FDAs Draft Process Validation Guidance

Overview and Implications for C&Q Programs

Alice Redmond, C&Q Technical Director
09
th
March 2010
Reviews potential impact on
the current industry
approaches to science and
risk based design and
qualification activities which
support the process
validation program
The key changes in
relation to the 1987
guidance
This paper presents
an overview of the
draft FDA PV guidance
Overview Key Changes Impact

Guidance for Industry
Process Validation: General
Principles and Practices
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments andsuggestionsregardingthisdraft document shouldbesubmittedwithin60daysof
publicationintheFederal Register of thenoticeannouncingtheavailability of thedraft guidance.
SubmitcommentstotheDivision of Dockets Management (HFA-305), FoodandDrug
Administration, 5630FishersLane, rm. 1061, Rockville, MD20852. All commentsshould be
identifiedwith thedocket number listedinthenoticeof availability that publishesintheFederal
Register.
For questionsregardingthisdraft document contact Brian Hasselbalchor GraceMcNally
(CDER) 301-796-3286 or 301-796-3279, Christopher Joneckis (CBER) 301-827-0373, or
DennisBensley(CVM) 301-827-6956.
U.S. Department of Health and Human Services Food and Drug Administration Center for
Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research
(CBER) Center for Veterinary Medicine (CVM)
November 2008 Current Good Manufacturing Practices (CGMP)










1.
1.
2.
2.
3.
3.
FDAs Guidance for Industry on Process Validation has
been welcomed for
The clarity of its integrated
3 stage lifecycle process
The elimination of the 3
Golden Batches concept.
Its emphasis on the need
for effective scientific
knowledge led programs

Guidance for Industry
Process Validation: General
Principles and Practices
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments andsuggestionsregardingthisdraft document shouldbesubmittedwithin60daysof
publicationintheFederal Register of thenoticeannouncingtheavailability of thedraft guidance.
SubmitcommentstotheDivision of Dockets Management (HFA-305), FoodandDrug
Administration, 5630FishersLane, rm. 1061, Rockville, MD20852. All commentsshould be
identifiedwith thedocket number listedinthenoticeof availability that publishesintheFederal
Register.
For questionsregardingthisdraft document contact Brian Hasselbalchor GraceMcNally
(CDER) 301-796-3286 or 301-796-3279, Christopher Joneckis (CBER) 301-827-0373, or
DennisBensley(CVM) 301-827-6956.
U.S. Department of Health and Human Services Food and Drug Administration Center for
Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research
(CBER) Center for Veterinary Medicine (CVM)
November 2008 Current Good Manufacturing Practices (CGMP)










Once Published
It will replace the FDAs
1987 Guideline on General
Principles of Process
Validation
It sets out the approaches
that the FDA consider to
be appropriate elements
of process validation
It represents the FDAs
current thinking in regard
to process validation
1.
1.
2.
2.
3.
3.
Stage 1 Process Design: The commercial process is
defined during this stage based on knowledge gained
through development and scale-up activities
Stage 2 Process Qualification: During this stage,
the process design is confirmed as being capable of
reproducible commercial manufacturing
Stage 3 Continued Process Verification: Ongoing
assurance is gained during routine production that the
process remains in a state of control
3 Stages of Process Validation
1.
1.
2.
2.
3.
3.
In
Scope
Human
Drugs
Veterinary
Drugs
APIs
Biologicals
Out of
Scope
Investigational
Medicinal
Products
Medical
Devices
Effective Process Validation contributes significantly to
assuring drug quality
Basic Principles of Quality Assurance
A drug should be produced that is fit for its intended use;
Quality, safety, and efficacy are designed or built into the product.
Quality cannot be adequately assured merely by in-process and
finished-product inspection or testing
Each step of a manufacturing process is controlled to assure that
the finished product meets all design characteristics and quality
attributes including specifications
Ref : Guidance for Industry Process Validation: General Principles and Practices (Nov 2008)
Guidance is Intended to Promote
modern
manufacturing
principles
process
improvement
& innovation
sound
science
Product Product
Lifecycle Lifecycle
Approach Approach
Product Product
Lifecycle Lifecycle
Approach Approach
Emphasizing the importance of the links between
Product and process
design and development
Qualification of the
commercial
manufacturing
equipment and
process
Maintenance of the
process in a state of
control during routine
commercial production
Validation of the process is not a
one off event but represents an
ongoing continuum of scientific
knowledge development and
ongoing assurance.
Ongoing Continuum.
Key Definition : Process Validation
The 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
Ref : Guidance for Industry Process Validation: General Principles and Practices (Nov 2008)
Key to this Success
0
50
100
150
200
250
2004 2005 2006 2007 2008 2009 2010
Description A Description B Description C
25
30
25
12
55
Description A Description B
Description C Description D
Description E
60%
30%
10%
Description C
Description B
Description A
100%
5
7
2
4
2
3
7
9
5
6
8
6
5
3
Company A Company B
Proficiency in the collection and
evaluation of information and data
about the performance of the
process
Importance of making the entire process validation
program more effective and efficient
General Considerations for PV
Good project management
Robust scientific knowledge collection, management and
archiving
Uniform collection and assessment of information methods
Reducing the burden of redundant information gathering
Use of an integrated team approach
Appropriately documented Project Plans
The support of senior management
Statistical assessment of data
3 Stages of Process Validation
Process
Design
Process
Qualification
Continuous
Process
Verification
Product Product
Lifecycle Lifecycle
Approach Approach
Key tenets of the lifecycle approach
Gain a high degree of assurance in the performance of the
process before distribution
Based on objective information from lab, pilot, and/or
commercial- scale studies
Success relies on skilled interpretation of the information
and knowledge gained
Understanding sources of variation, their impacts and
associated risks
Establishing appropriate control strategies
This scientific knowledge is verified by testing
(in-process, release, characterization) of each significant
step of the commercial manufacture process
Key Tenets of the Lifecycle Approach 2
Ongoing data analysis of both intra-batch and inter-batch
variability
Appropriate provisions to address deviations and
nonconforming data
Importance of both QA and Operators in providing
feedback for continued process verification
Emphasis is on maintaining the process in a
state of control
It provides a strong lead in acknowledging that
qualification programs devoid of process understanding
will not guarantee the assurance of quality required
Stage 1 Process Design
Design a process suitable for routine commercial manufacturing that
can consistently deliver a product that meets its CQAs
a. Building and Capturing Process Knowledge and Understanding
b. Establishing a Strategy for Process Control
DOE
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Variability
Stage 2 Process Qualification
Process design is confirmed as being capable of reproducible
commercial manufacturing
a. Design of a Facility and Qualification of Utilities and Equipment
b. Performance Qualification Approach
c. Performance Qualification Protocol
d. Protocol Execution and Report
Fit for Intended Use
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Role of QA
Enhanced Monitoring
The decision to begin
commercial distribution should
be supportedby data from
commercial batches
Released
Product and
Continued
Process
Verification
Batch
C
Batch B
Batch
A
Facility and
Equipment
'Qualified
HowMany ?
Approved for Commercial Distribution
Batch
C
Batch B
Released
Product and
Continued
Process
Verification
Facility and
Equipment
'Qualified
Approved for Commercial Distribution
The decision to begin
commercial distribution
shouldbe supportedby data
fromcommercial batches
HowMany ?
Batch B
Released
Product and
Continued
Process
Verification
Facility and
Equipment
'Qualified
Approved for Commercial Distribution
The decision to begin
commercial distribution shouldbe
supportedby data from
commercial batches
HowMany ?
Stage 3 Continued Process Verification
Continually assure that the process remains in a state of control (the
validated state) during commercial manufacture
Detection of Process Drift
Ongoing program to collect and analyze product and
process data that relate to product quality
Statistician led analysis
Detection, control, and/or mitigation strategies
Continued enhanced monitoring
Process Optimization
Maintenance
Overview Key Changes Impact
Reviews potential impact on
the current industry
approaches to science and
risk based design and
qualification activities which
support the process
validation program
The key changes in
relation to the 1987
guidance
This paper presents
an overview of the
draft FDA PV
guidance
to is controlled to assure. Wording revision from maximize
the probability that
to is designed or built. Principles of quality assurance
wording revision from designed
and built into the product
to cannot be adequately assured
merely by in-process and finished
product inspection or testing
Principles of quality assurance
wording revision from cannot be
inspected or tested into the finished
product
Defines validation in terms of
establishing scientific evidence
Defines validation as establishing
documented evidence.
2008 Draft 1987 PV Guidance
Key Changes between 1987 PV Guidance and 2008 Draft
New Guidance in 2008 Draft
2008 Draft 1987 PV Guidance
Emphasizes the use of qualitative
statistical methods to monitor,
evaluate and justify assurance of
process performance
Emphasizes Science Based
Knowledge development
Removes validation information for
medical devices;
Introduction of root cause
(e.g., review of customer
complaints and impact on process)
Introduction of Process Analytical
Technology (PAT) concepts for PV
exclusion of revalidationand
retrospective process validation.
Introduction of
product lifecycleconcept
Introduction of
integrated team approach
Overview Key Changes Impact
Reviews potential impact on
the current industry
approaches to science and
risk based design and
qualification activities which
support the process
validation program
The key changes in
relation to the 1987
guidance
This paper presents
an overview of the
draft FDA PV
guidance
Key Definition : Qualification
Activities undertaken to
demonstrate that utilities and
pieces of equipment are suitable for
their intended use and perform
properly is referred to in this
guidance as qualification
Ref : Guidance for Industry Process Validation: General Principles and Practices (Nov 2008)
Fundamental Change Needed
Current premise: Did we meet the
design (design is presumed to be
perfect)?
Future premise: Have we met
process requirements, and have we
controlled risks to quality?
Page 30
C&Q Model
Traditional V Model or Risk Based Verification
Lean Thinking is Equally Relevant
related to
System
Build
related to
related to
User
Requirements
Specification
Performance
Qualification
Functional
Specification
Operational
Qualification
Installation
Qualification
Design
Specification
Good Engineering Practice
Requirements
Specification
and Design
Verification
Acceptance
and Release
Operation &
Continuous
Improvement
Product
Knowledge
Process
Knowledge
Regulatory
Requirements
Company
Quality Reqs.
Risk Management
Design Review
Change Management
Figure 1 The Specification, Design and Verification Process
Process - The New V Model
Reference: Figure 1: ASTM E2500-07 A Standard Guide for the Specification, Design, and Verification
of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment, pg 3
GOOD ENGINEERING PRACTICE
OPERATION &
CONTINUOUS
IMPROVEMENT
RISK MANAGEMENT
DESIGN REVIEW
CHANGE REVIEW
PRODUCT
KNOWLEDGE
PROCESS
KNOWLEDGE
REGULATORY
REQUIREMENTS
COMPANY QUALITY
REGULATIONS
REQUIREMENTS
SPECIFICATIONS
& DESIGN
ACCEPTANCE
& RELEASE
VERIFICATION
ASTM Process Flow
Subject Matter Experts (SMEs) following GEPs
Verification
Plan
List of
Critical
Aspects
(CQA, CPP)
Verification Testing (Design to Performance)
to confirm Critical Aspects and
meet Acceptance Criteria
Acceptance
and
Release
Factory Acceptance Test
Site Acceptance Test
Installation Verification
Functional Verification
Performance
Testing
Verification Phase
Acceptance
and
Release
Approved by
Quality Unit
Approved by
Quality Unit
Review all completed verification test
documentation by a second, independent SME
Approved by
Quality Unit
Operation
Continuous
Improvement
Principles
Risk-Based Approach
Science-Based Approach
Critical Quality Attributes
Quality by Design
Good Engineering Practices
Subject Matter Experts
Use of Vendor Documentation
Continuous Improvement
MOC, operating principles & performance characteristics
Verifying built as designed;
Verifying operation (comparable load / interventions /
durations)
(1) Tests
(2) Criteria
(3) Timing
Summary report with conclusions that address criteria in
the plan
Qualification
Include
Include
Q Plan
Q Plan
Q Report
Q Report
(4) Responsibilities
(5) Procedures
(6) Changes
Approved
Approved
Summary FDA Draft PV vs. ASTM E2500
Y Y Flexibility on how effort is structured
Y Y Risk assessment to scaleeffort
Y Y QA approves
[qualification]/[verification] report
N* Acceptance
Criteria only
Y QA approves
[qualification]/[verification] plan
Y Y Equipment and facilities suitable for
intended use
Y Y Focus on science-based process
understanding and meeting process
requirements
ASTM FDA PV Qualification vs. Verification
Aspects
Summary FDA Draft PV vs. ASTM E2500
N Y Specific aspects to check for spelled
out
Y NA Critical aspects defined from risk
assessments and process
requirements
Y Y Use of project change management
Y Y Use of subject matter experts: how
to verify, adjudicate minor
departures from specification for CQ
Y NA Use of vendor documents
Y Y Design of facility, process,
equipment based on process
understanding
ASTM FDA PV Qualification vs. Verification
Aspects
Impact on Design & Verification
Endorses an Integrated Lifecycle
Approach
Seeks early alignment of product
& process requirements
Requires Multi Disciplined Teams
Welcome avoidance of traditional,
prescriptive terminology such as
DQ,IQ and OQ
Necessary from start of Concept
Design
Requires access / engagement of
R&D
Impacted by Contracting Strategy
Offers Opportunities to really
improve the CQ process
Real opportunities to look behind the prepared templates and
execute qualification and validation programs which are
not only validbut valuable
to the ongoing operation and continuous improvement
ISPE Singapore - C&Q Workshop 2009 Page 38
Other Drivers
ISPE Product Quality Lifecycle Implementation (PQLI) Initiative
- Practical Implementation of ICH Guidance and Quality by Design
ASTM E2500 Standard Guide for Specification, Design, and
Verification of Pharmaceutical and Biopharmaceutical Manufacturing
Systems and Equipment
GAMP 5 Guidance
ISPE GEP best practise guide
ISPE Draft C&Q best practise guide
ISPE Baseline Guide 12 Draft Verification guide
FDA: Quality Systems Approach to Pharmaceutical cGMP
Regulations 2006
EU Annex 20, Quality Risk Management March 2008
ICH Q8 Pharmaceutical Development - Nov 2005
ICH Q10 Quality Systems J une 2008
Focus of Baseline Guide 12
The Guide focuses on the process and facilitating the
translation of the scientific knowledge about the product and
process into good design of equipment, systems, and
facilities which:
meet documented process requirements
control documented risks to the patient
produce life cycle evidence which verifies that the as-installed
implementation of the design meets the above two objectives
Link From Baseline Guide 5 to New Baseline Guide 12
Concepts
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The Challenge
NEW GUIDANCE
NEW IDEAS
TIME TO APPROVAL
Alignment
Questions and Answers
Questions Tomorrow ?
Alice Redmond
C&Q Technical Director, PM Group
Alice.redmond@pmg.ie
+353 21 452 2916
+353 86 8385088