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

• “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

“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

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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; 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 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+

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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 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

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“Continuous” Manufacturing To Date

• 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

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“Continuous” Manufacturing Regulatory Considerations

“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

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“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

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

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 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

What to Expect During 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

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What to Expect from 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 – 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