1. FDA’s Advisory Committee for Pharmaceutical Science The Subcommittee on Process Analytical Technologies (PAT): Overview and Objectives Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science, CDER, FDA February 25, 2002, Gaithersburg, MD.

2. Outline Overview of the FDA’s PAT Initiative –What? –Why? –When? –How? Goals and Objectives of the PAT- Subcommittee and Working Groups –What does FDA need/expect from you?

3. What are PAT? Systems for continuous analysis and control of manufacturing processes based on real-time measurements, or rapid measurements during processing, of quality and performance attributes of raw and in-process materials and processes to assure acceptable end product quality at the completion of the process. –Process analytical chemistry tools + information management tools + feedback process control strategies + product & process design and optimization strategies

4. PAT for Pharmaceuticals: Why? Optimal applications of PAT can improve the capability and the efficiency of pharmaceutical processes while maintaining or improving product quality –improve process understanding and help to ensure quality was “built in” or “by design” –reduce the risk of scrap and recalls –reduce production cycle times and enhance capacity utilization –in the long run, reduce product development time

5. PAT for Pharmaceuticals: Why? Current level of product quality is generally adequate for the intended use The process by which we achieve this level of quality is inefficient –The current manufacturing paradigm is skewed towards testing to document product quality and rejecting (or recalling) products of unacceptable quality

6. PAT for Pharmaceuticals: Why? Ensuring high efficiency of the US pharmaceutical manufacturing sector –Provide high quality drugs to the US public in a timely manner by taking advantage of the many new drug development opportunities offered by advances in biology and chemistry –Ensure optimal utilization of public and private resources to meet the growing health care needs of the US public Minimize risks due to sub-optimal pharmaceutical process quality

7. PAT for Pharmaceuticals: Why? Low manufacturing efficiency, waste (time and resources) and a high “cost of compliance” Need for very high level of regulatory scrutiny (review and inspections) –High proportion of FDA resources needed to ensure adequate product quality –Recurring problems that do not seem to get resolved –Continued debates between FDA-industry, few permanent resolutions

8. Risks Due to Sub-optimal Pharmaceutical Process Quality Development (Quality specifications) Manufacturing (Process capability)Regulatory approval and compliance

9. Minimum Regulatory “Sigma” Level for Drugs? Under cGMP when failures/recalls exceeds 10% - no longer “validated.” The minimum regulatory "Sigma” ~ 1.65? FDA Science Board 11/16/01: PricewaterhouseCooper Presentation (Modified by AH) Pharmaceuticals Semiconductor

10. Pharmaceutical OOS & Batch “Failures” Rates Scrap and rework - we plan for 5-10% (accepted as necessary) PWHC 11/16/01 “It is authors’ experience that... validation exercise precedes a trouble-free time period in the manufacturing area only to be followed by many hours (possibly days or weeks) of troubleshooting and experimental work after a batch or two of product fails to meet specifications. This becomes a never-ending task.” Harwood and Molnar. Using DOE techniques to avoid process problems. Pharm. Dev. Tech. 1998.

11. Risks Due to Sub-optimal Pharmaceutical Process Quality Risk of releasing a “poor” quality product –Recalls are not effective quality control tools Drug shortages –Delay in approval of important drug products –High potential for disruption in the availability of important drugs –Production of low volume “essential” drugs may be adversely effected

12. Risks Due to Sub-optimal Pharmaceutical Process Quality Regulatory commitments on an inefficient manufacturing process –Continued optimization activities in the post approval phase (or live with the “validated” but inefficient process) –Recurring manufacturing difficulties leading to very low efficiency and capacity utilization –Higher manufacturing and regulatory compliance costs “locked-in”

13. Risks Due to Sub-optimal Pharmaceutical Process Quality Increased risk of non-approval or delayed regulatory approval –Increased potential for quality problems confounding the clinical safety and efficacy databases –Past quality (compliance) problems can delay new drug approvals –Industry and FDA resources being spent on recurring problems

14. When? When was this initiative started? 3rd quarter 1999 (building on the AOAC International Special Symposium: “ Pharmaceutical Process Control and Quality Assessment by Non-Traditional Means,” October 1993, St. Louis, Missouri) FIP’s Millennium Congress, New Technology Forum of the Royal Pharmaceutical Society, PhRMA Technical Conclave,... –19 July 2001, ACPS Meeting –16 November 2001, FDA Science Board Meeting –28 November 2001, ACPS Meeting Recommendation to form a PAT Subcommittee

15. When? When can companies submit PAT based applications or submissions to FDA? –Any time a company is ready to do so they should contact the OPS/CDER/FDA to discuss their proposed PAT applications or submissions There are many hurdles that seem to hold back PAT applications –It is widely perceived that FDA will not accept PAT based applications, this is not true

16. Need for FDA to Facilitate Introduction of PAT Industry is hesitant to introduce PAT in US –Regulatory uncertainty/risk leads to “Don’t Tell” or “Don’t Use” practice New Technology = New Questions –Method suitability, chemometrics and validation Old products + New technology = New Regulatory Concerns –Problems not visible under the current system –Mindset: Why change? PAT application will add to current regulatory requirements

17. How does FDA plan to facilitate introduction of PAT? Eliminate regulatory uncertainty –#1. FDA will accept PAT applications that are based on “good” science Develop standards for PAT –Method suitability and validation –Multivariate statistical/computer pattern recognition –Critical process control points and specifications –Changes, OOS…. –#2. Current system “adequate for intended use” –#3. Introduction of PAT not a requirement

18. How does FDA plan to facilitate introduction of PAT? Eliminate regulatory uncertainty –#4. Define conditions under which PAT may replace current “end product release testing” –#5. Process for addressing existing “invisible” problems in marketed products –#6. Review and inspection practices –#7. International harmonization

19. How does FDA plan to facilitate introduction of PAT?: Two Tracks General Guidance on PAT –Information source: ACPS Subcommittee on PAT and working groups Meeting #1 2/25-26/02 Meeting #2 (6/02?) –Draft Guidance Implementation –CDER-ORA Team Invite companies to propose submissions –Expect to receive proposals for submissions (~3 by 4q 02) –Review-Inspection plans and teams for these submissions Plan for concurrent development -review- inspection

20. General (principles) Guidance on PAT Proposed Goals and Objectives –General principles and terminology Bring the community on the “same page” –Address issues related to “regulatory uncertainties” – Clarify the regulatory process Review and inspection –Other tangible benefits Serve as a tool for building within-company consensus Promote research and development activities in the pharmaceutical PAT area

21. Guidance Development Process PAT Steering Committee –CDER (OPS/OC) and ORA Douglas Ellsworth, Mike Olson/Diane Obrien, Joe Famulare, Frank Holcomb, Moheb Nasr, Yuan Yuan Chiu, Ajaz Hussain (Chair) Guidance writer: Raj Uppoor Project management: Chris Cole Communication tools - Web based and electronic tools (PAT@CDER.FDA.GOV)

24. Options for Introducing PAT A. Currently marketed “robust” products. PAT to improve efficiency (minimal improvement in quality assurance) B. Currently marketed products that need improvement. Step wise PAT approach - first improve quality and then improve the efficiency C. New products. PAT utilized throughout development and scale-up. Lab based tests to ensure shelf-life and/or for establishing “public standards.”

25. PAT Subcommittee A major source of information for the FDA’s General Guidance on PAT –At the end of this meeting: Topics to be covered in the guidance (outline) Layout general principles for setting specifications, validation, chemometrics Consensus on benefits, definitions, terminology –Meeting #2? More details on “optimal” applications, identification and control of critical formulation and process variables, specifications, validation, chemometrics, addressing OOS, ……. Illustrative examples (for inclusion in the guidance)

26. PAT Subcommittee Organization –Industry presentations to focus the discussion –Questions (see background packet) to stimulate and focus discussion –Four working groups Benefits, technology, definitions/terminology Process + Analytical Validation Chemometrics Product/Process Development –Only two meetings planned

27. Chemometrics (Kowalski and Wold) Multivariate data collection and analysis –DOE, PCA, PLS, non-linear PLS, neural networks,…... –Calibration, process modeling, pattern recognition and classification, signal correction and compression –Statistical process control,…. Need information of the type of tools and general principles (and examples) for “verification” and “validation” of such analyses

28. Challenges Different perspectives, expertise, and affiliations - can we come on the “same page” by the end of this meeting? Are two meetings sufficient to gather the information necessary to develop the general guidance? Is the “general guidance” approach the most effective approach?