Process Analytical Technology (PAT): What’s in a name?

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

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. Why PAT? Industry Perspective 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 Doug Dean, FDA Science Board, Nov 16, 2001 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 Blending Compression Identification Tests (Chemical Only) No Tests (Time Based) Test Product Quality for Release (Active Only) Process at Risk End-Product Focused Testing to Document Quality

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. NIR Image Visible Image Pure Active Pure Excipient One “Innovative” Approach 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 ProductQuality? • 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)” Parameter 1 Disintegrant Level* Parameter 3 Parameter 4 Active Particle Size* Interaction 1 Interaction 2 Interaction 3 Interaction 4 Interaction 5 *Critical to Product Quality

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

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

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

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

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. PAT and CGMP Initiative • 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

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 The Critical Path Encourage Innovation Process Analytical Technology Risk-Management CGMP’s for the 21st Century New Technologies 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