Welcome to the CMC Strategy Forum Prior Knowledge: Learning from Our Successes and Failures to Improve Product Development and Manufacturing

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1 Welcome to the CMC Strategy Forum Prior Knowledge: Learning from Our Successes and Failures to Improve Product Development and Manufacturing We are pleased to welcome you to the 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 regulatory experts to introduce the topic and the key issues of concern. Workshop sessions, which consist of panel discussions and Q&A, 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: Amgen Inc., Biogen, Bristol- Myers Squibb Company, Celgene Corporation, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, a Member of the Roche Group, Janssen Pharmaceutical R&D, LLC, MedImmune, A member of the AstraZeneca Group, Merck & Co., Inc., National Institute of Standards and Technology (NIST), Novo Nordisk A/S and Pfizer, Inc. We are grateful for the expert management from CASSS and the audiovisual expertise of Michael Johnstone from MJ Audio-Visual Productions. Their experience and guidance in the preparation of this Forum has been invaluable.

2 ACKNOWLEDGEMENTS CMC STRATEGY FORUM NORTH AMERICA PROGRAM COMMITTEE Siddharth Advant, Celgene Corporation John Bishop, CBER, FDA Barry Cherney, Amgen Inc. Fiona Cornel, Health Canada JR Dobbins, Eli Lilly and Company Julia Edwards, Allergan Sarah Kennett, Genentech, a Member of the Roche Group Joseph Kutza, MedImmune, A member of the AstraZeneca Group Kimberly May, Merck & Co., Inc. Anthony Mire-Sluis, AstraZeneca Stefanie Pluschkell, Pfizer, Inc. Nadine Ritter, Global Biotech Experts, LLC Timothy Schofield, GlaxoSmithKline Zahra Shahrokh, ZDev Consulting Jeffrey Staecker, BioPhia Consulting, Inc. Andrew Weiskopf, Biogen Heidi Zhang, Genentech, a Member of the Roche Group Marcel Zocher, Bristol-Myers Squibb Company CMC STRATEGY FORUM GLOBAL STEERING COMMITTEE Siddharth Advant, Celgene Corporation, USA Daniela Cerqueira, ANVISA-Brasilian National Health Surveillance Agency, Brasil Yasuhiro Kishioka, PMDA-Pharmaceutical and Medical Devices Agency, Japan Steven Kozlowski, CDER, FDA, USA Junichi Koga, Daiichi Sankyo Co., Ltd., Japan Rohin Mhatre, Biogen, USA Ingrid Markovic, CBER, FDA, USA Anthony Mire-Sluis, AstraZeneca, USA Wassim Nashabeh, F. Hoffmann-La Roche Ltd., Switzerland (Chair) Ilona Reischl, AGES-Austrian Medicines and Medical Devices Agency, Austria Anthony Ridgway, Health Canada, Canada Nadine Ritter, Global Biotech Experts, LLC, USA Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Mark Schenerman, MAS Consulting-CMC Biotech, USA Karin Sewerin, BioTech Development AB, Sweden

3 The Scientific Organizing Committee gratefully acknowledges the pharmaceutical and biotechnology industry for their generous support of the CMC Strategy Forum North America series: STRATEGIC DIAMOND PROGRAM PARTNERS F. Hoffmann-La Roche Ltd. Genentech, a Member of the Roche Group STRATEGIC PLATINUM PROGRAM PARTNERS Amgen Inc. Biogen MedImmune, A member of the AstraZeneca Group STRATEGIC GOLD PROGRAM PARTNERS Eli Lilly and Company Novo Nordisk A/S Pfizer, Inc. STRATEGIC SILVER PROGRAM PARTNER Merck & Co., Inc. FORUM PROGRAM PARTNERS Bristol-Myers Squibb Company Celgene Corporation Janssen Pharmaceutical R & D, LLC National Institute of Standards and Technology (NIST)

4 The Scientific Organizing Committee gratefully acknowledges the following media for their promotional consideration of the CMC Strategy Forum North America January 2018: LEADING MEDIA PARTNERS BioProcess International International Pharmaceutical Quality MEDIA PARTNERS American Laboratory / LabCompare American Pharmaceutical Review BioProcessing Journal Genetic Engineering & Biotechnology News LC/GC Pharmaceutical Outsourcing Technology Networks

5 CASSS Mobile App Does the printed program look a little bit thinner this year? That s because we re going mobile. This year, we are pleased to once again offer the CASSS Mobile App for the CMC Strategy Forum January and WCBP 2018! Top Ten Reasons You Need to Have the App: o Connect and network with fellow attendees, speakers, and exhibitors o View the schedule and create a personalized agenda o Download speaker abstracts and handouts o Take notes during the presentations and export later o Play the Exhibitor Trivia game and Mobile App Challenge for chance to win great prizes o Provide instant feedback on the speakers and sessions o Receive all the latest information on schedule changes or updates o View poster abstracts and connect with poster presenters o Have all your questions answered during sessions through the activity feed o Learn about everything Washington, DC has to offer! Log on and be a part of the CMC/WCBP Community! STEP 1 OPTION 1: On your mobile phone, go to the App Store (Apple App Store, Google Play Store) and search "CASSS 365 OPTION 2: Use a QR code reader to scan the QR code on this page. OPTION 3: To use the HTML version of the app, go to the internet browser on your mobile phone, tablet, or computer and go to the link STEP 2: Follow store instructions to download the CASSS 365 mobile app. STEP 3: Open the app. It will ask for your username and password. THIS IS THE SAME INFORMATION YOU USE TO REGISTER FOR A CASSS MEETING. STEP 4: Go to Events and select "CMC/WCBP" from the list. Enter your username and password again. This is the same username and password used in step three. You now have access to the entire schedule, session abstracts, speaker handouts and bios as well as the ability to connect with your fellow attendees. Need Help? Still not sure how to sign in and get the most out of the mobile app? Don t miss the Mochas and Mobile Apps: Mobile App Training on Tuesday, January 30 at 10:15 in the Cabinet Room. You can also contact CASSS Meeting Coordinator Anna Lingel (alingel@casss.org) or stop by the registration office in the Senate Room.

6 Forum Abstract Prior Knowledge: Learning from Our Successes and Failures to Improve Product Development and Manufacturing FORUM CO-CHAIRS: Julia Edwards, Allergan Joseph Kutza, MedImmune, A member of the AstraZeneca Group Heidi Zhang, Genentech, A member of the Roche Group SCIENTIFIC ORGANIZING COMMITTEE: Fiona Cornel, Health Canada JR Dobbins, Eli Lilly and Company Earl Dye, Genentech, A member of the Roche Group Robert Kuhn, Amgen Inc. Joanna Zhou, CDER, FDA Biotechnology-based therapeutic products have been on the market for almost 35 years. Through that time, the biopharmaceutical industry and regulatory authorities around the world have together brought hundreds of biological drugs to patients suffering from a variety of diseases. The development and manufacture of new products is often based on the same principles and technologies. There is now a wealth of prior knowledge that we can and should leverage to improve the efficiency of developing new products and the manufacturing of existing products. Some areas of CMC already use prior knowledge effectively such as in the assessment of quality attributes, establishing analytical and process control strategies, and in the design of viral clearance and inactivation studies. Although the potential is clear, and it s time to expand upon existing efforts, how a given manufacturer maintains, interprets, and applies such a large amount of information across multiple products in a regulated environment remains a challenge. This forum will explore ways the industry can leverage these concepts to speed drug development and enhance manufacturing efficiency to deliver safe and effective products to patients as quickly as possible. This CMC Strategy Forum will address the following topics from both industry and regulators perspectives: 1. What is prior knowledge and how is it captured? 2. How to apply prior knowledge to process design and validation? What can we learn about stability and degradation from prior knowledge? 3. Application of prior knowledge in the selection, design, and validation of analytical methods. Can prior knowledge be leveraged to determine the criticality of quality attributes? And when is it appropriate to use prior knowledge to justify CQA-ACs beyond clinical experience? 4. What are the benefits, and challenges, associated with leveraging prior knowledge to enable accelerated development programs? 5. What are the best practices for how to incorporate data and information from other products in a regulatory submission? What are the global considerations for use of prior knowledge in regulatory submissions?

7 CMC Strategy Forum Program Summary Prior Knowledge: Learning from Our Successes and Failures to Improve Product Development and Manufacturing Monday, January 29, :30 17:00 Registration in the Senate Room 07:30 08:30 Breakfast in the Chinese Room / Palm Court Ballroom 08:30 08:45 CASSS Welcome and Introductory Comments in the Grand Ballroom Wassim Nashabeh, F. Hoffmann-La Roche Ltd. CMC Strategy Forum Welcome and Introductory Comments in the Grand Ballroom Julia Edwards, Allergan Joseph Kutza, MedImmune, A member of the AstraZeneca Group What is Prior Knowledge and How Can it be Used to Enhance Product Development and Support Regulatory Decisions? Workshop Session One in the Grand Ballroom Session Chairs: Earl Dye, Genentech, a Member of the Roche Group, Robert Kuhn, Amgen Inc. and Joanna Zhu, CDER, FDA 08:45 09:10 A Vision for Prior Knowledge and How to Manage as an Asset Martin Lipa, Merck & Co., Inc., West Point, PA USA 09:10 09:35 Prior Knowledge: What It Is and How We Use It Josefine Persson, Genentech, a Member of the Roche Group, South San Francisco, CA USA 09:35 10:00 A Regulatory Perspective on the Use of Prior Knowledge Cristina Ausin, CDER, FDA, Silver Spring, MD USA 10:00 10:25 CQA Identification, Criticality Assessment and Clinical Relevancy Barbara Rellahan, Amgen Inc., Rockville, MD USA 10:30 11:00 Networking Break in the Palm Court Ballroom 11:00 12:15 PANEL DISCUSSION Questions and Answers Cristina Ausin, CDER, FDA Martin Lipa, Merck & Co., Inc. Ingrid Markovic, CBER, FDA Josefine Persson, Genentech, a Member of the Roche Group Barbara Rellahan, Amgen Inc. Annie Sturgess, Bristol-Myers Squibb Company

8 Monday, January 29 continued 12:15 13:45 Networking Lunch in the Palm Court Ballroom Putting Prior Knowledge in Action Workshop Session Two in the Grand Ballroom Session Chairs: JR Dobbins, Eli Lilly and Company and Heidi Zhang, Genentech, a Member of the Roche Group 13:45 14:10 Applying Prior Knowledge to Streamline Early-stage Analytical Development of Monoclonal Antibody Li Zang, Biogen, Cambridge, MA USA 14:10 14:35 Modular Retrovirus Clearance in Support of Clinical Development Dayue Chen, Eli Lilly and Company, Indianapolis, IN USA 14:30 15:25 Summary of the 2017 EMA Workshop on Prior Knowledge and Its Use in Regulatory Applications Markus Goese, F. Hoffmann-La Rochet Ltd., Basel, Switzerland Mats Welin, Medical Products Agency (MPA), Uppsala, Sweden 15:30 16:00 Networking Break in the Palm Court Ballroom 16:00 17:15 PANEL DISCUSSION Questions and Answers Dayue Chen, Eli Lilly and Company Fiona Cornel, Health Canada Markus Goese, F. Hoffmann-La Rochet Ltd. Mats Welin, Medical Products Agency (MPA) Li Zang, Biogen Joanna Zhou, CDER, FDA 17:15 17:45 Recap of Program Summary Slide Presentation Charles Morgan, Genentech, a Member of the Roche Group Kimberly Wolfram, Biogen 17:45 18:00 Closing Remarks and Invitation to the CMC Strategy Forum July 2018 Julia Edwards, Allergan 18:00 19:30 Networking Reception in the Chinese Room / Palm Court Ballroom 19:30 Adjournment

9 What is Prior Knowledge and How Can it be Used to Enhance Product Development and Support Regulatory Decisions? Workshop Session One Session Chairs: Earl Dye, Genentech, a Member of the Roche Group, Robert Kuhn, Amgen Inc., Joanna Zhou, CDER, FDA Extensive and appropriate knowledge of both the product and process is central to the enhanced or QbD approach to development. A variety of sources of prior knowledge can be effectively applied to drive informed, risk and science based product and process development, with the potential to decrease development times while improving outcomes. This session will focus on: 1. What is prior knowledge? How can it be applied to improve product and process design? How can it be used to focus and streamline product and process development? 2. What is the regulatory viewpoint on the use of prior knowledge for product and process development, and how does it need to be reflected in regulatory filings. 3. How can prior knowledge be used to inform the molecular design of products, enhance the understanding of product quality attributes and drive the development of effective risk and knowledge based control strategies, NOTES:

10 Presenter s Abstracts A Vision for Prior Knowledge and How to Manage as an Asset Martin Lipa Merck & Co., Inc., West Point, PA USA We are in a knowledge business. Most everything we do in the biopharmaceutical industry is based on what we know and our ability to grow and transfer that knowledge. The opportunity to leverage prior knowledge what we already know to improve and accelerate understanding of our product and processes will in turn deliver better outcomes for our patients, our employees and our respective organizations. Yet our ability to define the most critical knowledge and to be able to find and apply this knowledge when needed is generally poor. This presentation will help define key concepts including the data-information-knowledge-wisdom continuum, knowledge management and tacit knowledge. It will also challenge the scope of what we think of as prior knowledge and what barriers organizations may face today in effectively managing knowledge today. A vision for leveraging knowledge will be shared and the practice of knowledge management will be introduced, along with an existing framework in use at Merck & Co., Inc. s Manufacturing Division to help ensure knowledge flows and can deliver greater benefit. NOTES:

11 Prior Knowledge: What It Is and How We Use It Stephanie Wong, Kimberly Kaleas, James Patch, Josefine Persson Genentech, a Member of the Roche Group, South San Francisco, CA USA About twenty years ago, the Biotech Industry started to develop processes to produce monoclonal antibodies (mab s). To enable a fast and efficient development, most companies created a default process to use as the start point for new mab entering the pipeline. Consequently, a decade or two later, there are now several commercial mab s on the market and when looking, within one company, there is clear similarity between these processes. We have compiled and examined our historic validation data (our Prior Knowledge) from several of our unit operations and have identified major similarities between the validation data for different mab s. In this presentation we will describe how we leverage this prior validation knowledge to enable a fast and streamlined validation procedure for new mab s. NOTES:

12 A Regulatory Perspective on the Use of Prior Knowledge Cristina Ausin CDER, FDA, Silver Spring, MD USA Prior knowledge can be used to design and support development of manufacturing processes, formulations, presentations, and process and product control strategies of biological products. The extent of prior knowledge used to support a marketing application depends on how its applicability to the product in question is justified in the submission. This presentation will provide an overview of potential applications of prior knowledge described in regulatory guidance such as ICH, FDA guidances for industry and related documents. In addition, the presentation will describe the Agency s expectations regarding the use of prior knowledge as supportive information for product and process control strategies in applications. Examples of both the opportunities and the limitations of using this type of information to support development will also be described. NOTES:

13 CQA Identification, Criticality Assessment and Clinical Relevancy Barbara Rellahan Amgen Inc., Rockville, MD USA Since 1999, ICH Q6B has been the primary guidance document outlining the general principles for setting specifications for biological products. While ICH Q6B still provides guiding principles for establishment of specifications, such as the definition of a specification and acceptance criteria, it does not account for the knowledge gained from the systematic QbD development process most companies currently utilize. Adoption of the principles in ICH Q8, Q9, Q10 & Q11 allows the use of science and risked based approaches that can potentially justify elimination of tests for non-critical attributes as well as establishment of limits beyond those based solely on clinical exposure. Recently, Amgen performed a holistic review of our integrated control strategy, fully utilizing approaches described in ICH Q6B as well as QbD principles to facilitate development of clinically relevant testing programs for our products. Prior knowledge of process and product both within and across modalities is used throughout development to establish testing plans which eliminate non-value-added testing, provide timely evaluation of product quality and informative data for process/product monitoring, and focuses on the risk to product quality as it relates to clinical performance. This presentation will discuss the approaches taken in selecting the tests to be employed, as well as the types of information that could be useful in establishing clinically relevant acceptance criteria. Case studies will be provided to illustrate the various strategies used when establishing the integrated control strategy and specifications, and responses received from various regulatory agencies. NOTES:

14 What is Prior Knowledge and How Can it be Used to Enhance Product Development and Support Regulatory Decisions? Workshop Session One Panel Members: Cristina Ausin, CDER, FDA Martin Lipa, Merck & Co., Inc. Ingrid Markovic, CBER, FDA Josefine Persson, Genentech, a Member of the Roche Group Barbara Rellahan, Amgen Inc. Annie Sturgess, Bristol-Myers Squibb Company The following questions will guide the panel discussion: What is prior knowledge? Data vs. knowledge vs. wisdom? What are the scope and potential sources of prior knowledge, internal vs external? How do platforms enable prior knowledge and what are the differences? How can prior knowledge from similar products or different product classes be used in product development? How can prior knowledge be used to inform the molecular design of products and facilitate a QbD approach to product development? How can prior knowledge of the biological properties of common product quality attributes inform assessment of their criticality and clinical relevance? How much product specific data is needed in product development? How can predictive modeling using prior knowledge be used to complement gaps and reduce the need for subsequent process validation? Can concurrent validation and ongoing process modeling complement use of prior knowledge and predictive modeling to reduce number of validation batches needed to file MA? How is prior knowledge (vs data) captured and presented in regulatory submissions? NOTES:

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16 Putting Prior Knowledge in Action Workshop Session Two Session Chairs: JR Dobbins, Eli Lilly and Company and Heidi Zhang, Genentech, a Member of the Roche Group This session will focus on how prior knowledge has been used to advance the development and commercialization of biopharmaceuticals. Practical examples and case studies will be shared. The examples will include leveraging prior knowledge and platform information for analytical method development, viral safety, and overall process design. NOTES:

17 Presenter s Abstracts Applying Prior Knowledge to Streamline Early-stage Analytical Development of Monoclonal Antibody Li Zang Biogen, Cambridge, MA USA Monoclonal antibody has been in development for therapeutic use since the introduction of hybridoma technology in 1976; so far more than 40 mab or mab fragments have been approved especially in the therapeutic areas of cancer, autoimmune and other inflammatory diseases. The rich development knowledge gathered by the industry working with mabs can be used to streamline the development process for those therapeutic agents. Narrowing down to the analytical development area, the understanding of the mab structure and function relationship, as well as the process impact on the mab quality can be leveraged to design efficient pathways for method development, qualification and testing strategy design while taking calculated risks. This talk will review two case studies in streamlining development and qualification of analytical method as well as establishment of cell line screening testing strategy based on the learnings made from mab development in Biogen. NOTES:

18 Modular Retrovirus Clearance in Support of Clinical Development Dayue Chen Eli Lilly and Company, Indianapolis, IN USA Three proven dedicated viral clearance unit operations, detergent viral inactivation (DVI), low ph viral inactivation, and viral filtration, are incorporated into our platform downstream purification processes for therapeutic proteins such as monoclonal antibodies (MAb). Based on our extensive in-house experience and good understanding of critical process parameters (CPP) of these three-unit operations, we have taken a modular claim approach to demonstrate adequate retrovirus clearance in support of clinical trials. The modular approach is discussed in context of achieving CM&C effectiveness and meeting regulatory expectations. NOTES:

19 Summary of the 2017 EMA Workshop on Prior Knowledge and Its Use in Regulatory Applications Markus Goese F. Hoffmann-La Rochet Ltd., Basel, Switzerland Mats Welin Medical Products Agency (MPA), Uppsala, Sweden Prior knowledge has always been an important tool in designing both manufacturing processes and control strategies for medicinal products. In recent years, it has gained more focus in EU guidelines (e.g. process validation for biotech drug substances; process validation for finished products). Making use of such prior knowledge in regulatory application dossiers, to support manufacturing and control strategies, could be justifiable in certain circumstances. For prior knowledge to be used in this way, good understanding among regulators and industry of the expectations of how it should be documented in regulatory application dossiers is essential. For this reason, a joint regulator-industry workshop was held at EMA on 23 November, The speakers will present the regulator and industry views expressed and the outcome of the discussions on topics in relation to making use of prior knowledge in establishment of product and process design and in establishing a control strategy including assessment of criticality of attributes as well as current experience from accelerated processes where making use of appropriate prior knowledge will be a very important tool to allow early access to the market. NOTES:

20 Panel Members: Dayue Chen, Eli Lilly and Company Fiona Cornel, Health Canada Markus Goese, F. Hoffmann-La Rochet Ltd. Mats Welin, Medical Products Agency (MPA) Li Zang, Biogen Joanna Zhou, CDER, FDA Putting Prior Knowledge in Action Workshop Session Two The following questions will guide the panel discussion: 1. How do you apply prior knowledge to process design and validation? 2. What can we learn about stability and degradation from prior knowledge? 3. Application of prior knowledge in the selection, design, and validation of analytical methods. Can prior knowledge be leveraged to determine the criticality of quality attributes? 4. When is it appropriate to use prior knowledge to justify CQA-ACs beyond clinical experience? NOTES:

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