ICH Q10 – Delivering a Modern Effective Pharmaceutical Quality System

1. ICH Q10 – Delivering a Modern Effective Pharmaceutical Quality System 1

2. Discussion Topics Why do we need a modern PQS? Structure and key areas of ICH Q10 Implementation opportunities and challenges 2

3. Why do we Need a ‘Modern Effective PQS’? Good business practice ! Significant changes in external business environment Fewer new products / ‘blockbusters’ Reduced margins / greater competition / low-cost sources Focus on efficient, effective organisations and lean processes Public health issues Pharmaceutical industry way behind other industries in Quality Management philosophies / practices Marketed products ARE safe and efficacious BUT costs of quality are high Often reactive, not designed-in / preventative THE STATUS QUO IS NO LONGER AN OPTION !! 3

4. Why do we Need a ‘Modern Effective PQS’? Historically innovation and improvement have been constrained Inflexible regulatory environment Focus on Compliance, not Science and Risk-Based approach = BLIND COMPLIANCE Industry margins didn’t provide drive for change GMPs do not provide a ‘full modern’ Quality System Originated in 1970s – only incrementally added to ISO Quality Management thinking not embedded SOPs focused on GMP compliance Need to be complemented 4

5. Where are we Currently ? Evolution of regional GMPs 1970s Evolution of ISO 9000 approaches 1980s FDA 21st Century initiative 2002 ICH Quality Vision / Q8, Q9, Q10 2003 FDA Quality Systems guide 2006 * ICH Q10 Pharmaceutical Quality System 2008 ICH Q8/9/10 IWG 2008 * FDA commitment to update or withdraw when Q10 issued 5

6. ICH Quality Vision “Develop a harmonised pharmaceutical quality system applicable across the lifecycle of the product emphasising an integrated approach to quality risk management and science.” Brussels July 2003 Resulting in ICH Q Guidelines: Q8: Pharmaceutical Development (step 5) Q8 (R): (step 2/3) Q9: Quality Risk Management (step 5) Q10: Pharmaceutical Quality System (step 4) Q11: Development and Manufacture of Drug Substances (step 1) For maximum utility need to consider 8/9/10 together Q8/9/10 Implementation Work Group 6

7. What is the Purpose of Q10? ICH Q10 aims to promote a paradigm shift from discrete GMP compliance procedures at each stage of the product lifecycle to a comprehensive quality systems approach over the lifecycle of the product 7

8. ICH Q10 -Pharmaceutical Quality System The objective of Q10 is to establish a new tripartite guideline describing the model for an effective quality management system for the pharmaceutical industry, referred to as the Pharmaceutical Quality System It describes one approach deemed acceptable to regulators 8

9. Q10 Key Messages - Introduction Q10 will complement and facilitate implementation of Q8‘Pharmaceutical Development’ and Q9 ‘Quality Risk Management’ ICH Q10 is not intended to create any new expectations beyond current regulatory requirements The content of ICH Q10 that is additional to current GMP requirements is optional ‘Strongly recommended’ Within the EU having a ‘Quality System’ is mandated A Q10 approach would satisfy expectations 9

10. Q10 Key Messages - Scope Applies to systems supporting the development and manufacture of pharmaceutical drug substances (API) and drug products, including biotechnology and biological products, throughout the product lifecycle Both newly developed and existing products fall within the scope Apply in a manner appropriate and proportionate to the stage of lifecycle 10

11. Q10 Key Messages - Enablers The enablers provide the means for science and risk based decisions related to product quality through the lifecycle Knowledge Management Manage knowledge from development through commercialisation to discontinuation Quality Risk Management (Q9) Proactive approach to managing risks to quality 11

12. Q10 Key Messages -Pharmaceutical Quality System Implementation of Q10 should facilitate: Innovation and continual improvement throughout the product lifecycle; and Strengthen the link between pharmaceutical development and manufacturing organisations 12

13. Q10 Key Messages - Regional GMPs Q10 will: Augment existing GMPs with specific PQS elements and management responsibilities Encourage science and risk based approaches Be used together with existing GMPs Cover all stages of the product lifecycle as defined (beyond GMPs) 13

14. Q10 Key Messages -Regulatory Approaches Regulatory approaches for a specific product or manufacturing facility should be commensurate with: The level of product and process understanding The results of quality risk management The effectiveness of the PQS 14

15. Q10 Key Messages - Regulatory Approaches The effectiveness of the PQS can normally be confirmed during a regulatory inspection at the manufacturing site Potential opportunities to enhance science and risk based regulatory approaches are identified in Annex 1of Q10 ICH Q8/9/10 IWG set up to clarify implementation questions Regulatory processes will be determined by region 15

16. ICH Q10 - Summary of Aims If adopted by industry (on a voluntary basis) would: Complement and serve as a bridge between regional GMP regulations Facilitate application of ICH Q8, Q9… Link development and manufacturing through product the lifecycle Facilitate continual improvement in pharmaceutical manufacturing Be based upon the well accepted ISO 9000 structure within a pharmaceutical context Facilitate ‘appropriate levels of regulatory scrutiny’ Post approval change Inspections 16

17. Composition of the Q10 Document The document is divided into 5 sections and 2 annexes  Pharmaceutical Quality System  Management responsibility  Continual improvement of process performance and product quality  Continual improvement of the pharmaceutical quality system  Glossary Annex 1 - potential opportunities to enhance science and risk based regulatory approaches Annex 2 - diagram of the Q10 model 17

18. Q10 - Structure Pharmaceutical Quality System Introduction Scope Relationship of ICH Q10 to regional GMP requirements and ISO Standards Relationship of ICH Q10 to Regulatory Approaches ICH Q10 Objectives Enablers - KM and QRM Design and Content Considerations Quality Manual 18

19. Q10 - Structure Management Responsibility Management Commitment Quality Policy Quality Planning Resource Management Internal Communication Management Review Management of Outsourced Activities and Purchased Materials Management of Change in Product Ownership 19

20. Q10 - Structure Continual Improvement of Process Performance and Product Quality Lifecycle Stage Goals Pharmaceutical Quality System Elements 20

21. Q10 - Structure Continual Improvement of the Pharmaceutical Quality System Management Review of the Pharmaceutical Quality System Monitoring of Internal and External Factors impacting the Pharmaceutical Quality System Outcomes of Management Review and Monitoring Glossary 21

22. Q10 - Structure 22 Annex 1 - Potential Opportunities to Enhance Science and Risk Based Regulatory Approaches Annex 2 - Diagram of the ICH Q10 PQS Model

23. So What are the Key Q10 Areas? GMPs Management Responsibility Continual Improvement Products and Processes PQS itself Quality Risk Management Knowledge Management Lifecycle approach Opportunities for science and risk based regulatory approaches 23

24. Q10 and GMP / ISO - Augments Existing Documents GMP ISO 9000 FDA QS Q10 GMPs       Management          Δ Continual Imp       QRM      Knowledge      Lifecycle      Opportunities     24

25. ICH Q10 Pharmaceutical Quality System GMP Pharmaceutical Development Technology Transfer CommercialManufacturing Discontinuation Investigationalproducts Management Responsibilities Process Performance & Product Quality Monitoring Corrective Action / Preventive Action (CAPA) Change Management Management Review PQS elements Knowledge Management Enablers Quality Risk Management 25

26. ICH Q10 and the ‘Bigger Picture’ Another diagram - The EU regulatory point of view on integration of different ICH quality concepts Quality Risk The Regulatory System Management (Q9) Quality system Management Pharmaceutical Development (Q8) Pharmaceutical Development Quality Risk Management Quality Existing GMP Existing GMP s s System (Q10) 26

27. Key Implementation Points to Consider 27

28. The PQS Must be Adaptable To meet the needs of the organisational structure Site, Region, Division, Corporate Inclusive of Outsourcing Activities To meet the needs of the goals of the lifecycle Development Tech Transfer Commercial Manufacturing Discontinuance The effectiveness of a PQS should be demonstrated at a commercial site 28

29. ICH Q10 - Implementation Approach How do we see implementation of Q10 occurring? Firms / sites choose to implement Q10 Gap analysis of current quality system - action plans PQS will formally integrate QbD / QRM / Knowledge Management / Corporate PQS processes Internal evaluations at site level, including any corporate PQS processes Request regulatory assessment of Q10 by inspection at manufacturing site Regulators confirm and document Q10 status Regulators need to take the lead role in implementing the opportunities described in the Annex 29

30. ICH Q10 - Implementation Approach 30 • Where are we now? • Unlikely any firm is fully Q10 compliant? • Many have undertaken a gap analysis • Several at different stages of implementation plans • Many examples of real $ benefits / case studies • CAPA • Product and process understanding and monitoring • Management reviews • Quality Risk Management • Others waiting to see how things develop • It is simply good business practice – so why wait???

31. Implementation - Management Responsibilities Essential component Not just about compliance Visible leadership to establish and maintain a company wide culture and commitment to quality and improvement Monitor performance of the PQS and act Internal and Outsourced activities Quality cannot be owned by the Q Unit Management is accountable But independent assessments / audits are key 31

32. Implementation - Management Responsibilities Clear roles, responsibilities and governance processes are essential Quality Policy - standards and direction of organisation Quality Planning - convert into objectives / plans Resources - allocations and competence Communication - Q items to appropriate audiences Management Reviews Product and Process performance PQS performance 32

33. Implementation - Continual Improvement CAPA system Investigation of non-conformances e.g. deviations, rejections, complaints, recalls, observations from audits & inspections = reactive e.g. feedback from trends = proactive Structured investigations to seek root cause Use QRM to ensure degree and formality is commensurate with level of risk Should result in enhanced knowledge and improvement Not just reacting to non-conformances Focus on preventative actions Need effective tracking / follow up processes 33

34. Implementation - Continual Improvement Change Management System Change can be good ! Proactively driven by outputs from monitoring / trending / improvement / innovation Not just by reacting to problems Use expert teams and knowledge to evaluate and set success criteria Use QRM commensurate with level of risk Consider impact on regulatory filings Undertake in timely and effective way and track Assure no unintended consequences > Self management by competent manufacturers 34

35. Implementation - Continual Improvement Product Quality and Process Performance Monitoring System Use knowledge, QbD, Product and Process understanding and QRM to set Control Strategy What and when to monitor / measure / test Based on critical product quality attributes and critical process parameters to deliver them Confirm and maintain a state of control Feed-back and feed-forward loops Reduce and control variation to appropriate levels Drive continual improvement Continual verification 35

36. Implementation - Quality Risk Management (Q9) Essential integrated part of PQS – 2 key principles The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk. Proactive use to identify and control risk Support decisions through lifecycle Integrate into key parts of PQS e.g. change management, CAPA, GMPs, Validation, etc Help set meaningful specifications / CPPs to ensure product CQAs are met 36

37. Systematic and lifecycle approach to acquiring, analysing, storing and disseminating knowledge on products, processes, components… Not just an IT solution Processes, Organisation, People Provides the basis for science and risk based approaches in the PQS Product and process development Manufacturing Change management Continual improvement Implementation - Knowledge Management 37

38. Implementation - Lifecycle Approach A modern PQS needs to be holistic and cover the product lifecycle Design and development Manufacturing Withdrawal Challenges and removes some traditional organisational silos Within Industry Within Regulatory Agencies With outsourcing partners 38

39. Q10 Implementation - Opportunities and Challenges 39

40. How Might Industry and Regulators use Q10 with Q8 & Q9? Potential opportunity for: Increased use of risk based approaches for regulatory inspections To facilitate science based pharmaceutical quality assessment To optimise science and risk based post-approval change processes to maximise benefits from innovation and continual improvement To enable innovative approaches to process validation / establish real time release mechanisms 40

41. Challenges to a Future Successful Implementation Trust and culture change - enhanced two-way trust Clear understanding of the stakeholders’ needs and options Industry - regulator trust and openness in working together towards the new vision - learning together Culture change in both Industry and Regulators Overcome internal conservatism and ‘silo’ thinking Organisational change management – resistance to change, new competencies needed, e-access to data… Harmonisation and mutual understanding ICH members and observers, ROW, emerging markets Big Pharma is a global operation, but often with regional / national regulatory processes 41

42. ICH Q10 - Implementation How can we work together to ensure consistent implementation? At ICH level - via IWG for Q8/9/10 At regional level regular interactions (e.g. joint work groups, external events) needed to address e.g. How Q10 implementation will be confirmed How Q10 Annex opportunities will be delivered What is ‘regular GMP’ (mandated) versus what is Q10 (optional) Understanding of Lifecycle and Knowledge Management Engage other regions (e.g. via PICS and ICH GCG) 42

43. Special Thanks To ICH Q10 EWG members Efpia Q10 Topic team members PDA-FDA Quality Systems team members 43

44. Thank you David Begg Associates www.DBA-global.com DBA 44