Advisory Committee for Pharmaceutical Science April 13, 2004 OPS Update

1. Advisory Committee for Pharmaceutical ScienceApril 13, 2004OPS Update Helen Winkle Director, Office of Pharmaceutical Science Center for Drug Evaluation and Research Food and Drug Administration

2. Outline of Presentation • OPS Mission, Vision and Goals • Developing a new paradigm for CMC review in ONDC • Building on the Pharmaceutical Quality Initiative for the 21st Century • New Personnel in OPS • Meeting Agenda

3. Mission Statement To ensure timely availability of high quality drug products to the US patients through • effective and efficient scientific assessment of relevant pharmaceutical and biotechnology information in regulatory submissions and • by facilitating those scientific and technological innovation that improve understanding of product performance, quality and efficiency of development, manufacturing, and quality assurance processes

4. Vision OPS is an international champion and leader in regulatory application of contemporary scientific knowledge of design, development, manufacture, and clinical performance of pharmaceutical and biotechnology products

5. http://www.fda.gov/cder/gmp/21stcenturysummary.htm Goals and Objectives • OPS programs and projects will support the achievement of the following attributes of drug products: • Drug quality and performance is achieved and assured through design of effective and efficient development and manufacturing processes • Regulatory specifications are based on a mechanistic understanding of how product and process factors impact product performance • Continuous "real time" assurance of quality

6. http://www.fda.gov/cder/gmp/21stcenturysummary.htm Goals and Objectives • OPS will implement a review quality system and procedures that will: • Recognize the level of scientific knowledge supporting product applications, process validation, and process capability • Apply a risk based regulatory scrutiny that will relate to • level of scientific understanding of how formulation and manufacturing process factors affect product performance, and • the capability of process control strategies to prevent or mitigate risk of poor product performance

7. Setting the Stage For the Future • FDA Strategic Action Plan • Pharmaceutical Quality for the 21st Century • Resources • Other Influences

8. FDA Strategic Plan - Responding to Challenges and Opportunities • Efficient risk management - the most public health bang for our regulatory buck • Empowering consumers - improving health through better information • Improving patient and consumer safety • Protecting America from terrorism • More effective regulation through a stronger workforce

9. Strong Public Health Protection Time International cooperation Integrated quality systems orientation Science-based policies and standards Risk-based orientation FDA’s Initiative on Pharmaceutical Quality for the 21st Century FDA Unveils New Initiative To Enhance Pharmaceutical Good Manufacturing Practices http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html (August 21, 2002 )

10. Directional Vectors • Ensure regulatory review and inspection policies are based on state-of-the-art pharmaceutical science • Encourage new technological advances • Encourage risk-based approaches that focus both industry and Agency attention on critical areas • Facilitate modern quality management techniques, including implementation of quality systems • Enhance the consistency and coordination of FDA's drug quality regulatory programs, in part, by integrating enhanced quality systems approaches into the Agency's business processes and regulatory policies concerning review and inspection activities Second Progress Report and Implementation Plan. http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm (September 3, 2003)

11. Covering the Space Defined by the Directional Vectors Preapproval Inspection Compliance Program Dispute Resolution Process Risk Pharmaceutical Inspectorate Product Specialists on Inspection Process Systems/Integration Guidance on CFR Part 11 Aseptic Processing Comparability Protocol ICH P2, QbD, & Risk Management PAT Science

12. Opportunities • Develop strategy for ensuring product quality • Revisit processes - all aspects of pharmaceutical quality - incorporate best practices • Focus more on manufacturing and associated issues relating to quality of products • Focus both review and inspection more on science • Enhance interactions between review, inspection and compliance • Foster communication with industry • Early discussion of CMC questions • Dispute resolution • Leverage resources to get “best bang for buck” • Simplify regulatory requirements and reduce regulatory burden • Eliminate “check box” approach

13. More Opportunities • Enhance training opportunities • Plant residency • Cross training opportunities • Pharmaceutical inspectorate • Enhance FDA’s knowledge regarding new technologies in manufacturing and encourage innovation • Develop processes which are more focused on product risk • Revisit how quality of product relates to ensuring safety and efficacy - ensuring clinical relevance • Alleviate industry’s concerns regarding “reprisal” • Enhance international involvement • Pharmaceutical Development • Risk Management

14. Resources • CMC Workload for FY 2003 • 159 NDAs (103 originals and 56 resubmitted) • 342 commercial INDs • 507 research INDs • 1858 CMC supplements, not including efficacy and labeling • 1132 annual reports • Fewer review staff

15. Other Influences • 1995 - ONDC established - collocated with clinical divisions • Shorter PDUFA deadlines • FDAMA • Harmonization/globalization • SUPAC, BACPAC • New technologies in pharmaceutical manufacturing

16. Other Influences • PAT • Counterterrorism • Counterfeit products • BSE • Focus on generic products • Changes in industry - more global, mergers, etc. • Electronic submissions • Focus on risk management and quality systems

17. How to Achieve the Future CMC Review Paradigm • Develop risk-based CMC review • Establish quality systems which help set framework for ensuring dynamic organization • Focus resources towards efforts that improve quality - not hinder or interfere with innovation • Focus on all aspects of CMC - chemistry - manufacturing - controls

18. Advantages of New Paradigm in CMC Review • FDA • More product and process knowledge shared by industry for a better understanding of products and where manufacturing processes are in control • More efficient resource allocation for review and inspection • Increased trust and understanding of industry decision making

19. Advantages - cont. • Industry • Fewer, more efficient, science based inspections • Faster, more consistent reviews • Potential for reduced regulatory burden • Manage changes with less FDA oversight • Focus resources on critical issues • Flexibility to focus on what should be done, not what can be done • Improve communication with FDA

20. Advantages - cont • Ultimate beneficiary - The public • Increased availability of drugs on the market • Faster approval of new products • Continued assurance of high quality products • Increased confidence • {And hopefully, reduced costs}

21. What the New Paradigm Will Include • Develop strategies to recruit and train reviewers with expertise in drug discovery, analytical chemistry, pharmaceutical engineering, etc. • Build a learning organization “A learning organization is an organization skilled at creating, acquiring, and transferring knowledge, and at modifying it behavior to reflect new knowledge and insight” • Set specifications based on science and process understanding • Reengineer process • Best practices • Metrics • Customer oriented

22. New Paradigm • Increase emphasis on manufacturing science - ask the “right” questions at the “right” time • Implement peer review by FDA scientists and clinicians • Establish a program to better integrate review and inspection - team approach - product specialists on inspection • Develop processes which ensure regulatory relief based on: • Process understanding and control • Quality systems in manufacturing processes • Continuous improvement • Create better work environment and promote job satisfaction

23. Challenges to Moving Ahead • Current culture - both inside and outside of FDA • Hiring • Establishing performance metrics • Identify gaps in requirements • Reevaluate review process to determine right questions to ask to ensure product quality • Understanding what is relevant science • Determine what needed from pharmaceutical development data to assist in better understanding of manufacturing process • Develop a science-based risk model • Integrate better into inspection process including participating on inspections

24. OPS New Additions • Dr. Vincent Lee (OPS) • Dr. Mansoor Khan (DPQR/OTR/OPS)

25. ACPS Meeting Topics • Day 1 • Subcommittee Report • Proposal for PTIT (Parametric Toleerance Interval Test for Dose Content Uniformity) • PAT Update and PAT for Office of Biotechnology Products • Day 2 • Bioequivalence topics (highly variable drugs, bioINequivalence, and topical products) • Awareness topic - Nanotechnology