The Ever-increasing Complexity of Biotech Changes - A Pledge for Global Convergence

Transcription

1 The Ever-increasing Complexity of Biotech Changes - A Pledge for Global Convergence CMC Strategy Forum, Sorrento, May 7th, 2014 Susanne Ausborn, Pharma Technical Regulatory Policy F. Hoffmann-La Roche, Basel, Switzerland

2 Presentation Outline Summarize complexity and current challenges of global life-cycle management Illustrate issues using typical examples Conclude with some reflections for pragmatic solutions to drive global convergence of post-approval change regulations 2

3 Many pharmaceutical companies manufacturing biotherapeutics are operating globally and have global manufacturing sites Global registration with Health Authorities Global supply chain Multiple sourcing strategy 3

4 Life Cycle Complexity and Challenges Complexity Some case studies Reflections on pragmatic solutions 4

5 The content differences at original submission are the first main cause for life-cycle complexity Approximately 192 recognized states Activities in ~140 countries Two categories of CMC packages ICH-like requirements in 20 countries Countries accepting less detailed information Trend towards introduction of country-specific or regional data Degree of detail Declarations Raw data Submission of GMP documents - paper inspections 5

6 Approved details differ from country to country after Q&A compared to the submitted dossier 100 Approval 20 Approval 6

7 One global submission can lead to multiple locally registered contents For Example: Each pin reflects a dossier with separate regulatory commitments for one product application..24 separate registrations for one product Adapted from: Colgan; ISPE annual meeting Nov

8 Introducing changes to the manufacturing process or the control system is an essential part of a products life-cycle Ensure market access and continuous supply of live-saving drugs to patients by reacting to supply demands Support continuous improvement and optimization of manufacturing process and quality of the medicinal products Remain state-of-the-art with manufacturing methods and analytical techniques Fulfill regulatory agency requirements 8

9 Approved details differ from country to country after Q&A compared to the submitted dossier 100 Approval Change 1 20 Approval 20 9

10 Post approval change requirements and need for sequential submission complicate further Change classifications different or not available Country-specific requirements (e.g., stability, raw data) Long/unpredictable approval timelines Backlog due to high review demand at Health Authorities CPP* needed for submission? Complex supply planning/ high bridging stocks Drug shortage Hinder innovation and continual improvement of process and product Quality and safety *CPP= Certificate of Pharmaceutical Product 10

11 Any change is a multiple year endeavor when it is executed on a global scale Data Doc Review 0-10 m CPP Wave 1: ICH dossier countries Doc Reviews 6-20 m Wave 2: Non-CPP Wave 3: CPP countries Review 6-24 m Time (elapsed months) 11

12 Life cycle complexity is resource intensive for authorities and industry Complexity Some case studies Reflections on pragmatic solutions 12

13 Case Study 1: an apparently minor change in an in-process analytical method Change description Modification of a Virus IPC test method of cell culture fluids 13

14 Case Study 1: Product A is registered in 127 countries at the time of the minor change 14

15 Case Study 1: The dispatch to all concerned countries was done mid May

16 Case Study 1: Actual submission occurred following dispatch between May and December 2011 Within 30 days Submission not required Not submitted Within 6 months 16

17 Case Study 1: The last approval took 20 months from submission and closure was after 26 months Within 30 days More than 12 months Submission not required Within 6 months Within 12 months 17

18 Case study 2: a technology transfer for a Drug product Change description Technology transfer of the Drug Product manufacturing process to an additional site 18

19 Case study 2 Product 2 is registered in 120 countries at the time of the Drug Product Site change 19

20 Case study 2: The change was dispatched to all but three countries in 2 waves Mar-Jun 2006 May Jul 2007 Not required 20

21 Case study 2 : The actual submission was performed within 10 months by the majority of countries Not recorded Less than 1 m More than 12 m 2 to 12 m Not required 21

22 Case study 2: The time from submission to approval where recorded varied substantially Not recorded 2-12 m Less than 1m Not required More than 12 m 22

23 Case study 2: A majority of countries approved in 24 months after dispatch but global implementation took 41 months Less than 12 m Less than 36 m More than 36 m Less than 24 m Not required 23

24 Life cycle complexity is resource intensive for authorities and industry A global change requires multiple years until complete implementation Reflections on pragmatic solutions 24

25 Harmonization of key principles will accelerate implementation of changes globally Change Classification concept Procedural guidance incl. timelines Documentation and data requirements... 25

26 WHO could coordinate convergence of regulation Change classification driven by potential to impact patient safety and efficacy. Risk based categorization Post-approval change management plans / comparability protocols Development of global classification and procedural guidance Drive progress: Fast track changes that improve quality Definition of documentation and data requirements for each change type Remove GMP elements 26

27 Driving global regulatory convergence Efforts under discussion - Expand the scope of WHO draft guideline for changes to a vaccine to biotherapeutic products and Biotherapeutic Products 27

28 Overview of the guideline (ToC) 1. ABBREVIATIONS 2. INTRODUCTION AND SCOPE 2.1 Introduction 2.2 Scope 3. GLOSSARY 4. GENERAL CONSIDERATIONS 5. REPORTING CATEGORIES FOR QUALITY CHANGES 5.1 Major Quality Changes 5.2 Moderate Quality Changes 5.3 Minor Quality Changes 6. REPORTING CATEGORIES FOR SAFETY, EFFICACY AND/OR PRODUCT LABELING INFORMATION CHANGES 6.1 Safety and Efficacy Changes 6.2 Product Labeling Information Changes 6.3 Administrative Product Labeling Information Changes 7. PROCEDURES 7.1 Procedures for Prior Approval Supplement 7.2 Procedures for Minor Quality Changes 7.3 Procedures for Administrative Product Labeling Information Changes 7.4 Accelerated Procedures for Urgent Changes 8. SPECIAL CONSIDERATIONS 8.1 Adjuvants 8.2 Influenza Vaccines 8.3 Bridging Studies 9. REFERENCES APPENDIX 1 - Reporting categories and suggested review time lines APPENDIX 2 - Post approval changes to the antigen APPENDIX 3 - Post approval changes to the final product APPENDIX 4 - Safety, efficacy and product labeling information post approval changes 28

29 Extract from WHO draft guideline for vaccines 2 INTRODUCTION AND SCOPE This document provides guidelines for NRAs and MA holders who intend to make changes to the original MA or product license for an approved vaccine on: a) procedures and criteria for the appropriate categorization and reporting of changes; and b) the data required to enable NRAs to evaluate the impact of the change on the quality, safety and efficacy of the vaccine. Additionally, the purpose of this guidance is to assist NRAs in establishing procedures for post approval changes of vaccines. This guidance applies to the manufacture and use of approved prophylactic vaccines for humans. However, general principles of this document may apply to other biological products. Proposal to expand the scope of the guideline to Biotherapeutic products prepared by rdna technology 29

30 Extract from WHO draft guideline for vaccines 5. REPORTING CATEGORIES FOR QUALITY CHANGES Based on the potential effect of the quality change (e.g., manufacturing change) on the quality attributes (i.e., identity, strength, quality controls, purity, potency) of the vaccine and on their potential impact on the quality, safety or efficacy of the vaccine, changes are categorized into major, moderate and minor and are identified as: - Major Quality Changes, - Moderate Quality Changes, or - Minor Quality Changes. Quality changes listed in Appendices 2 and 3 should be reported in one of the reporting categories described in this section. If a quality change may have a potential impact on the quality, safety and efficacy of the vaccine and is considered to be major, moderate or minor, but is not included in Appendix 2 or 3, then the NRA should be consulted for proper classification. Classification concept is applying risk-based approach 30

31 Extract from WHO draft guideline for vaccines Category Supplement Maximum Review Time Quality Changes Major Quality Changes Significant potential to have negative impact on Q;S;E Prior Approval Supplement 6 months Moderate Quality Changes Minor Quality Changes Moderate Potential to have negative impact on Q;S;E Prior Approval Supplement Moderate Potential to have negative impact on Q;S;E Do not require notification to the NRA 1 3 months N/A clear procedural guidance and review timelines are proposed 31

32 Extract from WHO draft guideline for vaccines detailed dossier requirements are provided Key elements for biotherapeutics have to be included: Describe relevant changes Identify the conditions Define supporting data for given change, eg batch analysis data, stability standards (eg. accelerated stability studies + NMT 6 months real time data to maintain shelf-life...) 32

33 Global guidance established by WHO could drive convergence Global LIFE-CYCLE Management will be a topic at the APEC biotherapeutic workshop (parallel to WHO meeting in May 2014, Korea) 33

34 Life cycle complexity is resource intensive for authorities and industry A global change requires multiple years until complete implementation Convergence of requirements and mutual recognition can reduce the complexity of life cycle changes, efforts are on the way 34

35 Global convergence of post-approval change regulations offers a «Win-Win» outcome for regulators, industry & patients Harmonized post-approval regulations Change classification, procedures, dossier requirements Regulators Industry Patients -Prioritize based on criticality of change -Facilitate assessment of changes -Enhance collaboration/ knowledge sharing with other agencies -Allow better planning and execution of changes -No additional country-specific data to be created -Reduce complexity in supply chain -Improved drug quality rapidly accessible to the market - High quality standard maintained globally Reliable supply of high quality drugs to all patients GLOBALLY Mutual recognition of regulatory decisions Transparency 35

36 Acknowledgements Ralf Gleixner, Wassim Nashabeh, Thomas Schreitmueller & Kowid Ho- Roche / Genentech Richard Lit - Amgen, Inc. 36

37 Doing now what patients need next