cGMP and Regulatory Considerations of Continuous
Manufacturing Processes
LCDR Patric Klotzbuecher U.S. FDA/Office of Regulatory Affairs/New York District
2nd FDA/PQRI Conference on Advancing Product Quality
October 5-7, 2015
Pharmaceutical Manufacturing: The Path Ahead…
“Right now, manufacturing experts from the 1950s would easily recognize the pharmaceutical manufacturing processes of today. It is predicted that manufacturing will change in the next 25 years as current manufacturing practices are abandoned in favor of cleaner, flexible, more efficient continuous manufacturing.” Dr. Janet Woodcock, AAPS Annual Meeting, October 2011
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Continuous Manufacturing: Stepping Down The Path
• Differences between “Batch” and “Continuous” processing – Engineering perspective – Quality perspective
• Regulatory considerations for continuous manufacturing
• Continuous processing to date
• Pre-approval inspections and concluding remarks
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“Batch” vs. “Continuous”: Engineering Definition
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“Batch” vs. “Continuous”: Variations
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Traditional Tablet Manufacturing
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• Semi-finished product collected after each unit operation • In process and release testing off-line • Actual processing time = days to weeks
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Real Advantages of “Continuous” Processing
• Reduced overhead costs due to minimized inventory of semi-finished goods
• On-line monitoring and control for increased product quality assurance and consistency
• Facilitates Real Time Release Testing
• Potential to reduce operating costs 8
“Batch” “Continuous” Processing • Lag time of discharge & charge between unit operations,
testing & analysis, etc. Integrated processing with fewer steps/shorter turnover time, leads to increased operational efficiency
• Minimizes operator interactions—increased safety, reduced risk of human error and occurrence of deviations
• Smaller equipment & facility footprint; flexible operation (direct compression, dry and wet granulation capability)
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“Continuous” Manufacturing: Quality Management
• No specific regulations or guidance for continuous manufacturing, other than the definition of a “batch” or “lot”
• 21 CFR 210.3 definition refers to the quantity of material intended to have uniform character & quality
• Ways to define a batch/lot at product collection step? – Production time period, variation (ie: different lots of feedstock) – Dependent on equipment cycling capability Nomenclature & definition will vary by application
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“Continuous” Manufacturing: Quality Management
• Implementation of QbD Control Strategy Enables quality to be directly built into process design
• Process Analytical Technology/Feedback Mechanisms
• Dissolution Model/Real Time Release Testing
• Scale of data points used for batch review & disposition: ~1.0e5 1.0e6+
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• Facility Inspections: 1 foreign contract manufacturer; 16-20FEB2015 1 domestic manufacturer/control testing laboratory; 21-29APR2015
• Product: Fixed dose combination, immediate release tablet, designated as a breakthrough therapy
• Innovative manufacturing aspects: – QbD based application with established design spaces – Semi-/fully-continuous manufacturing processes – Including on-line/at-line in-process control and RTR Testing
Near-infrared spectroscopy Particle size distribution 12
“Continuous” Manufacturing To Date
• Batches composed of numerous “Product Keys” (PKs) Target mass of intragranular blend Multi-variable function defined by: 1) Granulation flow rate 2) Fluid bed dryer capacity/design limitations 3) Individual chamber fill time *Maintenance of traceability & distinction through continuous process
• Introduction of concept of residence time distribution Probability function describing amount of time a PK could spend in a given stage of continuous process
• Waste by range
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“Continuous” Manufacturing To Date
“Continuous” Manufacturing: Regulatory Considerations
• 3 primary objectives of pre-approval inspection program
1. Ascertain Readiness for Commercial Mfrg.
2. Verify Conformance to cGMPs and Application
3. Data Integrity Audit
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“Continuous” Manufacturing: Application Data
• Verification of QbD Design of Experiments (DoE) – Ensure proper analysis of DoE data (ie: statistical significance of various parameters on critical quality attributes) – Determination of criticality of process parameters (CPPs) – Appropriate establishment of Design Space Limits (DSLs) &
Nominal Operating Ranges (NORs)
• Control of CPPs & NCPPs Management of critical/major/minor data & deviations
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“Continuous” Manufacturing: Readiness
• “Quality cannot be adequately assured merely by in-process and finished-product inspection or testing”
• “Each step of a manufacturing process is controlled to assure that finished product meets all quality attributes”
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“Continuous” Manufacturing: Readiness
• Focus on evaluating Quality Systems that support control strategy. For example:
– Implementation of appropriate in-process controls/RTRT
– Equipment qualification across proposed design space
– Computerized system & software validation Consistent with user requirement & functional specifications Demonstrate ability of PAT to detect excursions System “tagging” /”flagging” of out-of-limit PKs Verify reject mechanisms & implementation of “waste by range” 17
V-Model
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VP VR
URS PQ/ VAT
Build/Test
DS + CS IQ
FS OQ
Business Process (Intended Use)
Functional
Design (Structural)
Critical Data
SOPs, Training,
etc.
Process Engineering vs. Optimization vs. Validation
• Systems engineering V-model Traceability of User Requirement Specs to individual test scripts & back
• Build detailed understanding of data flow; development of production recipes
• Demonstrate ability to identify excursions consistently and reliably
• Negate bow-wave effect of deviations/excursions
• Continuous process verification of disso model & RTRT 19
Real Concerns of “Continuous” Processing
• Adjustment of models based on variability in raw materials, process equipment fatigue/wear, etc.
• Sub-batch waste by range loosening of standard yield specification limits
• Challenge of recall decision-making/tracing/tracking – Sub-batch vs. batch – Intra-batch homogeneity – Inter-batch consistency
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Real Concerns of “Continuous” Processing
• Ability to identify and compensate for excursions from design space/defects before moving downstream
• In-/at-line monitoring and control ↑, risk ↓
• Lifecycle approach: perception of criticality as a continuum rather than a binary state
• Significant up-front investment of time, personnel, and capital to reduce long-term operating costs
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• Leveraging regulatory requirements to encourage voluntary compliance
• Reached agreements with firms regarding implementation of risk mitigation steps within the control strategy – Without CDER/ORA collaboration this would have warranted
several Information Request cycles
• Acceptance of requests for additional risk-based monitoring and formal evaluation of “NCPP”/”FYI only” data during PV
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Outcome of PAIs
• Non-conventional regulatory tools considered to generate post-inspectional commitments:
Demonstrate capabilities to continuously manufacture 1. Intended commercial batch size 2. According to established process parameters
(ideally within NORs)
• Evaluation of process issues typically managed by Quality System, but essential to determining the adequacy of control strategy stated in NDA
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Outcome of PAIs
Acknowledgements • CDER/OPQ/Office of Process & Facilities Review Team
– Sharmista Chatterjee (Inspection 1) – Celia Cruz (Inspection 2) – Bogdan Kurtyka (Inspection 2) – Rapti Madurawe
• CDER/OPPQ/DIPAP – Vibhakar Shah
• CDER/OPQ/OS/DQIRAM/QIB – Alex Viehmann
• Co-Investigators, ORA – Junho Pak, PHI-DO (Inspection 1) – LCDR Samina Khan, NYK-DO (Inspection 2) – Arie Menachem, NWE-DO (Inspection 2) 24
