Validation Strategy for Continuous

Manufacturing
October 2016

©2016Vertex Pharmaceuticals Incorporated

 Changing Landscape for Drug Development requires
constant Innovation

• More complex targets, more complex molecules, breakthrough

therapies and personalized medicine
• CMC strategy needs to change to keep apace
– Accept challenging molecules
– Deep process understanding
– Open to different modalities
– Rapidly advance molecules from development to commercial

FDA and EMA have been open to

partnering on Innovative approaches

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Vertex’s Commitment to Manufacturing Innovation

Continuous Manufacturing Commercialization

“Data rich” QbD commercial design space

High quality, consistent product

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 CMC Challenges for Breakthrough Product
Development

Earlier
Formulation
Development

Scale Up
Process

Stability Studies &

Commercial
Readiness

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 Innovation in Manufacturing Continues with Validation
• FDA Process Validation Guidance (2011)
“Process validation involves a series of activities taking
place over the lifecycle of the product and process.”
Stage 1 -
Process
Design
“A successful validation program depends upon
information and knowledge from product and process
development.”
Stage 2 -
• EMA Guideline on PV for Finished Products Process
Qualification
(2014)
Continuous Process Verification (CPV)
Stage 3 -
“Manufacturing process performance is continuously Continued
monitored and evaluated (ICH Q8)” Process
Verification

““It is a science and risk-based real-time approach to

verify and demonstrate that a process that operates
within the predefined specified parameters consistently
produces material which meets all its Critical Quality
Attributes (CQAs) and control strategy requirements.”

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 Products manufactured with CM are well-suited for CPV

• QbD development to build extensive product

Good Process knowledge
Understanding • Integrated QbD runs executed on full line after
process transfer

• Data is collected continuously throughout

Data-Rich manufacture
Environment • Process Control Strategy based on PAT

• Continuous Manufacturing Platforms

Advanced • High Level of Process Automation
Technology • Spectroscopic and non-spectroscopic PAT and
RTRT

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Current Guidelines Support CPV Approach
Stage 1: Process Design
Key Activities:
•Primary Stability Batches
•Clinical Batches
•DoE Studies at Scale
•Initial Characterization of Process
Variability
•Develop Sampling Requirements
•Process Risk Assessment
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Stage 2: Process Qualification
Key Activities:
•Equipment and Facility Qualification
•Implement Control Strategy
•Commercial Batch Manufacture
•Validation Sampling/Testing
•Confirm Sampling Requirements
•Confirm Design Space Compliance
•Verify Validation State
•Batch Release
CPV Requirements
Stage 3: Cont Improvement
Key Activities:
•Equipment Calibration/PM &
Re-Qualification
•Inter-Batch Trend Analysis
•Quarterly Management Review
•ID & Resolve Sources of Variability
•Model Maintenance
•Update Process Risk Assessment
•APR Process
 CPV: Shift in Validation Paradigm
• QbD Studies
Stage 1: Process • Stability Batches
Design • Product Development History
(Development Activities) • Implementation of VMP

Traditional Validation vs CPV

Stage 2: Process • 3 Batch campaign • Justify <3 batches
Qualification
• Inc sampling plan (val only) • Inc sampling plan continues
(Demonstrate Commercial
Readiness) • Validation Protocol & Report • Validation Master Plan is
executed and complete lifecycle document

• Commercial Manufacturing
Stage 3: Continued • Batch Trend Analysis
Process Verification • Quarterly Management Review
(Post Approval Activities)

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 CPV Strategy Implementation

• Leverage existing systems and procedures to implement a

compliant and efficient validation strategy
 QbD Process
 Continuous Manufacturing
 PAT (IPCs / RTRT) and Model Maintenance
 QA Batch Release
 Trending Process

• Process Verification
 Confirmation of proposed commercial control strategy
 Use of all levels of control: in-line, on-line or at-line
monitoring/controls systems
 Process is validated if Batch Deposition Checklist is complete

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 Commercial Control Strategy Building Blocks

Release
In-Process
Controls

Process Design Space

Unit Operation control to set point

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 CPV Batch Disposition Checklist

(C)PPs assessed against DSLs

IPCs assessed against acceptance criteria

Material outside IPC or (C)PP design space criteria is properly segregated from the process

Residence Time Distribution (RTD) appropriately applied for segregated material

RTRT and IPC minimum sampling requirements are met

All deviations have been investigated, assessed (including their impact on CPV), and closed

Changes assessed with no impact on the material quality.

• All changes between start of registration and validation are assessed for impact to product
quality/stability, etc.

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 Documentation Required for Inspection Readiness

Approved VMP

Approved commercial batch record

Manufacturing and release documentation for 1 commercially

representative batch

Supporting development and clinical batch documentation

Historical context for assessment of the single commercially representative batch data

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 CPV Proposal Summary

No single process validation campaign (3 batches)

• Overall PV requirements still met

• Process characterization
• Process understanding
• Control process variability

No additional CPV requirements beyond the proposed

VMP elements

• Conclusion: consistent manufacture of high quality product

Inspection readiness (EMA) achieved after the

manufacture of a single, commercially representative
batch and CPV / release criteria are met
• VMP becomes lifecycle document and is maintained within quality system

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 Acknowledgements

• Vertex Team
• Pharmaceutical and Preclinical Science
• Technical Operations
• Supply Chain Management
• Quality
• CMC Regulatory
• Facilities
• Global Information Systems
• Equipment Manufacturers

• Our CMOs, Suppliers, and Research Collaborators

• Regulatory Agencies (FDA, EMA, MHRA, etc)

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