1. 1 PAT and Biological Products Tom Layloff FDA-SGE Management Sciences for Health www.msh.org The views expressed here are those of the author and not necessarily those of the FDA or MSH.

2. 2 Charges to the Process Analytical Technology (PAT) Sub-Committee What is to be gained by embracing PAT? What is state-of-the-art for Biological process monitoring? What are the problems, hurdles, and solutions? How should FDA be prepared to adapt to dealing with PAT? What are the staff educational issues and how should competencies be assessed?

3. 3 PAT Subcommittee Meetings 25-26 February 2002 −Applications and Benefits, –Process and Analytical Validation, and –Chemometrics. 12-13 June 2002 –Product-Process-Development, –Process and Analytical Validation, and –Proposed PAT Training and Certification Program 23 October 2002 –Computer systems validation--21 CFR 11 PAT issues, –PAT case study, and –Rapid microbiology testing.

4. 4 Process Analytical Technology is: a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. It is important to note that the term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner.

5. 5 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

6. 6 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.”

7. 7 How? General guidance –Conceptual framework –Regulatory position, process and incentives FDA PAT Team –Science and risk based approaches –Integrated systems approach

8. 8 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).

9. 9 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

10. 10 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 data –No intention to inspect research data from evaluation of experimental PAT tools for existing process

11. 11 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. –Process consistency assessments. –Defining process end-points.

12. 12 Guidance for Industry PAT - A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance September 2003

13. 13 I. INTRODUCTION This guidance is intended to describe a regulatory framework that will encourage the voluntary development and implementation of innovative pharmaceutical manufacturing and quality assurance. …

14. 14 The scientific, risk-based framework outlined in this guidance, … should help manufacturers develop and implement new efficient tools for use during pharmaceutical development, manufacturing, and quality assurance while maintaining or improving the current level of product quality assurance. The framework we have developed has two components: –(1) a set of scientific principles and tools supporting innovation and –(2) a strategy for regulatory implementation that will accommodate innovation.

15. 15 Among other things, the regulatory implementation strategy includes creation of a PAT Team approach to CMC review and CGMP inspections and joint training and certification of PAT review and inspection staff. … The Agency is encouraging manufacturers to use the PAT framework described here to develop and implement new pharmaceutical manufacturing and quality assurance technologies.

16. 16 This guidance is written for a broad industry audience in different organizational units and scientific disciplines. To a large extent, the guidance discusses principles with the goal of highlighting technological opportunities and developing regulatory processes that encourage innovation.

17. 17 Biologics and PAT The umbrella Guidance covers biologics production within the scope. However, process differences will require additional skills and an expansion of the training and certification program.

18. 18 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