Process Understanding and PAT

1. Process Understandingand PAT D. Christopher Watts, Ph.D. Office of Pharmaceutical Science, CDER, FDA ACPS, Manufacturing Subcommittee July 21, 2004

2. The Questions • What is PAT? • Who is involved with PAT? • Engine for Success • How will PAT benefit? • Industry • Agency • Public Health • Where are we going with PAT?

3. 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

4. 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

5. The FDA PAT Team (ORA, CDER, CVM) Review - Inspection Investigators: Robert Coleman (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 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 Policy Team Chris Watts, OPS/CDER Ali Afnan, OPS/CDER Huiquan Wu, OPS/CDER PAT Training Coordinators John Simmons, Karen Bernard and See Lam

6. The FDA PAT Team: Training & Certification • Team Building • FDA PAT Team (CDER, ORA, CVM) • Two Didactic Sessions • FDA • Three Practica • University of Washington (CPAC) • Purdue University (CPPR) • The University of Tennessee (MCEC)

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

8. Team Approach to Review/Inspection: Implementation Options • Supplement (CBE, CBE-30, or PAS) can be submitted • if necessary, an inspection can be performed • Implemented under the facility's own quality system • CGMP inspections by the PAT Team or PAT certified Investigator may follow • Implemented following an inspection • by the FDA PAT Team or a PAT certified Investigator • recommendations in the inspection report serve as a summary basis of final approval • Comparability Protocol can be submitted • one or a combination of the above regulatory pathways can be adopted for implementation

9. How does PAT benefit?Example: Current Tablet Production Raw Material Dispensing Blending Milling Blending (Time Based) Identification Tests (Chemical Only or Certificate of Analysis) Test Product Quality (Active Only) Compression End-Product Focused Testing to Document Quality

10. PAT Approach: Quality by Design Focus on Process Understanding • What parameters are critical to ProductQuality? (How? Why?) • Experimental Design • How do we analyze these parameters? • Appropriate Instrumentation • How do we control these parameters throughout the process? • Control Strategy

11. 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

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

13. Blending Courtesy AstraZeneca PAT: Analyze and Control Understand and Control Blend • Analyzer on Blender • Particle Size? • Disintegrant mixed? • Stop blend with desired mix (not time based) • Mill? • No lab-based Uniformity or PSD Test

14. How does PAT benefit?Example: Current Tablet Production Raw Material Dispensing Blending Milling Blending (Time Based) Identification Tests (Chemical Only or Certificate of Analysis) Test Product Quality (Active Only) Compression End-Product Focused Testing to Document Quality

15. Raw material Functionality & Dispensing Blending/Milling 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

16. How does PAT benefit? • Efficiency • No “lab analysis” of blend or PSD • Blend to end-point • Mill only if necessary • Real Time Release • Optimization • Blend to end-point • Feed-forward from Raw Material Characterization • Feed-forward from Blending • Mill? • Regulatory Burden • Process no longer “frozen in time” • No supplement for process change • Team Approach (if Review/Inspection necessary)

17. Summary:Process Understanding and PAT • 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 • Team Approach to Review/Inspection • Several Options for Implementation

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

19. 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