On the Road to “Process Understanding”

1. On the Road to “Process Understanding” Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science CDER, FDA Arden House 2004, London

2. “Learning is not compulsory…. neither is survival” W. Edwards Deming

3. Contributions of the PAT Initiative in Developing a Shared Vision for Pharmaceutical Product Development and Manufacturing in the 21st CenturyVision 2020: “I Can See Clearly Now”

4. On the road to PAT • AOAC International Special Symposium • “ Pharmaceutical Process Control and Quality Assessment by Non-Traditional Means,” October 1993, St. Louis, Missouri • Champions, conceptualization, charting the course • FIP’s Millennium Congress • New Technology Forum of the Royal Pharmaceutical Society • [PhRMA Technical Conclave] • The proposal - July 2001, Advisory Committee for Pharmaceutical Science

5. The message has not changed! FIP Millennium Conference San Francisco

6. PAT Initiative: From a Reactive to Proactive Initiative • FDA Science Board Meetings (11/01, 4/02) • Emerging Science Issues in Pharmaceutical Manufacturing • Current state of Pharmaceutical Manufacturing • G. K. Raju (M.I.T) and Doug Dean (PriceWaterHouseCoopers) • Opportunities for improvements • Norman Winskill and Steve Hammond (Pfizer) • New Technology - “Don’t Use” or “Don’t Tell” approach • Ray Scherzer (CAMP/GlaxoSmithKline) • Challenge to Phrama Industry - Quality By Design • Science Board support for FDA’s proposal to facilitate innovation http://www.fda.gov/cder/OPS/PAT.htm#scienceboard

7. Quality by Design: A Challenge to the Pharma Industry (CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)

8. Strong Public Health Protection Time International cooperation Integrated quality systems orientation Science-based policies and standards Risk-based orientation Dimensions of the FDA’s Initiative on Pharmaceutical Quality for the 21st Century FDA Unveils New Initiative To Enhance Pharmaceutical Good Manufacturing Practices http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html (August 21, 2002 )

9. The Scientific Opportunity • Pharmaceutical (development and) manufacturing is evolving from an art form to one that is now science and engineering based. • Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes. http://www.fda.gov/cder/gmp/21stcenturysummary.htm

10. The Risk Mitigation and Communication Opportunity • Intuitive/Subjective to Quantitative • HCCP • FMEA • Quality by Design • “Reliability is a design engineering discipline which applies scientific knowledge to assure a product will perform its intended function for the required duration within a given environment. This includes designing in the ability to maintain, test, and support the product throughout its total life cycle. Reliability is best described as product performance over time.” http://www.ewh.ieee.org/soc/rs/Reliability_Engineering/index.html

11. cGMPs The Quality Systems Opportunity A Historical Note on Quality: Milestones in Quality Journey or Lurching from Fad to Fad? • Sampling Plans (‘50s) • Zero-Defect Movement (‘60s) • ISO-9000 (‘80s) • QS-9000 • Malcolm Baldrige Award • European Quality Award • Total Quality Management • Six Sigma • The Ultimate Six Sigma - “The Big Q” Pharmaceutical Quality System for the 21st Century K. R. Bhote and A. K. Bhote. World Class Quality (2000) ISBN 0-8144-0427

12. A Two Year Journey to Take Advantage of these Opportunities • This initiative is designed to leverage this opportunity through an integrated systems approach to product quality regulation founded on sound science and engineering principles for assessing and mitigating risks of poor product and process quality in the context of the intended use of pharmaceutical products. http://www.fda.gov/cder/gmp/21stcenturysummary.htm

13. A Two Year Journey. What is the Destination? • “Vision 2020 - I can see clearly now” • The “Desired State” http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt

14. http://www.fda.gov/cder/gmp/21stcenturysummary.htm Desired State • Product quality and performance achieved and assured by design of effective and efficient manufacturing processes • Product specifications based on mechanisticunderstanding of how formulation and process factors impact product performance • Continuous "real time" assurance of quality

15. http://www.fda.gov/cder/gmp/21stcenturysummary.htm Desired State • Regulatory policies tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability • Risk based regulatory scrutiny relate 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

16. Directional Vectors • Ensure regulatory review and inspection policies are based on state-of-the-art pharmaceutical science • Encourage new technological advances • Encourage risk-based approaches that focus both industry and Agency attention on critical areas • Facilitate modern quality management techniques, including implementation of quality systems • Enhance the consistency and coordination of FDA's drug quality regulatory programs, in part, by integrating enhanced quality systems approaches into the Agency's business processes and regulatory policies concerning review and inspection activities Second Progress Report and Implementation Plan. http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm (September 3, 2003)

17. Covering the Space Defined by the Directional Vectors Preapproval Inspection Compliance Program Dispute Resolution Process Risk Pharmaceutical Inspectorate Product Specialists on Inspection Process Systems/Integration Guidance on CFR Part 11 Aseptic Processing Comparability Protocol ICH P2, QbD, & Risk PAT Science

18. Moving forward towards a “shared vision” Process Understanding TIME TIACC Generic AER/Complaints. Approval Phase III Phase II Phase I Discovery DISCIPLINE Epidemiology Pharm. Engg. Clinical Clin.Pharm Pharm/Tox Pharmaceutics Chemistry Biology ORGANIZATION Marketing Information Technology Quality Assurance Manufacturing Regulatory Development Discovery Optimization Continuous Improvement (including CAPA) 1st Principles Modeling Intended Use Risk based Regulatory Assessment QbD

19. What is Process Analytical Technology (PAT)? • PAT 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 • The term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner

21. PAT Framework ………... • Two components • a set of scientific principles and tools supporting innovation, and • a strategy for regulatory implementation that will accommodate innovation • creation of a PAT Team approach to CMC review and CGMP inspections and • joint training and certification of PAT review and inspection staff

22. Key Principles • Process understanding; quality by design • Flexible, risk based regulatory scrutiny • Reduce regulatory uncertainty • Continuous improvement • Research Data - “Safe Harbor” • Real time release • Integrated systems approach • Opportunity for innovation; not a requirement

23. Process Understanding • A process is generally considered well understood when • all critical sources of variability are identified and explained; (Level 1) • variability is managed by the process (Level 2); and, • product quality attributes can be accurately and reliably predicted over the ranges of acceptance criteria established for materials used, process parameters, and manufacturing environmental and other conditions (Level 3)

24. D. A. Gravin. Building a learning organization. HBR. July 1993 Stages of Knowledge • Production and operating knowledge can be classified by the level of understanding • Lowest • “Art”: little is known other that characteristics of a “good” product • few clearly articulated standards • Highest • All aspects of production are known and understood • All material and processing variation are articulated and accounted for, with rules and procedures for every contingency

25. Eight Levels of Process Understanding (#1-3) • Recognizing prototypes • What is a good product? • Recognizing attributes within prototypes • Ability to define some conditions under which process gives good output • Discriminating among attributes • Which attributes are important? Experts may differ about relevance of patterns; new operators are often trained through apprenticeships

26. Eight Levels of Process Understanding (#4-6) • Measuring attributes • Some key attributes are measured; measures may be qualitative and relative • Locally controlling attributes • Repeatable performance; process designed by experts, but technicians can perform it • Recognizing and discriminating between contingencies • Production process can be mechanized and monitored manually

27. Eight Levels of Process Understanding (#7 & 8) • Controlling contingencies • Process can be automated • Understanding procedures and controlling contingencies • Process is completely understood

28. Process Understanding - Innovation • Provides a range of options for qualifying and justifying new technologies and to achieve real time release • less burdensome approaches for validating new technologies for their intended use • in absence of process knowledge the test-to-test comparison between an on-line process analyzer (e.g., NIR spectroscopy for content uniformity) and a conventional test method (e.g., a wet chemical test) on collected samples may be the only available option

29. Process Understanding - Validation • Can provide a high assurance of quality on every batch and provide alternative, effective mechanisms to achieve validation • process validation can be enhanced and possibly consist of continuous quality assurance where a process is continually monitored, evaluated, and adjusted using validated in-process measurements, tests, controls, and process endpoints

30. Process Understanding - Justifying “Real Time Release” • Real time release is the ability to evaluate and ensure acceptable quality of in-process and/or final product based on process analytical data • Process understanding, control strategies, plus on-, in-, or at-line measurement of critical attributes that relate to product quality can provide a scientific risk-based approach to justify how real time quality assurance may be equivalent to, or better than, laboratory-based testing on collected samples

31. Process Understanding - Specifications • Ideally PAT principles and tools should be introduced during the development phase • Using PAT principles and tools during development provides opportunities to improve the mechanistic basis for establishing regulatory specifications • Manufacturers are encouraged to develop and discuss approaches for establishing mechanistic-based regulatory specifications for their products

32. Process Understanding - Risk Based Regulatory Scrutiny • Within a quality system and for a particular manufacturing process, an inverse relationship between the level of process understanding and the risk of producing a poor quality product is expected • For processes that are well understood, opportunities exist to develop less restrictive regulatory approaches to manage change

33. Process Understanding - Risk FMEA • Harm • Understand factors and failure modes • Probability • Reduce through design • “Detection ability” • Control/Prevention • Risk based CMC Review & Inspections

34. Tools for Process Understanding and Control • Multivariate data acquisition and analysis tools • Modern process analyzers or process analytical chemistry tools • Process and endpoint monitoring and control tools • Continuous improvement and knowledge management tools

35. Multivariate Data Acquisition and Analysis • Pharmaceutical products and processes are complex multi-factorial physical-chemical and biological systems • Development knowledge base necessary to support and justify flexible regulatory paths for innovations in manufacturing and post-approval changes • Opportunities need to be identified to improve the usefulness of available relevant product and process knowledge during regulatory decision making — without affecting a manufacturer's development program

36. Knowledge Base • Structured • DOE based on statistical principles of orthogonality, reference distribution, and randomization to identify and characterize formulation/process factors and interaction • Knowledge base • Using DOE as the foundation as an institutional knowledge base grows in coverage (range of variables and scenarios) and data density, it can be mined to determine useful patterns for future development projects • Focus on knowledge and not data • applicability and reliability of knowledge e.g., in the form of mathematical relationships and models can be assessedby statistical evaluation of model predictions

37. Process Analyzers or Process Analytical Chemistry Tools • Available tools have evolved from those that take simple process measurements, such as pH, temperature, and pressure, to those that measure chemical composition and physical attributes • Many recent innovations make real-time control and quality assurance feasible during manufacturing • Chemometrics • Process signatures • Correlations - causal links

38. Application of Process Analyzers • Design and construction of the process equipment, the analyzer, and their interface are critical to ensuring that collected data are relevant and representative of process and product attributes • A review of current practice standards (e.g., ASTM) for process analyzers in other industries can provide useful information and facilitate discussions with the Agency

39. Process Monitoring, Control, and End Points • Design a process with • measurement system to allow real time or near-real time monitoring of all critical attributes • process controls that provide adjustments (based non feed-forward or feed-back information) to ensure control of all critical attributes • A process endpoint need not be a fixed time, but can be the achievement of the desired material attributes • Design strategies should accommodate • the attributes of input materials • the ability and reliability of process analyzers to measure critical attributes, and • the achievement of pre-established process endpoints to ensure consistent quality of the output materials and the final product.

40. Quality of Relationship Quality of Thinking Quality of Results Quality of Action The PAT Team: The Engine of Success A team is a group of interdependent individuals with complimentary skills who are organized and committed to: 1. Achieving a common purpose 2. Applying a common process, and 3. Sharing a common destiny

41. “Performers” “Changers” Steering Committee Review-Inspection Team “Perfectors” “Conservators” Organizational Engineering

42. Steering Committee ideally suited to situations that require people who are responsive to new and creative solutions able to generate a continuing stream of new, sometimes unorthodox ideas may wander a bit under a relatively constant stream of new ideas tends to resolve issues by using analysis, assessment and planning Review-Inspection Team Capable of handling complex situations that require careful assessment and precise execution. The group is unlikely to miss anything of significance in their review When given detailed and exhaustive operational specification, the team will probably produce highly reliable results of consistent quality Examples of “Strengths”

43. Progress? • PAT now a part for the 21st Century Initiative and FDA’s Strategic Plan • ASTM Committee E55: Pharmaceutical Applications of PAT • http://www.astm.org • Interagency Agreement with NSF • CRADA with Pfizer on Chemical Imaging as a PAT tool • Academic and industry champions world wide – to ensure steady progress towards the desired state • Communication and cooperation with other regulatory agencies

44. Next Steps • Final Guidance • Discussions to expand the scope of the guidance to include CBER and CDER/OPS’s Office of Biotechnology Products • April 13, 2004 Advisory Committee for Pharmaceutical Science Meeting • Training and certification program • Lessons learned exercise • New and improved training program with sufficient focus on Biotech • 2nd team and its training • PATRIOT a model for Product Specialist on Inspection program in CDER?

45. Next Steps • Quality System for CMC Review • Starting with New Drugs • Peer review • Customer focus • Team approach to review • Asking the “right” questions • This afternoon Jon Clark and Ken Morris will discuss this further

46. What do we wish to accomplish with ICH Q8 • Ensure Q8 facilitates movement towards the “desired state” we have articulated • This will • Help us better understand the proposed product and process design and its relation to the intended use • improve process of establishing regulatory specifications • Improve our ability to identify and understand critical product and process factors • improve our understanding and confidence in risk mitigation strategies • Allow us to utilize risk based approaches and recognize good science and facilitate continuous improvement • Improve communication and systems thinking • More efficient review and inspection process • Be a “win win” for public health and industry

47. Drug Substance or API Intended Use Route of administration Patient population ….. Product Design P2.1 and 2.6 Components of drug product P2.2, 2.4, 2.5, 2.6 Drug Product Container Closure System Microbiological Attributes Compatibility (e.g., recon) Design Specifications (Customer requirements) P2.3 Manufacturing Process Development Manufacturing Process CTD-P2 Sec. QbD and Risk FDA comments (2/4/04)on draft 1.1 reflect an attempt to integrate "quality by design," and aspects of the "risk assessment, mitigation and communication," objectives within the CTD-Q P2 format.

48. “Learning Before Doing” a prerequisite to “Building Quality In” • Identify and develop most promising NME’s • Accurate prediction of clinical performance using prior information and pre-clinical data • Drug Delivery system attributes optimized for therapeutic objectives and manufacturing processes designed to ensure consistent drug delivery objectives • Clinical trials designed using all available knowledge to document clear safety and efficacy profile in the target or intended patient population • How can we (FDA) help? • Ask the “right”question and insist on the “right” answer

49. Discovery Development ReviewMarketing Pre-clinical Clinical I, II, III Approval IV AER’s Pre-formulation Formulation (Clinical) (Optimization) OptimizationScale-Up Manufac. Changes ? Appropriate labeling and risk management Safety & Efficacy ? ? ? Building Quality In Appropriate Controls & Specifications Systems Approach: Integration across disciplines, organization, and over time

50. Quality by Design Process Design Yes, Limited to the Experimental Design Space Maybe, Difficult to Assess GMP/CMC FOCUS Design qualification Focused; Critical Process Control Points (PAT) Extensive; Every Step (CURRENT) 1st Principles MECHANISTIC UNDERSTANDING CAUSAL LINKS PREDICT PERFORMANCE DECISIONS BASED ON UNIVARIATE APPROACH DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION Product and Process Quality Knowledge: Science-Risk Based cGMP’s