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.

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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

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CHALLENGES & COMPLEXITIES OF POST-APPROVAL CMC / LABELING CHANGES

Setting the Scene

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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

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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 complexity6

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

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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

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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 post-approval 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?

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STRATEGIES TO MITIGATE THE COMPLEXITY OF REPORTABLE CHANGE MANAGEMENT

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Module 3 Content is Critical Driver• Size of Module 3 has increased ~200-400% 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

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Optimized Module 3 Content is Critical to Mitigating Maintenance Obligations

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Strategy Opportunity ChallengesStandardized Module 3 core content for country/regional groupings

Common “core” Module 3 enables multiple parallel MAAs & simplifies post-approval change assessment

Defining Module 3 content (per granule) which meets all regional requirements

Author at right level of detail, consider potential future changes

Provide necessary detail with appropriate flexibility

What is the necessarylevel of detail?

Delineate during authoring Sections containing Regulatory Commitments vs. Supporting Data

Clarity of which sections contain regulatorycommitments subject to reporting

- Residual uncertainty of what is a “commitment”- CTD structure may result in repetition

Optimized Module 3 Content is Critical to Mitigating Maintenance Obligations

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Strategy Opportunity Challenges

Apply QbD-based product & process understanding to define optimal control strategy

- 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

- Requires significant upfront investment

- Understanding & implementing Agency expectations is work in progress

Incorporate change management protocols into initial MAAs

- Pre-approve planned changes

- Downgrade reportabilitycategory

- Predictability of supporting data requirements and approval timings

- Applicable to only a few regions

- Requires significant upfront investment to definechange scope and planned supporting data

- Scope change can require filings to amend CMP

- Agency ability to upgrade reportability category necessitates redundancy planning

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Strategy Opportunity ChallengesGranularization of coreModule 3

Enables re-use of granules across multiple regions; avoids submission of unnecessary info

Granules need to be standalone – some duplication of information

Manage Country specific documents (CSDs) separately to Module 3 core

Meet regional requirements via combination of Core and CSD sections, at publishing stage

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

Optimized Module 3 Format is Critical to Mitigating Maintenance Obligations

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

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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

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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

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ICH Q12 OPPORTUNITIES

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ICH Q12: OpportunitiesVision: 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 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

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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 ?

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Application of Established Conditions: One Proposal

Source: J-L Robert & G Cook: Joint Biologics Working Party/ Quality Working Party/ Good Manufacturing and Distributing Practice Inspectors Working Group – European industry workshop on lifecycle management

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

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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

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

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Acknowledgements

• Barry Cherney

• Nathan Lee

• Teresa Pepper

• Mike Abernathy

• Stephan Roenninger

• James Sesic

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