Validation Lifecycle Case StudyManufacturing checklist completed 6. Evaluation of PAI readiness 7. FMEA, Risk Control Strategy Report [RCS] updated as required 8. Continued Process

Validation Lifecycle Case Study

Use of Stage 1 Data in Stage 2

and Beyond

David Dolgin – Senior Validation Consultant, PSC Biotech

Discussion OverviewHypothetical case-study – not a real product or

company process

Follow the development of both new DS and

new DP

Examine data and process knowledge gathered

at various points on an example development

continuum

Consider how Process Qualification plans and

subsequent activities are impacted by above

data

Background

Discussion will use terminology common

to Process Validation Lifecycle

Stage 1 = “Process Design”

Stage 2 = “Process Qualification”

Sub-Stage ”2a” = Facility Qualification

Sub-Stage “2b” = Process Validation

Stage 3 = “Continued Process Verification”

Process Validation Definition

U.S. FDA 2011

The collection and evaluation of data, from the

process design stage through commercial

production, which establishes scientific

evidence that a process is capable of

consistently delivering quality product.

Relationship Between Stages

Stage 1

Process DesignConfirmation

Stage 2

Process Qualification

Design of

Facilities and

Qualification

of E/F/U

Process

Performance

Qualification

(PPQ)

Stage 3

Continued Process VerificationDistributeDistribute

Grace McNally,

FDA CDER Office of Compliance Division of Manufacturing & Product Quality

2010 PDA/FDA Joint Regulatory Conference September 15, 2010

High-Level Description: Stage 1

Stage 1 Objectives

Develop functional

understanding of

relationships between

materials, methods, and

quality attributes

Design a process suitable

for routine commercial

manufacturing that can

consistently deliver a

product that meets its

quality attributes

Stage 1 Activities

Building and capturing

process knowledge and

understanding

Establishing a Process

Control Strategy to be

carried forward to Stage 2

Process Control Strategy

Understand the sources of variation

Detect the presence and degree of

variation

Understand the impact of variation –

ultimately on product attributes

Control variation commensurate with risk

U.S. FDA as stated in 2011 Process Validation Guideline

Understanding Variation

ControlControl

Sources of Variability

Total Process

Variability

Raw

Materials

Process

Parameters

Equipment

Used

Personnel

Mfg. Run

Conditions

Environ.

Conditions

ProceduresInstruments

Validating the Control Strategy

Stage 1 – Process Design

• Define Control Strategy

Stage 2 – Process Qualification

• Confirm Control Strategy in Commercial Site

Stage 3 – Continued Process Qualification

• Ensure Control Strategy is effective

Lifecycle of Process Knowledge

Stage 1 Stage 2

Co

mm

erc

ial

Stage 3

FDA Process Validation Lifecycle StagesP

PQ Ongoing

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review

API:TT Strategy Review

DP: Scale-Up Review

API: Val. Review

DP: Demo Lot

KR 1 KR 2 KR 3 KR 4 KR 5 KR 6 KR 7 KR 8

DP Val. Review /

Launch Ready?

Mfg. Quality History

Review/APR/PQR

Registration

Batches

Review

Example Knowledge Review (KR) Schedule

KR 1 – Pre-Commercial Development Review

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review

1. Target dosage form and dosage strength range identified (TPP)

2. Process/equipment chains identified for design or development

3. Stability data reports for Phase 1 materials

4. Excipient compatibility studies completed

5. PAT Analytical Strategy drafted (if applicable)

6. Potential critical quality attributes (CQAs) identified

Potential KR 1 Process Knowledge Items

KR 2 – Pilot Scale Review

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review


1. Formulation, mfg. process and potential CPP’s, IP’s, CQA’s at pilot scale

2. Draft formulation justification available

3. Dosage strength (range) confirmed

4. Commercial package evaluation studies completed

5. Stability data available for prototype commercial formula

6. PAT Strategy Defined – Pilot Scale (if applicable)

7. Target Operational Profile - Prepare QbD documentation (if applicable)

8. Updated Risk Assessments for product and process design

KR 3 – API Synthetic Route

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review


1. Commercial synthetic route identified, Final steps for API purity defined

2. Special processing, equipment, and containment needs identified

3. Tentative starting material, in-process controls and intermediate

specifications and analytical methods proposed

4. Test methods and specs established as appropriate for stage of

development

5. Registration batches bulk physical properties established

6. API impurity profile of the commercial synthetic route established for

registration batches

7. Identification of SVHC (substances of very high concern) and controls

KR 4 – API TT Strategy

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review

Potential KR 4 API Process Knowledge Items:

1. Registration runs completed and data analyzed

2. Commercial synthetic process defined

3. PJ (Design Space) timeline & process optimization strategy available

4. Analytical transfer gap analysis and validation timeline & strategy

5. Preliminary Commercial PAT strategy is proposed (if applicable)

6. Initial commercial site(s) identified with capability analysis

7. Risk Assessment for product and process design timeline & strategy

KR 4 – DP Scale-Up Review

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review

Potential KR-4 DP Process Knowledge Items

1. Preliminary Design Space Determined

2. Commercial process/formulation defined (Commercial scale)

3. CPP and CQA revised/updated based on scale up studies

4. Primary package(s) finalized

5. Proposed product test methods and tentative specs

6. Test method validation complete

7. Stability data available for product in commercial package

8. Studies of the effect of API properties on the DP complete

9. PAT Strategy Defined [Scale-up]

10. Risk Assessment for product and process design updated

11. Commercial Product Definition complete

KR 5 – Registration Batch Review

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review

Potential API Process Knowledge Items:

1. Appropriate validation of analytical methods completed

2. Process Performance Qualification strategy defined and PPQ

protocols approved if Biologic DS

3. Analytical methods transfer strategy defined

4. Cleaning validation strategy developed and proposed

5. Manufacturing FMEA, Risk Control Strategy Report [RCS] Updated

KR 5 – Registration Batch Review

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review

Potential DP Process Knowledge Items :

1. Summary of registration run manufacturing experience

2. Demonstration lot plan

3. Update Design Space -- Process range justification

4. Launch scale plan

5. Risk Assessment for product and process design updated --

FMEA initiated

KR 6 – API Val Review

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review

Potential API Process Knowledge Items:

1. PJ (Design Space) updated as required

2. PPQ Report completed, analyzed, approved

3. Analytical method transfer completed

4. Potential post-approval changes identified

5. Manufacturing checklist completed

6. Evaluation of PAI readiness

7. FMEA, Risk Control Strategy Report [RCS] updated as required

8. Continued Process Verification Plan approved

KR 6 – DP Demo Lot

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review


1. Results of demonstration lot manufacture analyzed

2. Results of test method transfer to QA labs

3. Design Space finalized - Critical process parameters confirmed at

commercial scale

4. Rework/reprocess procedures available, if applicable

5. PPQ strategy defined and protocol complete and approved if

Biologic product

7. FMEA, Risk Control Strategy Report [RCS] Updated

KR 7 – DP Val Review / Launch Readiness

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review


1. PPQ results complete and analyzed (including process

capability) and approved

2. Any PPQ investigations or events closed

3. Technology transfer report complete and approved

4. Post-validation monitoring plan approved and ready to

implement

5. FMEA, Risk Control Strategy Report [RCS] updated

KR 8 – Manufacturing Quality History…

Pre-commercial

Development Review

Pilot Scale

Review

API Synthetic

Route Review


DP: Scale-Up Review

API: Val. Review

DP: Demo Lot


DP Val. Review /

Launch Ready?


Review/APR/PQR

Registration

Batches

Review

Potential API and/or DP Process Knowledge Items

1. Enhanced CPV Monitoring Report with Updated Monitoring

Schedule

2. Review of compliance/CAPA history

3. Any post-approval commitments completed

4. Manufacturing history – process capability

5. Test method history – performance of test methods

6. Stability history

7. Risk Assessment of drug product process [FMEA, Risk Control

Strategy Report [RCS]] updated as required; Identification of new

risks [post-launch]

8. Update Design Space based on manufacturing history

…and the Road Goes on Forever

(or at least until product discontinuation)

PROCESS QUALIFICATION &

CPV

Impact of Stage 1 Process Knowledge

First Principle

“Uncontrolled variation is the enemy of

quality.”

Dr. W. Edwards Deming

…and a corollary

“Ignorance of variation is the enemy of

Quality Assurance.”

Dave Dolgin ( nobody really)

FDA Expectations

Manufacturers should:

• Understand the sources of variation

• Detect the presence and degree of variation

• Understand the impact of variation –ultimately on product attributes

• Control variation commensurate with risk

“Guidance for Industry - Process Validation: General Principles and Practices”

Impact of Stage 1 Knowledge –Facility and Equipment Qualification

CPPs and ranges required

Chemical and Microbial Stability of Product

Environmental Requirements

Cleaning/Disinfection/Sterilization Strategy

Material Compatibilities

Critical I-P Data Collection Requirements

Primary Package Requirements

Site-Specific Requirements

Process

User

Requirements

for Systems

and Facilities

Impact of Stage 1 Knowledge –Process Performance Qualification (PPQ)

• Number of PPQ lots required to demonstrate control based on process variability

• Sampling Plans and Acceptance Criteria

• PPQ Lot Manufacturing

– Equipment used

– Process parameters used

– Materials used

– Personnel used

PPQ - Demonstration of Control

“A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected.”

“The number of samples should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches.” (underlines by

presenter)

“Guidance for Industry - Process Validation: General Principles and Practices”

Known Variability vs.

Number of PPQ Lots/Samples• Fundamental PPQ plan question:

What do we need to do in order to provide sufficient confidence of process control so that we are justified in commencing commercial sale?

• Process variability is the key factor:

Greater variability = more lots and more samples

Actually CPV is a two-phase stage:

“Enhanced” CPV – sampling/testing of

selected attributes at levels approaching PPQ

until statistical confidence established

“Routine” CPV - sampling/testing adjusted as

indicated by SCP and process data and

adjusted periodically as more data becomes

available

Impact of Stage 1 Knowledge –Continued Process Verification (CPV)

Stage 1 Knowledge Guides

Ongoing CPV PriorityFocus on least capable CQAs

Focus on trended CPPs

Medical assessment of event significance

to CQA

Focus on variability – inherent in product

design and/or manufacturing process

Key Take-Aways• Understanding and characterizing degree and

criticality of process variability is a key deliverable of Stage 1

• Understanding process variation is key to process control

• Process control is the objective and requirement of the PV lifecycle

• Degree of variation impacts all 3 stages:– Amount and type of data developed in Stage 1

– Stage 2 PPQ; number of lots, sampling plans, criteria

– Whether Stage 3a is required and if so, sampling plans

– Stage 3b CPV monitoring activities and reporting

David DolginSenior Validation ConsultantPSC Biotech [email protected]

Questions or Comments?

Documents

Validation Lifecycle Case StudyManufacturing checklist completed 6. Evaluation of PAI readiness 7. FMEA, Risk Control Strategy Report [RCS] updated as required 8. Continued Process