CONSIDERATIONS OF CONTINUOUS MANUFACTURING PROCESSES

Transcription

1 LCDR Patric Klotzbuecher U.S. FDA/Office of Regulatory Affairs/New York District 3 rd FDA/PQRI Conference on Advancing Product Quality March 22 24, 2017 CGMP AND REGULATORY CONSIDERATIONS OF CONTINUOUS MANUFACTURING PROCESSES 1

2 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. CGMP AND REGULATORY CONSIDERATIONS OF CONTINUOUS MANUFACTURING PROCESSES 2

3 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 3

4 Batch vs. Continuous 4

5 Batch vs. Continuous 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 (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 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; flexibility of operations (direct compression, dry, and wet granulation example) 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, intra batch variation, etc. (ie: different lots of feedstock) Dependent on equipment cycling capability Nomenclature & definitions to vary 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 (batch) 1,000,000s+ (continuous) 11

12 Continuous Manufacturing Experiences To Date 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 spectroscopy Particle size distribution 12

13 Batch definition Continuous Manufacturing Regulatory Considerations 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 Amount of time material could spend in a given stage of process Segregation of non conforming material 13

14 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 14

15 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 15

16 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 16

17 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 17

18 Continuous Manufacturing Readiness Quality cannot be adequately assured merely by in process and finishedproduct 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 18

19 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 19

20 V Model VP VR Critical Data URS Business Process (Intended Use) PQ/ VAT FS Functional OQ SOPs, Training, etc. DS + CS Design (Structural) IQ Build/ Test 20

21 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 21

22 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 22

23 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 23

24 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 24

25 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 25

26 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 validation studies 26

27 Outcome of PAIs Non conventional regulatory tools considered to generate postinspectional 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 27

28 Paradigm Shifts in Pharmaceutical Modernization Regulatory considerations for Continuous Manufacturing Continuous Processing Experiences to date What to expect from Pre Approval Inspections LCDR Patric Klotzbuecher U.S. FDA/Office of Regulatory Affairs/New York District E mail: Patric.Klotzbuecher@fda.hhs.gov Phone: