Setting the Scene CHALLENGES & COMPLEXITIES OF POST-APPROVAL CMC / LABELING CHANGES

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1 Disclaimer The views expressed herein represent those of the presenter and do not necessarily represent the views or practices of the presenter s employer or any other party. 2

2 Agenda The challenge and complexity of post-approval manufacturing changes Current strategies to manage implementation of reportable changes into supply chain Opportunities afforded by Q12 3

3 Setting the Scene CHALLENGES & COMPLEXITIES OF POST-APPROVAL CMC / LABELING CHANGES 4

4 Post-approval Manufacturing Changes are Normal and Necessary Industry typically & routinely implements dozens of facility, equipment, manufacturing process & testing changes per product per year Implement optimized manufacturing & supply strategy Continuous innovation & improvement Risk mitigation >80% are very minor and managed within QMS <20% are reportable based on legislation/guidance (in turn often determined by Module 3 content) A small % are more significant and/or have the potential to impact product quality 5

5 Post-Approval CMC/Labeling Changes are Highly Regulated & Complex Global regulations require significant Regulatory Authority oversight of post-approval CMC & Labelling changes Global reportability criteria are complex, divergent & often (intentionally) vague Based on Module 3 content Based on significance of change/potential impact to product quality Often subjective; interpretation of laws/guidance & corporate experience Global reportability filing categories are divergent One country s AR/Type IA is another s PAS/Type II Spectrum of categories vs. Report/Do not report approaches Agency requirements for supporting data are divergent Agency review, approval & implementation timelines are divergent Review window for the same change can be 1m to 36m Requirements for implementation of changes into supply inhibit clustered implementation & drive additional complexity 6

6 Management of Reportable CMC Changes is More Challenging for Biotech Regulatory bar is set higher for Biotechnology-derived products Significantly more complex vs. chemically-derived products Mfg process contributes significantly to product quality profile Legislation often written to factor full spectrum of biologic products (highly characterized vs poorly characterized) Manufacturing complexity (& niche indications) drives a more centralized manufacturing strategy Not unusual for small manufacturing campaign at a single manufacturing site to supply > 50 countries for > 2 years Determination of when to implement a reportable change into production & supply chain requires significant upfront & continuous iterative planning Many biotech players are US- and EU-centric & underestimate the challenges of global expansion 7

7 Complexity of Change Management Inhibits Innovation, Efficiency & Risks Patient Supply Biopharmaceuticals manufacturing innovation is lagging significantly behind many other high tech industries Many nice-to-have manufacturing/qc changes are not progressed due to regulatory hurdles & associated costs to implement Divergent review / implementation timelines inhibit supply efficiencies & drives SKU proliferation Uncertainties in review timelines, & restrictive implementation expectations, drives redundancy & scrap Even with redundancies in place, stock-out of compliant supply is often a constant risk 8

8 Implications of Accelerated Clinical Development Accelerated development initiatives eg Breakthrough Designation will result in more immature processes, analytical methods, etc Maturity of the manufacturing and testing will occur in the postapproval setting & will be subject to much more stringent regulatory oversight vs. traditional development approach Emerging safety profile will likely necessitate multiple labeling changes in post-approval environment Implications for consideration Should a label with enhanced safety language be implemented prior to approval? Should a CMC change to implement an improved product quality profile (e.g. improved analytical method) be delayed to ensure compliance in all markets? 9

9 STRATEGIES TO MITIGATE THE COMPLEXITY OF REPORTABLE CHANGE MANAGEMENT 10

10 Module 3 Content is Critical Driver Size of Module 3 has increased ~ % in last 20 years New development approaches (e.g. QbD) drive need from Agencies to include more information Previously maintained internally in QMS / within the GMP inspectional space Level of detail in Module 3 influenced by post-approval reporting obligations Reluctance to provide details which then could become part of the registered details & subject to reporting 11

11 Optimized Module 3 Content is Critical to Mitigating Maintenance Obligations Strategy Opportunity Challenges Standardized Module 3 core content for country/regional groupings Author at right level of detail, consider potential future changes Delineate during authoring Sections containing Regulatory Commitments vs. Supporting Data Common core Module 3 enables multiple parallel MAAs & simplifies post-approval change assessment Provide necessary detail with appropriate flexibility Clarity of which sections contain regulatory commitments subject to reporting Defining Module 3 content (per granule) which meets all regional requirements What is the necessary level of detail? - Residual uncertainty of what is a commitment - CTD structure may result in repetition 12

12 Optimized Module 3 Content is Critical to Mitigating Maintenance Obligations Strategy Opportunity Challenges Apply QbD-based product & process understanding to define optimal control strategy Incorporate change management protocols into initial MAAs - Focus Module 3 registered details on CPPs & CQAs - Apply control measures at the right place; avoid redundant testing - Leverage QMS to support use of Action limits for IPCs, for Release & during Stability evaluation - Pre-approve planned changes - Downgrade reportability category - Predictability of supporting data requirements and approval timings 13 - Requires significant upfront investment - Understanding & implementing Agency expectations is work in progress - Applicable to only a few regions - Requires significant upfront investment to define change scope and planned supporting data - Scope change can require filings to amend CMP - Agency ability to upgrade reportability category necessitates redundancy planning

13 Optimized Module 3 Format is Critical to Mitigating Maintenance Obligations Strategy Opportunity Challenges Granularization of core Module 3 Manage Country specific documents (CSDs) separately to Module 3 core Enables re-use of granules across multiple regions; avoids submission of unnecessary info Meet regional requirements via combination of Core and CSD sections, at publishing stage Granules need to be standalone some duplication of information May not meet specific requirements for format Maximize functionality of EDMS, & decentralize compilation - Content independent of format; enables flexibility of format - Utilize local RA expertise to determine format nuances Requires investment in & adherence to robust systems and processes 14

14 Fully Leverage Internal Regulatory Infrastructure High level regulatory legislation & guidance places onus on Industry RA professionals to make & defend robust reportability decisions Ensure reportability assessment is robust A reportable change can take 5 years to implement A non-reportable change can be implemented internally within weeks Change scope drift is a challenge but can be managed Optimize regulatory infrastructure Leverage experience of regulatory professionals Encourage science- and risk-based decision-making Implement training, tools & processes to standardize, minimize subjectivity Secure endorsement from internal Global/Regional/Local stakeholders Leverage all regulatory avenues where they exist (e.g. ARMC, EU Reflection Paper on QP discretion) Employ transparent mechanisms to inform Agencies of implementation proposals Implementation notifications for submitted changes which are critical for communication of risk/benefit, or for supply continuity 15

15 Invest in Cross-functional Planning Infrastructure Plan, Plan and Plan again! Effective implementation of reportable changes requires iterative planning & triangulation between Change Owner, Regulatory Affairs and Supply Chain At Global, Regional and Local level Processes & tools to enable end to end planning are critical Business case for change Clear delineation of roles & responsibilities Cross-functional planning tools Be ambitious, but realistic about what is in your sphere of control 16

16 Invest in External Regulatory Engagement Invest in local and regional regulatory intelligence, benchmarking Invest in local and regional advocacy via professional associations Engage with Regulatory Agencies (& legislators) to understand reportability expectations & to share implications of divergent & overly restrictive reporting requirements Proactive engagement / negotiation with Agencies for critical changes where predictability of approval/implementation is critical to supply 17

17 ICH Q12 OPPORTUNITIES 18

18 ICH Q12: Opportunities Vision: Increased leverage of Q8-Q11 opportunities will greatly enhance continual innovation, efficiency, while ensuring supply continuity Expand GMP Change Management principles more broadly; manage less significant changes within QMS Focus Agency resources toward reliance on an audited / certified system (QMS) rather than reviewing 100s of individual submissions Required Enablers: A trusted QMS Harmonised Reporting Mechanisms Shift focus toward Do and Tell & Tell, Wait and Do mechanisms An aligned set of reportability categories across ICH countries is significant progress Harmonised Established conditions as basis for Reportability: Clarity on what Module 3 content is subject to change management Reportability based on Potential Impact to Product Quality rather than M3 content Provides the necessary flexibility to manage different types of molecules and different company approaches Harmonised review & implementation 19 timelines?

19 ICH Q12: Opportunities in non-ich countries ICH links to non-ich countries since 2003 via GCG ICH organisation changes in 2015 emphasise expansion beyond USA, EU & JP CH & CA are formal members Aspirations to include many more countries/regions via GCG ICH Q12 will establish a reference point for non-ich countries Potential for aligning regulatory systems in non-ich countries 20

20 How would Change Management using Established Conditions work in Practice? Some points for consideration: Are we looking for different ways to operate within existing legislation, or is there potential for legislative change? Should change assessments be made primarily based on product quality impact, or on Module 3 content? Are Established Conditions high level concepts or line by line details? Optimal structure & # of reporting categories? Graduated Spectrum? Report/Do Not Report? 21

21 Application of Established Conditions: One Proposal Source: J-L Robert & G Cook: Joint Biologics Working 22 Party/ Quality Working Party/ Good Manufacturing and Distributing Practice Inspectors Working Group European industry workshop on lifecycle management

22 Case Study: Raw Materials Source: Joint Biologics Working Party/ Quality Working Party/ Good Manufacturing and Distributing Practice Inspectors Working Group European industry workshop on lifecycle management 23

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27 ICH Q12: Potential Challenges Are changes to regional legislation feasible? Consistent implementation of Q12 into regional legislation/guidance is critical: Potential for different established conditions for the same product across ICH regions Potential for different established conditions boundaries across different products for same company Opportunities for harmonized established conditions are greatly diminished if reporting categories, mechanisms & timelines are not harmonized Implications for Regulatory Authorities? Increased focus on inspection/audit of QMS Fewer variation submissions for review How do we mitigate potential for rogue players? 28

28 Conclusions Global Regulatory framework for reporting CMC / Labeling changes can inhibit innovation, efficiency and create supply risks, especially for biotech Management of reportable changes into the supply chain in a compliant manner is a massive logistical challenge for Industry Multiple strategies can be employed to mitigate complexity of reportable change management Q12 provides a unique partnership opportunity to converge regulatory framework whilst continuing to ensure appropriate Regulatory Authority oversight 29

29 Acknowledgements Barry Cherney Nathan Lee Teresa Pepper Mike Abernathy Stephan Roenninger James Sesic 30