FDA’s Draft Process Validation Guidance.pdf

8/11/2019 FDAs Draft Process Validation Guidance.pdf

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FDAs Draft Process Validation Guidance

Overview and Implications for C&Q Programs

Alice Redmond, C&Q Technical Director09th March 2010


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Reviews potential impact onthe current industryapproaches to science andrisk based design and

qualification activities whichsupport the processvalidation program

The key changes inrelation to the 1987guidance

This paper presentsan overview of thedraft FDA PV guidance

Overview Key Changes Impact


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Guidance for Industry

Process Validation: General

Principles and Practices

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of

publication in theFederal Register of the notice announcing the availability of the draft guidance.

Submit comments to the Division of Dockets Management (HFA-305), Food and Drug

Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be

identified with the docket number listed in the notice of availability that publishes in the FederalRegister.

For questions regarding this draft document contact Brian Hasselbalch or Grace McNally

(CDER) 301-796-3286 or 301-796-3279, Christopher Joneckis (CBER) 301-827-0373, or

Dennis Bensley (CVM) 301-827-6956.

U.S. Department of Health and Human Services Food and Drug Administration Center forDrug 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 integrated3 stage lifecycle process

The elimination of the 3Golden Batches concept.

Its emphasis on the need

for effective scientificknowledge led programs


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Guidance for Industry

Process Validation: General

Principles and Practices

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of

publication in theFederal Register of the notice announcing the availability of the draft guidance.

Submit comments to the Division of Dockets Management (HFA-305), Food and Drug

Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be

identified with the docket number listed in the notice of availability that publishes in the Federal

Register.

For questions regarding this draft document contact Brian Hasselbalch or Grace McNally

(CDER) 301-796-3286 or 301-796-3279, Christopher Joneckis (CBER) 301-827-0373, or

Dennis Bensley (CVM) 301-827-6956.

U.S. Department of Health and Human Services Food and Drug Administration Center forDrug 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 FDAs1987 Guideline on GeneralPrinciples of Process

Validation

It sets out the approachesthat the FDA consider tobe appropriate elementsof process validation

It represents the FDAscurrent thinking in regardto process validation

1.1.

2.2.

3.3.


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Stage 1 Process Design: The commercial process isdefined during this stage based on knowledge gainedthrough development and scale-up activities

Stage 2 Process Qualification: During this stage,

the process design is confirmed as being capable ofreproducible commercial manufacturing

Stage 3 Continued Process Verification: Ongoingassurance is gained during routine production that theprocess remains in a state of control

3 Stages of Process Validation

1.1.

2.2.

3.3.


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In

ScopeHumanDrugs

Veterinary

Drugs

APIs

Biologicals


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Out ofScopeInvestigational

MedicinalProducts

Medical

Devices


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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 builtinto the product.

Quality cannot be adequately assuredmerely by in-process andfinished-product inspection or testing

Each step of a manufacturing process is controlled to assure that

the finished product meets all design characteristics and qualityattributes including specifications

Ref : Guidance for Industry Process Validation: General Principles and Practices (Nov 2008)


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Guidance is Intended to Promote

modernmanufacturing

principles

processimprovement& innovation

soundscience

ProductProduct

LifecycleLifecycle

ApproachApproach


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ProductProduct

LifecycleLifecycle

ApproachApproach

Emphasizing the importance of the links between

Product and processdesign and development

Qualification of thecommercialmanufacturingequipment andprocess

Maintenance of theprocess in a state of

control during routine

commercial production


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Validation of the process is not aone off event but represents anongoing continuum of scientific

knowledge development andongoing assurance.

Ongoing Continuum.


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Key Definition : Process Validation

The collection and evaluation of data,from the process design stage

throughout production, which establishesscientific evidencethat a process is

capable of consistently delivering quality

products



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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

2512

55

Description A Description B

Description C Description DDescription E

60%

30%

10% Description C

Description B

Description A

100%

5 7

2

4

2

3

7

9

56

8

6

5

3

Company A Company B

Proficiency in thecollection and

evaluationof information and dataabout the performance of the

process


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Importance of making the entire process validationprogram 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


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3 Stages of Process Validation

Process

Design

ProcessQualification

ContinuousProcess

Verification

ProductProduct

LifecycleLifecycle

ApproachApproach


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Key tenets of the lifecycle approach

Gain a high degree of assurance in the performance of theprocess before distribution

Based on objective information from lab, pilot, and/or

commercialscale studies Success relies on skilled interpretation of the information

and knowledge gained

Understanding sources of variation, their impacts andassociated risks

Establishing appropriate control strategies

This scientific knowledge is verified by testing

(in-process, release, characterization) of each significantstep of the commercial manufacture process


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Key Tenets of the Lifecycle Approach 2

Ongoing data analysis of both intra-batch and inter-batchvariability

Appropriate provisions to address deviations andnonconforming data

Importance of both QA and Operators in providingfeedback for continued process verification

Emphasis is on maintaining the process in astate of control

It provides a strong lead in acknowledging thatqualification programs devoid of process understandingwill not guarantee the assurance of quality required


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Stage 1Process Design

Design a process suitable for routine commercial manufacturing thatcan consistently deliver a product that meets its CQAs

a. Building and Capturing Process Knowledge and Understanding

b. Establishing a Strategy for Process Control

DOE

GMP/NonG

MP

PAT

CommercialScale

Functionalityand

Constraints

Variability


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Stage 2Process Qualification

Process design is confirmed as being capable of reproduciblecommercial manufacturing

a. Design of a Facili ty and Qualification of Utili ties and Equipment

b. Performance Qualification Approach

c. Performance Qualification Protocol

d. Protocol Execution and Report

Fit for Intended UseQualification

Productsmanufactured

duringthisstage,ifacceptable,canbereleased

Role of QA EnhancedMonitoring


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The decision to begincommercial distribution should

be supported by data fromcommercial batches

Released

Product and

ContinuedProcess

Verification

Batch

C

Batch B

Batch

AFacility and

Equipment'Qualified

How Many ?

Approved for Commercial Distribution


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Batch

C

Batch B

Released

Product and

ContinuedProcess

Verification

Facility and

Equipment'Qualified


The decision to begincommercial distribution

should be supported by datafrom commercial batches

How Many ?


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Batch B

Released

Product and

ContinuedProcess

Verification

Facility and

Equipment'Qualified


The decision to begincommercial distribution should be

supported by data fromcommercial batches

How Many ?


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Stage 3Continued Process Verification

Continually assure that the process remains in a state of control (thevalidated state) during commercial manufacture

Detection of Process Drift

Ongoing program to collect and analyze product andprocess data that relate to product quality

Statistician led analysis Detection, control, and/or mitigation strategies

Continued enhanced monitoring

Process Optimization Maintenance


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Reviews potential impact onthe current industryapproaches to science andrisk based design andqualification activities whichsupport the processvalidation program


This paper presentsan overview of thedraft FDA PVguidance


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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 Draft1987 PV Guidance

Key Changes between 1987 PV Guidance and 2008 Draft


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New Guidance in 2008 Draft

2008 Draft1987 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 revalidation and

retrospective process validation.

Introduction of

product lifecycle concept

Introduction of

integrated team approach


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Reviews potential impact onthe current industryapproaches to science andrisk based design andqualification activities whichsupport the processvalidation program


This paper presentsan overview of thedraft FDA PVguidance


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Key Definition : Qualification

Activities undertaken todemonstrate that utilities and

pieces of equipment are suitable fortheir intended use and performproperly is referred to in this

guidance as qualification



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Fundamental Change Needed

Current premise: Did we meet the

design (design is presumed to be

perfect)?

Future premise: Have we metprocess requirements, and have we

controlled risks to quality?


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Page 30

C&Q Model

Traditional V Model or Risk Based Verification

Lean Thinking is Equally Relevant

related to

SystemBuild

related to

related toUser

RequirementsSpecification

PerformanceQualification

FunctionalSpecification

OperationalQualification

InstallationQualification

DesignSpecification

Good Engineering Practice

Requirements Specificationand Design

VerificationAcc eptan ceand Release

Operation &

Continuous

Improvement

ProductKnowledge

ProcessKnowledge

RegulatoryRequirements

CompanyQuality Reqs.

Risk Management

Design Review

Change Management

Figure 1 The Specification, Design and Verification Process


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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 &

CONTINUOUSIMPROVEMENT

RISK MANAGEMENT

DESIGN REVIEW

CHANGE REVIEW

PRODUCT

KNOWLEDGE

PROCESS

KNOWLEDGE

REGULATORY

REQUIREMENTS

COMPANY QUALITY

REGULATIONS

REQUIREMENTS SPECIFICATIONS& DESIGN ACCEPTANCE& RELEASEVERIFICATION


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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 andmeet Acceptance Criteria

Acceptance

and

ReleaseFactory Acceptance Test

Site Acceptance Test

Installation VerificationFunctional 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


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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


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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

IncludeInclude

Q PlanQ Plan

Q ReportQ Report

(4) Responsibilities

(5) Procedures(6) Changes

Approved

Approved


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Summary FDA Draft PV vs. ASTM E2500

YYFlexibility on how effort is structured

YYRisk assessment to scale effort

YYQA approves

[qualification]/[verification] report

N* Acceptance

Criteria only

YQA approves

[qualification]/[verification] plan

YYEquipment and facilities suitable for

intended use

YYFocus on science-based process

understanding and meeting process

requirements

ASTMFDA PVQualification vs. Verification

Aspects


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Summary FDA Draft PV vs. ASTM E2500

NYSpecific aspects to check for spelled

out

YNACritical aspects defined from riskassessments and process

requirements

YYUse of project change management

YYUse of subject matter experts: how

to verify, adjudicate minor

departures from specification for CQ

YNAUse of vendor documents

YYDesign of facility, process,

equipment based on process

understanding

ASTMFDA PVQualification vs. Verification

Aspects


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Impact on Design & Verification

Endorses an Integrated LifecycleApproach

Seeks early alignment of product& process requirements

Requires Multi Disciplined Teams

Welcome avoidance of tradit ional,prescriptive terminology such as

DQ,IQ and OQ

Necessary from start of ConceptDesign

Requires access / engagement ofR&D

Impacted by Contracting Strategy

Offers Opportunities to reallyimprove the CQ process

Real opportunities to look behind the prepared templates and

execute qualification and validation programs which arenot only valid but valuable

to the ongoing operation and continuous improvement

O h D i


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ISPE Singapore - C&Q Workshop 2009Page 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, andVerification 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 June 2008

F f B li G id 12


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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


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Concepts

Pro

duc

t/

Process

Know

ledge

Requ

iremen

ts

De

fin

ition

Risk

Assessmen

t

Des

ign

Rev

iews

Ver

ifica

tion

Accep

tance

an

dRe

lease

Qua

lity

Managemen

t

Sys

tems

Ch

ange

Ma

nagemen

t

Ro

les

&

Re

spons

ibilities

Th Ch ll g


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The Challenge

NEW GUIDANCE NEW IDEAS

TIME TO APPROVAL


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Alignment

Questions and Answers


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Questions and Answers


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Questions Tomorrow ?

Alice RedmondC&Q Technical Director, PM Group

[email protected]

+353 21 452 2916

+353 86 8385088

Documents

FDA’s Draft Process Validation Guidance.pdf