FDA’s Advisory Committee for Pharmaceutical Science The Subcommittee on Process Analytical Technologies (PAT): Overview

1. FDA’s Advisory Committee for Pharmaceutical ScienceThe 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. Development (Quality specifications) Risk Managment Regulatory approval and compliance Manufacturing (Process capability) Risks Due to Sub-optimal Pharmaceutical Process Quality

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

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. 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 How does FDA plan to facilitate introduction of PAT?: Two Tracks

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)

22. Proposed/Draft NOT An NIR Guidance!

23. Proposed/Draft

24. 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.” Options for Introducing PAT

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?