Quality Systems and Risk Management (Q9 & Q10)

1. Quality Systems and Risk Management (Q9 & Q10) Advisory Committee of the Office of Pharmaceutical Science, Center for Drug Evaluation and Research, USFDA October 5, 2006 Frederick Razzaghi CHPA

2. Agenda • Introduction • Quality Risk Management Q9 • Relation of Q9 to Q10 • The guidance • Next step

3. Establishing the science to help settle questions. (developing the knowledge) Doing what is important. (Can we afford to do everything?)

4. Doing what is important(Risk based) • Non-science and precedence based Requirements have an accumulative effect. • Overwhelm organizations. • Organizations can not answer the value question! • Highlighted in part by the current period of dwindling resources and demand for faster and better outcomes.

5. Risk based Quality Risk Management: Using established knowledge to determine what is important

6. What is Q9 • Q9 is a systemic process oriented approach to decision making that is intended to be practical, applicable, predictive, flexible, consistent and integrated. • The ICH Q9 document: • Main body explains the “What?” • Annex (I) give ideas on the “How?” • Annex (II) give ideas on the “Where?” • It is designed to be implemented by industry and regulators • Pharmaceutical development (ICH Q8) and Quality Systems (ICH Q10) will facilitate the “What?”, “How?” and “Where?” • “It helps to simplify and prevent overly prescriptive and unnecessary requirements.

7. What does Q9 offer • Quality risk management serves as a foundation to support, other ICH Quality documents and complement best quality practices, requirements, standards, and guidelines within industry and regulators. It specifically provides guidance on the principles and some of the tools of quality risk management to enable consistent risk based decisions across the product lifecycle.

8. Reasons for writing Q9 The circumstances affecting regulators & industry • Increasing external requirements • Increasing demands and costs • Growing complexity and scope of risks Empowerment & Flexibility • Master complexity and streamline decision making • Proactive disclosure and build trust and understanding • Improve communication through sharingbest practice and science based knowledge • Convert data into knowledge

9. Reasons for writing Q9 • Establish a common understanding of Quality Risk Management (QRM) among industry and competent authorities • Facilitate moving to the “Desired State” • By enhancing communication and transparency • Moving from ‘fire fighting’ to proactive management of risk

10. Benefits of risk management • Enhanced public confidence in decision making on pharmaceutical quality • Promotes more effective use of regulator and industry resources • Establishes systematic and better-informed decision making. • Increases knowledge of risk • Fosters quality by design and continuous improvement

11. Benefits of risk management • Understand the factors that impact regulators and industry operations. • Create awareness and a culture • Supports pro-active behaviour • Open factual dialogue • Make decisions traceable and consistent • Provide assurance • Risks are adequately managed • Compliance to external and internal requirements • Recognise risks at a desired level • Zero risk not possible

12. Q9 links back to patient safety . Opportunities to impact risk using quality risk management Design Process Materials Manufacturing Facilities Distribution Patient

13. Q9 was constructed using knowledge gained from established standards • ISO/IEC Guide 73: 2002 - Risk Management - Vocabulary - Guidelines for use in Standards • ISO/IEC Guide 51:1999 - Safety Aspects - Guideline for their inclusion in standards • WHO Technical Report Series No 908, 2003 Annex 7 Application of Hazard Analysis and Critical Control Point (HACCP) methodology to pharmaceuticals • GAMP Good Practice Guide ISPE, 2005 A risk-based approach to compliant electronic records and signatures • ISO 14971:2000 - Application of Risk Management to Medical Devices

14. Developing the knowledge:(Science based) • The Q documents are a part of the knowledge. • Establishing new knowledge • Combining basic disciplines & practices • Core: Engineering, Pharmaceutical sciences, • Gap: Technology, Economics, Management (risk, ….)

15. Q9 integrated into Q10

16. ICH Q documents • Q1 Stability • Q2 Analytical Validation • Q3 Impurities • Q4 Pharmacopoeias • Q5 Quality of Biotechnological Products • Q6 Specifications • Q7 Good Manufacturing Practice • Q8 Pharmaceutical Development • Q9 Quality Risk Management • Q10 Pharmaceutical Quality Systems

17. Q9 enables quality systems to address the following problems • Product may not be available to patients • Increase the potential for release of unacceptable product • Delay in new product introductions • Delays in the implementation of changes and improvements • Recall of drugs • Inefficient allocation of resources

18. Q8, Q9 and Q10 are aligned with the new approach • GMP Workshop in July 2003: 5 year vision: “Develop a harmonised pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to quality risk management and science” • Consequent ICH Expert Working Groups (EWG): • ICH Q8, on Pharmaceutical Development, doc. approved Nov. 2005 • ICH Q9, on Quality Risk Management, doc. approved Nov. 2005 • ICH Q10, on Quality Systems, topic accepted 2005

19. How Q9 interacts with Q8 and Q10 envision Risk from Manufacturing site High Q10 Pharm. Quality Systems Low Q8 Pharmaceutical Development Low High Product / Process Risk

20. New Q distinctions Pharmaceutical Development (Q8)Past: Data transfer / Variable output Present: Knowledge transfer / Science based / Consistent output Quality Risk Management (Q9) Past: Used, however poorly defined Present: Opportunity to use structuredprocess and integrated thinking Pharmaceutical Quality Systems (Q10)Past: GMP checklist Future: Quality Systems across product life cycle

21. New Q distinctions

22. The Guidance • Process • Formula • Relationship to uncertainty • Tools • Application & integration

23. Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation unacceptable R i n s o k i t a M Risk Control c a i n n a u g Risk Reduction m e m m o e C n t k t Risk Acceptance s o i o R l s Output / Result of the Quality Risk Management Process Risk Review Review Events The process

24. Dimensions of a risk based approach . Parameters for evaluating risks high probability medium detectability low risk severity

25. Risk and Uncertainty . Tomorrow ? Upper Specification Limit (USL) Process Parameter  Lower Specification Limit (LSL) Time today RISK: Control options are scenarios for risk management. Note that this scenario shows the best estimate is below the USL.

26. Risk and uncertainty • Components of uncertainty: • Limitations of human knowledge • Absence of established science. • Limitations of Technology

27. Some Risk assessment tools • Failure Mode & Effects Analysis (FMEA) • Failure Mode, Effects and Criticality Analysis (FMECA) • Fault Tree Analysis (FTA) • Hazard Analysis of Critical Control Points (HACCP) • Hazard Operability Analysis (HAZOP) • Preliminary Hazard Analysis (PHA) • Risk ranking and filtering

28. Application & Integration

29. Q9 applies across the lifecycle . Research Preclinical Phase Clinical Phases Launch Manufacturing & Distribution Safety GLP GCP Efficacy GMP Quality ICH Q9 GDP

30. Integrating QRM into product life cycle Gain experience Analyse root cause: Continuous improvement (Risk of) Failure ? Manufacture Quality Risk Management(QRM) Improve it Do, what you say Update information Approval Say, what you do

31. Integration into operations: industry & regulators • Foundation for “science-based” decisions • Degree of rigor and formality commensurate with the complexity and/or criticality of the issue • Implement QRM principles when updating existing guidelines

32. Regulatory operations Inspection and assessment activities Internal systems Industry operations Development Facilities, equipment and utilities Materials management Production Laboratory control and stability testing Packaging and labelling Application

33. Application • Integrated quality management • Documentation • Training and education • Quality defects • Auditing / Inspection • Periodic review • Change management / change control • Continual improvement

34. Application • Quality risk management is intended to enable and enhance compliance with regulatory requirements and science-based decisions when integrated into quality systems. • It is also meant to be applied where it is practical and feasible.

35. Implementation of Q9 can help identify weak links

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

37. Way Forward • Review • Implementation

38. Implementation • Work to Adapt existing structures, organizations and systems • Raise awareness of rationales for decision making • Education: Develop training • Do not create new requirements

39. Implementation • Work to Improve communication and transparency • More specific projects: (e.g. DMF’s) • Academic collaborations

40. Review and determine gaps • Examine need for additional guidance: (e.g. Excipients, Packaging/Distribution) • Adapt and update existing requirements using quality risk management

41. Thank you