Continuous Manufacturing, Emerging Technology and the Office of Pharmaceutical Quality ISPE Continuous Manufacturing Conference Baltimore, MD Robert Iser, M.S. Acting Director, Office of Process & Facilities FDA/CDER/OPQ 1
Objectives Discuss how Emerging Technology fits within the Office of Pharmaceutical Quality Introduce OPQ s Integrated Quality Assessment Approach Share Pre-Approval Inspection Considerations for Continuous Manufacturing Sites 2
Pharmaceutical CGMPs for the 21st Century - A Risk-Based Approach Encourage the early adoption of new technological advances by the pharmaceutical industry Enhance the consistency and coordination of FDA's drug quality regulatory programs, in part, by further integrating enhanced quality systems approaches into the Agency s business processes and regulatory policies concerning review and inspection activities Ensure that regulatory review, compliance, and inspection policies are based on state-of-the-art pharmaceutical science 3
Office of Pharmaceutical Quality (OPQ) Mission The Office of Pharmaceutical Quality assures that quality medicines are available to the American public Vision The Office of Pharmaceutical Quality will be a global benchmark for regulation of pharmaceutical quality Slogan One Quality Voice 4
The Office of Pharmaceutical Quality A single unit in CDER dedicated to drug product quality The creation of one quality voice streamlining quality oversight throughout the lifecycle of a drug product Encourages the use of modern, more efficient manufacturing technologies Established consistent quality standards and clear expectations for industry Balances potential quality risks with the risk of a patient not getting a drug Anticipated quality problems before they develop to help prevent drug shortages Emphasizes quality metrics and surveillance techniques to help monitor quality across facilities 5
OPQ Immediate Office Acting Director: Mike Kopcha Deputy Director: Lawrence Yu Office of Program and Regulatory Operations Acting Director: Giuseppe Randazzo Office of Policy for Pharmaceutical Quality Acting Director: Ashley Boam Office of Biotech Products Director: Steven Kozlowski Office of New Drug Products Director: Sarah Pope Miksinski Office of Lifecycle Drug Products Director: Susan Rosencrance Office of Testing and Research Director: Cindy Buhse Office of Surveillance Acting Director: Russ Wesdyk Office of Process and Facilities Acting Director: Robert Iser
Emerging Technology (ET) Technology with which the FDA has limited review or inspection experience, but that has the potential to modernize the body of knowledge associated with pharmaceutical development New technology (or technology not previously applied to pharmaceutical applications) intended to support more robust, predictable, and/or cost- effective processes or novel products Innovative or novel products, manufacturing processes, or analytical technology subject to CMC review Examples of ET include: Continuous manufacturing of drug substances and drug products On-demand manufacturing of drug products Use of robots in pharmaceutical manufacturing 3-D printed tablets New container and closure systems for injectable products 7
FDA s Emerging Technology Program The Emerging Technology (ET) Program provides a centralized collaborative platform for FDA and industry to accelerate the development and adoption of emerging technologies 8
Emerging Technology Team (ETT) A small cross-functional team with representation from all relevant CDER and ORA review and inspection programs Chair: Sau (Larry) Lee, Associate Director of Science, OPQ PM: Cheryl Kaiser (OPQ/OPRO) Current Members: Thomas O Connor(OPQ/IO-SRS), Celia Cruz (OPQ/OTR), Mohan Sapru & Ray Frankewich (OPQ/ONDP), Geoffrey Wu (OPQ/OLDP), Kurt Brorson (OPQ/OBP), Grace McNally, Sharmista Chatterjee & Bryan Riley (OPQ/OPF), Tara Gooen (OPQ/OPPQ), Rebeca Rodriguez & Susanne Richardson (ORA) Other subject matter experts as needed Contact ETT: CDER-ETT@fda.hhs.gov 9
Emerging Technology Team Functions Serve as a centralized location for external inquiries on novel technologies Provide a forum for firms to engage in early dialogue with FDA to support innovation Ensure consistency, continuity, and predictability in review and inspection ETT member(s) plays an active or leadership role in the OPQ quality assessment team for applications containing an emerging technology Identify and evaluate roadblocks relating to existing guidance, policy, or practice Help establish quality standards and policy, as needed Facilitate knowledge transfer to relevant CDER and ORA review and inspection programs 10
DRAFT ET Guidance Provides recommendations to companies interested in participating in a program involving the submission of CMC information containing emerging manufacturing technology to FDA. Applicable to companies that intend the technology to be included as part of an: investigational new drug application (IND) or original or supplemental new drug application (NDA), abbreviated new drug application (ANDA), or biologic license application (BLA) reviewed by the Center for Drug Evaluation and Research (CDER), and where that technology meets other criteria described in this guidance. 11
CONTINUOUS MANUFACTURING 12
What is Continuous Manufacturing? In a continuous manufacturing process, the material(s) and product(s) are continuously charged into and discharged from the system, throughout the duration of the process. 1 13
Why Continuous Manufacturing? FDA recognizes that continuous manufacturing (CM) has the potential to increase the efficiency, flexibility, agility, and robustness of pharmaceutical manufacturing Integrated processing with fewer steps No manual handling, increased safety Shorter processing times Smaller equipment and facilities More flexible operation Lower capital costs, fewer work-in-progress materials Reduced environmental foot print Feasible for manufacturing small batch sizes On-line monitoring and control for increased product quality assurance in real time Amenable to Real Time Release Testing approaches 14
Continuous Manufacturing Emerging Technology FDA has identified CM as an emerging technology CM is still a new manufacturing approach for pharmaceutical application in comparison with other industries (e.g., food and chemicals) Adoption and advancement of system engineering tools (e.g., model-based design and optimization and advanced process control) may be needed to maximize potential benefits CM has a great deal of potential to increase the efficiency, flexibility, agility, and robustness of pharmaceutical manufacturing, and thus have a huge impact on product quality CM could provide benefits to both patients and industry 15
Trends in Continuous Manufacturing NDA approvals ~15 ETT & Industry meetings since the launch of ET program in early 2014 providing feedback on the development of CM processes (FYI - 30+ for all ET proposals) Drug substances Drug products Small molecules and biotechnology products Facility visits 16
INTEGRATED QUALITY ASSESSMENT 17
Integrated Quality Assessment (IQA) IQA team provides an aligned, patient-focused and riskbased drug product quality recommendations for BLAs, NDAs, and ANDAs, inclusive of drug substance, drug product, manufacturing, and facilities. IQA Teams consist of: Application Technical Lead (ATL) Regulatory Business Process Manager (RBPM) Discipline Reviewers (includes OPF & ORA) Advisors - Lab (OTR), Policy (OPPQ), Surveillance (OS), etc. 18
ANDA IQA Team Roles Role / Task Scientific Content / Initial Risk Assessment Process and Timeline IQA Executive Summary Assessment of Drug Substance / DMF Assessment of Drug Product Assessment of the Manufacturing Process Assessment of Facilities Assessment of Biopharmaceutics Assessment of Microbiology Assessment of Environmental Analysis Labeling & Package Insert PAI Inspections Lifecycle Knowledge Management Responsible (General Case) ATL / IQA Team RBPM ATL / IQA Team DS/DP Reviewer DP Reviewer Process Reviewer Facility Reviewer Bio pharm Reviewer Micro Reviewer EA reviewer DP Reviewer ORA Lead / SMEs participate ATL/ IQA Team 19
Integrated Quality Assessment & PAIs The IQA aligns review and PAI functional areas A PAI is part of the overall quality assessment performed by the Integrated Quality Assessment (IQA) team IQA team members (ORA, OPF, others) share knowledge regarding the manufacturing process described in the application and any information from a pre-operational review PAI team led by ORA, includes OPF, perhaps ONDP, and ETT member. Inspection findings are fed back into IQA team Communication within the IQA team regarding the inspection findings and firm s corrective actions 20
Benefits of IQA Fully informed risk-based decision making related to quality Benefit to review team, as team better understands the implementation of the process and controls Benefit to inspection, as team contributes their knowledge and expertise of review process Unified voice from inspection and review functions of the IQA team Enhanced risk-based decision making related to quality 21
OPQ-ORA Interaction OPQ and ORA members may participate on a Pre- Operational Review/Visit (POR/POV) Interactions prior to the PAI Harmonize on critical areas of focus for the PAI Based on expertise, clear division of areas to evaluate during the PAI Interactions during the PAI PAI team members consistently apprised each other of any findings or concerns Home Team at White Oak routinely informed throughout inspection Interactions after the PAI Each PAI team member contributed to drafting the EIR (Establishment Inspection Report) & contributes to IQA assessment recommednations 22
Pre-Operational Reviews of Manufacturing Facilities Provides CDER and ORA an opportunity to visit the manufacturing facility prior to the pre-approval inspection. FDA can review and discuss any manufacturing facility, equipment and process issues. Valuable feedback to the manufacturer prior to review and inspection. Provides FDA the opportunity to become aware of future manufacturing operations and new technologies. Early involvement with new technology will increase efficiency and timely quality evaluation of manufacturing operations. 23
Will there be a PAI for my ET Application? Considerations: Expected to be significant changes to manufacturing facility, equipment, and process Novel technology for which manufacturer and FDA do not have extensive experience Presents challenges to readiness for manufacturing objective of the pre-approval inspection program Complexity and criticality of manufacturing process Aspects of automation and equipment design can be more readily assessed during inspection than review 24
Pre-Approval Inspection (PAI) Determination - Risk Based Approach Facility Risk: Are there manufacturing risks associated with the inspectional history and current operations at this facility that impact may application? Facility Changes. Process Risk: What are the manufacturing risks associated with the proposed unit operations in this application? Experience with this process. Product Risk: Is there limited knowledge about the manufacture of this product? What s the connection between manufacturing and clinical efficacy and patient safety? OPF Facility Reviewers assess these three risks to make the PAI Inspection recommendation Product Process Facility 25
Post-PAI Follow-Up Initial Recommendation on PAI by the District Office Completion of Establishment Inspection Report (EIR) Communication between District Office and OPQ regarding inspection and corrective actions Evaluation of PAI EIR and firm 483 response within OPQ to make final recommendation Feedback to application review committee regarding inspection findings Final recommendations for all facilities related to application made by OPF (as part of IQA team recommendations) Inspection information factored into lifecycle management for facility, determine need for future inspections 26
CM & PAIs 27
Inspection Considerations (1) Pharmaceutical Quality System (PQS): Are there any modifications to the existing PQS that is needed for CM? Structure of effective QA Unit should handle CM, although processes and definitions may need revisions Definition of a lot or batch Traceability for segments of the production run; for systemic quality events impacting many segments, may need a look back for previously released segments 28
Inspection Considerations (2) PQS (continued): Collection of conforming product When will product diversion occur? Will this be planned in advance; criteria established? Is there data to support decisions on product collection or diversion (Start; Pause; Shutdown)? Expected or Unexpected Events? Who makes the decision? 29
Inspection Considerations (3) PQS (continued): Process for reviewing batch records: Timelines for review (tight deadlines) Quantity of information reviewed (large quantity of electronic process information) Sequence of batch record review and product segment release Batch review after product segment complete; or simultaneous review during production? 30
Inspection Considerations (4) Automation of Manufacturing Processes: Level of software validation dependent upon risks Written requirements documents for functionality Appropriate level of QA involvement in development, testing, and change control Clarity on automated actions versus operator actions Adequacy of training of operators to use software Resolution of alarms; impact on product quality Proactive anticipation of events; involvement of the QA Unit 31
Inspection Considerations (5) Electronic Batch Records: What level of review performed for process and analytical data needed for batch release Define the information to be reviewed by QA How are atypical events and work-around situations recorded Controls in place to assure that records are Attributable, Legible, Contemporaneous, Original, Accurate (ALCOA) 32
Inspection Considerations (6) Facilities and Equipment: Dedicated or Multi-Product Equipment (identification, cleaning) Single Use or Reusable Equipment (equipment durability; leachables) Detection of accumulated materials within equipment (observability) Cleaning of complex equipment; many connections; extensive tubing Equipment function over long durations (maintenance, calibration) 33
Inspection Considerations (7) Facilities and Equipment: Continuous operations or shut downs during operations (overnight); duration of product hold and impact on quality Bioburden levels for wet processes Equipment temperature and impact on product stability 34
Inspection Considerations (8) Process Validation: Design Facilities; Qualification of Equipment and Utilities Materials appropriate for intended use Verifying utility and equipment; built and installed in accordance with design specifications Verification that utility systems and equipment operate in accordance with process requirements in anticipated operating ranges Different approaches used for this stage 35
Final Thoughts Emerging Technology Guidance is available Innovation (including CM) is encouraged and FDA appreciates transparent communication OPQ s Integrated Quality Assessment lends itself to assessment of Emerging Technology Variety of mechanisms in place to provide feedback related to both review and inspection Inspection Considerations for ET are adapted from assessment of traditional technologies 36
Acknowledgements Christina Capacci-Daniel Sharmista Chatterjee Dave Doleski Arwa El Hagrasy Sau (Larry) Lee Rapti Madurawe 37
Thank you for your attention! Additional Questions: CDER-OPQ-Inquiries@fda.hhs.gov 38