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 product’s 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 – same • Single to Multi-Product Facitliies – sharp increase • Analytical Methods - none before 2006, since then on par with last two

Detailed industry examples of what did and did not succeed for eCPs (and stealth eCPs, ie submitted within QbD pilot program): •Biogen-Idec, Amgen, GSK, Genetech AMOTRG •Among the “best of the best” vis-à-vis historical and emerging expertise in WCBP processes and products •Apparent that huge cross-functional efforts went into these exercises – why do it? 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 •“White Elephant” paradigm (thanks, Julia!) – Excitement but unknown outcome; was it/ will it be worth the effort?

• Biogen-Idec = Retrofitting eCP to Approved Product • Amgen = Post-Approval Changes vis eCP • GSK = Managing Changes throughout the Product Lifecycle (DS and DP • Genentech AMOTRG = Leveraging eCP for MPF and Multiple Sites

Considerable convergence in the strategies used by each group:

“Paper” exercises:

• Identification and justification of CPPs and CQAs • Thorough risk assessments with risk ranking scores • Grouping of categories and design of data packages needed • Leveraging historical experiences and PD data • Defined QSM and PQS to support control and confidence in operations

“Wet Chem” studies:

• Confirmation of key parameters using process models • Data plan included release tests, characterization/comparability

(extended analytics), stress stability (physical stress), real-time stability (target and accelerated; note waiver of 3 M stab if other data confirm)

Similar feedback from regulators: •Clearly define scope and limitations of what you plan to include; omit any changes that “potentially present higher risk to product quality” (FDA feedback) •Drill down on acceptance criteria: preliminary data, detailed information on how to set appropriate AC even if they are not submitted in eCP •EU: needed GMP certification of facility compliance (lower energy barrier for existing, experienced sites vs new sites/new products) Classical CPs limited in scope and duration; eCP meant to be a living, breathing, transparent documented strategic and tactical plan to effectively manage changes necessary to manufacturing and supply of products eCP cannot be a collection of opportunistic (eg yield) and vague changes (undefined RMs); can’t just say ‘Trust Us – we’ll fill in the details when we get to them’

Was it worth the effort? •Got highly valuable feedback from regulators that informed many aspects of product development, even for products in early development •Once the heavy lifting is done with the first exercise, it serves as a working template for all future exercises – rest of them should be much easier to complete •Forces teams to go through the process of defining, outlining, planning, corroborating, etc.. with a tangible deliverable that contains the best of the best knowledge from the SMEs on the process/product •Changes are already in the works for the product supply chain the day it is approved; providing prospective plans to regulators means they can hit the ground running when the product goes commercial •Seems ideally suited to platform processes where large bodies of data are relevant to many products (ie Mabs) although each Mab itself is unique

What are the remaining roadblocks to wider use of eCPs? •Good news, everyone! Gating items all seemed procedural, not scientific. -Suitable approaches meet the need of industry to manage their business needs while providing the information needed for regulators to make effective decisions (call it what you will….) •Differences in regional regulatory authorities’ allowance of CPs means that each exercise is targeted to a specific agency, with approval tied to their jurisdiction. •Lead time to have changes reviewed and approved globally is very long and heterogeneous – Makes it challenging to manage global specifications in different regions while waiting for all of them to finally catch up •A multinational ‘convergence’ effort on the regional regulatory requirements that could provide guidance on elements of eCPs that would be acceptable globally (eg nature and extent of data to support size of process design space); must be driven by industry because regulators have legal constraints on what they can share among international agencies