Update on Pharmaceutical Manufacturing Initiative

1. Update on Pharmaceutical Manufacturing Initiative Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science, CDER, FDA

2. Outline • Pharmaceutical Manufacturing Initiatives • Process Analytical Technology Initiative • CGMP for the 21st Century Initiative • PAT: Progress report and Strategy for Moving Forward • CGMP’s for the 21st Century • Defining the “desired state” • Questions for the Science Board

3. PAT Initiative • FDA Science Board Meetings (11/01, 4/02) • Emerging Science Issues in Pharmaceutical Manufacturing • Current state of Pharmaceutical Manufacturing • G. K. Raju (M.I.T) and Doug Dean (PriceWaterHouseCoopers) • Opportunities for improvements • Norman Winskill and Steve Hammond (Pfizer) • New Technology - “Don’t Use” or “Don’t Tell” approach • Ray Scherzer (CAMP/GlaxoSmithKline) • Challenge to Phrama Industry - Quality By Design • Science Board support for FDA’s proposal to facilitate innovation http://www.fda.gov/cder/OPS/PAT.htm#scienceboard

4. PAT Progress • Advisory Committee for Pharmaceutical Science (PAT Subcommittee) deliberations • Definitions, benefits, and scope • Perceive/real regulatory “hurdles” • Internal (with-in company) “hurdles” • Need for across discipline communication • Pharmacy+Chemistry+Engineering = Pharmaceutical Engineering • Approaches for removing these “hurdles” • Case studies • General approaches for validation • PAT Training curriculum for FDA staff

5. PAT Teams: ORA, CDER & CVM PAT Steering Committee Doug Ellsworth, ORA/FDA Dennis Bensley, CVM/FDA Mike Olson, ORA/FDA Joe Famulare, CDER/FDA Yuan-yuan Chiu, CDER/FDA Frank Holcomb, CDER/FDA Moheb Nasr, CDER/FDA Ajaz Hussain Chair, CDER/FDA PAT Review - Inspection Team Investigators: Robert Coleman (ORA/ATL-DO) Rebecca Rodriguez (ORA/SJN-DO) Erin McCaffery (ORA/NWJ-DO) George Pyramides (PHI-DO) Compliance Officers: Albinus D’Sa (CDER) Mike Gavini (CDER) William Bargo (CVM) Reviewers: Norman Schmuff (CDER) Lorenzo Rocca (CDER) Vibhakar Shah (CDER) Rosario D’Costa (CDER) Raafat Fahmy (CVM) PAT Policy Development Team Raj Uppoor, OPS/CDER Chris Watts, OPS/CDER Huiquan Wu, OPS/CDER (Ali Afnan, OPS/CDER) PAT Training Coordinators John Simmons, Karen Bernard and Kathy Jordan

6. Why Process Analytical Technologies? • PAT provides an opportunity to move from the current “testing to document quality” paradigm to a “Continuous Quality Assurance” paradigm that can improve our ability to ensure quality was “built-in” or was “by design” - ultimate realization of the true spirit of cGMP! • Greater insight and understating of processes • At/On/In-line measurement of “performance” attributes • Real-time or rapid feedback controls (focus on prevention) • Potential for significant reduction in production and development cycle time • Minimize risks of poor process quality and reduce (regulatory) concerns

7. Development/Optimization/Continuous Improvement (DOE, Evolutionary optimization, Improved efficiency) Incoming Materials. Specifications Relevant to “Process-ability” LT Control of process critical control points (PCCP). Process end point (PEPs’) range based on “performance” attributes. Multivariate Systems Approach Risk Classification and Mitigation Strategies PAC PAC PCCP PEP’s At-line In/On-Line Process Analytical Chemistry Tools Laboratory or other tests CM IT PAC LT Incoming material attributes used to predict/adjust optimal processing parameters within established bounds (more flexible bounds) Chemometrics (CM) and IT Tools for “real time” control and decisions Direct or inferential assessment of quality and performance (at/on-line) PAT Conceptual Framework for Regulatory Policy Development

8. Regulatory Framework • PAT tools not a requirement • Research exemption • Continuous improvement without the fear of being considered non-compliant • Regulatory support and flexibility during development & implementation • Eliminate the fear of delayed approval • Dispute avoidance/resolution • Science & Risk based regulatory approach • Low risk categorization based on a higher level of process understanding

9. Strategy for Moving Forward • Scientific Workshops • Several FDA co-sponsored and other workshops conducted (US and Europe) • Scientific discussion and debate • across disciplines (pharmacy, chemistry, chemical engineering) • organizational units (development, manufacturing, quality control, and regulatory departments) • General guidance on PAT to be released • Training workshop • Bring together different Associations (disciplines)

10. Strategy for Moving Forward • Champions to drive this initiative towards a “shared vision” or “desired state” • Industry: Pfizer, GSK, BMS, Aventis, Lilly, Novartis,... • Academia: MIT, Purdue, Washington, Tennessee, Michigan, Rutgers, Maryland, Minnesota, Connecticut, Puerto Rico, Duquesne.., London, Bradford, Basel,… (planned - Gifu and other universities in Japan) • PAT introduced in Pharmaceutical Engineering programs at Purdue, Michigan and Rutgers • (Instrument vendors - moving towards a association to address common issues)

11. Strategy: Moving forward • Improving the FDA knowledge base for technical policy development • Several experts recruited • Intramural research refocused to address technical needs and for in-house training • Significant increase in peer reviewed contributions • Learn from other industries (e.g., link with ASTM) • CRADA with Pfizer developed, awaiting final FDA approval (focus on chemical imaging) • Collaborate with NSF (Center for Pharmaceutical Processing Research)

12. Strategy: Moving forward • PAT Initiative a part of the broader cGMP Initiative for the 21st Century (announced 12 August 2002) • An example of science and risk-based systems approach to product quality regulations

13. A Drug Quality System for the 21st Century: Goals • “..it is time to step back and evaluate the currency of these programs so that:” • the most up-to-date concepts of risk management and quality systems approaches are incorporated while continuing to ensure product quality; • the latest scientific advances in pharmaceutical manufacturing and technology are encouraged; • management of the program encourages innovation in the pharmaceutical manufacturing sector; http://www.fda.gov/oc/guidance/gmp.html

14. A Drug Quality System for the 21st Century: Goals • the submission review program and the inspection program operate in a coordinated and synergistic manner; • regulations and manufacturing standards are applied consistently; • FDA resources are used most effectively and efficiently to address the most significant health risks. http://www.fda.gov/oc/guidance/gmp.html

15. Scope and Timeline • Veterinary drugs and human drugs, including human biological drug products • Organizations • ORA, OC, CBER, CDER, CVM • CFSAN and CDRH for issues that impact these centers (e.g., electronic records,..) • 14 Task groups (13 groups active) • Chair, Dr. Janet Woodcock • 2 years (immediate - 2/03, intermediate - 8/03, and long term projects)

16. Current Progress • Issued a draft Guidance on 21 CFR Part 11 implementation • The draft guidance clarifies the scope and application of the regulation and provides for enforcement discretion in certain areas that have been problematic • Issued a draft guidance entitled "Comparability Protocols-Chemistry, Manufacturing and Controls Information." • Encouraging innovation within the existing framework • Under appropriate circumstances, use of a comparability protocol can allow manufacturers to implement changes to their processes without submission of a prior approval supplement to the FDA.

17. Current Progress • Center review of drug cGMP warning letters • Technical dispute resolution process for cGMP disputes • Emphasizing a risk-based approach to the work planning process • Including product specialists on inspection teams • Improving the operations of Team Biologics • Enhancing expertise in pharmaceutical technologies • Pharmaceutical Inspectorate • Quality management system • International collaboration • Holding scientific workshops with stakeholders

18. Defining the “desired state” • As we move forward with this initiative it is essential to define what we wish to achieve • What should be the “desired state” of pharmaceutical manufacturing and associated regulatory policies in the 21st Century? • A shared vision to guide further evolution of this initiative • Enroll all stakeholders in this journey to better serve the patients • Highlight, for the academic and research community, the scientific needs in pharmaceutical engineering

19. A Drug Quality System for the 21st Century • Pharmaceutical manufacturing is evolving from an art form to one that is now science and engineering based. • Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes. • This initiative is designed to do just that through an integrated systems approach to product quality regulation founded on sound science and engineering principles for assessing and mitigating risks of poor product and process quality in the context of the intended use of pharmaceutical products. http://www.fda.gov/cder/gmp/21stcenturysummary.htm

20. http://www.fda.gov/cder/gmp/21stcenturysummary.htm Desired State • Product quality and performance achieved and assured by design of effective and efficient manufacturing processes • Product specifications based on mechanisticunderstanding of how formulation and process factors impact product performance • Continuous "real time" assurance of quality

21. http://www.fda.gov/cder/gmp/21stcenturysummary.htm Desired State • Regulatory policies tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability • Risk based regulatory scrutiny relate to the: • level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance, and • the capability of process control strategies to prevent or mitigate risk of producing a poor quality product

22. Question for the Science Board • Please recommend • how we may improve our articulation of the “desired state” • considerations for communicating the “desired state” with stakeholders • public, health care providers, academia and industry • additional considerations for aligning our activities to ensure efficient progress