Welcome to the WCBP CMC Strategy Forum

Transcription

1 Welcome to the WCBP CMC Strategy Forum We are pleased to welcome you to the 24 th 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 sponsors: Amgen, Inc.; Biogen Idec Inc.; Biologics Consulting Group, Inc.; Eli Lilly and Company; Genentech, a Member of the Roche Group; Genzyme Corporation; GlaxoSmithKline; Johnson & Johnson Pharmaceutical R&D; MedImmune; Novartis Pharma AG; 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 Inc. 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

2 The Organizing Committee gratefully acknowledges the pharmaceutical and biotechnology industry for their generous support of the WCBP CMC Strategy Forum series: PROGRAM PARTNERS Amgen, Inc. Biogen Idec Inc. Biologics Consulting Group, Inc. Eli Lilly and Company Genentech, a Member of the Roche Group Genzyme Corporation GlaxoSmithKline Johnson & Johnson Pharmaceutical R&D MedImmune Novartis Pharma AG Novo Nordisk A/S Pfizer, Inc. MEDIA PARTNERS BioPharm BioProcess International

3 Forum Abstract Challenges and Considerations for Multiproduct Facility Design and Control for Biologics Program Planning Committee: Bo Chi, CDER, FDA, Bethesda, MD USA Julia Edwards, Genentech, a Member of the Roche Group, South San Francisco, CA USA Jun Park, CDER, FDA, Bethesda, MD USA Stefanie Pluschkell, Pfizer, Inc., Groton, CT USA Nancy Waites, CBER, FDA, Rockville, MD USA Elizabeth Yamashita, Savient Pharmaceuticals, Inc., East Brunswick, NJ USA Forum Co-Chairs: Siddharth Advant, ImClone Systems Corporation, Branchburg, NJ USA Wassim Nashabeh, Genentech, a Member of the Roche Group, South San Francisco, CA USA Multi-product facilities are increasingly integral to corporate biologics network and supply chain strategies. Manufacturing capacity strategies ensuring appropriate facility design and procedural controls to manage the risks of producing multiple products is critical to the successful deployment of commercial and clinical supply plans. The purpose of this forum is to highlight various challenges, risks and control strategies associated with multi-product facilities. Multi-product strategies for the manufacture of a variety of product types at different stages in the lifecycle and potentially using different host cells will be presented with case studies. Experts from both industry and global Health Authorities will discuss facility design considerations as well as procedural controls such as cleaning validation and product testing. The importance of Quality Risk Management to multi-product operations and controls will also be discussed using practical examples of risk-based approaches to meet the challenges of multi-product manufacturing.

4 WCBP CMC Strategy Forum Program Summary Challenges and Considerations for Multiproduct Facility Design and Control for Biologics Forum Co-Chairs: Siddharth Advant, ImClone Systems Corporation and Wassim Nashabeh, Genentech, a Member of the Roche Group MONDAY, AUGUST 1, :30 08:30 Registration in the Lister Hill Auditorium Foyer 07:30 08:30 Breakfast in the Lister Hill Auditorium Foyer 08:30 08:45 Welcome and Introductory Comments to the WCBP CMC Strategy Forum Wassim Nashabeh, Genentech, a Member of the Roche Group, South San Francisco, CA USA Session One: Multi-product Facility and Design Considerations Session Chair: Stefanie Pluschkell, Pfizer, Inc. 08:45 09:15 FDA Regulatory Perspectives on Multi-product Biological Facilities Patricia Hughes, OMPQ, CDER, FDA, Bethesda, MD USA 09:15 09:45 Design Through Start-up of a Multi-product mab Launch Facility Pat O Driscoll, Eli Lilly S.A.-Irish Branch, Kinsale, Ireland 09:45 10:15 Challenges for Multi-product Operation from a CMO Perspective Michael Howaldt, Boehringer-Ingelheim Pharma GmbH & Co., KG, Ingelheim, Germany 10:15 10:45 AM Break in the Lister Hill Auditorium Foyer 10:45-12: 00 Panel Discussion: Michael Howaldt, Boehringer-IngelheimPharma GmbH & Co., KG, Germany Patricia Hughes, DMPQ, CDER, FDA USA Pat O Driscoll, Eli Lilly S.A., Ireland Anthony Ridgway, Health Canada, Canada Kathryn Simon, Fujifilm Diosynth Biotechnologies, USA 12:00 12:15 Discussion Wrap-Up 12:15 13:30 Lunch Break in the Lister Hill Auditorium Foyer

5 MONDAY, AUGUST 1 continued Session Two: Case Studies on the Application of Risk-based Principles to Multi-product Facilities Session Chair: Julia Edwards, Genentech, a Member of the Roche Group 13:30 14:00 A Risk-based Scientific Approach to Multi-product Operations Karen Williams, ImClone Systems Corporation, Branchburg, NJ USA 14:00 14:30 Benefits of a Risk-based Cleaning Validation Approach during New Product Introduction Jenna Carlson, Genentech, A Member of the Roche Group, South San Francisco, CA USA 14:30 15:00 Navigating the Complexity of MPFs: Matching QRM Approaches with Flexible Design Paradigms Kristin Murray, Pfizer, Inc., Andover, MA USA Stephen Reich, Pfizer, Inc., Andover, MA USA 15:00 15:30 PM Break in the Lister Hill Auditorium Foyer 15:30 16:45 Panel Discussion Jenna Carlson, Genentech, a Member of the Roche Group Kristin Murray, Pfizer, Inc. Stephen Reich, Pfizer, Inc. Patrick Swann, CDER, FDA Karen Williams, ImClone Systems Corporation 16:45 17:00 Discussion Wrap-Up 17:00 17:15 Depart Lister Hill Auditorium 18:00 19:30 Networking Reception in the Concours Terrace at the Hyatt Regency Bethesda

6 TUESDAY, AUGUST 2, :30 17:00 Registration in the Lister Hill Auditorium Foyer 07:30 08:30 Breakfast in the Lister Hill Auditorium Foyer Session Three: Process and Product-specific Considerations Session Chair: Elizabeth Yamashita, Savient Pharmaceuticals, Inc. 08:30 09:00 PDA Task Force for Single Use Systems: Technical Report Overview Robert Repetto, Pfizer, Inc., Chesterfield, MO USA 09:00 09:30 Concurrent Manufacturing in a Manual Facility Carla Rumazza, Bristol-Myers Squibb Company, Princeton, NJ USA 09:30 10:00 Regulatory Considerations on Multi-product Facilities for Biotechnology Products Jun Park, Office of Biotechnology Products, CDER, FDA, Bethesda, MD USA 10:00 10:30 Multi-product Facility Considerations for Biological Products Nancy Waites, CBER, FDA, Rockville, MD USA 10:30 11:00 AM Break in the Lister Hill Auditorium Foyer 11:00 12:15 Panel Discussion Martin Nemec, Health Canada Jun Park, CDER, FDA Robert Repetto, Pfizer, Inc. Carla Rumazza, Bristol-Myers Squibb Company Nancy Waites, CBER, FDA 12:15 12:30 Discussion Wrap-Up 12:30 13:45 Lunch Break in the Lister Hill Auditorium Foyers Session Four: Regulatory Strategies for Multi-product Facilities Session Co-Chairs: Jun Park, CDER, FDA and Nancy Waites, CBER, FDA 13:45 14:15 From a Multi-product to Multi-host Manufacturing Facility: A Case Study Kathleen Sniff, Amgen, Inc., Thousand Oaks, CA USA 14:15 14:45 Regulatory Practicalities of Multi-purpose Biologics Manufacturing Facilities from the European Perspective Christopher Holloway, ERA Consulting, London, United Kingdom 14:45 15:15 Multi-product Facilities for Biologics: BGTD (Health Canada) Perspective Martin Nemec, Health Canada, Ottawa, Ontario, Canada

7 TUESDAY, AUGUST 2 continued 15:15 15:45 PM Break in the Lister Hill Auditorium Foyer 15:45 17:00 Panel Discussion Bo Chi, CDER, FDA Christopher Holloway, ERA Consulting Martin Nemec, Health Canada Kathleen Sniff, Amgen, Inc. 17:00 17:15 Recap of Program Summary Slide Presentation 17:15 17:30 Invitation to CMC Strategy Forum January :30 Adjournment

8 Multi-product Facility and Design Considerations In this session, the principle challenges in designing and operating a multiproduct facility for biologics will be introduced. Regulatory agency and industry perspectives regarding the opportunities for and limitations to multi-product facility flexibility will be discussed. Specific considerations for contract manufacturing organizations will also be highlighted. Questions: 1. What are the principle challenges in building a flexible, scalable, multi-product manufacturing network? 2. What are the boundaries/limitations to multi-product facility flexibility (e.g., phase of development, product type, etc.)? 3. Are companies designing facilities for multiple products up front or retrofitting? What's the primary difference in approach? What are the advantages or disadvantages to retrospective v. prospective approaches? 4. What multi-product considerations and challenges are unique to CMOs? What should customers and service providers focus on and be prepared to provide when entering a CMO agreement? 5. What are some of the expectations with respect to the future direction of multiproduct facility design?

9 Presenter Abstracts FDA Regulatory Perspectives on Multi-product Biological Facilities Patricia Hughes OMPQ, CDER, FDA, Bethesda, MD USA An overview of the FDA regulatory expectations for multi-product biological facilities will be provided. Risks associated with various cell substrates, product categories, raw materials and manufacturing processes will be discussed. A review of facility design and equipment requirements in the context of multi-product facilities will be provided. The presentation will cover traditional and newer manufacturing approaches that may be pursued to assure product quality. Some of newer approaches should lead to greater manufacturing flexibility.

10 Design Through Start-up of a Multi-product mab Launch Facility Pat O Driscoll Eli Lilly S.A. Irish Branch, Kinsale, Ireland As a result of a maturing biotech pipeline, Eli Lilly & Co. commenced design of a commercial monoclonal antibody manufacturing plant in The facility is situated at an existing Eli Lilly small molecule API site at Kinsale, Ireland. The facility was designed to support multiproduct commercial manufacturing. The design was based on Eli Lilly s biotech development platform/ facility situated in Indianapolis, USA. In conjunction with design/ delivery of the facility, significant focus was given to developing staff technical capability at an early stage. Process validation for the first molecule is currently ongoing. It is planned to manufacture molecules for worldwide supply on a campaigned basis.

11 Challenges for Multi-product Operation from a CMO Perspective Michael Howaldt Boehringer Ingelheim Pharma GmbH & Co., KG, Ingelheim, Germany Biopharmaceutical companies are streamlining their operations to gain efficiencies: platform technologies, standard process formats, corporate quality systems and quality procedures are typical examples. A CMO, whose business it is to develop and manufacture for multiple companies and to serve the customers needs, has to deal with these differences, incorporate them in his own system and at the same time be compliant, efficient, and cost competitive. This presentation will address these challenges both from a hardware point of view facility capabilities, new technologies such as disposables and from a software point of view process formats, quality procedures, cooperation between client and CMO - and discuss approaches how to achieve mutually beneficial solutions.

12 Case Studies on the Application of Risk-based Principles to Multiproduct Facilities Risk-based approaches to multiproduct facilities will be discussed. Specifically, how these approaches have been leveraged during cleaning validation and case studies from industry will be presented. This session will include explanation around how the use of different QRM to address diverse multi-product facility problem statements may influence the risk assessment outputs and associated control plans. Discussion topics will include leveraging Quality Risk Management in determining appropriate crosscontamination controls for multiproduct facilities. Questions: 1. Does the execution of complex quality risk management QRM approaches enhance or limit network flexibility? Are there examples of both scenarios? 2. What are the limitations of applying QRM principles in the design of a multiproduct facility producing products for the global supply chain (e.g., regional regulations/laws, conflicting interpretations of GMP guidelines, etc.)? How could these challenges be overcome? 3. Although QRM is important, what cross-contamination controls are critical to successful multiproduct strategies in the absence of a formal risk assessment? How might the use of the wrong QRM tool influence the risk assessment outputs and resulting control plan? 4. What are appropriate cleaning validation limits and approaches? What studies and analysis can be performed to reduce the amount of testing required during cleaning validation? Are there any circumstances, e.g. in vaccine manufacture, under which it is acceptable to use the same direct product contact equipment (e.g. filling needles, pumps, formulation vessels) for multiple products?

13 Presenter Abstracts A Risk-based Scientific Approach to Multi-product Operations Karen Williams ImClone Systems Corporation, Branchburg, NJ USA Many biologics manufacturing facilities are operated as multi-product production units. Fast, effective and efficient changeovers between product campaigns in such facilities are essential in today s environment where making the most out of existing capacity and controlling costs are a necessity. Imclone Systems Corporation manufactures recombinant biotechnology products (monoclonal antibodies) from mammalian cell culture in its multi-product, multi-suite facility. This facility incorporates common areas including media, buffer and component preparation supporting the needs of the multiple suites. The monoclonal antibody products produced in the multi-product facility are for both clinical and commercial use, are from multiple cell lines (mouse myeloma and Chinese hamster ovary) and are manufactured utilizing a platform process. The presentation details the risk based, scientific approach employed at Imclone to ensure that processes are capable of consistently maintaining product quality and safety while simultaneously manufacturing multiple products in the facility.

14 Benefits of a Risk-based Cleaning Validation Approach during New Product Introduction Jenna Carlson Genentech, a Member of the Roche Group, South San Francisco, CA USA New product introduction must demonstrate that cleaning procedures are capable of removing the new product/process residues and analytical methods can effectively detect process residues. The purpose of this case study is to present the tools and techniques that have been used to reduce the amount of cleaning validation effort required during New Product Introduction. Three key tools used to reduce the amount of testing are: 1. FMEA to identify, analyze, and evaluate any cross-contamination or operational risks associated with multiuse operations including cleaning. 2. Laboratory studies used to support analytical sampling methods and product grouping 3. ADE based MAC calculations. 4. Pre-introduction cleaning studies to challenge the ability of the standard cleaning procedures to remove the new process residues from representative equipment surfaces. Questions: 1. What are the benefits of a holistic New Product Introduction program in regards to cleaning validation? 2. What can be done to reduce the amount of testing required during cleaning validation? 3. What studies and analysis can be performed to reduce the amount of sampling techniques required during cleaning validation?

15 Navigating the Complexity of Multi-product Facilities: Matching QRM Approaches with Flexible Design Paradigms Kristin Murray and Stephen Reich Pfizer, Inc., Andover, MA USA Quality Risk Management (QRM) is a proven enabling methodology for evaluation of the risks associated with increasingly progressive and flexible biologic multi-product facility designs and operating paradigms. Recent examples of progressive and complex multi-product facility designs include facilities performing host cell (mammalian / microbial) changeover, facilities where clinical and commercial products are manufactured in the same suite areas with shared product contact equipment, and concurrent manufacturing operations in shared facility areas. Such manufacturing facility designs or operating paradigms present different risk types for consideration. Different hazards (physical, chemical and biological) require consideration during changeover risk assessments, fault modes around nonconformance and human performance factors are critical risk types during concurrent operation evaluations, and failure modes associated with equipment operations and cleaning chemistries are important considerations during daily multi-product facility operations risk assessments. Different QRM tools (HACCP, FMEA, FTA, Fishbone, HAZOP, etc.) have unique capabilities that make them more or less compatible with the different problem statements and their associated risk types in multi-product facilities. This presentation will briefly review four different multi-product facility operating scenarios (area/line clearance, host cell changeover, changeover chronology, and concurrent operations) and demonstrate the use of different QRM tools to evaluate the risk types associated with the problem statement for each. The speakers will highlight specific important outcomes achieved during the QRM process in addition to what might have been missed if a different QRM tool had been utilized.

16 Process and Product-specific Considerations This session will begin with an update on the PDA Task Force for Single-Use systems. Industry experience will then be presented concerning the special considerations necessary to operate and control manufacture of concurrent processes for biotechnology products. The regulatory perspective for biotechnology and classic biologics from an inspectional viewpoint will also be discussed. Questions: 1. Under what circumstances is concurrent manufacturing feasible? What are some of the productspecific challenges and limitations? 2. Going beyond facility controls to the product itself, what elements of detection and control for cross-contamination are important? For example, identity testing, adventitious agents detection, etc.? 3. What additional controls are needed for raw materials in the case of a multiproduct facility operation? 4. How can a holistic approach to cross-contamination controls be developed keeping in mind facility, equipment, and product? Can QRM be effectively applied in such an approach?

17 Presenter Abstracts PDA Task Force for Single Use Systems: Technical Report Overview Robert Repetto Pfizer, Inc., Chesterfield, MO USA The lack of a roadmap and best practices for the implementation of single use technologies in pharmaceutical manufacturing has been a recognized challenge within the industry. The Parenteral Drug Association has developed a technical document establishing a framework by which organizations can establish a manufacturing strategy for implementing single use technologies with special consideration for their individual needs, goals and competencies. A successful manufacturing strategy must balance business and industry drivers to ensure that the primary customer based goals of patient safety, product availability, product, and process understanding are met when implementing new technology. This technical report presents a flexible approach for achieving these goals, outlining science and risk-based considerations from the following areas of focus: Technologies and System Integration, Business Drivers, Qualification and Implementation. This presentation will give the audience an introduction to the new Technical Report, which is intended to support the decision process when considering implementing single use technologies.

18 Concurrent Manufacturing in a Manual Facility Carla Rumazza Bristol-Myers Squibb Company, Princeton, NJ USA Abstract was not provided by time of printing.

19 Regulatory Considerations on Multi-product Facilities for Biotechnology Products Jun Park Office of Biotechnology Products, CDER, FDA, Bethesda, MD USA Abstract was not provided by time of printing.

20 Multi-product Facility Considerations for Biological Products Nancy Waites CBER, FDA, Rockville, MD USA This talk will outline the Center for Biologics Evaluation and Research s (FDA / CBER) expectations for a multi-product facility. The topics highlighted will include concerns for multi-product facilities, considerations during facility design, cleaning validation, product change over, and introduction of new products into a multi-product facility.

21 Regulatory Strategies for Multi-product Facilities Expectations for multi-product facilities from different global regulatory authorities will be presented and discussed in this session. Possible strategies intended to facilitate the dossier review and inspection of multi-product facilities will also be discussed. Questions: 1. What are the highest priority items regulators look for regarding multi-product controls during an inspection? 2. Does submission of a robust multi-product facility strategy as part of the BLA help companies during inspection? Which elements should be included as part of the dossier, and which ones can be left for review during inspection? 3. What are some of the key differences in evolving global regulatory expectations? 4. How can regulatory submission strategies be effectively applied to enhance network flexibility while ensuring cross-contamination controls? 5. What commonalities or guiding principles can be concluded from the different approaches to multi-product controls that were presented? What opportunities for streamlining multi-product facility approvals could be effectively leveraged to support increasingly complex operational strategies?

22 Presenter Abstracts From a Multi-product to Multi-host Manufacturing Facility: A Case Study Kathleen Sniff Amgen, Inc., Thousand Oaks, CA USA Economic pressures may require that a facility take on new responsibilities and products to reduce the costs. Operation of a multi-product facility is more difficult than one dedicated to a single product. Moving into the space of multi-host operations raises the bar significantly higher. Navigating the path toward a multi-host facility requires careful identification, assessment, mitigation and control of risks associated with potential cross-contamination. Given the severity of viral contamination in a microbial process and product, a body of data must be presented which demonstrates that the cleaning cycles employed during host changeover are virally inactivating based on both the conditions and the material surfaces. In the end, patient safety is paramount and the collaborative effort between the manufacturer and the Health Authorities can lead to robust procedures, controls and safe-guards to ensure successful multi-host operation.

23 Regulatory Practicalities of Multi-purpose Biologics Manufacturing Facilities from the European Perspective Christopher Holloway ERA Consulting, London, United Kingdom Abstract was not provided by time of printing.

24 Multi-product Facilities for Biologics: BGTD (Health Canada) Perspective Martin Nemec Health Canada, Ottawa, Ontario, Canada Multi-product facilities for the manufacture of biological therapeutic products are becoming the norm. Regulatory submissions for products from such facilities must adequately describe the strategies implemented to prevent cross-contamination and mix-ups. This presentation seeks to provide an overview of requirements for multi-product facility information from the perspective of a Health Canada reviewer. For illustration, selected issues identified during submission review and on-site evaluations are highlighted.