fda’s draft process validation guidance overview and ... redmond - process... · fda’s draft...

FDA’s Draft Process Validation GuidanceOverview and Implications for C&Q Programs

Alice Redmond, C&Q Technical Director09th 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 IndustryProcess 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DRAFT GUIDANCE This guidance document is being distributed for comment purposes only.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be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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 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.

FDA’s 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 IndustryProcess 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DRAFT GUIDANCE This guidance document is being distributed for comment purposes only.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be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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 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 FDA’s1987 ‘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 FDA’s 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 ScopeHuman

Drugs

VeterinaryDrugs

API‘s

Biological’s

Out of ScopeInvestigational

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 ApproachApproach


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


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 BDescription 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 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 archivingUniform collection and assessment of information methodsReducing the burden of redundant information gathering Use of an integrated team approach Appropriately documented Project Plans The support of senior managementStatistical assessment of data

3 Stages of Process Validation

Process Design

Process Qualification

Continuous Process Verification


Key tenets of the lifecycle approach

Gain a high degree of assurance in the performance of the process before distributionBased on objective information from lab, pilot, and/or commercial- scale studiesSuccess relies on skilled interpretation of the information and knowledge gained Understanding sources of variation, their impacts and associated risksEstablishing 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 variabilityAppropriate provisions to address deviations and nonconforming dataImportance 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 CQA’s’

a. Building and Capturing Process Knowledge and Understanding

b. Establishing a Strategy for Process Control

DOE

GMP/ Non GMP

PAT

Commercial Scale

Functionality and

ConstraintsVariability

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 Approachc. Performance Qualification Protocol d. Protocol Execution and Report

Fit for Intended UseQualificationProducts manufactured

during this stage, if acceptable, can be released Role of QA Enhanced Monitoring

“The decision to begincommercial distribution should

be supported by data fromcommercial batches“

ReleasedProduct and ContinuedProcessVerification

BatchC

Batch B

BatchA

Facility and Equipment 'Qualified‘

How Many ?

Approved for Commercial Distribution

BatchC

Batch B




“The decision to begincommercial distribution

should be supported by datafrom commercial batches“

How Many ?

Batch B




“The decision to begincommercial distribution should be

supported by data fromcommercial batches“

How Many ?

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 DriftOngoing program to collect and analyze product and process data that relate to product qualityStatistician led analysisDetection, control, and/or mitigation strategies Continued enhanced monitoringProcess OptimizationMaintenance

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

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”

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’


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?

C&Q Model

Traditional ‘V’ Model or Risk Based Verification

Lean Thinking is Equally Relevant

related to

SystemBuild

related to

related toUser

RequirementsSpecification

PerformanceQualification

Functional Specification

OperationalQualification

InstallationQualification

DesignSpecification

Good Engineering Practice

Requirements Specificationand Design Verification Acceptance

and Release

Operation & Continuous Improvement

Product Knowledge

ProcessKnowledge

RegulatoryRequirements

CompanyQuality 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 & CONTINUOUSIMPROVEMENT

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

VerificationPlan

List of Critical Aspects

(CQA, CPP)

Verification Testing (Design to Performance) to confirm Critical Aspects and

meet Acceptance Criteria

Acceptanceand

ReleaseFactory Acceptance TestSite Acceptance Test

Installation VerificationFunctional Verification

PerformanceTesting

Verification Phase

Acceptanceand

Release

Approved byQuality Unit


Review all completed verification testdocumentation by a second, independent SME


OperationContinuous

Improvement

Principles

Risk-Based ApproachScience-Based ApproachCritical Quality AttributesQuality by DesignGood Engineering PracticesSubject Matter ExpertsUse of Vendor DocumentationContinuous 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’

IncludeInclude

Q PlanQ Plan

Q ReportQ Report

(4) Responsibilities(5) Procedures (6) Changes

Approved

Approved

Summary FDA Draft PV vs. ASTM E2500

YYFlexibility on how effort is structured

YYRisk assessment to “scale” effort

YYQA approves [qualification]/[verification] report

N* AcceptanceCriteria 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

Summary FDA Draft PV vs. ASTM E2500

NYSpecific aspects to check for spelled out

YNACritical aspects defined from risk assessments 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

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 valid but valuableto the ongoing operation and continuous improvement

ISPE Singapore - C&Q Workshop 2009

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 EquipmentGAMP 5 GuidanceISPE GEP best practise guide ISPE Draft C&Q best practise guideISPE Baseline Guide 12 Draft Verification guideFDA: Quality Systems Approach to Pharmaceutical cGMP Regulations – 2006EU Annex 20, Quality Risk Management – March 2008ICH Q8 Pharmaceutical Development - Nov 2005ICH Q10 – Quality Systems – June 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

Prod

uct/

Proc

ess

Kno

wle

dge

Req

uire

men

ts

Def

initi

on

Ris

k A

sses

smen

t

Des

ign

Rev

iew

s

Verif

icat

ion

Acc

epta

nce

and

Rel

ease

Qua

lity

Man

agem

ent

Syst

ems

Cha

nge

Man

agem

ent

Rol

es &

Res

pons

ibili

ties

The Challenge

NEW GUIDANCE NEW IDEAS

TIME TO APPROVAL

Alignment

Questions and Answers

Questions Tomorrow ?

Alice RedmondC&Q Technical Director, PM Group

[email protected]+353 21 452 2916+353 86 8385088

fda’s draft process validation guidance overview and ... redmond - process... · fda’s draft...

Documents