Welcome to the CMC Strategy Forum Phase-appropriate Method Validation Strategies: Policies and Practices to Support Clinical Development

Transcription

1 Welcome to the CMC Strategy Forum Phase-appropriate Method Validation Strategies: Policies and Practices to Support Clinical Development 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 Phase-appropriate Method Validation Strategies: Policies and Practices to Support Clinical Development FORUM CO-CHAIRS: Alfred Del Grosso, CBER, FDA Brian Janelsins, CDER, FDA Sandra McSheffrey, Health Canada Nadine Ritter, Global Biotech Experts, LLC SCIENTIFIC ORGANIZING COMMITTEE: Melody Gossage, Eli Lilly and Company Mary Beth Pelletier, Biogen Daisy Richardson, Merck & Co., Inc. Michael Sadick, Catalent Pharma Solutions Jason Starkey, Pfizer, Inc. Marcel Zocher, Bristol-Myers Squibb Company Numerous regulatory statutes and guidance documents expect increasing levels of cgmp compliance of CMC during clinical trial phases, including the state of validation of the analytical test methods used to test clinical trial materials. But the description of method validation activities as an evolving process is confounded by statements (even in the same guidance) that method validation data should be provided in Phase 2 and 3 IND/CTA filings. Moreover, the proposed USP <1220> chapter on Analytical Method Lifecycles does not use the term method validation at all; instead, it defines three method assessment stage gates which do not align with the clinical phases of product development. There is considerable information on what is required at the end of clinical trial phases for method validation studies and data packages. ICHQ2(R1) provides guidance on the type and nature of experiments to be conducted for the validation of methods to meet commercial product cgmp compliance. Recent FDA guidance documents provide substantial clarity on the complete information sets to be included in a BLA method validation package, as well as their expectations for validation of computerized analytical systems to control data integrity for cgmp compliance. However, except in the case of methods related to product safety, the Phase 1, 2 and 3 guidance documents do not provide clear information on expectations for the phase-appropriate rigor of the validation study protocol, or the contents of validation report produced. Is there a risk-based approach that can be applied to each method at each phase, based on the nature of the product? Is there a possibility of leveraging prior knowledge of similar methods for similar products to support the early phase validation of methods? This Forum will discuss the current FDA and Health Canada regulatory perspectives on method validation for Phase 1, 2 and 3, and the expectations for validation data to be submitted in the IND/CTA versus the BLA/MAA Module 3 for method validation. The Forum will highlight industry strategies for application of phase-specific method validation for biomolecular assays (e.g. HPLC, CE) and bioassays (e.g. ligand binding and cell based).

7 CMC Strategy Forum Program Summary Phase-appropriate Method Validation Strategies: Policies and Practices to Support Clinical Development 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 District Ballroom Nadine Ritter, Global Biotech Experts, LLC CMC Strategy Forum Welcome and Introductory Comments in the District Ballroom Nadine Ritter, Global Biotech Experts, LLC Part One: Regulatory Considerations for Phase-appropriate Method Validation Workshop Session One in the District Ballroom Session Chairs: Daisy Richardson, Merck & Co., Inc. and Jason Starkey, Pfizer, Inc. 08:45 09:15 Analytical Method Validation during Clinical Development: A Regulator s Perspective Jayda Siggers, Health Canada, Ottawa, ON Canada 09:15 09:45 Regulatory Perspective on Analytical Method Validation During Product Development Jacek Cieslak, CDER, FDA, Silver Spring, MD USA 09:45 10:15 Common Issues in Qualification and Validation of Analytical Procedures Alexey Khrenov, CBER, FDA, Silver Spring, MD USA 10:15 10:45 Networking Break in the District Ballroom 10:45 12:00 PANEL DISCUSSION Questions and Answers Justin Aldridge, Biogen Jacek Cieslak, CDER, FDA Sarah Demmon, Eli Lilly and Company Alexey Khrenov, CBER, FDA Timothy Schofield, GlaxoSmithKline Jayda Siggers, Health Canada

8 Monday, January 29 continued 12:00 13:30 Networking Lunch in the District Ballroom Part Two: Industry Considerations for Phase-appropriate Method Validation Workshop Session Two in the District Ballroom Session Chairs: Melody Gossage, Eli Lilly and Company and Michael Sadick, Catalent Pharma Solutions 13:30 14:00 Analytical Validation Challenges During the Rapid Development of Keytruda Athena Nagi, Merck & Co., Inc., West Point, PA USA 14:00 14:30 Phase-appropriate Method Validation: Eating the Elephant One Bite at a Time Mary Beth Pelletier, Biogen, Research Triangle Park, NC USA 14:30 15:00 Phase-appropriate Validation Design for Potency Assays: From INDenabling Studies through Method Validation for Licensure Ruojia Li, Bristol-Myers Squibb Company, Pennington, NJ USA 15:00 15:30 Networking Break in the District Ballroom 15:30 16:45 PANEL DISCUSSION Questions and Answers Alfred Del Grosso, CBER, FDA Ruojia Li, Bristol-Myers Squibb Company Sandra McSheffrey, Health Canada Athena Nagi, Merck & Co., Inc. Mary Beth Pelletier, Biogen Rashmi Rawat, CDER, FDA Jason Starkey, Pfizer, Inc. 16:45 17:15 Recap of Program Summary Slide Presentation Shiva Bolourchi, MedImmune, A member of the AstraZeneca Group 17:15 17:30 Closing Remarks and Invitation to the CMC Strategy Forum July 2018 Nadine Ritter, Global Biotech Experts, LLC 17:30 19:00 Networking Reception in the Chinese Room / Palm Court Ballroom 19:00 Adjournment

9 Part One: Regulatory Considerations for Phase-appropriate Method Validation Workshop Session One Session Chairs: Daisy Richardson, Merck & Co., Inc. and Jason Starkey, Pfizer, Inc. Analytical method validation is an essential component to the overall control strategy for biotherapeutics. Validated analytical procedures are a regulatory requirement at time of registration with an emphasis to demonstrate that suitable methods are in place to reflect product quality. However, there are a range of risk-based approaches across the industry on when method validation occurs and how this fits into the evolving method lifecycle for a product. This session will focus on perspectives from regulators on approaches to method validation across clinical development from Ph 1 to Ph 3/commercialization. Regulatory expectations for different validation scenarios at filing milestones will be discussed and practical experiences with biotech and vaccines method validations and common problems encountered will be shared. NOTES:

10 Presenter s Abstracts Analytical Method Validation during Clinical Development: A Regulator s Perspective Jayda Siggers Health Canada, Ottawa, ON Canada Validated analytical methods are a critical component of the manufacturing process control strategy. The overall objective of method validation is to demonstrate that the analytical method is suitable for the intended purpose. Therefore, during the development program, it is important to understand the purpose of the analytical method at each phase; ensuring product safety and potency during early development, monitoring manufacturing consistency during late-stage development, to final method validation as per ICH guidelines for market application. This presentation will provide a regulator s perspective on the type and degree of information suggested for phase-appropriate analytical method validation during clinical development. The presentation is illustrated with examples from representative submissions. NOTES:

11 Regulatory Perspective on Analytical Method Validation During Product Development Jacek Cieslak CDER, FDA, Silver Spring, MD USA Development and validation of the analytical procedures used for testing product quality during product development is a continuous and evolving process. Developing and implementing assays suitable to assure patient safety in early clinical stages and transitioning to validated assays that can support a commercial license application may present unique development and regulatory challenges. This presentation will provide regulatory expectations for qualification and validation of analytical methods at different stages of product development, including discussion of case studies. NOTES:

12 Common Issues in Qualification and Validation of Analytical Procedures Alexey Khrenov CBER, FDA, Silver Spring, MD USA Use of qualified and validated analytical procedures is critical to ensure the reliability and quality of analytical data used to support investigational and marketing applications. Fully validated analytical procedures should be used in commercial manufacturing process described in the marketing application, with validation reports included. However, validation is just a final phase of the process of demonstrating the suitability of the procedure to its intended purpose. A successful validation exercise may be performed only after gaining sufficient knowledge of the procedure capabilities through development and qualification activities. Qualification should be based on sound scientific judgement and assessment of characteristics critical for the intended use of the procedure. Inadequate qualification carries significant risk of subsequent failure of validation and a delay in product commercialization, especially if full validation is undertaken late in the development cycle. In this presentation, there will be a discussion, with case studies provided, of the typical issues observed in the validation of analytical procedures NOTES:

13 Part One: Regulatory Considerations for Phase-appropriate Method Validation Workshop Session One Panel Members: Justin Aldridge, Biogen Jacek Cieslak, CDER, FDA Sarah Demmon, Eli Lilly and Company Alexey Khrenov, CBER, FDA Timothy Schofield, GlaxoSmithKline Jayda Siggers, Health Canada The following questions will guide the panel discussion: 1. Are the terms validation and qualification methods generally understood and consistently applied? 2. What is meant for Ph 1, 2 and 3 by method validation data should be available upon request? 3. Have the Agencies seen a wide variety of approaches? If so, what is the range of options? 4. Could regulators elaborate on what additional method performance criteria are expected as development moves through Ph 1, Ph 2, and Ph 3? a. Increasing the level of performance rigor (e.g. going from wider to more narrow performance acceptance criteria)? b. Increasing the number of replicates/runs for intermediate precision? c. Adding specific method performance data (e.g. forced degradation for stability-indicating methods)? d. Confirming method robustness ranges defined in the procedure? 5. While there is guidance on the phase-specific qualification and calibration state of analytical instruments, is there also a phase-specific need for the validation of electronic data processing systems? 6. In general, are regulators comfortable with the current phase-specific strategies utilized by companies for method validation to support clinical development? 7. Are regulators accepting contract lab generic method validations filed in lieu of a complete product-specific method validation package? NOTES:

14 NOTES:

15 Part Two: Industry Considerations for Phase-appropriate Method Validation Workshop Session Two Session Chairs: Melody Gossage, Eli Lilly and Company and Michael Sadick, Catalent Pharma Solutions The application of analytical methods to the support of therapeutic molecules is an evolving path of continuous maturation, from the early IND stages of a project to the commercialization and ongoing postcommercialization phases of the molecules. This is particularly true for the validation of those methods. The maturation of method validation is based upon the concept of phase-appropriate validation. Thus, during the progression from the early clinical phase (IND/Phase 1) to late phase (Phase 3/commercialization) there is an ever-increasing level of stringency applied to assay performance requirements. This session will provide insights to the viewpoints of the biopharmaceutical industry, responsible for the actual application of the regulatory guidelines and expectations, and challenges thereof, to development, production and delivery of safe and effective therapeutic biologic molecules. NOTES:

16 Presenter s Abstracts Analytical Validation Challenges During the Rapid Development of Keytruda Athena Nagi Merck & Co., Inc., West Point, PA USA Early positive clinical results drove rapid development of Keytruda, including analytical method development and establishment, product characterization and specification setting. This presentation will provide several examples of method development challenges when early-phase transitions quickly to latephase, method updates during commercialization and beyond, and points to consider in establishing specifications and reference standards with limited product history. NOTES:

17 Phase-appropriate Method Validation: Eating the Elephant One Bite at a Time Mary Beth Pelletier Biogen, Research Triangle Park, NC USA The path to establishing and maintaining a validated analytical method suitable for release and stability testing of a commercial biologic is a continuum that begins prior to initiation of clinical trials and lasts through the lifecycle of the commercial product. Having a strong phase-appropriate method validation strategy is key not only to ensuring that the suitable quantity and quality of data are available at the appropriate stage of development, but also to optimizing investment of resources during development and to preparing for lifecycle management of the validated method. An overview of Biogen s phaseappropriate method validation strategy for biologics will be presented, as well as multiple case studies outlining how implementation of this approach has provided efficiencies and enabled streamlined lifecycle maintenance of methods. NOTES:

18 Phase-appropriate Validation Design for Potency Assays: From IND-enabling Studies through Method Validation for Licensure Ruojia Li Bristol-Myers Squibb Company, Pennington, NJ USA This talk will provide an overview of potency method phase-appropriate validation considerations, and offer insights into a scientific/statistically-driven approach for setting meaningful validation acceptance criteria. The approach uses the expected specification as a starting point to define required method performance parameters. A sequence of statistical assessments is then applied to establish validation acceptance criteria that provide sufficient confidence that the validated method is suitable for intended purpose, and that a suitable method will pass the validation criteria. This concept can be applied across methodologies beyond potency assays. Case studies will be used to illustrate the respective approaches. NOTES:

19 Part Two: Industry Considerations for Phase-appropriate Method Validation Workshop Session Two Panel Members: Alfred Del Grosso, CBER, FDA Ruojia Li, Bristol-Myers Squibb Company Sandra McSheffrey, Health Canada Athena Nagi, Merck & Co., Inc. Mary Beth Pelletier, Biogen Rashmi Rawat, CDER, FDA Jason Starkey, Pfizer, Inc. The following questions will guide the panel discussion: 1. Is a full GMP method validation package (e.g. as defined in 2015 FDA guidance) needed prior to Ph 3? If so, what is the rationale for needing that level of method validation? Are sponsors usually submitting similar method validation packages going into Ph 1, Ph 2, Ph 3? Are these different from what is submitted for BLA/MAA? 2. In what scenario would it be appropriate to execute an assay qualification with no pre-determined parameter criteria as well as no QA signatures, either for protocol or report? 3. Since method validation is an evolving process during development, what additional method performance criteria are typically added as development moves through Ph 1, Ph 2, and Ph 3? For example: a. Increasing the level of performance rigor (e.g. going from wider to more narrow performance acceptance criteria)? b. Increasing the number of replicates/runs for intermediate precision? c. Adding specific method performance data (e.g. forced degradation for stability-indicating methods)? d. Confirming method robustness ranges defined in the procedure? e. Adding validation of computerized spreadsheets and/or analytical data electronic processing steps? 4. In general, have sponsors been successful with recent FDA and HC product IND/IMPD/CTAs in filing their phase-specific strategies for method validation during biotech product development? 5. When certifying another lab how do you decide whether to perform a co-validation or a method transfer? Are these executed differently with different criteria? If the method procedures differ slightly between two labs can a co-validation be performed? 6. What are the challenges if the contract lab and the sponsor have significantly different approaches to phase-appropriate method validation? Who is responsible if it is later discovered there are gaps to be filled before the next phase? NOTES:

20 NOTES: