1. D. Christopher Watts, Ph.D. Office of Pharmaceutical Science, CDER, FDA Science Seminar Series for the Office of Commissioner April 9, 2004 Process Analytical Technology (PAT): What’s in a name?

2. The Questions What is PAT? Why is PAT necessary? How will PAT help? –Industry –Agency –Public Health How does PAT relate to other FDA Initiatives? Where are we going with PAT?

3. What is PAT? A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance 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. 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

7. Doug Dean, FDA Science Board, Nov 16, 2001 Current Paradigm: Utilisation levels - 15% or less Scrap and rework - plan for 5-10% Time to effectiveness - takes years Hesitant to Innovate –Incentive? Manufacturing Costs: $90 Billion Why PAT? Industry Perspective Ray Scherzer, FDA Science Board, Apr 2, 2002

8. 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

9. 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

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

11. 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

12. 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

13. One “Innovative” Approach Visible Image NIR Image Pure Active Pure Excipient Ideal Tablet “New Technology” in Manufacturing Process Analyze every tablet

14. “Innovative” Approach: Still Testing to Document Quality What is the Product Test? –Test every tablet (all 1,000,000) What process Information does this provide? –None. Testing is still Product focused. –Better estimate of Variability in Final Product Why the variability? –? –Change acceptance criteria? Allow some outside 75%-125% Facilitate process understanding and control? –No

15. PAT Approach: Quality by Design Focus on Process Understanding What parameters are critical to Product Quality? –Experimental Design How do we analyze these parameters? –Appropriate Instrumentation How do we control these parameters throughout the process?

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

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. Next Steps for PAT First PAT Approval Finalize PAT Guidance Continued Training of FDA Staff Expand the Scope of PAT –Office of Biotechnology Products ASTM Technical Committee Research (Intra- and Extramural) –Office of Testing and Research –Pfizer CRADA –NSF IAG –Support Policy Development and Training

27. Next Steps FDA Science Forum –Quality by Design (QbD) Breakout Session –Chair: Dr. Janet Woodcock

28. Acknowledgements Office of the Commissioner Committee for the Advancement of FDA Science (CAFDAS) Dr. Arifa Khan Linda Huntington Joanne Locke Mrs. Helen Winkle Dr. Ajaz Hussain Dr. Ali Afnan Dr. Rob Lyon Dr. Pat Faustino

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