2. FDA’s Advisory Committee for Pharmaceutical Science The Subcommittee on Process Analytical Technologies (PAT): Opening Remarks Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science, CDER, FDA June 12, 2002, Gaithersburg, MD.

3. Goals and Objectives Using PAT as a model technological opportunity, develop a regulatory framework to facilitate introduction of new manufacturing technologies that enhance process efficiencies and understanding –Identify and eliminate perceived/real “regulatory hurdles” –Develop a dynamic, team-based, scientific approach for regulatory assessment (review & inspection) of new technologies –International harmonization

4. Why PAT? 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

5. Strategy A “win-win” approach with input from the ACPS and the FDA Science Board –Internal Collaboration: CDER & ORA FDA PAT Steering Committee –External Collaboration: Industry & Academia FDA/ACPS Subcommittee on PAT PQRI Two parallel tracks –Guidance for industry on PAT Step 1: General principles (not focused on any one technology) –Encourage submission Team approach for review & inspection during development phase

6. Progress Report: Timeline –19 July 2001: Advisory Committee for Pharmaceutical Science 16 November 2001: FDA Science Board Meeting –28 November 2001: Advisory Committee for Pharmaceutical Science –24-25 February 2002: FDA/ACPS PAT-Subcommittee Meeting 9 April 2002: FDA Science Board Meeting –8 May 2002: Advisory Committee for Pharmaceutical Science –12-13 June 2002: FDA/ACPS PAT-Subcommittee Meeting

7. PAT Initiative:Timeline (2002) JANFEBMARAPRMAYJUNJULAUGSEPOCTNOVDEC PAT Track #1: Guidance Development Activities ACPS-PATSC Training ACPS-PATSC#2 Draft Guidance IFPAC, Aventis, BMS, PDA (Basel), Pfizer (Friberg), AstraZeneca (Plankstad), Barton Creek, GMP (Athens), CAMP, PITTCON,MCEC,.. PAT Track #2 ACPS-PATSC#3

8. Meeting #3 Computer validation and Part 11 issues Rapid microbial testing as part of the PAT initiative Simulated PAT Applications –Using “mock appli./submission/inspection” –Drug substance manufacture (on-line GC/HPLC/Raman/other) –Drug product manufacture (on-line NIR/other)

9. PAT Subcommittee Meeting #2: Day 1 Developing a shared vision for PAT –Definitions Minimizing real/perceived “regulatory risks and uncertainties” –Invited guests from industry Training/Certification Program Identify questions for in-depth discussion by working groups on Day 2

10. PAT Subcommittee Meeting #2: Day 2 Process Validation Working Group Product/Process Development Working Group Other Working Groups? –Training and Certification? –Regulatory process?

11. Questions for WG Please identify and describe approaches for introducing PATs (existing “validated” products; new products…) PAT R&D efforts in pilot plant (proof of concept and suitability for application in manufacturing) –What should be documented to justify suitability? PAT R&D efforts in manufacturing –What should would constitute acceptable verification of suitability and validation? Routine manufacturing using PAT –What should be the regulatory standard for accepting an on-line measurement to replace end product testing? –Level of built-in redundancy? Identify steps for resolving OOS observations –Under what conditions can end product testing be used to resolve OOS observations?

12. Questions for WG Using on-line NIR (for blend, dry, content, dissolution) and HPLC as examples of PAT, please outline the essential experiments (hypothesis or questions) that should be conducted by a company to successfully develop and validate these tools for use in manufacturing operations. What criteria should be used to ensure that relevant critical formulation/process variables have been identified and appropriate PAT tools selected to ensure their optimal control? What information should be collected to justify use of indirect measurements (e.g., signatures or correlations) that relate to product quality/performance attributes? When and to what extent would FDA involvement facilitate PAT R&D and Application projects?

13. 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 consensus Promote research and development activities in the pharmaceutical PAT area

14. General principles and terminology PAT: Definitions and Scope (regulatory) –Current State - Desired future state Shared vision for PAT and a “win win” approach –Higher level of process understanding –Functional or performance indicating process controls and specifications (uses of “systems approach”) –Higher level of process quality –Minimal reliance on end product testing –Improve the scientific basis of regulatory functions –Rationale, risk- based, documentation requirements –Higher efficiencies of all (industry/FDA) operations

15. 19001918193719601980 Operator Foreman Inspection Statistical Total Quality Control Evolution TQM A. V. Feigenbaum. Total Quality Control. 3rd Ed., McGraw-Hill, 1983 PAT enables QC Evolution

16. A Historical Note on Quality: Lurching from Fad to Fad? Sampling Plans (‘50s) Zero-Defect Movement (‘60s) ISO-9000 (‘80s) QS-9000 Malcolm Baldrige Award European Quality Award Total Quality Management Six Sigma –The Ultimate Six Sigma - “The Big Q” cGMPs K. R. Bhote and A. K. Bhote. World Class Quality (2000) ISBN 0-8144-0427 PAT a tool

17. On/At-Line Assurance of Acceptable Dissolution Rate? PS = Drug particle size (specification) Ex1 = Excipient #1 (USP/NF) Ex2= Excipient #2 (USP/NF) P1 = Process parameter #1 (time) P2 = Process parameter #2 (cf, in-process test for hardness) Level IQA: Specs for incoming materials, SOPs, Process Controls,.. Level II QA= Test conformance to dissolution specification (and other specifications) An hypothetical case study

18. % Dissolution PredObs. Test10599 Test10999 Test10398 Test11199 Test3028 Test2523 Test1512 Test611 Test95102 Test101101 Test8994 Test8796 Test97101 Test98100 An hypothetical case study: Furosemide, direct compression formulation (setting R&D lab; small/pilot scale). At-line Tablet NIR Spectra - Dissolution Correlation Black-Box, Validation based only on predictive performance of the calibration (similar to the current IVIVC approach) Unpublished Data from DPQR/CDER/FDA

19. Dissolution predominantly effected by disintegrant level and by interaction terms involving disintegant and dilutent and dilutent and mg stearate. An hypothetical case study: Critical Formulation variables? Unpublished Data from DPQR/CDER/FDA

20. An hypothetical case study: Relevance of the NIR Calibration? Building confidence by establishing causal-links?

21. An hypothetical case study: Scale-up effects and calibration transfer issues? Process/Analytical Validation?

23. Built-in Redundancy? General Quality System Product specific SOP’s,... PAT Based Measurements and Controls Systems Approach