Validation Strategy for Continuous ManufacturingOctober 2016

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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

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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

Stability Studies & Commercial Readiness

Scale Up Process

Earlier Formulation

Development

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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.”

“A successful validation program depends upon information and knowledge from product and process development.”

• EMA Guideline on PV for Finished Products (2014)

Continuous Process Verification (CPV)“Manufacturing process performance is continuously monitored and evaluated (ICH Q8)”

““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.”

Stage 1 -Process Design

Stage 2 -Process

Qualification

Stage 3 -Continued Process

Verification

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Products manufactured with CM are well-suited for CPV

• QbD development to build extensive product knowledge

• Integrated QbD runs executed on full line after process transfer

Good Process Understanding

• Data is collected continuously throughout manufacture

• Process Control Strategy based on PAT

Data-Rich Environment

• Continuous Manufacturing Platforms• High Level of Process Automation• Spectroscopic and non-spectroscopic PAT and

RTRT

Advanced Technology

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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

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

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 Requirements

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CPV: Shift in Validation Paradigm

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• QbD Studies• Stability Batches• Product Development History• Implementation of VMP

Stage 1: Process Design

(Development Activities)

Stage 2: Process Qualification

(Demonstrate Commercial Readiness)

• Commercial Manufacturing• Batch Trend Analysis• Quarterly Management Review

Stage 3: Continued Process Verification (Post Approval Activities)

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Traditional Validation vs CPV

• 3 Batch campaign • Justify <3 batches

• Inc sampling plan (val only) • Inc sampling plan continues

• Validation Protocol & Report executed and complete

• Validation Master Plan is lifecycle document

CPV Strategy Implementation

• Leverage existing systems and procedures to implement a compliant and efficient validation strategyQbD ProcessContinuous Manufacturing PAT (IPCs / RTRT) and Model MaintenanceQA Batch ReleaseTrending Process

• Process Verification Confirmation of proposed commercial control strategyUse of all levels of control: in-line, on-line or at-line

monitoring/controls systemsProcess 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

Supporting development and clinical batch documentation

Historical context for assessment of the single commercially representative batch data

Manufacturing and release documentation for 1 commercially representative batch

Approved commercial batch record

Approved VMP

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CPV Proposal Summary

• Overall PV requirements still met• Process characterization• Process understanding• Control process variability

No single process validation campaign (3 batches)

• Conclusion: consistent manufacture of high quality product

No additional CPV requirements beyond the proposed VMP elements

• VMP becomes lifecycle document and is maintained within quality system

Inspection readiness (EMA) achieved after the manufacture of a single, commercially representative batch and CPV / release criteria are met

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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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