Joseph C. Famulare Senior Director Pharma Global Technical Operations – Quality & Compliance Genentech Inc., A Me

1. Globalization and Harmonization in the Pharmaceutical Industry August 18, 2011 Joseph C. Famulare Senior Director Pharma Global Technical Operations – Quality & Compliance Genentech Inc., A Member of the Roche Group

2. FDA Compliance Trends and Reorganization • PIC/S Update • ICH Update • Other Hot Topics • Questions? 2

3. Globalization Source: “FDA International GMP Inspection and Compliance” FDA’s Carmelo Rosa at DIA Chicago (June 2011)

4. Results of Globalization - Increased HA Scrutiny (focus on Supply Chain) FDA Warning Letters for GMP Violations (FY2008 vs. FY2010) 40 + 53% 26 CMOs & Suppliers received approximately 75% of the 40 WLs issued by FDA in FY2010 Sources: (2010) based on publically available information from FDA website as of 25Jan2011; (2008) FDA Presentation at GPhA/FDA Fall Technical Conference, 2010

5. Results of Globalization – Increased HA Scrutiny Internationally Source: “FDA International GMP Inspection and Compliance” FDA’s Carmelo Rosa at DIA Chicago (June 2011)

6. Recent WL Activity – Key Messages Establish and Maintain State of Control (Systemic, Comprehensive and Global) “It is our [FDA] expectation that firms take a systematic approach to correcting and complying with CGMP to ensure the identity, strength, quality, and purity of their drug products.” “In your response to this [warning] letter, please include an explanation of how you intend to implement, support, and sustain a comprehensive quality system at your firm that is consistent with CGMP.” “It appears that you have not taken a global quality systems approach to corrective actions at your firm…It is your responsibility to review your operations at all facilities and apply appropriate corrective actions to address deficiencies present at multiple sites.” Source: FDA Warning Letters, at http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

7. Recent WL Activity – Key Messages Corporate-Wide Quality Practices (Multi-Facility) “These identical CGMP violations demonstrated a lack of adequate process controls and raised serious questions regarding your corporation’s quality and production systems.” Source: FDA Warning Letters, at http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

8. Recent WL Activity – Key Messages Management Commitment “It is our expectation that firm’s senior management ensure a systematic approach to designing their products, processes, and quality systems, and require that deviations and flaws are promptly identified and corrected to assure the identity, strength, quality, and purity of their drug products.” “Be advised that FDA expects that your corporate management will undertake a comprehensive evaluation of manufacturing operations to ensure compliance with CGMP.” Source: FDA Warning Letters, at http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

9. Recent WL Activity – Key Messages Product and Process Understanding “Your response, however, is inadequate in that it does not address: 1) specific details about your re-validation plans and in particular, whether you will determine the root cause to clearly demonstrate a full understanding of your products and processes before initiating the re-validations, and; 2) the controls involved with issuing, reviewing, and revising manufacturing batch records to ensure validation criteria are captured and accurate. “ Source: FDA Warning Letters, athttp://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm

10. US Manufacturing Quality Enforcement Recent Case Studies • Recent consent decrees involving GSK, Genzyme, and McNeil follow the typical regulatory pattern for FDA injunctions, meaning: • multiple violative inspections; • the issuance of a warning letter; and • potential or actual patient safety issues. - Notable in recent consent decrees: • Naming of top quality officials brought in by the company to fix quality problems; • How FDA handled McNeil despite its ongoing corrective actions; and • FDA used disgorgement in the Genzyme case.

11. US Manufacturing Quality Enforcement Individual Liability - Park Doctrine • Under the Park doctrine, the government may hold an individual responsible for violations of CGMP if the individual is in a position with authority to have prevented the violation or promptly to have corrected it. • Recently, FDA revised its Regulatory Procedures Manual (RPM) to describe criteria for Park prosecution, including whether • the violation is obvious, widespread, serious, and • a pattern of illegal behavior exists or a failure to heed prior agency warnings.

12. Recent FDA Organizational Changes New FDA/CDER Super Office of Compliance Structure to Reflect Emerging Global Supply Chain Concerns (reflecting changes made through July 13, 2011)

13. CDER Office of Compliance – Super Office Structure Office of Compliance Office of Drug Security, Integrity & Recalls Office of Manufacturing & Product Quality Office of Unapproved Drugs & Labeling Compliance Office of Scientific Investigations Div. Bioequivalence & GLP Compliance Div. Import Operations & Recalls Div. International Drug Quality Div. Prescription Drugs Div. Good Clinical Practice Compliance Div. Supply Chain Integrity Div. Domestic Drug Quality Div. Non-Prescription Drugs & Health Fraud Div. Policy, Collaboration & Data Operations Div. Safety Compliance Div. of GMP Assessment

14. FDA Compliance Trends and Reorganization • PIC/S Update • ICH Update • Other Hot Topics • Questions? 14

15. What does the Pharmaceutical Inspection Cooperation Scheme (PIC/S) offer? • PIC/S GMP- Guide • Follows the EU-GMPs and comparable with US GMPs as of acceptance of FDA in PIC/S • Guidance documents • e.g. Parametric release, Validation of aseptic processing • Q&A documents • e.g. Distribution of APIs, ICH Q7 in the new paradigm (coming soon) • Aide mémoire (questions Inspectors might ask) • e.g. Clinical trial Manufacturing, Utilities, Biotech API, Laboratories • Training and Workshops • e.g. Aseptic processing, ICH Q7 (jointly with PDA) http://www.picscheme.org

16. Value and Challenges of PIC/S • Communication • Harmonisation • Collaboration • Trust Tor Gradberg at PIC/S 40th Anniversary

17. Opportunities within PIC/S • Harmonisation of requirements • Continue to link the EU-GMP and to WHO GDP requirements to make the PIC/S GMP guide identical or equivalent • Facilitate trust and understanding • Joint visits of member inspectorates • Joint accession process for new PIC/S members e.g. gap analysis, trainings performed by inspectors • Training and developing harmonised guidance • Expert Cycle Groups • Export increased • In most of the counties if inspectorate got PIC/S membership

18. PIC/S in the future? • More opportunities to harmonisation • Continue to keep standards identical or equivalent to the EU-GMP; US requirements might influence • Share work among new member inspectorates • Try to minimize and simplify • Share information to avoid duplication of inspections • May extend the scope to other GxP processes • The idea of a 'inspectorate academy' Helena Baião, Deputy Chairman of PIC/S

19. Future PIC/S membership? • Which other countries foreseen in PIC/S? • ICH partner Japan • Emerging countries e.g. China, Brazil, Turkey, Mexico, South Korea

20. Nov 2005 & Nov 2008 November 2005 June 2008 PIC/S supports the ICH ‘New Quality Paradigm’ Q9 Q8 (Q11) Q10 Implementation support ‘Points to consider’ ‘Training & Workshop’ ‘Questions and Answers’

21. The Environment… AssessorsInspectorates Industry

22. The Environment… • Communication • Harmonisation • Collaboration • Trust AssessorsInspectorates Industry ?

23. Opportunities for Harmonisation of Authorities and Industry processes Over all process Opportunities for Harmonisation Scheduling based on risk factors Identification of the Scope, Format, Duration etc. Risk ranking tool for Observations Evaluation matrix for the Compliance status Elements of the GMP Certificate

24. Globalization and PIC/S Source: “FDA International GMP Inspection and Compliance” FDA’s Carmelo Rosa at DIA Chicago (June 2011)

25. FDA’s Relationship to PIC/S • Very strong management support at FDA • Encourage other countries to join PIC/S • PIC/S is • Seen as a global leader to ensure quality of drugs • A new partner for FDA • It represents a safety net on drug oversight Dr Hamburg at PIC/S Anniversary

26. FDA Benefits from PIC/S • FDA is happy to support PIC/S with resources due to anticipated benefits, including: • Performing and hosting e.g. training; • Opportunity to not duplicate FDA’s inspections efforts by other PIC/S member states; • Facilitate sharing inspection reports; and • Exchange recall alerts. Source: Dr Hamburg at PIC/S Anniversary

27. FDA Compliance Trends and Reorganization • PIC/S • ICH Update • Other Hot Topics • Questions? 27

28. About ICH: Members: ‘6 parties’ in 3 regions • United States of America • Food and Drug Administration • Pharmaceutical Research and Manufacturers of America • Europe • European Union / European Commission • European Federation of Pharmaceutical Industries and Associations • Japan • Ministry of Health, Labour and Welfare / PMDA • Japan Pharmaceutical Manufacturers Association

29. About ICH: Observers and Interested Parties • Observers (Regulators) • World Health Organisation (WHO) • Health Canada, Therapeutic Products Directorate (TPD) • European Free Trade Association (EFTA)represented by Swissmedic • Interested Parties (Industry) for Q-IWG • International Generic Pharmaceutical Alliance (IGPA) • World Self-Medication Industry (WSMI)

30. Nov 2005 & Nov 2008 November 2005 June 2008 The ‘New Quality Paradigm’ Q9 Q8 (Q11) Q10 Implementation support ‘Points to consider’ ‘Training & Workshop’ ‘Questions and Answers’

31. Achievements of the ICH Quality Implementation Working Group (ICH Q-IWG) in Cincinnati • ‘Points to Consider’ document completed • Criticality of Quality Attributes and Process Parameters • Control Strategy • Level of Documentation in enhanced (QbD) regulatory Submissions • Further training on ICH documents established

32. Introduction to ‘Points to Consider’ ‘Points to Consider’ • Supplement the existing • Questions & Answers (Q&A) and • Workshop training materials • There is a need considered all together • Based on • Questions raised during the ICH Q-IWG training workshops • Are NOT intended • To be new guidelines and/or to introduce new or increased regulatory requirements Intended to provide clarity

33. Introduction to ‘Points to Consider’ • The development approach should be adapted based on the complexity and specificity of product and process • Applicants are encouraged to contact regulatory authorities regarding questions related to specific information to be included in their application • Using Quality by Design (QbD) approach • Does not change regional regulatory requirements • Can provide opportunities for more flexible approaches to meet these requirements • In all cases, GMP compliance is expected.

34. Points to Consider document:Criticality of Quality Attributes and Process Parameters The information developed to determine CQAs and CPPs will help to • Develop control strategy • Ensure quality of the product throughout the product lifecycle • Increase product and process knowledge • Increase transparency and understanding for regulators and industry • Evaluate changes

35. Points to Consider document:Criticality of Quality Attributes and Process Parameters • Considerations for Establishing CQAs and CPPs • Relationship between risk and criticality: • The level of risk can change as a result of risk management. • Quality Attribute criticality is primarily based upon severity of harm • Process Parameter criticality is linked to the parameter’s effect on any critical quality attribute…and therefore can change as a result of risk management.

36. Points to Consider document:Criticality of Quality Attributes and Process Parameters • Considerations for Establishing CQAs and CPPs • Considerations for identifying and documenting CQAs can include the: • Severity of harm (safety and efficacy) before taking into account risk control and the rationale for distinguishing CQAs from other quality attributes • Link to the patient as described in the QTPP. • Basis on which the CQAs have been developed (e.g. prior knowledge, scientific first principles, and experimentation). • Inter-dependencies of the different CQAs.

37. Points to Consider document:Criticality of Quality Attributes and Process Parameters • Considerations for Establishing CQAs and CPPs • Considerations for identifying and documenting CPPs can include the: • Risk assessment and experimentation to establish the linkage between potential CPPs and CQAs • Basis on which the CPPs have been identified (e.g. prior knowledge, scientific first principles, QRM, Design of Experiment (DoE), and other appropriate experimentation). • Inter-dependencies of the different CPPs. • Selected Control Strategy and the residual risk.

38. Points to Consider document:Criticality of Quality Attributes and Process Parameters • Considerations for Establishing CQAs and CPPs • CQAs and CPPs can evolve throughout the product lifecycle, for example: • Change of manufacturing process (e.g. change of synthetic route). • Subsequent knowledge gained throughout the lifecycle (e.g. raw material variability, pharmacovigilance, clinical trial experience, and product complaints). • Relationship of Criticality to Control Strategy • Considered when designing the control strategy • The control strategy plays a key role & hence to realise QTPP

39. Points to Consider document:Criticality of Quality Attributes and Process Parameters • What is critical? High risk of significant impact to product quality, safety or efficacy, which requires a degree of control

40. Points to Consider: Control Strategy • Life-cycle of the control strategy • Development of control strategy • Continual improvement of the control strategy • Change management of the control strategy • Different control strategies for the same product • Knowledge management

41. Points to Consider: Control Strategy • Suitability of control strategy at different scales • Management of risk on scale-up • Scale-up considerations for elements of Control Strategy • Complexity of product and process • Differences in manufacturing equipment, facilities and/or sites • Raw materials • Process parameters • In-process controls • Product specification

42. Points to Consider: Control Strategy • Specifications and Certificate of Analysis (CoA) for Real Time Release Testing (RTRT) The use of RTRT has been addressed (see ICH Q8(R2) Section 2.5.; ICH Q-IWG Q&A Chapter 2.2. • Specific points to consider are provided for: • Quality attributes • Methods of control • Acceptance criteria • CoA elements • Reported results e.g. values calculated from models, established calibrations and actual test results • Acceptance criteria related to the method used • Method references

43. Points to Consider: Control Strategy Process for a batch release decision

44. ‘Points to Consider’: Level of Documentation in Enhanced (QbD) Regulatory Submissions • It is helpful for regulators to have a statement…describing the proposed regulatory outcome and expectations • It is important…that not all the studies performed and/or data generated during product development need to be submitted • Sufficient supporting information and data should be submitted in the application to address the following: • The scientific justification of the proposed Control Strategy • The scientific rationale for the studies conducted • A concise description of methodologies used to conduct these studies and to analyze the generated data • The summary of results and conclusions drawn from these studies

45. ‘Points to Consider’: Level of Documentation in Enhanced (QbD) Regulatory Submissions • Risk Management Methodologies Sufficient detail to demonstrate how the conclusions were reached • Designation of QTPP and identification of CQAs • Material attributes, process parameters and prior knowledge that were considered during risk assessment • Relevant known risk factors, e.g. degradation, solubility • Identification of potential residual risk and how to manage • A list of critical and other quality attributes & process param. • The linkage between CPP's , CQAs and the QTPP • Comment on interaction of attributes and process parameters and effect of equipment and scale

46. ‘Points to Consider’: Level of Documentation in Enhanced (QbD) Regulatory Submissions • Design of Experiments • Inclusion of a full statistical evaluation…is not expected. • A summary table…will be helpful. • Facilitate assessment by the regulators: • Rationale for selection of DoE variables • Any evidence of variability in raw materials • Listing of the parameters that would be kept constant • Type of experimental design used and a justification • Indicate if factors are expected to be scale-dependent • Reference to the type of analytical methods • Results and statistical analysis of DoE

47. ‘Points to Consider’: Level of Documentation in Enhanced (QbD) Regulatory Submissions • Manufacturing Process Description • Regional regulatory requirements with regard to the level of detail in describing manufacturing processes • Describing the proposed design space, including critical and other parameters studied, and its role in the development of the control strategy • Manufacturing changes should be managed in accordance with regional regulatory requirements. Where relevant, applicants can also consider submitting post-approval change management plans or protocols to manage post-approval manufacturing changes based on regional requirements

48. ICH Q-IWG at the ICH Web Page Q8/9/10 Implementation PtC Added

49. Next training activities • Perform enhanced training workshop • Health Canada collaboration: Ottawa, Sept 26/27 2011 • Global Cooperation Group collaboration: Seoul, Oct 04/05 2011

50. Next steps in the ‘Points to Consider’ • Process validation / Process verification • Role of modeling in QbD • Design space