Overview and Feedback from the Practical use of Expanded Change Protocols CMC Strategy Forum January 2013

Julia Edwards

Genentech, a member of the Roche Group

On behalf of the eCP CMC Forum Planning Committee

8 May 2013

picture placeholder

eCP Forum Program Overview Putting the e in eCP: Definitions and Case Studies Patrick Swann, CDER, FDA

The continuum between traditional and enhanced approaches

Stephen Nortarnicola, Biogen Idec Applying an ECP to an Existing Commercial Biotech Process

Duane Bonam and Toshi Mori-Bajwa, Amgen, Inc. Use of the eCP Concept for Post-Approval Change Management

Is the e worth our time? Benefits and Challenges Alan Gardner, GlaxoSmithKline

Application of Enhanced Product and Process Knowledge to Facilitate the Lifecycle Management of a Biopharmaceutical Product

Julia Edwards, Genentech, a member of the Roche Group The Benefits and Challenges of Expanded Change Protocol Strategies

Presentations on www.casss.org white paper coming soon!

Questions and Discussion

E is for

4

Excellent

Expensive

Elegant

Everything

Easy

.

Elephant!

Expanded Comparability Protocols (eCPs)

Leverages existing regulations for change protocols in the US

US Regulatory agreement [21 CFR 601.12(e)]

Submitted as Prior Approval Supplements (4 month approval timeline)

Prospective definition of change requirements allow for reduction in submission category upon change implementation (e.g., PAS CBE-30)

A range of QbD concepts (ICH Q8, Q9, Q10) can be applied

5

a continuum between Traditional and Enhanced Approaches Patrick Swann, CDER, FDA

Differentiating CPs v. eCPs

Traditional (CP)

Single product

Single change

Narrowly defined scope

Defined acceptance criteria

Single execution

Immediate business need

Range of Enhanced Concepts (eCP)

Multiple products, changes, lifecycle perspective

Risk-based categorization of post-approval changes

Quality Risk Management in addition to acceptance criteria

Design space definition

Multiple potential executions

Potential future business need

cGMP, Inspectional considerations

6

Site Transfer of Product A to Site Y Leveraging traditional CP in the US

Product A

Execute transfer

per defined

requirements in CP

Drug Substance

Receiving Site Y

D

CBE-30

Supplement with

data demonstrating

acceptance criteria

met

Drug Substance

Donor Site X

A B C

Submit CP

describing site

transfer acceptance

criteria for product-

site combination

Defined business need

7

A

Leveraging eCPs to Support Site Transfer

A network of Drug

Substance Donor Sites

B C

D

A

Execute transfer

per defined

requirements in

eCP

B

C

D

Site Y or Z

Site X or Z

Site X or Z

Site X or Y

Site X

Site Z

SiteY

A network of Drug Substance

Receiving Sites

Submit eCP describing

acceptance criteria broadly

for both Site and Product

CBE-30 Supplement

with data

demonstrating

acceptance criteria met

Potential Future Network

Requirements

8

A

Traditional change protocols have long and successful history for many products for many types of changes. Ideally all changes throughout the products lifecycle should form part of a continuum of systematically orchestrated and scientifically justified plans that link process capability and product quality to safety and efficacy as demonstrated in clinical trials. Noted that it is important to keep in mind what kinds of changes are and are NOT needs to be appropriate for a pre-approved CP whether traditional or expanded. Supported comprehensive risk ranking of parameters and communicate risk basis. Regulatory reporting should be commensurate with the risk ( e.g. PAS, CP in BLA, quality system).

Lifecycle & Risk

While the intent eCP is to allow for more expanded

changes, your proposal to include undefined and

significant process improvement changes is not

supported by the product and process knowledge

conveyed to the Agency. (FDA Feedback)

The importance of scope

QbD Pilot program showed that the requested changes to be covered in the eCP cannot be too ambitious to adequately measure/monitor, or too vague to predict the body of data that would be needed; neither allows confidence in assuring foreseeable consequences

Clearly define scope and limitations of what you plan to include; omit any changes that potentially present higher risk to product quality (FDA feedback)

Benefits of eCPs Downgraded regulatory reporting category (not pre-approved

regulatory absolution!). Business need: More products from more sources; continuous

improvements in existing processes; increase capacity (new products) and decrease risk to supply chain (interruptions); faster/cheaper management mandate.

Risk-based decision making continues throughout the lifecycle. Generally enhanced visibility into the decision making processes in

the regulatory submission. Consistent approach to changes when done on

a multi-product basis. Efficient Regulatory processes. Cost and time savings. Ensures supply to patients and risk mitigation.

eCP Roadblocks

Large cross-functional effort.

Gating items to eCPs are generally procedural, not scientific.

Differences in regional regulations require that each exercise is targeted to a specific agency, with approval tied to a specific jurisdiction.

Lead time to have changes reviewed and approved globally is very long and heterogeneous.

Supply chain fractionation and business implications.

Setting appropriate acceptance criteria.

Facility inspections and cGMP considerations.

When Elephants Fly..?

A multinational convergence effort on the regional regulatory requirements that would be acceptable globally is needed.

Acknowledgements

Recap of Program and Summary slides Nadine Ritter, Biologics Consulting Group, Inc. CMC Strategy Forum Planning Committee Chana Fuchs, CDER, FDA Rebekah Logan, Eli Lilly and Company Stefanie Pluschkell, Pfizer, Inc. Suzanne Stella, Biogen Idec CMC Strategy Forum Chairs Rohin Mhatre, Biogen Idec Wassim Nashabeh, Genentech, a Member of the Roche Group All speakers and participants!

Appendix

eCP CMC Forum Summary Slides Courtesy of Nadine Ritter

FDA perspectives on decade of experiences in biotech change protocols (2003 FDA draft guidance document, set of ICH Q docs up to Q11): Reminded us of the statutory requirements for assessing changes, as well as the slate of US and international guidance docs to help manage it Indicated that ideally all changes during product development and post-approval should form part of a continuum of systematically orchestrated scientifically justified plans that link process capability and product quality to S&E as demonstrated in clinical trials Noted that it is important to keep in mind what kinds of changes are and are NOT appropriate for a pre-approved CP (traditional or expanded) Traditional change protocols have long and successful history for many products for many types of changes Pilot program showed that the requested changes to be covered in the eCP cannot be too ambitious to adequately measure/monitor, or too vague to predict the body of data that would be needed; neither allows confidence in assuring foreseeable consequences

FDA perspectives on decade of experiences in biotech change protocols (2003 FDA draft guidance document, set of ICH Q docs up to Q11): While the intent ECP is to allow for more expanded changes, your

proposal to include undefined and significant process improvement

changes is not supported by the product and process knowledge

conveyed to the Agency.

Encouraged improved analytical tools for assessing process/products:

Adequately sensitive to changes (relative sensitivity and specificity of orthogonal methods

Use of fingerprint methods esp for PTM (eg improved glycosylation analysis)

Impact of manufacturing equipment on product quality (changes in SVPs from filling equipment changes)

More effective (objective) analysis of data (equivalency testing of degradation rates)

FDA perspectives on decade of experiences in biotech change protocols (2003 FDA draft guidance document, set of ICH Q docs up to Q11): Supported comprehensive risk ranking of parameters : generate the exercise and communicate to regulators; grouped risks (high, med. low) with corresponding reg reporting level (PAS, CP in BLA, manage via PQS) Noted there is a direct linkage between PV and CPs; characterization/validation of process design space is a critical consideration in risk assessment of proposed changes (hence why it is in QbD discussions) Gave us a retrospective on number and type of CPs submitted to FDA in last decade or so - # Mab products increased each year, but CPs peaked in 2006-2010 window then have sharply dropped; combined CPs now rather than one-by-one? Types of Mab CPs

Facilities/Bldg/Labs increase Mfr Process and/or Scale