gmp and regulatory considerations of continuous...
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LCDR Patric KlotzbuecherU.S. FDA/Office of Regulatory Affairs/New York District
3rd FDA/PQRI Conference on Advancing Product QualityMarch 22‐24, 2017
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CGMP AND REGULATORY CONSIDERATIONS OF CONTINUOUS MANUFACTURING PROCESSES
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This is an informal communication that represents my best judgment at that time but does not constitute an advisory opinion, does not necessarily represent the formal position of FDA, and does not bind or otherwise obligate or commit the agency to the views expressed.
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CGMP AND REGULATORY CONSIDERATIONS OF CONTINUOUS MANUFACTURING PROCESSES
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Continuous Manufacturing “Innovate or Stagnate”
• Pharmaceutical Industry Modernization: modern manufacturing infrastructure needed to reduce risk (PIC/S QRM Expert Circle)
• Differences between “Batch” and “Continuous” processing– Engineering & Quality perspectives
• Regulatory considerations for continuous manufacturing
• Continuous processing experiences to date
• Pre‐approval inspections and concluding remarks
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Batch vs. Continuous
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Batch vs. Continuous
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Traditional Tablet Manufacturing
• 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 ofContinuous Processing
• Reduced overhead costs due to minimized inventory (semi‐finished goods, work in progress, etc.)
• On‐line monitoring and control increased product quality assurance and consistency
• Facilitates Real‐Time Release Testing
• Potential to reduce operating costs & time to market
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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; flexibility of operations(direct compression, dry, and wet granulation example)
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Continuous ManufacturingQuality 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, intra‐batch variation, etc.(ie: different lots of feedstock)
– Dependent on equipment cycling capability
Nomenclature & definitions to vary
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Continuous ManufacturingQuality Management
• Implementation of a Risk‐Based Control StrategyEnables quality to be directly built into process design
• Process Analytical TechnologyFeed‐forward or feed‐back mechanisms
• Real‐Time Release TestingModels as surrogate for traditional in‐process/release testing
• Scale of data points used for batch review & disposition: ~100,000s (batch) 1,000,000s+ (continuous)
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• Multiple companies involved in CM– Existing and novel drug substances & products– Fully continuous and semi‐continuous process trains– Integrated drug substance and drug product– Dosage forms for different routes of administration
• Innovative manufacturing aspects– QbD based applications with established design spaces – Semi‐/fully‐continuous manufacturing processes– Including on‐line/at‐line in‐process control and RTR Testing
Near‐infrared spectroscopyParticle size distribution
Continuous Manufacturing Experiences To Date
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• Batch definitionTarget mass/time intervalDefined by multi‐variable functions incl. process design limitations*Maintenance of traceability & distinction through continuous process
• Introduction of concept of residence time distributionProbability functionAmount of time material could spend in a given stage of process
• Segregation of non‐conforming material
Continuous Manufacturing Regulatory Considerations
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Continuous Manufacturing Regulatory Considerations
State of Control:• A condition in which the set of controls consistently
provides assurance of continued process performance and product quality. (ICH Q10)
• “After establishing and confirming the process, manufacturers must maintain the process in a state of control over the life of the process, even as materials, equipment, production environment, personnel, and manufacturing procedures change.” (U.S. FDA 2011 Process Validation Guidance)
• Maintained throughout lifecycle
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Continuous Manufacturing Regulatory Considerations
Lifecycle Quality Risk Management (ICH Q10)• “A proactive approach to identifying, scientifically evaluating, and
controlling potential risks to quality. It facilitates continual improvement of process performance and product quality throughout the product lifecycle.”
1. Identify process vulnerabilities to variation
2. Mitigate risk by designing robust operations; limit impact of external factors
3. Review original risk acceptance decisions
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Continuous Manufacturing Inspectional Considerations
• 3 primary objectives of pre‐approval inspection program
1. Ascertain Readiness for Commercial Mfrg.
2. Verify Conformance tocGMPs and Application
3. Data Integrity Audit
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Continuous ManufacturingApplication Data
• Verify integrity of data supporting Design of ExperimentsData submitted allowing reviewers to 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 & nCPPsManagement of critical/major/minor data & deviations
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Continuous ManufacturingReadiness
• “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”
• Process Performance Qualification Continuous Process Verification– Model based design and optimization– Advanced process control
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Continuous ManufacturingReadiness
• 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 validationConsistent with user requirement & functional specificationsDemonstrate ability of PAT to detect/manage excursionsSystem “tagging” /”flagging” of out‐of‐limit sublotsVerify appropriate implementation of reject mechanisms
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V‐ModelVP VR
URS PQ/VAT
Build/Test
DS + CS IQ
FS OQ
Business Process(Intended Use)
Functional
Design(Structural)
Critical Data
SOPs, Training,
etc.
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Process Engineering vs. Optimization vs. Validation
• Systems engineering V‐model– Traceability of URSs to individual test scripts & back
• Build detailed understanding of data flow; development of production recipes
• Demonstrate ability to identify excursions consistently
• Negate bow‐wave effect of deviations/excursions
• Continuous process verification of disso model & RTRT
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Information Management• General system architecture
• Hierarchal control structure & system integration– Instrument‐to‐system interfaces; compatibility– Process automation, industrial IT, data storage, data portals, and
management (orchestration) systems
• PAT function (including method validation) & automation– Variability managed to deliver a consistent process output– Accurate & reliable prediction of product quality attributes
• Operability in the qualified production environment– System‐to‐system interfaces; robustness
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Issues to Consider with Continuous Processing
• Adjustment of models based on variability in raw materials, process equipment fatigue/wear, etc.
• Sub‐batch segregation/reject mechanisms (bracketing) 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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Issues to Consider with 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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• Review of documents & evidence relating to:
Master validation plan; specific protocolsStartup/shutdown/restart procedures Production of submission batches Material traceability/segregation/rejection
– Equipment & computer system capabilitiesProduction recipes; system user controls Model orchestration and maintenance plans Process Performance Qualification; CPVDeviation/non‐conformance management procedures
• Employee knowledge/training
What to Expect During PAIs
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• Leverage regulatory requirements to encourage voluntary compliance
• Reach agreements regarding implementation of risk mitigation steps within the control strategy– Without CDER/ORA collaboration this would have warranted several
Information Request cycles
• Risk‐based monitoring and formal self‐evaluation of data acquired during validation studies
What to Expect from PAIs
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• Non‐conventional regulatory tools considered to generate post‐inspectional commitments:
Demonstrate capabilities to continuously manufacture1. Intended commercial batch size2. 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
Outcome of PAIs
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LCDR Patric KlotzbuecherU.S. FDA/Office of Regulatory Affairs/New York District
E‐mail: [email protected]: +1.787.366.1469
• Paradigm Shifts in Pharmaceutical Modernization
• Regulatory considerations for Continuous Manufacturing
• Continuous Processing Experiences to date
• What to expect from Pre‐Approval Inspections