1. 1 PAT Subcommittee Closing Report 12 March 2003 Tom Layloff Acting Chair

2. 2 50 mg API in a 275 mg IR Tablet ComponentWt per Tab (mg) %Weight for 1 Million Tab Active501850 kg + 5g 1 pp 10,000 Diluent(s)20072200 kg + 200 g 1 ppt Disintegrant25925 kg + 25 g 1 ppt Lubricant0.30.1 300 g + 0.3 g 1 ppt

3. 3 Currently the API Serves As the Process Quality Surrogate Marker Uni-variate handle on a poly-variate process Focus on API with little regard for excipients and process Poor surrogate marker for many components and the process

4. 4 PAT Optimal applications of process analytical chemistry tools, feedback process control strategies, information management tools and/or product/process optimization strategies to the manufacture of pharmaceuticals

5. 5 1978 21 CFR 210, 211 Preamble “There is no prohibition in the regulations against the manufacturing of drug products using better, more efficient, and innovative methods.” USP “Compliance may be determined also by the use of alternative methods, chosen for advantages in accuracy, sensitivity, precision, selectivity, or adaptability to automation or computerized data reduction or in other special circumstances.”

6. 6 Charges to the Process Analysis Technology (PAT) Sub-Committee What is to be gained by embracing the technology? What is the state-of-the-art? What are the problems, hurdles, and solutions? How should the new technologies be regulated? How should FDA be prepared to adapt to dealing with the new technologies? What are the staff educational issues and how should competencies be assessed?

7. 7 PAT Subcommittee Meetings 25-26 February –Applications and Benefits, –Process and Analytical Validation, and –Chemometrics. 12-13 June –Product-Process-Development, –Process and Analytical Validation, and –Proposed PAT Training and Certification Program 23 October –Computer systems validation--21 CFR 11 PAT issues, –PAT case study, and –Rapid microbiology testing.

8. 8 How? General guidance –Conceptual framework –Regulatory position, process and incentives PATRIOT –Science and risk based approaches –Integrated systems approach

9. 9

10. 10 Tools? The Assessment Tools, Data Support Systems And Technologies Are Available To Improve Product Consistency And Reduce Bad Production And Recalls

11. 11 USP Content Uniformity Test Issues* # of tablets with drug content outside of: % RSD75 - 125%**85 -115% 6.0%3012,419 7.0%36032,124 7.8%1,35054,470 *Assumptions: One Million Tablet Batch, Normal Distribution, Mean = 100%, RSD = Relative Standard Deviation. **USP Limit for compliance = NMT 1/30 Stella Machado, Ph.D., Meiyu Shen, Ph.D., Charles Anello, Sc.D., CDER/FDA

12. 12 Agency’s Perspectives Use existing knowledge, experience, and guidances from other FDA components, NIST, ASTM, ANSI, etc.Use existing knowledge, experience, and guidances from other FDA components, NIST, ASTM, ANSI, etc. –“Design Control Guidance for Medical Device Manufacturers” March 11, 1997 Provide framework to manufacturers with flexibility needed to develop design controls to comply with regulations, and also appropriate for their own design and development of processes and Standard Operating Procedures (SOPs).Provide framework to manufacturers with flexibility needed to develop design controls to comply with regulations, and also appropriate for their own design and development of processes and Standard Operating Procedures (SOPs).

13. 13 Future Issues Validation Data and Retention In-Process End-Point Detection and Data Acquisition and Storage. Documentation and E-Sig Closure of Decision Points Incoming Material Stream Consistency Robustness Assessments

14. 14 Regulatory Incentives Not a requirement Regulatory support and flexibility during development & implementation –Eliminate the fear of delayed approval –Dispute avoidance/resolution Science & Risk based regulatory approach –Low risk categorization based on a higher level of process understanding Research exemption –Continuous improvement without the fear of being considered non-compliant

15. 15 What’s Missing? Industry Political Will FDA Is/Has Been Encouraging

16. 16 How To Move Forward. Don’t Try to Eat the Elephant in One Bite. Evolution not Revolution. Bring on Stream Validated PAT Systems Piecemeal. –Incoming materials id, moisture, particle size, etc., are straightforward. –In process moisture assessments. –Blender consistency assessments.

17. 17 Colleagues On, and Presenters To the “Process Analytical Technology Sub-Committee Acknowledgements FDA CDER: Ajaz Hussain, Rajendra Uppoor, Colleagues at the DPA, DPQR Colleagues On, and Presenters To the “Process Analytical Technology Sub-Committee Compilation of Reports and Activities http://www.fda.gov/cder/OPS/PAT.htm http://www.fda.gov/cder/OPS/PAT.htm Comments, suggestions, etc. to: –PAT@cder.fda.gov