validation lifecycle case studymanufacturing checklist completed 6. evaluation of pai readiness 7....
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Validation Lifecycle Case Study
Use of Stage 1 Data in Stage 2
and Beyond
David Dolgin – Senior Validation Consultant, PSC Biotech
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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
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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”
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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.
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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
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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
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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
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Understanding Variation
ControlControl
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Sources of Variability
Total Process
Variability
Raw
Materials
Process
Parameters
Equipment
Used
Personnel
Mfg. Run
Conditions
Environ.
Conditions
ProceduresInstruments
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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
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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
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KR 1 – Pre-Commercial Development Review
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
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
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KR 2 – Pilot Scale Review
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
Potential KR 2 Process Knowledge Items
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
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KR 3 – API Synthetic Route
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
Potential KR 3 Process Knowledge Items
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
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KR 4 – API TT Strategy
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
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
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KR 4 – DP Scale-Up Review
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
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
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KR 5 – Registration Batch Review
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
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
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KR 5 – Registration Batch Review
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
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
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KR 6 – API Val Review
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
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
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KR 6 – DP Demo Lot
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
Potential DP Process Knowledge Items :
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
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KR 7 – DP Val Review / Launch Readiness
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
Potential DP Process Knowledge Items :
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
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KR 8 – Manufacturing Quality History…
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
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
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…and the Road Goes on Forever
(or at least until product discontinuation)
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PROCESS QUALIFICATION &
CPV
Impact of Stage 1 Process Knowledge
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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)
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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”
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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
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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
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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”
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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
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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)
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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
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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