Upload
dinhlien
View
215
Download
0
Embed Size (px)
Citation preview
Validation Strategy for Continuous ManufacturingOctober 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
2
FDA and EMA have been open to partnering on Innovative approaches
©2016 Vertex Pharmaceuticals Incorporated
3
Vertex’s Commitment to Manufacturing Innovation
Continuous Manufacturing Commercialization
“Data rich” QbD commercial design space
High quality, consistent product
©2016 Vertex Pharmaceuticals Incorporated
CMC Challenges for Breakthrough Product Development
Stability Studies & Commercial Readiness
Scale Up Process
Earlier Formulation
Development
©2016 Vertex Pharmaceuticals Incorporated4
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
©2016 Vertex Pharmaceuticals Incorporated5
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
©2016 Vertex Pharmaceuticals Incorporated6
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
7 ©2016 Vertex Pharmaceuticals Incorporated
CPV: Shift in Validation Paradigm
8
• 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)
©2016 Vertex Pharmaceuticals Incorporated
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
9 ©2016 Vertex Pharmaceuticals Incorporated
Commercial Control Strategy Building Blocks
Release
In-Process Controls
Process Design Space
Unit Operation control to set point
©2016 Vertex Pharmaceuticals Incorporated10
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.
11 ©2016 Vertex Pharmaceuticals Incorporated
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
©2016 Vertex Pharmaceuticals Incorporated12
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
©2016 Vertex Pharmaceuticals Incorporated13
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)
©2016 Vertex Pharmaceuticals Incorporated14