FDA/PQRI Innovator Industry Perspectives on Lifecycle Management - Current Practices, Challenges

and Opportunities

Mark Rosolowsky, Ph.D. Vice President Global Regulatory Sciences- CMC

Bristol-Myers Squibb Oct. 5, 2015

Disclaimer

The contents of this presentation are my own, and do not necessarily reflect the views and/or policies of Bristol-Myers Squibb or any other group with which I am affiliated.

Current State of Lifecycle Management

• Lack of incentive for proactive implementation of manufacturing improvement

• Inefficient use of industry and regulatory resources addressing less important issues

• QbD and recent ICH Guidelines have not fully produced the expected benefits and operational flexibility

• Challenges in lifecycle management can lead to, for example, disruption in supply chain and drug shortage

Current Practice of Lifecycle Management

Idea for a Change Planned changes (e.g. new sites, new method, improved process) Unplanned changes (e.g. new supplier, inspection driven)

Change Management (CM) within Pharmaceutical Quality System

What type of filing? US, EU, ROW

Technical aspects of CM Data collection (independent of whether submission occurs) Validation, if appropriate Assessment pre- and post-change Prepare document and submit to HA, if necessary Inventory quarantined until global approval

Lifecycle Management Challenges

• Lack of strategic and proactive planning by industry • Regulatory processes are complex and not always

risk-based, leading to unnecessary delays in manufacturing improvements and intensive use of resources

• Lack of harmonisation within and outside of ICH for key principles e.g.

• Established conditions for manufacture and control

• Best practice for change management • Different timelines and data requirements

Lifecycle Management Challenges

• Regulatory processes are complex and not always risk-based, leading to unnecessary delays in manufacturing improvements and intensive use of resources Inventory fragmentation

– Drug supply/shortage Not pursuing change if global implementation not easy

Lifecycle Management Challenges • Lack of harmonisation within and outside of ICH

for key principles e.g. Established conditions for manufacture and control

– Clarity on what changes need to be submitted to HA – Incentives to share more information in dossier – Telling the story succinctly in CTD format

• Conveying confidence in quality

Best practice for change management – Knowledge of manufacturer’s CM processes

Different timelines and data requirements – Certificate of Pharmaceutical Product – Stability testing

Post Approval Changes - submission timelines

© 2015 DIA, Inc. All rights reserved.

Examples of timeline for submissions of initial MAA and a subsequent post-approval variation in countries with different requirements/filing dependencies and review timelines

6

LEGEND Estimated Readiness Dependency for filing Initial MAA filing-approval Launch Prior approval variation (PAV) Dependent on Reference country approval and launch

Country 1 (C1)-reference (e.g. USA) C2-12mo review (e.g. EU) C3-Stability-6mo C4-Stability-12mo C5-C1 approval + CPP legalized C6-Tech transfer report C7-New site regist. (EL,GMP insp.) C8-C1 approval +CPP-24mo review C9-C2 approval +CPP-24mo review

Cou

ntry

Approval Time (months)

1- 2- 3- 4- 5- 6- 7- 8- 9-

0 12 24 36 48 60

Complexities in Drug Product Inventory Example of how overlapping change approvals complicate drug product inventory

Lifecycle Management Opportunities

ICH Q12: Technical and Regulatory Considerations of Pharmaceutical Product Lifecycle Management

Objectives include:

• Provide a framework to facilitate the management of post-approval Chemistry, Manufacturing and Controls (CMC) changes in a more predictable and efficient manner across the product lifecycle

• Optimization of industry and regulatory resources • Support innovation and continual improvement

and help to assure drug product supply

ICH Q12 Opportunities

• Clarify established conditions for manufacture and control based on risk, product type, development approaches, manufacturing experience, GMP status

• Provide harmonized tools to facilitate prospective changes over the product lifecycle

• Establish ICH expectations of assessment and implementation of frequent manufacturing changes

• Promote development of proactive product lifecycle strategy

Lifecycle Management Opportunities • Develop a Framework for Establishing Regulatory Commitments in a

Submission FDA Draft guidance on Established Conditions

• Enhance Risk-based Approaches to Regulatory Oversight of Post-Approval Changes Risk-based approaches and expanded Post Approval Change Management Protocols

(PACMP) should be adopted to provide the manufacturing operational flexibility needed for continual improvement, while maintaining appropriate regulatory oversight of post-approval changes

Post Approval Change Management Protocol (PACMP) (Japan)

Renewed thinking about managing more changes within PQS

Provide a lifecycle management roadmap or strategy in dossier

New OPQ value statements – Put patients first by balancing risk and availability – Encourage innovation by advancing new technology and manufacturing science

Lifecycle Management Opportunities • Foster Enhanced Collaboration Between Offices Within FDA to

Leverage Opportunities to Streamline Post-Approval Changes

New OPQ objectives – Provide seamless integration of review, inspection, surveillance,

and research across the product lifecycle

• Effective communication of knowledge gained during development and commercialization

Leverage knowledge to make changes based on risk evaluation How to present knowledge across regions ? How can industry manage changes more efficiently and not be bound by

different regulatory requirements ?

Ultimate Objective

Improve the regulatory process by ensuring confidence in quality through a product’s lifecycle without increasing regulatory burden to enable reliable supply of high quality medicines

acknowledgement to Roger Nosal, Pfizer

Let’s not constrain ourselves!

Acknowledgements

• PhRMA ICH Q 12 EWG members: Liam Feely, Moheb Nasr, and Mary Oates

• ICH Q12 EWG • Roger Nosal and PhRMA LD-KIT members on

CMC Risk-based Regulatory Review