1. Final Report on Process Analytical Technology (PAT) and Manufacturing Science Ajaz S. Hussain, Ph.D. Deputy Director, Office of Pharmaceutical Science, CDER, FDA FDA Science Board Meeting 5 November 2004

2. Outline Previous FDA Science Board discussion “Emerging science issues in pharmaceutical manufacturing” Opportunities for improving pharmaceutical manufacturing The “desired state” of pharmaceutical manufacturing in the 21 st Century Progress made by the (PAT &) CGMP Initiative Continuing the scientific and technological progress towards the “desired state” Industrialization dimension of the Critical Path Initiative

3. Protracted Production Cycle Times: Example (Source: G. K. Raju, M.I.T. FDA Science Board Meeting, November 16, 2001)

4. Resolution of process problems slow/difficult: (Source: G. K. Raju, M.I.T. FDA Science Board Meeting, November 16, 2001)

5. OOS or Exceptions Further Increase Cycle Times (Source: G. K. Raju, M.I.T. FDA Science Board Meeting, November 16, 2001)

6. Low Process Capability (Source: Doug Dean.PricewaterhouseCoopers. FDA Science Board Meeting November 16, 2001)

7. New Technologies: “Don’t Use or Don’t Tell” (Source: Norman Winskill; FDA Science Board Meeting November 16, 2001)

8. Quality by Design: A Challenge to Pharma Industry (Ray Scehrzer, FDA Science Board, 9 April 2002 )

10. Current State of Pharmaceutical Manufacturing Static Based predominantly empirical approaches Industry reluctant to use new technology Fundamental science and engineering principles generally less well developed High degree of uncertainty that precludes risk based (regulatory) decisions Manufacturing difficulties Very low efficiency and high cost May be inadequate to meet future needs

11. Steve Hammond, Pfizer Technology may not be rate limiting

12. Wildfong, et al. J. Pharm. Sci. Vol.91, 3 Pages: 631-639

13. ACPS PAT Subcommittee: David Rudd Technology may not be rate limiting

14. S.Lonardi, P.J.Newby, D.Ribeiro, B.Johnson. PAT Subcommittee meeting October 23, 2002 Rapid Microbial Methods

15. Use of new technology may support fundamental science Prof. Ken Morris, Purdue University

16. Opportunity Over the last two decades we have developed or utilized methods to solve complex multi- factorial problems Multivariate empirical methods (e.g., Response Surface Methods) New measurement, control and information technologies Improved ability to predict and assure quality & performance Regulatory utility of fundamental science and engineering principles is likely to accelerate development of these principles

17. Challenge Scientific information related to pharmaceutical product/process development is often filtered out of CMC sections of regulatory submissions “regulatory” uncertainty “fear” delayed approval High degree of uncertainty – precludes risk based decisions Culture & organizational barriers

18. Overcoming the Challenge Incentive for companies that acquire extensive understanding about their product and manufacturing process and share this with the regulators Enhanced science and risk-based regulatory quality assessment will be possible Setting specifications Reduction in the volume of data to be submitted – replaced by more knowledge based submissions, Flexible post approval change management - continuous improvement

19. Overcoming the Challenge Understand and define the problem Ensure current regulations and policies facilitate innovation and continuous improvement Overcome cultural & organizational barriers- “turf issues” Develop new policies and procedures Ensure FDA staff are trained and work as a team to address review and inspection issues

20. Understand and define the problem: In absence of relevant information… Conditions used (e.g., mixing time) for clinical materials become regulatory commitments Process control is predominantly based on documented evidence of conformance to SOP's Generally includes fixed process conditions and laboratory based testing of in-process materials

21. Understand and define the problem: In absence of relevant information… Acceptable quality characteristics, or specifications, are generally described in terms of discrete or attribute data e.g., pass/fail; or no unit outside 75-125% (n=30) Rate of “failure” increases with increasing sample size – drives the industry to “minimalist” testing schemes and discourages collection of information

22. Understand and define the problem: In absence of relevant information… Material characteristics (e.g., excipients) and their relation to “process-ability” are not well understood Variability in (physical) material characteristics, fixed process conditions (e.g., time), testing approaches that do not provide robust estimates of variability and complex SOP’s can lead to frequent deviations and out of specification (OOS) observations

23. Understand and define the problem: In absence of relevant information… OOS investigations take significant (time) resources and have a low rate of success for preventing recurrences; batches have to be rejected (internal failure) due to an inability to document quality Low efficiency and costs associated with manufacturing far exceed those for R&D operations in innovator pharmaceutical firms

24. Understand and define the problem: In absence of relevant information… “Test to test” comparison is the only available option for validating new tools and technology New control systems (“don’t tell mode”) are additional methods and companies still have to continue USP or regulatory testing Post approval changes generally require regulatory notification and in many cases prior approval

25. Current regulations and policies facilitate innovation and continuous improvement Regulations are generally broad and flexible Exception CFR Part 11? However, current regulatory practices and procedures reflect the current state of information in submissions Process validation & inspection CMC review

26. Overcome cultural & organizational barriers- “turf issues”: A Shared Vision for the 21 st Century Reason to change – current state is untenable Need to facilitates innovation and continuous improvement in the interest of public health Opportunities for continuous learning and professional development Articulate the “desired state” for 21 st Century pharmaceutical manufacturing Presented to the FDA Science Board (April, 2002)

27. The PAT Team: Teambuilding (the engine of success) A systems approach for regulatory assessment of PAT applications PAT Team for CMC review and CGMP inspection was created A comprehensive scientific training program was developed University of Washington, Seattle; National Science Foundation (NSF) Center for Process Analytical Chemistry Purdue University; NSF Center for Pharmaceutical Process Research University of Tennessee; NSF Measurement Control Engineering Center

28. “Desired State”: Manufacturing As adopted by the International Conference on Harmonization (ICH) Product quality and performance achieved and assured by design of effective and efficient manufacturing processes Product specifications based on mechanistic understanding of how formulation and process factors impact product performance An ability to affect continuous improvement and continuous "real time" assurance of quality

29. “Desired State”: Regulatory Regulatory policies and procedures tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability Risk based regulatory scrutiny that relates to the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance and the capability of process control strategies to prevent or mitigate risk of producing a poor quality product

30. FDA Definition of PAT – (now also ASTM & ICH definition) 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

31. Removing the Obstacles Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Final, September 2004) A framework for supporting innovation in the interest of the public health – not a “how to” guidance Removes regulatory “uncertainty” Supported by the PAT Team approach (review, compliance, and inspections) and ASTM International (E55) Emerging infrastructure in the pharmaceutical community EU PAT Team,….

32. ICH Q8: Pharmaceutical Development Currently being developed and is expected to reach the ICH Step 2 in November 2004. Creates an opportunity for an applicant to demonstrate an enhanced knowledge of product performance over a wider range of material attributes (e.g. particle size distribution, moisture content, and flow properties), processing options and process parameters.

33. Summary: Through the CGMP Initiative FDA was able to Understand and define the problem Establish a sense of urgency Create a powerful guiding coalition Develop a vision – “desired state” Communicate and build consensus on the “desired state” Remove obstacles Plan for short term wins Take steps towards anchoring changes in the corporate culture and the pharmaceutical community

34. Created opportunities for significant cost savings Efficiency improvements estimated to save billions of dollars every year $15-50 billion every year in US as a result of the FDA Initiatives (Prof. Jackson Nickerson, Washington University in St. Louis) World-wide cost-savings from efficiency improvement is suggested to be $ 90 billion each year (Benson and MacCabe. Pharmaceutical Engineering, July 2004).

35. Preparing for the future In the future, pharmaceutical manufacturing will need to employ innovation, cutting edge scientific and engineering knowledge, and the best principles of quality management to respond to the challenges of new discoveries Complex drug delivery systems and nanotechnology Individualized therapies or genetically tailored treatments.

36. The Critical Path Initiative Industrialization dimension Strengthen “Quality – Clinical” connection Sound scientific approaches for calibration and validation of new technologies Encourage development of fundamental science and engineering principles E.g., material (nano-materials) science and processing Support the US pharmaceutical academic programs

37. Thank you FDA Science Board Advisory Committee for Pharmaceutical Science PAT Subcommittee Manufacturing Subcommittee Others