Regulatory Aspects of Product Development ICH Process Q8, Q9, Q10 WHO Workshop, October 2007

1. Regulatory Aspects of Product DevelopmentICH Process Q8, Q9, Q10 WHO Workshop, October 2007 Sultan Ghani, Director Bureau of Pharmaceutical Sciences Therapeutic Products Directorate, Health Canada

2. Focus of Presentation • ICH Process • ICH Q8, Q9, Q10 • Pharmaceutical Development

3. ICH BACKGROUND • ICH established in 1990 as joint industry/ regulatory project to improve through harmonization the efficiency of the process for developing and registering new medicinal products • The Fourth International Conference on Harmonization (ICH 4), Brussels, 1997 marks the completion of the first phase • It was agreed that the second phase of harmonization continue to ensure the future activities of ICH

4. ICH FUTURE OF ICH • A Continuation of Harmonization • Activity/Mechanism to harmonize new technical requirements • Process for updating and supplementing the current ICH Guidelines • Prevent future disharmony through early collaboration and exchange of information

5. ICH ICH STRUCTURE • Founding Members: • Europe • European Commission (EC) • European Federation of Pharmaceutical Industries Associations (EFPIA) • Japan • Ministry of Health and Welfare (MHW) • Japan Pharmaceutical Manufacturers Association (JPMA) • U.S.A. • U.S. Food and Drug Administration (FDA) • Pharmaceutical Research and Manufacturers of America (PhRMA)

6. ICH ICH STRUCTURE(cont’d) • Other Members: • Observers • World Health Organization (WHO) • Therapeutic Products Programme (TPP) • European Free Trade Association (EFTA) • Extended Working Group Members • Pharmacopoeial Authorities • Generic Industry Association • Non-Prescription Pharmaceutical Industry • Secretariat • The International Federal of Pharmaceutical Manufacturers Association (IFPMA)

7. The Five Steps in the ICH Process forHarmonization of Technical Issues

8. New Era With New Challenges Q8 Q9 Q10 “risk-based” concepts and principles of ICH Ref: ICH

9. Pharmaceutical Development Paths Q8 is not yet finalized by ICH Design Space For Continuous Improvement

10. ICH’s Vision of the Future Adapted from EFPIA, PAT Topic Group, 2005

11. QbD- a Well Known Concept of the 50’sRef: Out of Crisis (1986): W. Edwards Deming • Depending on inspection is like treating a symptom while the disease is killing you. The need for inspection results from excessive variability in the process. The disease is the variability. Ceasing dependence on inspection means you must understand your processes so well that you can predict the quality of their output from upstream activities and measurements. To accomplish this you must have a thorough understanding of the sources of variation in your processes and then work toward reducing the variation. Ceasing dependence on inspection forces you to reduce variability. Ref: http://deming.eng.clemson.edu/pub/den/files/varman.txt http://deming.eng.clemson.edu/pub/den/files/varman.txt

12. Traditional PD versus QbD • Traditional Product Development: • Limited development and scale-up work • Final confirmation by validation of 3 batches • ‘Worst-case' scenarios supposed to be included • Market recalls and underutilization of capacity indicate this approach has had limited success. • QbD: • Complete understanding of process and monitoring of all critical steps. Corrective actions are taken to prevent product failure. • Acceptable quality of the product is ensured: • No recalls • Innovation encouraged • Maximize utilization of capacity

13. Quality by Design Traditional Process Validation • Establish documented evidence which will provide a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specification”

14. Quality by Design Traditional Process Validation (cont’d) • Process Validation Protocol • Three lots • Extensive and frequent sampling • More than routine testing • Proven homogeneity within a lot • Consistent product quality between three lots

15. Quality by Design Traditional Process Validation (cont’d) • Well documented Protocol and Report • Well prepared demo that product can be produced three times • Resolution of all deviation • Investigation report with justification • Review and approval

16. Quality by Design Traditional Product Development . . Complex multivariate physiochemical system • Treated as uni-variate system (one factor at a time) • Materials not well characterized • Process factors not well understood • Time crunch • Reluctant for post approval changes

17. Quality by Design Traditional Establishment of Product Specification • Compendial (mostly) • Critical process parameter • Can be related to product safety and efficacy as per clinical trials • Based on process capability • Literature • Experience

18. Design Space

19. Quality by Design

20. Quality by Design Definition Design of Experiment (DOE) • “Mechanistic understanding of how formulation and process factors affect product performance and quality”.

21. Quality by Design Definition Process Analytical Technology (PAT) • “A system of designing, analyzing and controlling manufacturing through timely measurements (during processing) of critical quality attributes of in-process materials and processes with the objective of ensuring end product quality in each lot”.

22. Quality by Design Definition Risk Management • “Systematic process for the identification, assessment and control of risk to the quality of pharmaceutical across the product lifecycle” • FMEA “A structured process for identifying the way a product or process can fail”

23. Quality by Design Definition Critical Quality Attributes (CQA) • “Property of a material, product or output of a process that is key to the process performance” Critical Process Parameters (CPP) • “A process parameter, e.g. temp, time, speed, when variable it can affect the CQA of a product or process” Cause and Effect Analysis (C&E) • “An investigational tool to find and quantify the cause and effect relationship for a process or product failure”

24. Quality by Design Good DOE requires • Scientific understanding of how formulation and process factors effect product performance • Understanding and identification of CPP and their effects on CQA • Experiment based on the principles of statistics • Identifying and studying the effect and interaction of product and process variables • Use of the multivariate data analysis

25. Quality by Design Risk Assessment • Process of risk assessment to mitigate risks • Identify the root causes of process failure • Help prevent problems from happening • Quantitative prioritization of potential failure • Improve quality and reliability of product • Documented proof of action taken to reduce and eliminate risks • Key inputs of risk assessment

26. Quality by Design Traditional • Online Control (QA Inspection) • Statistical and process controls applied at manufacturing stage (hard work after the examination) Future • Offline Control (quality by design) • Statistics and process engineering application at design phase of the product

27. Quality by Design Establishment of Product Specification • Provide assurance to maintain product quality • Specification to confirm the quality vs characterization • Linked to manufacturing process • Account for the stability • Linked to preclinical and clinical studies • Linked to analytical procedures

28. Quality by Design The outcome • Provision of greater understanding of pharmaceutical and manufacturing sciences creates a basis for flexible regulatory approach • Establishing a meaningful product specification (Q6) and the risk-based approach (Q9) can create flexibility for the continuous improvement (e.g. post-approval changes) without the need for prior approval supplement • Industry can assist the CMC reviewer and GMP inspectors by providing the optional information in CTD

29. Quality by Design The outcome (cont’d) • Gives Industry the opportunity via a harmonized standard to realize the full potential of Q8 and to utilize Q9 • Encourages and motivates Industry to improve and optimize processes, equipment, facilities, systems and procedures • Gives Regulators the confidence that Industry can be responsible for greater self-management of improvements and changes • Companies with good quality management systems • Well controlled processes and products

30. Future Vision Is Driven by ICH Q9 • Manage risk to patient, based on science: • Product, process and facility • Robustness of Quality System • Relevant controls to assess & mitigate risk • Level of oversight required commensuratewith the level of risk to patient for: • Marketing authorization applications • Post-approval change review • GMP inspections Ref: ICH

31. Quality Risk Management • Quality:Degree to which a set of inherent properties of a product, system or process fulfills requirements. • Risk: defined as the combination of the probability of occurrence of harmand the severityof that harm. • Management:Systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle.

32. Pharmaceutical Development • To design a quality product and its manufacturing process to deliver the intended performance of the product • To provide scientific understanding to support the establishment of design, specifications and manufacturing • Product development studies form a basis of quality risk management

33. Pharmaceutical Development • Quality cannot be tested in the product; it should be built in by design • Design space proposed by applicant is subject to regulatory assessment and working within the space is not a change • Movement out of design space is considered to be a change and requires post-approval change process

34. Pharmaceutical Development • Critical aspect of drug substances, excipients, container closure system and manufacturing process should be determined • Opportunities exist to develop more flexible regulatory approach, e.g. • Risk-based regulatory decisions • Process improvement within the approved design space without further regulatory review • Reduction in post-approval submissions • Real time quality control, leading to a reduction of end product testing

35. Q8: Pharmaceutical Development PathsCurrent Understanding at ICH

36. Quality by Design Summary • The quality of drug substances and drug products is defined by their design, development, in-process controls, process validation, and by specifications applied to them throughout the development and manufacture • With the use of mathematics and statistical approaches, the DOE will prove theoretical critical control points in a process • Optimum yield, reduce variation, build robustness in the product and process requires Design of Experiment

37. Quality by Design Summary (cont’d) • Optimization of product and process performance • Cost and Quality built in the product and process • Fast to market – substantial reduction of R&D cost and time • Reduce complaints, recalls and on-conformances • Scientific approach toward setting the specifications

38. Thank you