Life-cycle Approach toCMC – Challenges andOpportunities

Michael J James Ph.D.

Director

Global Regulatory Affairs

GlaxoSmithKline

26th AnnualEuroMeeting

25-27 March 2014ACV, 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

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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

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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 InitiativeIntroduces concept of ‘staggered approval’ Also known as adaptive or progressive licensing Envisaged for situations not covered by conditional

marketing authorisationsProspectively 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

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Expedited Development and Approval for Innovative Medicines (2)

• FDA Breakthrough Therapy DesignationIntended 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

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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 ??

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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 improvement10

Variation Categories - EU, US and Japan

Variation Category

EU US Japan

Major Type II Prior Approval Supplement (PAS)

Partial ChangeApproval Application

Moderate Type IB Change-Being-Effected-in-30-Days (CBE-30)

Minor Type IAIN

Type IAAR

Change-Being-Effected (CBE-0)

Annual ReportMinor Partial ChangeNotification

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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 theapplication 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 ?

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Limited Regulatory Opportunities (2)EU• Revision to EU Variations RegulationTo 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

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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 needed14

Limited Regulatory Opportunities (4)US• FDA’s CMC Post-approval Management Plan (CMC-

PMP) proposalsProvides clarity on regulatory commitment Facilitates product lifecycle managementDemonstrated product/process understanding and

controls could lead to significant reduction of post-approval 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

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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’

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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

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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)

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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/QbDchanges 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?

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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

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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 forMore 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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