critical need model document

VALIDATION PLAN -- INTRODUCTION

VALIDATION PLAN -- TECHNICAL INFORMATION

WRITTEN FOR THE READER

DETAILS OF ABOVE PROVIDED IN PROTOCOLS

02 XXX Dryer Engineering Study

03 XXX Dryer Qualification

04 XXX Process Scale-up Engineering Study

05 XXX Process Validation