Life-cycle Approach to CMC – Challenges and Opportunities

Michael J James Ph.D. Director Global Regulatory Affairs GlaxoSmithKline

26th Annual EuroMeeting 25-27 March 2014 ACV, Vienna Austria

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Contents • Introduction • Drivers for CMC Life-Cycle Management • Expedited Development and Approval of Innovative Medicines • Challenges • Limited Regulatory Opportunities • Future Opportunities • Concluding Remarks 3

Life-cycle Management of CMC (1) • CMC life-cycle management is becoming increasingly important due to a number of factors including: Globalisation of development and manufacture of pharmaceuticals Increased and diverse global regulatory expectations Supply chains becoming more complex Advances in technology Implementation of ICH Q8, Q9, Q10 and Q11 Environmental considerations Expedited development and approval timelines for innovative medicines 4

Life-cycle Management of CMC (2) • Important technical drivers for change include: Manufacturing sustainability Manufacturing efficiencies (economic and environmental) Ensuring security of supply Response to regulatory developments Advances in manufacturing and control technology Commitment to continual improvement in quality

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Expedited Development and Approval for Innovative Medicines (1) • EMA Adaptive Licensing Initiative Introduces concept of ‘staggered approval’ Also known as adaptive or progressive licensing Envisaged for situations not covered by conditional marketing authorisations Prospectively planned, adaptive approach to regulation of drugs through iterative phases of evidence gathering, followed by regulatory evaluation and license adaptation Balances timely access for patients with the need to provide adequate evolving information on benefits and harms 6

Expedited Development and Approval for Innovative Medicines (2) • FDA Breakthrough Therapy Designation Intended to expedite development and review of drugs for serious or life-threatening conditions Manufacturing development process and capabilities will need to keep pace with clinical development Requires a well thought out CMC life-cycle plan which will need to encompass:  Manufacturing process, capability, facilities and equipment  Process validation - scale up and comparability  Specifications  Stability 7

Expedited Development and Approval for Innovative Medicines (3) • These initiatives will have significant CMC impact if earlier access to patients is to be achieved • How can iterative phases of evaluation of CMC data be managed effectively?  A ‘rolling’ review’?  What would a ‘progressive license’ look like? • Control Strategy - continually evolving • Innovative manufacturing approaches may be needed  e.g. continuous processing • Appropriate stability data package • Process validation – ongoing verification • Role for extended Post-approval change management protocol ?? 8

Challenges • The current system is challenging to industry and regulators • (QbD) Submissions are becoming more complex  Leading to more detail being submitted  Potential for more information to become registered (compliance related)  Still lack of clarity on what information is required and where it should be located  May discourage transparency in regulatory filings

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Challenges • Different approaches in 3 ICH regions Variation categories (see next slide) Use of protocols to prospectively manage changes (EU and US) JNDA application form describes “matters subject to approval” • Regulatory requirements of non-ICH regions/countries even more diverse – adds another level of complexity • Often a checklist approach, rather than a science and risk based evaluation • Complex, costly and resource intensive • Hinders innovation and continual improvement 10

Variation Categories - EU, US and Japan Variation Category

EU

US

Japan

Major

Type II

Prior Approval Supplement (PAS)

Partial Change Approval Application

Moderate

Type IB

Change-BeingEffected-in-30-Days (CBE-30)

Minor

Type IAIN

Change-BeingEffected (CBE-0)

Type IAAR

Annual Report

Minor Partial Change Notification

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Limited Regulatory Opportunities (1) ICH • Implementation of Q8, Q9, Q10 (and Q11) “Demonstrate effective pharmaceutical quality system, and product and process understanding, including the application of quality risk management principles Opportunity to: • Optimise science and risk based post-approval change processes to maximise benefits from innovation and continual improvement” • Provides opportunities for a more science and risk based approach to assessing changes across the life cycle • But have these opportunities and benefits been fully realised ? 12

Limited Regulatory Opportunities (2) EU • Revision to EU Variations Regulation To establish a simpler, clearer and more flexible legal framework To adapt to the ICH new quality concepts Q8, Q9 and Q10 • Commission Public Consultation Paper (Oct 2007) Introduced the concept of Design Space Acknowledged that continuous improvement of manufacture should be supported, e.g. by providing further flexibility to manufacturers who have undertaken the efforts to put in place quality tools 13

Limited Regulatory Opportunities (3) EU • Commission Variations Classification Guideline (Jan 2010) Included variations for the introduction of a new design space or extension of an approved design space Changes to non-CPP Type II variation by default Introduced variation categories for a post approval change management protocol • Questions and answers on post approval change management protocols (Mar 2012) • Commission Variations Classification Guideline (revised May 2013) No significant changes for CMC aspects Ongoing dialogue needed 14

Limited Regulatory Opportunities (4) US • FDA’s CMC Post-approval Management Plan (CMCPMP) proposals Provides clarity on regulatory commitment Facilitates product lifecycle management Demonstrated product/process understanding and controls could lead to significant reduction of postapproval manufacturing supplements Utilize Existing Regulatory Framework 21 CFR 314.50 (CMC Submission for DS and DP) 21 CFR 314.70 (Post-approval changes) • Initial progress followed by implementation stoppage 15

Limited Regulatory Opportunities (5) US • Comparability Protocols for Approved Drugs: Chemistry, Manufacturing, and Controls Information (Draft, Feb 2003) • CMC Post-approval Manufacturing Changes to be documented in Annual Reports (Final, Mar 2014) Down regulation of some low risk CMC changes from CBE-30 and CBE-0 to annual report • Specified Biotechnology and Specified Biological Products – Annual Report (Planned draft, 2014) • Comparability Protocols for Approved Drugs: CMC information (Planned draft, 2014) • FDA is exploring ‘regulatory commitments’ 16

Optimised Regulatory Framework (1) • The following components are considered necessary to establish an optimised framework to effectively manage the life cycle of CMC: Clear definition of ‘regulatory commitments’ for manufacture and control in the regulatory submission Identification of these ‘regulatory commitments’ from development data, required by the assessor to carry out initial review ‘Regulatory commitments’ would provide basis for compliance and change management across the life-cycle 17

Optimised Regulatory Framework (2) Clear presentation of ‘operational flexibility’ proposed by the applicant for approval by the authorities Removes any ambiguity about what that has been approved Increased role of the control strategy to facilitate compliance across the life-cycle Harmonized approach on technical requirements to assess manufacturing changes Technical criteria should consider risks, development knowledge, manufacturing history and impact of change on quality (CQAs and control strategy) 18

Optimised Regulatory Framework (3)  Opportunity for some low risk CMC changes to be managed as part of a robust change management system within a Company’s Pharmaceutical Quality System  Expanded use of post-approval change management protocols to prospectively manage complex CMC/QbD changes across the life-cycle  Support continual improvement for QbD submissions  Enable multiple changes in a single protocol (where acceptance criteria are relevant)  Role for ‘extended’ protocol? 19

Concluding Remarks • The life-cycle management of CMC is becoming increasingly important to industry, regulators and patients, as a result of several factors, including: Continual improvement and innovation Expedited development and approval of innovative medicines QbD implementation • The current regulatory system is challenging to both industry and regulators  The “new” ICH quality guidelines and regional regulatory initiatives provide only marginal benefits  However elements of these could be used as building blocks for future system 20

Concluding Remarks • Ideally, ICH harmonized guideline on Life-Cycle Management of CMC developed  Clear definition of ‘regulatory commitments’  More extended application of post-approval change management protocols  Agreement on technical requirements to assess manufacturing changes

• But also opportunities in Europe for  More flexible use of PACM Protocols  Management of changes to non-CPPs (within a Design Space) with appropriate level of regulatory oversight  Future revisions to the Variations Classifications guideline

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Thank you for your attention Any questions???

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