INTRODUCTION TO ICH Q8 & Q9 GUIDELINES

1. INTRODUCTION TO ICH Q8 & Q9 GUIDELINES K. S. BABU Head - Corporate Regulatory Affairs Watson Pharma., India November 29, 2007

2. FOREWORD EMPHASIS • Interpretation of guidance documents • Regulatory relevance & applications • Bonus: Q10 guideline, due to its relevance

3. WHAT ARE THESE GUIDELINES ABOUT? Q8: - “Pharmaceutical Development” (“Implemented”) - Contents of 3.2.P.2 Section of Module 3, CTD Q8 – Annexure (“Draft stage”) - Provides further clarification to Q8 concepts - Links ‘’QbD’’ & “PAT” (FDA), & ‘’QRM’’ (EU), “FEMA” Q9: - “Quality Risk Management” (“Implemented”) Q10: - “Pharmaceutical Quality System” (“Draft stage”)

4. REGULATORY STATUS OF ICH Q 8 Reached Step 5 – Regulatory Implementation EU: Transmission to CHMP and to Interested Parties in December 2004. Issued as EMEA/CHMP/167068/2004-ICH. Deadline for comments : June 2005. Final approval by CHMP: November 2005. Date for coming into operation: May 2006. MHLW: Adopted on September 1, 2006, PFSB/ELD Notification N° 0901001 FDA: Published in the Federal Register, Vol. 71, No 98, May 22, 2006

5. REGULATORY STATUS OF ICH Q 8 - Annexure Reached Step 3 in Nov. 2007: • Regulatory Consultation & Discussion • Draft Guideline EU / MHLW / FDA: TO BE NOTIFIED

6. REGULATORY STATUS OF ICH Q 9 Reached Step 5 – Regulatory Implementation EU: Published on the EMEA website MHLW: Adopted on September 1, 2006, PFSB/ELD Notification n° 0901004 FDA: Published in the Federal Register, Vol. 71, No 106, pages 32105-32106, June 2, 2006

7. REGULATORY STATUS OF ICH Q 10 Reached Step 3 in May 2007: - Regulatory Consultation & Discussion - Draft Guideline EU: Transmission to CHMP and to Interested Parties May 2007. Issued as EMEA/CHMP/ICH/214732/2007. Deadline for comments: November 2007. MHLW: Released for consultation 13th July 2007, PFSB/ELD, deadline for comments 1st October 2007 FDA: Published in the Federal Register July 13, 2007, Volume 72, No. 134, pages 38604-38605. Deadline for comments October 11, 2007.

8. BRIEF NOTE ON ICH Q10 : P.Q.S. • Based on ISO concepts • Includes applicable GMP regulations • Compliments ICH Q8 and ICH Q9 • Acts as a model for a pharmaceutical quality system that can be implemented throughout the different stages of a product lifecycle. • Content is currently specified by regional GMP requirements • Not intended to create any new expectations beyond current regulatory requirements • Consequently, the content of ICH Q10 that is additional to current GMP requirements is optional

9. Q8: OVERVIEW Talks about Pharmaceutical Dev. section in regulatory submissions Suggested Contents for 3.2.P.2 of CTD Quality Module 3: • 3.2.P.2.1Components of drug product (drug substance/ excipients) • 3.2.P.2.2 Formulation Dev. • 3.2.P.2.3 Manufacturing Process Development • 3.2.P.2.4 Container Closure System • 3.2.P.2.5 Microbiological Attributes • 3.2.P.2.6 Compatibility There is “much more” than meeting the filing requirements or CTD check-list

10. Q8: OVERVIEW (contd.) Greater understanding of the product / process & variables Science- and risk-based submissions Wider regulatory “flexibility” Q8 Annexure & “Q R M” (ICH Q9)

11. Q8: Related EU Directives and Guidelines 2003/63/EC, Annex I, 3.2.2.2 – Pharmaceutical Development CPMP/QWP/155/96Guideline on Development Pharmaceutics NTA Volume 2B - Common Technical Document Note for guidance on development pharmaceutics (EMEA/CHMP/167068/2004) Link to EU Directives: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev1.htm

12. Q8: Objectives of Pharmaceutical Dev. Section UNDERSTANDING: Provide a comprehensive understating of the product and manufacturing process for reviewers and inspectors EVIDENCE:Establish evidence that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the intended use ASSURANCE:Provide scientific discussion to support that – the design / process will consistently deliver a quality product SYSTEMATIC ASSESSMENT: Testing during developmental stage – Extensive & Different from routine Critical parameters of the formulation and process which can influence batch reproducibility, medicinal product performance and medicinal product quality shall be identified and described.

13. Q8: IMPORTANT CONSIDERATIONS • 3.2.P.2.1.1 Drug Substance: • Key physicochemical characteristics of the drug substance (e.g. solubility, water content, particle size distribution), which are variable and critical for the quality of the product and which can influence the performance of the drug product • Compatibility of drug substance with the excipients • For combination products, the compatibility of the drug substances with each other • Polymorphism issues

14. Q8: IMPORTANT CONSIDERATIONS (contd.) • 3.2.P.2.1.2 Excipients: • Choice of excipients (in particular relative to their respective functions) & their concentration (with justification) • Their characteristics that may influence the drug product performance • Compatibility of excipients with other excipients, where relevant • Justification for their inclusion, in some cases (e.g. preservatives, anti-oxidants) accompanied by experimental data • Safety of the excipients, where relevant

15. Q8: IMPORTANT CONSIDERATIONS (contd.) • 3.2.P.2.2.1 Formulation Development: • Differences between clinical formulations and current formulation • Summary describing the development of the formulation including identification of critical attributes to the quality of the drug product • The choice of drug product components (drug substance, excipients, container closure system etc.,) and the manufacturing process • Results of comparative in vitro studies (dissolution) and in vivo studies (bio-equivalence), when appropriate • Any special design features of the drug product (tablet score line,over fill etc.,)

16. Q8: IMPORTANT CONSIDERATIONS (contd.) • 3.2.P.2.2.2 Overages: • Use of an overage of a drug substance to compensate for degradation during manufacture or a product’s shelf life, or to extend shelf life, is discouraged • A justification of any overage on grounds of safety and efficacy • Information on amount of overage, reason for the overage and the justification for the amount of overage.

17. Q8: IMPORTANT CONSIDERATIONS (contd.) • 3.2.P.2.2.3 Physicochemical and Biological parameters: • The physicochemical and biological properties relevant to the safety, performance or manufacturability of the drug product should be identified and discussed • The selection of dissolution testing should be discussed.

18. Q8: IMPORTANT CONSIDERATIONS (contd.) 3.2.P.2.3 – Manufacturing Process Development • Basis for process improvement, process validation, continuous process verification and process control requirements. • The selection, the control, and any improvement of the manufacturing process. • Appropriateness of the equipment used for the intended product. • For the sterile products, appropriate method of sterilization and the primary packaging material selection should be discussed.

19. Q8: IMPORTANT CONSIDERATIONS (contd.) 3.2.P.2.3 – Manufacturing Process Development (contd.) • Significant difference between the manufacturing process of pivotal batches and intended commercial batches. • If differences are there, the influence of the difference on product performance, manufacturability and quality to be discussed. • Experiments of laboratory scale batches should be described. • Information from scaling up from laboratory through pilot to production scale to justify that scale-up can be achieved without a consequent loss in quality.

20. Q8: IMPORTANT CONSIDERATIONS (contd.) 3.2.P.2.4 – Container Closure System • Discussion on the suitability of the container closure system used for storage, transportation and use of the product • This discussion should consider • choice of the materials for primary packaging • protection from moisture and light • compatibility of the materials with the dosage form • performance of the dose delivery from the device if dosing device is used • Food grade certification

21. Q8: IMPORTANT CONSIDERATIONS (contd.) 3.2.P.2.5 – Microbiological Attributes Where appropriate the microbiological attributes of the dosage form should be addressed (according to Ph.Eur.). The discussion should include for example: • The rationale for performing or not performing microbial limits testing for non-sterile products. • The selection and effectiveness of preservative systems in products containing antimicrobial preservatives. • For sterile products, the integrity of the container closure system as it relates to preventing microbial contamination. The lowest concentration of antimicrobial preservative should be demonstrated to be effective in controlling microorganisms.

22. Q8: IMPORTANT CONSIDERATIONS (contd.) 3.2.P.2.6 – Compatibility • The compatibility of the drug product with reconstitution diluent(s) should be addressed to provide appropriate labelling information. • This information should cover the recommended in-use shelf life at the recommended storage temperature.

23. Q8: OVERVIEW (contd.) Greater understanding of the product / process & variables Science- and risk-based submissions Wider regulatory “flexibility” Q8 Annexure & “Q R M” (ICH Q9)

24. Specific Cases • Use of one lot of API for Exhibit batches : PSD Profile Optimization • Impact of age of API used in Exhibit batches • Blend time optimization • Switching to alternate sources for Excipients (E.g., Mg.Stearate– Animal grade to Veg. grade)

25. Focus of Q8 Annexure • Define Target Product Profile • Identify ‘CQAs’ – Critical Quality Attributes of Product • Determine QAs of inputs – materials/parameters etc. • Select appropriate process • Determine functional relationships between material attributes & process parameters to Product CQAs • Identify a control strategy • Propose a “design space” • Define and describe design space in regulatory submission

26. Focus of Q8 Annexure (contd.) Defining DESIGN SPACE: Options - • Ranges of input variables or parameters • Analysis of historical data can be basis • Scaling factors • Multivariate operations Operation within the design space results in a product that meets the defined quality attributes Periodic reassessment throughout life-cycle

27. ICH Q 9 (QRM) as part of development • To design a quality product and its manufacturing process • to consistently deliver the intended performance of the product • To enhance knowledge of product performance over a wide range of • material attributes (e.g. particle size distribution, moisture content, flow properties) • processing options • process parameters

28. QRM as part of development (contd.) • To assess the critical attributes of • Raw materials • Solvents • Active Pharmaceutical Ingredient (API) • Starting materials • Excipients • Packaging materials • To establish appropriate specifications, identify critical process parameters and establish manufacturing controls

29. QRM as part of development (contd.) • To decrease variability of quality attributes: • reduce product and material defects • reduce manufacturing defects • To assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up and technology transfer • To make use of the “design space” concept (annexure to ICH Q8)

30. Q9 : QUALITY RISK MANAGEMENT What is “risk”? Combination of the probability of occurrence of harm, and the severity of that harm. “Fact: No process is risk-free”

31. Company Strategic risks Operational risks Financial risks Compliance risks Environmental Regulatory filing Competitor Company Shareholder Patient advantage viability harm harm Quality / GMP Safety & Efficacy MANAGING RISKS IN A COMPANY … ICH Q9

32. EMEA NOTE ON Q9

33. Q9: Dangers from Absence of Risk Management • Pharmaceutical products may not be available to patients when needed, e.g. when a product is recalled from a market or where different risk decisions contribute to inefficient manufacturing processes and consequent delays • May increase the potential for the release of unacceptable product to the market • Delays may occur during implementation of changes and improvements to processes • Safe and effective drugs may be discarded or recalled from the market • Manufacturers may be reluctant to implement new technologies or continuous improvements to products or processes • Scarce resources may not be optimally allocated • Lack of appropriate date to evaluate risk most effectively

34. Q9: Purpose & Objectives • No national guidance documents in this area in any region • No common understanding of terms, principles and application of risk management • Development of a harmonised pharmaceutical quality system applicable across the life cycle of the product emphasising an integrated approach to risk management and science • Deriving common terminology, including a definition of quality, risk, risk management etc • Defining the principles for how risk management can be effectively applied and consistently integrated into decisions regarding product quality • Rationalization & Operationalization of the integration of risk management into the decision making process

35. Q9: Purpose & Objectives (contd.) • Defining criteria on how to apply the risk management process • Identification of circumstances, if any, when applying risk management principles is not feasible or appropriate • Defining what principles of risk management apply to industry, regulators or both across the life-cycle of the product • Establish - how, what & when information is exchanged between & within industry, to the regulators, and to both, throughout the product life cycle • Emphasize synergies with the pharmaceutical development project • Defining roles and responsibilities of regulators and industry • Discuss how risk can be incorporated into resource allocation decisions

36. Q9: Benefits of Quality Risk Management Approach • Enhancement of patient confidence worldwide in decision making on the quality of pharmaceuticals • Promotion of more effective use of regulatory and industry resources • Establishment of a systematic, well-informed and thorough method of decision making which leads to greater transparency and predictability • Increased knowledge of exposure to risk • A greater assurance to regulators of a company’s ability to deal with potential risks • Fostering continuous improvement and quality by design generally leading to enhanced product quality • Enables right “decision making”

37. Quality Risk Management Process

38. Risk Assessment 3 Stages: • Risk identification: what are the hazards? • Risk analysis: risk associated with identified hazards • Risk evaluation: comparison of identified and analyzed risk against a given risk criteria 3 fundamental questions: • What might go wrong? • What is the likelihood it will go wrong?: Probability • What are the consequences? : Severity

39. Risk Control • Decision making: • Risk reduction? Or • Risk acceptance? • Basis for Judgment: • Is the risk above an acceptable level? • What can done to reduce or eliminate risks? • What is the appropriate balance among benefits, risks and resources? • Are new risks introduced as a result of the identified risks being controlled?

40. Risk Management methodology • Recognized risk management tools: • Basic risk managementfacilitation methods (Flow charts, check sheets etc.). • Failure Mode Effects Analysis (FMEA). • Failure Mode, Effects and Criticality Analysis (FMECA). • Fault Tree Analysis (FTA). • Hazard Analysis and Critical Control Points (HACCP). • Hazard Operability Analysis (HAZOP). • Preliminary Hazard Analysis (PHA). • Risk Ranking and Filtering. • Supporting Statistical Tools.

41. Importance of Communication in QRM Communicationfacilitates trust and understanding Regulatorsoperation- Reviews - Inspections Industryoperation - Submissions - Manufacturing

42. Using ICH Q9 will… • Facilitate • Communication and transparency • More informed, scientifically based decision making • Patient focused actions on quality risks • Realistic and appropriate solutions • Use of existing solutions (Share best practice/prior knowledge) • Manage critical to quality aspects • Through systems, organisations, processes & products • Maintain responsibility & accountability for QRM • Focus activity towards patient protection It should never be used as a “hobby horse” / preconceived idea

43. Opportunity for the Industry & Competent Authorities • Using the same guideline apply QRM to industry (Development & Manufacture) and regulators (Reviewer & Inspectorate) • Provides for establishing a defined program for what we already do every day in our jobs • Supports science-based decision making • Optimisation of resources • Prevention from overly restrictive and unnecessary requirements • Facilitates communication and transparency

44. Challenges for Industry & Competent Authorities • Interpreting and adopting the concepts of quality risk management into specific areas • Embed this behavior into quality aspects of business, technology and regulation • Adopt in existing structures, organizations and Quality System • Balance the documented use of “informal” and “formal” quality risk management

45. QRM Integration into Industry & Reg Operations • QRM is a process that supports science-based and practical decisions when integrated into quality systems. • Effective QRM can facilitate better and more informed decisions. • Effective QRM can provide regulators with greater assurance of a company’sability to deal with potential risks. • QRM can facilitate better use of resources by all parties. • Training of both industry and regulatory personnel in QRM processes provides for greater understanding of decision-making processes & builds confidence in QRM outcomes.

46. Q8 Q9 Q10 The new paradigm “risk-based” concepts and principles

47. ChangedParadigm Incremental steps 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 thinking Pharmaceutical Quality Systems (Q10)Past: GMP checklist Future: Quality Systems across product life cycle Q8 Q10 Q9

48. Using Q9 Quality Risk Management principles How Q9 interacts with Q8 and Q10 Risk from Manufacturing site High Q10 Pharm. Quality Systems Low Q8 Pharmaceutical Development Low High Product / Process Risk

49. ICH Q9 Link back to patient risk Opportunities to impact risk using quality risk management Q8 Q9 Design Q10 Process Materials Manufacturing Facilities Distribution Patient

50. A Vision of the Future