The WCBP CMC Strategy Forum

Welcome to the WCBP CMC Strategy Forum

We are pleased to welcome you to the WCBP CMC Strategy Forum. The purpose of the CMC Strategy Forum is to provide a venue for biotechnology/biological product discussion. The meetings focus on relevant CMC issues throughout the lifecycle of a product and thereby foster collaborative technical and regulatory interactions. The Forum strives to share information with the regulatory agencies to assist them in merging good scientific and regulatory practices. Outcomes of the Forum meetings are published in an appropriate peer-reviewed journal.

Each meeting will focus on a CMC related issue such as product characterization, comparability, specifications, etc. The format of each meeting will consist of case studies and presentations by Industry and/or FDA experts to introduce the topic and the key issues of concern. Breakout sessions will then be conducted to allow for additional discussion on the technical and regulatory details of the topics. It is envisioned that the final outcome of the workshop discussions will be the development of a document to be submitted to the appropriate Regulatory Agency designees for their consideration in developing and/or clarifying good regulatory practice guidelines for biotechnology derived products.

The success of the CMC Strategy Forum will depend on your active participation in discussing and raising issues pertaining to development of biologics. We encourage you to participate wholeheartedly in the workshops that have been designed to stimulate exchange of ideas and information.

We would like to thank the speakers who are giving generously of their time and resources, and to you, for your attendance. We acknowledge the generosity of our program partners: AbbVie Inc., Amgen Inc., Biogen Idec, Biologics Consulting Group, Inc., Eli Lilly and Company, Genentech, a Member of the Roche Group, Janssen Pharmaceutical R&D, LLC, MedImmune, National Institute of Standards and Technology (NIST), Novo Nordisk A/S and Pfizer Inc. We are grateful for the expert management assistance of Karen Bertani and Stephanie Flores at CASSS. Their experience, guidance and skill in the preparation of this meeting have been invaluable.

CMC STRATEGY FORUM ADVISORY COMMITTEE

Siddharth Advant, ImClone Systems Corporation John Dougherty, Eli Lilly and Company Christopher Joneckis, CBER, FDA Rohin Mhatre, Biogen Idec Anthony Mire-Sluis, Amgen, Inc. Wassim Nashabeh, Genentech, a Member of the Roche Group Anthony Ridgway, Health Canada Nadine Ritter, Biologics Consulting Group, Inc. Mark Schenerman, MedImmune Keith Webber, CDER, FDA

The Organizing Committee gratefully acknowledges the pharmaceutical and biotechnology industry for their generous support of the WCBP CMC Strategy Forum series:

PROGRAM PARTNERS AbbVie Inc. Amgen Inc. Biogen Idec Biologics Consulting Group, Inc. Eli Lilly and Company Genentech, a Member of the Roche Group Janssen Pharmaceutical R & D, LLC MedImmune National Institute of Standards and Technology (NIST) Novo Nordisk A/S Pfizer, Inc.

LEADING MEDIA PARTNERS BioProcess International International Pharmaceutical Quality MEDIA PARTNERS BioProcessing Journal LCGC North America Technology Networks Limited

Forum Abstract

Practical Use of Expanded Change Protocols

Forum Co-Chairs: Rohin Mhatre, Biogen Idec Wassim Nashabeh, Genentech, a Member of the Roche Group

Scientific Organizing Committee: Julia Edwards, Genentech, a Member of the Roche Group Chana Fuchs, CDER, FDA Rebekah Logan, Eli Lilly and Company Stefanie Pluschkell, Pfizer, Inc. Suzanne Stella, Biogen Idec

Expanded change protocols (eCPs) were defined in the Office of Biotechnology Products’ Quality by Design (QbD) Pilot Program as a particular type of comparability protocol that will “describe the quality-by-design, risk-based approach linking attributes and processes to product performance safety, and efficacy.” A wide range of potential applications for eCPs has been explored by sponsors including movement within or beyond an established design space, site transfers, and additional process modifications supported by either a QbD or traditional regulatory submission. This Forum will evaluate this definition of eCPs from 2008 in light of case studies and examples that represent expanded change protocol concepts but may not fully realize the original vision. In addition to understanding what the “expanded” descriptor of an “e”CP really means, a list of potential eCP applications will be generated and the benefits, challenges, opportunities, and pitfalls to eCP strategies will be explored. Particularly, the relevance of eCP submissions to support global changes will be examined. For example, comparison of eCPs to Europe’s Post-approval Change Management Protocols (PACMP) will be made.

The Forum will answer the following questions:

• What is an expanded change protocol? • What type of changes should be considered for eCP? • What are the challenges and benefits of using eCP regulatory strategies? • How can we as an industry continue to evolve the eCP concept?

WCBP CMC Strategy Forum Program Summary

Practical Use of Expanded Change Protocols

Monday, January 28, 2013

07:30 – 17:00 Registration in the Cabinet Room

07:30 – 08:30 Breakfast in the Promenade Foyer

08:30 – 08:45 CASSS Welcome and Introductory Comments in the Chinese Room Wassim Nashabeh, Genentech, a Member of the Roche Group

WCBP CMC Strategy Forum Welcome and Introductory Comments in the Chinese Room Rohin Mhatre, Biogen Idec

Putting the “e” in eCP: Definitions and Case Studies In the Chinese Room Session Chairs: Rebekah Logan, Eli Lilly and Company and Suzanne Stella, Biogen Idec

08:45 – 09:15 A Regulatory Perspective on Biotechnology Product Comparability Protocols: On the Continuum between Traditional and Enhanced Approaches Patrick Swann, CDER, FDA, Bethesda, MD USA

09:15 – 09:45 Retrofitting an eCP to an Existing Commercial Biotech Process Stephen Notarnicola, Biogen Idec, Cambridge, MA USA

09:45 – 10:15 Use of the eCP Concept for Post-approval Change Management Duane Bonam, Amgen Inc., South San Francisco, CA USA Toshi Mori-Bajwa, Amgen Inc., South San Francisco, CA USA

10:15 – 10:45 AM Break in the Promenade Foyer

10:45 – 12:15 PANEL DISCUSSION – Questions and Answers Sally Anliker, Eli Lilly and Company Duane Bonam, Amgen Inc. Toshi Mori-Bajwa, Amgen Inc. Stephen Notarnicola, Biogen Idec Patrick Swann, CDER, FDA

12:15 – 13:45 Hosted Lunch in the Colonial Room Monday, January 28 continued…

Is the “e” Worth Our Time? Benefits and Challenges In the Chinese Room Session Chair: Stefanie Pluschkell, Pfizer, Inc.

13:45 – 14:15 Application of Enhanced Process and Product Knowledge to Facilitate the Lifecycle Management of a Biopharmaceutical Product Alan Gardner, GlaxoSmithKline, King of Prussia, PA USA

14:15 – 14:45 The Benefits and Challenges of Expanded Change Protocol Strategies Julia Edwards, Genentech, a Member of the Roche Group, South San Francisco, CA USA

14:45 – 15:15 PM Break in the Promenade Foyer

15:15 – 16:45 PANEL DISCUSSION – Questions and Answers Julia Edwards, Genentech, a Member of the Roche Group Chana Fuchs, CDER, FDA Alan Gardner, GlaxoSmithKline Anthony Ridgway, Health Canada

16:45 – 17:15 Recap of Program Summary Slide Presentation Nadine Ritter, Biologics Consulting Group, Inc.

17:15 – 17:25 Invitation to CMC Strategy Forum July 2013

18:00 – 19:30 Networking Reception in the Colonial Room

Presenters Abstracts

A Regulatory Perspective on Biotechnology Product Comparability Protocols: On the Continuum between Traditional and Enhanced Approaches

Patrick Swann

CDER, FDA, Bethesda, MD USA

Protocols for manufacturing changes for biologics are described in the regulations (21 CFR 601.12(e)). In addition, FDA has published draft guidance (2003) specific for comparability protocols as applied to protein drug products. In the case of monoclonal antibodies, the number of traditional comparability protocols has been increasing along with the number of licensed products. The scope and nature of these protocols has evolved over time. In 2008, the Office of Biotechnology Products asked for volunteers to participate in a pilot program involving the submission of quality (chemistry, manufacturing, and controls) information for biotechnology products to gain more information and facilitate agency review of quality-by-design and risk-based approaches for manufacturing. The notice for the pilot program stated that Expanded Change Protocols will describe the quality-by-design; risk-based approach linking attributes and processes to product performance, safety, and efficacy. Lessons learned from review of pilot applications as well as other recent comparability protocols will be summarized. The presentation will focus on opportunities and pitfalls of comparability protocols. Opportunities include an emphasis on the importance of analytical procedures capable to discern relevant differences that may occur after a manufacturing change. Enhanced analytical capability can lead to enhanced product/process understanding which can create the basis for more flexible regulatory approaches.

NOTES:

Retrofitting an eCP to an Existing Commercial Biotech Process

Stephen Notarnicola

Biogen Idec, Cambridge, MA USA

After approval and throughout the lifecycle of a product, a Company’s knowledge and understanding of their product and process continually expands. To leverage this knowledge and provide continuous improvement opportunities to an existing commercial monoclonal antibody process, the company proposes to apply select aspects of current regulatory and quality concepts to a traditional product application. To do this, we propose to identify Critical Quality Attributes (CQA’s) and develop an expanded change control protocol (ECP) to prospectively define the actions and criteria for implementing and managing process changes. This talk will discuss the process by which the Company will leverage manufacturing history, structure activity relationship investigations (SAR) and the scientific literature to establish the CQA’s and development of an eCP. Also discussed will be the Company’s proposed plans to obtain agency agreement with the defined CQA’s and implementation of an eCP. The Company believes that by proactively applying current regulatory and Quality concepts to legacy products, additional improvements to product consistency and process performance will result.

NOTES:

Use of the eCP Concept for Post-approval Change Management

Toshiko Mori-Bajwa and Duane Bonam

Amgen Inc., South San Francisco, CA USA

During the life-cycle of products, changes in the manufacturing process are expected due to many differing business drivers. The reality of implementing post –approval manufacturing changes using the traditional Regulatory pathways presents significant constraints on commercial manufacturing schedules and over all supply chain flexibility. This talk will focus on the development of an eCP as part of the QbD Pilot Program to streamline implementation of post-approval changes. This draft eCP was focused on risk and change assessments tools, the strategy for process validation using a representative scale model, assessment of comparability, Quality System descriptions and oversight, and the regulatory reporting plan to gain efficiencies for the introduction of manufacturing changes for a commercially licensed product. The discussion will also include the review of new risk assessment tools and novel elements included in the eCP, and key agreements and unresolved challenges with the Agency.

NOTES:

Putting the “e” in eCP: Definitions and Case Studies Workshop Session One

Panel Discussion – Questions and Answers

Sally Anliker, Eli Lilly and Company Duane Bonam, Amgen, Inc. Toshi Mori-Bajwa, Amgen, Inc. Stephen Notarnicola, Biogen Idec Patrick Swann, CDER, FDA

This session will focus on Agency and Industry expectations for eCP’s. Discussions will seek to provide clarity on the differences between a “traditional” comparability protocol and an eCP. Further, in this session we will discuss the use of eCP’s for both traditional and QbD applications. Industry examples of the approaches taken for the development and application of an eCP along with the types of changes proposed will be presented. The Panel forum will provide the opportunity for open Industry and Agency discussion on the practical application of eCP’s and what types of changes may be considered appropriate for the eCP. Industry and the Agency will work together in this session to develop a list of changes that are amenable to eCP approaches.

The following questions will guide the panel discussion:

1. What are the similarities and differences compared to a traditional comparability protocol? 2. What types of changes can “practically” be captured or have been successfully captured within an eCP? a. Is an eCP limited to process changes or can it be expanded to accommodate facility changes and site transfers? b. Is an eCP limited to only QbD applications or can the concepts employed in an eCP be applied to already approved traditional applications? 3. If a company develops a process using QbD approaches but files a traditional application, how can an eCP be applied?

NOTES:

Presenters Abstracts

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

Alan Gardner

GlaxoSmithKline, King of Prussia, PA USA

Abstract was not available at time of printing.

NOTES:

The Benefits and Challenges of Expanded Change Protocols

Julia Edwards

Genentech, a Member of the Roche Group, South San Francisco, CA USA

Genentech has two FDA approved expanded Change Protocols (eCPs). The first eCP approved by the FDA was for the introduction of new products and conversion of multi-product facilities. The second was for Drug Substance manufacturing site transfers and was approved by the FDA as part of the QbD Pilot Program. The benefits, challenges, and lessons learned will frame the story of these two eCPs through conception, approval, and execution.

NOTES:

Is the “e” Worth Our Time? Benefits and Challenges Workshop Session Two

Panel Discussion – Questions and Answers

Julia Edwards, Genentech, a Member of the Roche Group Chana Fuchs, CDER, FDA Alan Gardner, GlaxoSmithKline Anthony Ridgway, Health Canada

This session will explore how an eCP could best be leveraged as part of a marketing application or post- approval submission. We will discuss the challenges of different regulatory expectations and change management pathways in countries and regions outside of the US, for example in Europe. Lessons learned from industry experience to date will be presented, and a panel discussion will allow inclusive dialogue on the opportunities and barriers to making change protocols a value-added path for both industry and regulatory agencies.

The following questions will guide the panel discussion:

1. If the eCP gets approved in the US, how can sponsors bridge different global registrations? a. Is it worth navigating a potentially more complex BLA approval in the US when the rest of the world requires more traditional approaches? b. What are the supply chain and regulatory compliance implications? Impact to post- approval life cycle management? 2. What are the benefits and challenges of eCP submissions: a. What prevents sponsors from including eCPs in BLA submissions? b. What are the benefits and challenges of including eCPs in BLA submissions versus post- approval supplement? c. What are the benefits and challenges of leveraging platforms to submit eCPs for multiple products post-approval? 3. What are some key issues of change protocols that could be improved to increase their value to industry and regulators? Are eCPs practical given our current global environment?

NOTES: