cgmp and Regulatory Considerations of Continuous Manufacturing Processes

Transcription

1 cgmp and Regulatory Considerations of Continuous Manufacturing Processes LCDR Patric Klotzbuecher U.S. FDA/Office of Regulatory Affairs/New York District 2 nd FDA/PQRI Conference on Advancing Product Quality October 5-7, 2015

2 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

3 Continuous Manufacturing: Stepping Down The Path Innovate or stagnate 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 3

4 Batch vs. Continuous : Engineering Definition 4

5 Batch vs. Continuous : Variations 5

6 Traditional Tablet Manufacturing Semi-finished product collected after each unit operation In process and release testing off-line Actual processing time = days to weeks 6

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8 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

9 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) 9

10 Continuous Manufacturing: Quality Management No specific regulations or guidance for continuous manufacturing, other than the definition of a batch or lot 21 CFR 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 10

11 Continuous Manufacturing: Quality Management Implementation of a Risk-Based Control Strategy Enables quality to be directly built into process design Process Analytical Technology Feed-forward or feed-back mechanisms Real Time Release Testing Models as surrogate for traditional in-process/release testing Scale of data points used for batch review & disposition: ~100,000s 1,000,000s+ 11

12 Continuous Manufacturing 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 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 To Date 12

13 Continuous Manufacturing Regulatory Considerations Batch definition Target mass/time interval Defined by multi-variable functions incl. process design limitations *Maintenance of traceability & distinction through continuous process Introduction of concept of residence time distribution Probability function describing amount of time material could spend in a given stage of continuous process Segregation of non-conforming material 13

14 Continuous Manufacturing: Inspectional 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 14

15 Continuous Manufacturing: Application Data Verify integrity of data supporting Design of Experiments Data 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 & NCPPs Management of critical/major/minor data & deviations 15

16 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 16

17 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/manage excursions System tagging / flagging of out-of-limit sublots Verify appropriate implementation of reject mechanisms 17

18 VP V-Model VR Critical Data URS Business Process (Intended Use) PQ/ VAT FS Functional OQ SOPs, Training, etc. DS + CS Design (Structural) IQ Build/ Test 18

19 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 19

20 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 20

21 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 21

22 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 22

23 What to Expect During PAIs Review of documents & evidence relating to: Master validation plan; specific protocols Startup/shutdown/restart procedures Production of submission batches Material traceability/segregation/rejection Equipment & computer system capabilities Production recipes; system user controls Model orchestration and maintenance plans Process Performance Qualification; CPV Deviation/non-conformance management procedures Employee knowledge/training 23

24 What to Expect from PAIs 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 Process Validation 24

25 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 25

26 Acknowledgements CDER/OPQ/Office of Process & Facilities Review Team Sharmista Chatterjee Celia Cruz Bogdan Kurtyka Rapti Madurawe CDER/OPPQ/DIPAP Vibhakar Shah CDER/OPQ/OS/DQIRAM/QIB Alex Viehmann Co-Investigators, ORA Junho Pak, PHI-DO LCDR Samina Khan, NYK-DO Arie Menachem, NWE-DO 26