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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!