1. D. Christopher Watts, Ph.D. Office of Pharmaceutical Science, CDER, FDA ASQ/FDC October 22, 2004 Process Analytical Technology (PAT)

2. The Questions What is PAT? Why is PAT necessary? What does PAT mean to me? –Industry –Regulator –Consumer How does PAT relate to other FDA Initiatives? Where are we going with PAT?

3. PAT Guidance Released September 29, 2004 Scientific principles and tools supporting innovation –PAT Tools –Process Understanding –Risk-Based Approach –Integrated Approach Regulatory Strategy accommodating innovation –PAT Team approach to Review and Inspection –Joint training and certification of staff

4. What is PAT? A system for: –designing, analyzing, and controlling manufacturing –timely measurements (i.e., during processing) –critical quality and performance attributes –raw and in-process materials –processes “Analytical“ includes: –chemical, physical, microbiological, mathematical, and risk analysis –conducted in an integrated manner

5. PAT = Process Understanding A process is well understood when: –all critical sources of variability are identified and explained –variability is managed by the process –product quality attributes can be accurately and reliably predicted Accurate and Reliable predictions reflect process understanding Process Understanding inversely proportional to risk

6. Why PAT? FDA Perspective An increasing burden on FDA resources: ~ 4,000 manufacturing supplements annually Unable to meet statutory biennial GMP inspection requirement Lower scrutiny of non-domestic industry Cost implications for the industry from: Low manufacturing and QA efficiency Dr. Janet Woodcock,FDA Science Board

7. Why PAT? Public Health Perspective US Drug products are of high quality, BUT: Increasing trend toward manufacturing- related problems Recalls - 176 in 1998 rising to 354 in 2002 Loss of availability of essential drugs Disruption of manufacturing operations Negative impact on new drug approvals Efficient pharmaceutical development and manufacturing are vital components of the “Critical Path” leading to an effective U.S. health care system Dr. Janet Woodcock,FDA Science Board

8. Quality by Design: A Challenge to the Pharma Industry (CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)

9. The Genesis of PAT: A Proactive Initiative Began at ACPS Discussions in July, 2001 FDA Science Board Meetings (11/01, 4/02) –Current state of Pharmaceutical Manufacturing Industrial Practice FDA Regulation –Science Board support for FDA’s proposal to facilitate innovation http://www.fda.gov/cder/OPS/PAT.htm#scienceboard

10. How can PAT help? Example: Current Tablet Production Raw Material Dispensing BlendingCompression Identification Tests (Chemical Only) Test Product Quality for Release (Active Only) No Tests (Time Based) End-Product Focused Testing to Document Quality Process at Risk

11. Current Tablet Production: Testing to Document Quality What is the Product Test? –Typically 30 Tablets/batch (1,000,000) What process Information does this provide? –None. Testing is Product focused. Will we see “failures”? –Expect number of “failing” tablets/batch, even though 30 tablets/batch “pass” –4% of batches may fail, even though not different from a “passing” batch Does this facilitate process understanding and control? –No

12. PAT Approach: Quality by Design Focus on Process Understanding What parameters are critical to Product Quality? –Experimental Design How do we analyze these parameters? –K.I.S. How do we control these parameters throughout the process? –Feed-back/-forward

13. Experimental Design: Establishing the “Critical Parameter(s)” *Critical to Product Quality Parameter 1 Disintegrant Level* Parameter 3 Parameter 4 Active Particle Size* Interaction 1 Interaction 2 Interaction 3 Interaction 4 Interaction 5

14. PAT Approach: Particle Size Raw Material Dispensing Understand Raw Material Analyzer in Dispensing What is the material? What is Particle Size? Predictive Models for Blend

15. PAT: Analyze and Control Blending Analyzer on Blender Particle Size? Disintegrant mixed? Stop blend with desired particle size and mix (not time based) Understand and Control Blend

16. Example: Current Tablet Production Raw Material Dispensing BlendingCompression Identification Tests (Chemical Only) Test Product Quality for Release (Active Only) No Tests (Time Based) End-Product Focused Testing to Document Quality Process at Risk

17. PAT Tablet Production Compression Functional Tests (Chemical and Physical) Validate Process Control Control Blending (Particle Size & Disintegrant Distribution) Process Focused Mitigate the Process Risk Raw material Functionality & Dispensing Blending Predictive Models

18. PAT: Risk-Managed Approach to Regulatory Scrutiny Expect an inverse relationship between the level of process understanding and the risk of producing a poor quality product Well understood process  less restrictive regulatory approaches to manage change Focus on process understanding can facilitate risk- managed regulatory decisions and innovation

19. Implementation Options Under the facility's own quality system –Inspections by the PAT Team or PAT certified Investigator can precede or follow PAT implementation. A supplement (PAS, CBE, etc) can be submitted prior to implementation –if necessary, an inspection can be performed by a PAT Team or PAT certified Investigator before implementation. A comparability protocol can be submitted –Following approval of this comparability protocol by the Agency, one or a combination of the above regulatory pathways can be adopted for implementation To facilitate adoption or approval of a PAT process, manufacturers may request a preoperational review of a PAT manufacturing facility and process

20. The FDA PAT Team (ORA, CDER, CVM) PAT Steering Committee Doug Ellsworth, ORA/FDA Dennis Bensley, CVM/FDA Patricia Lefler, ORA/FDA Joe Famulare, CDER/FDA Keith Webber, 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) Rebeca Rodriguez (SJN-DO) Erin McCaffery (NWJ-DO) George Pyramides (PHI-DO) Dennis Guilfoyle (NELD) Compliance Officers: Albinus D’Sa (CDER) Mike Gavini (CDER) William Bargo (CVM) Brenda Uratani (CDER) Reviewers: Norman Schmuff (CDER) Lorenzo Rocca (CDER) Vibhakar Shah (CDER) Rosario D’Costa (CDER) Raafat Fahmy (CVM) Bryan Riley (CDER) PAT Policy Development Team Ali Afnan, OPS/CDER Chris Watts, OPS/CDER Huiquan Wu, OPS/CDER PAT Training Coordinators John Simmons, Karen Bernard and See Lam

21. The FDA PAT Team: Training & Certification Summary – Completed Initial Training Program – “Lessons Learned” – Continuing Education – Involve in Next Training – Guidance Finalization Team Approach – Review – Inspection – Peer Review

22. FDA CGMP Initiative –Risk-based regulation –“Non-impeding” regulation –Consistent regulation Success based on Broad Cooperation –Industry –Academia –FDA http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html PAT and CGMP Initiative

23. PAT and The “Critical Path” http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

24. PAT and The “Critical Path” http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

25. PAT, CGMP, and The Critical Path Process Analytical Technology Encourage Innovation New Technologies CGMP’s for the 21st Century The Critical Path Risk-Management Broad Cooperation: Industry, Academia, FDA

26. International Collaboration ASTM Technical Committee E55 International Regulators forming PAT Teams –Canada, Europe, Japan Invitation to Participate in Training

27. Guidance Workshops Co-sponsored Public Workshops on PAT Guidance –AAPS, ISPE, RPS US (Arlington, VA) –November 16, 2004 Tokyo, Japan –December 8, 2004 London, UK –December 14, 2004 Brussels, Belgium –February 22, 2005 Mumbai, India –February 25, 2005

28. Summary Finalized PAT Guidance –Guidance Workshops Expanded the Scope of PAT –Office of Biotechnology Products Continue Training of FDA Staff Various Workshops (Global) –AAPS, AIChE, IFPAC, ISPE ASTM Technical Committee E55 on the Pharmaceutical Application of PAT Research (Intra- and Extramural) –Pfizer CRADA –NSF IAG –Support Policy Development and Training

29. Contact Email: –PAT@cder.fda.gov –wattsc@cder.fda.gov PAT on the Web: –http://www.fda.gov/cder/OPS/PAT.htm Phone: –(301)-443-5197