Welcome to the CMC Strategy Forum Europe 2018

Transcription

1 Welcome to the CMC Strategy Forum Europe 2018 The 12 th annual CMC Strategy Forum Europe, organized by CASSS, will explore many critical topics focused on improving the quality in development and manufacturing of biopharmaceutical products. A series of plenary sessions and workshops led by experts from global regulatory agencies, academia and industry seek to explore emerging aspects of CMC technology and regulation in areas where existing modalities and systems are undergoing change. Topics will include: Regulatory Update from Around the World; Adding to the Complexity Combining Drugs and Devices; Clinical Relevance of Specifications; Current and Future Approaches to Enhance Development, QbD and Design Spaces; and Prior Knowledge. The EBE session will present updates on the following concept papers: Drug Device Combination Products / A Biopharmaceutical Industry Perspective on the Control of Visible Particles in Biotechnologyderived Injectable Drug Products; Quality Aspects of Antibody Drug Conjugates; EMA Guideline Reflection Paper on Statistical Methodology for the Comparative Assessment of Quality Attributes in Drug Development; as well as the workshop topic: CAR-T Cell Therapy. The CMC Strategy Forum is designed to maximize dialog between participants. Presentations are relatively short and focused and set the agenda for the panel discussions to engage all the participants who have experience and expertise to share. It should be important for you to attend this event as we come together to discuss important issues on how to ensure product safety and efficacy for the patients we serve. We would like to thank the speakers and panel members 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; Eli Lilly and Company; F. Hoffmann-La Roche Ltd.; IPSEN Biopharm Ltd.; MedImmune, A member of the AstraZeneca Group; MSD; Novo Nordisk A/S and Pfizer, Inc. We are grateful for the expert management from CASSS and the audio-visual expertise of Michael Johnston from MJ Audio-Visual Productions. Their experience and guidance in the preparation of this Forum has been invaluable.

2 ACKNOWLEDGEMENTS CMC STRATEGY FORM EUROPE PROGRAM COMMITTEE Michael Abernathy, Amgen Inc., USA Sandra Patricia Auguste-Bowler, Lundbeck Pharma A/S, Denmark Seán Barry, HPRA-Health Products Regulatory Authority, Ireland (Co-chair) Brigitte Brake, BfArM-Federal Institute for Drugs and Medical Devices, Germany Emmanuelle Charton, EDQM, Council of Europe, France Niklas Ekman, Finnish Medicines Agency, Finland Chana Fuchs, CDER, FDA, USA Ralf Gleixner, Ares Trading SA, An affiliate of Merck Serono, Switzerland Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland (Co-chair) Brendan Hughes, Bristol-Myers Squibb Company, USA Ronald Imhoff, Janssen Biologics BV, Netherlands (Co-chair) Alistair Kippen, IPSEN Biopharm Ltd., United Kingdom Ingrid Markovic, CBER, FDA, USA Jens Bjørn Nielsen, Novo Nordisk A/S, Denmark Fionnuala O Driscoll, Eli Lilly Kinsale Limited, Ireland Bridgett O Shea, Pfizer Ireland Pharmaceuticals Limited, Ireland Ilona Reischl, AGES-Austrian Agency for Health and Food Safety, Austria Tara Sanderson, UCB Pharma Ltd., United Kingdom Mark Schenerman, CMC Biotech-MAS Consulting, USA Martin Schiestl, Sandoz Biopharmaceuticals, Austria Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland R.M. (Martijn) van der Plas, CBG-MEB, Netherlands CMC STRATEGY FORUM GLOBAL STEERING COMMITTEE Siddharth Advant, Celgene Corporation, USA Daniela Cerqueria, 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 Anthony Mire-Sluis, AstraZeneca., USA Wassim Nashabeh, F. Hoffmann-La Roche Ltd., Switzerland (Chair) Ilona Reischl, AGES-Austrian Agency for Health and Food Safety, Austria Anthony Ridgway, Health Canada, Canada Nadine Ritter, Global Biotech Experts, LLC, USA Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Mark Schenerman, CMC Biotech-MAS Consulting, USA Karin Sewerin, BioTech Development AB, Sweden

3 The Scientific Organizing Committee gratefully acknowledges the program partners for their generous support of the CMC Strategy Forum Europe STRATEGIC DIAMOND PROGRAM PARTNER F. Hoffmann-La Roche Ltd. 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. SILVER PROGRAM PARTNERS Bristol-Myers Squibb Company BRONZE PROGRAM PARTNER IPSEN Biopharm Ltd.

4 The Scientific Organizing Committee gratefully acknowledges the following media for their promotional consideration of the CMC Strategy Forum Europe series. LEADING MEDIA PARTNERS BioProcess International International Pharmaceutical Quality MEDIA PARTNERS BioProcessing Journal Genetic Engineering & Biotechnology News Technology Networks The Analytical Scientist The Pathologist UBM Life Sciences

5 Monday, 14 May 2018 EBE-European Biopharmaceutical Enterprises Satellite Session 06:30 10:30 Breakfast in Oriento Restaurant (Breakfast is included in the CMC Strategy Forum group sleeping room rate; other attendees / guests can pay individually for breakfast if they are not included in the group room rate) 07:30 12:00 Registration in the Wintertuin Foyer 08:30 08:45 Welcome and Introduction to the European Biopharmaceutical Enterprises (EBE) Ongoing Activities and Initiatives in Wintertuin Markus Goese, F. Hoffmann-La Roche Ltd. Concept Paper 2018 Updates In Wintertuin Session Chairs: Fionnuala O Driscoll, Eli Lilly Kinsale Limited and Saroj Ramdas, GlaxoSmithKline 08:45 09:00 EBE s Approach to Development of Concept / Position Papers Saroj Ramdas, GlaxoSmithKline, USA 09:00 09:10 An Overview of EBE Advocacy Work on Drug/Biologics-Device Combination Products Serge Mathonet, Sanofi R&D, France 09:10 09:20 Position Paper in Preparation: EBE Position Paper on Regulatory Control of Antibody Drug Conjugates Karoline Bechtold-Peters, Novartis Pharma AG, Switzerland (on behalf of EBE Industry Consortium) 09:20 09:30 EMA Draft Reflection Paper on Statistical Methodology for the Comparative Assessment of Quality Attributes in Drug Development Richard Keane, Biogen Idec Limited, United Kingdom 09:30 10:00 Panel Discussion Questions and Answers 10:00 10:30 Networking Break in the WintertuinFoyer

6 Monday, 14 May continued CAR-T Cell Therapy Workshop In Wintertuin Session Chairs: Fionnuala O Driscoll, Eli Lilly Kinsale Limited and Karoline Bechtold Peters, Novartis Pharma AG 10:30 10:45 Regulatory Aspects of CAR-T Cell Therapy Marcel Hoefnagel, Medicines Evaluation Board, Netherlands 10:45 11:00 Manufacturing Challenge of CAR-T Andrea Schilz, BioNTech Innovative Manufacturing Services, Germany 11:00 11:15 Autologous Cell Therapy Challenges and Opportunities in Manufacturing Sam Yaghmour, Amgen Inc., USA 11:15 11:30 Potency Assessment of Kymriah Cell Therapy Product Erik Rutjens, Novartis Pharmaceuticals Corporation, USA 11:30 12:00 Panel Discussion Questions and Answers Marcel Hoefnagel, Medicines Evaluation Board, Netherlands Erik Rutjens, Novartis Pharmaceutical Corporation, USA Andrea Schilz, BioNTech Innovative Manufacturing Services, Germany Heli Suila, Finnish Medicines Agency, Finland Sam Yaghmour, Amgen Inc., USA 12:00 12:15 Concluding Remarks Barbara Freischem, EBE-European Biopharmaceutical Enterprises, Belgium

7 Monday, 14 May continued CMC Strategy Forum Europe 2018 Scientific Program Summary 12:15 13:45 Buffet Lunch in Oriento Restaurant 13:15 17:00 Registration in the Wintertuin Foyer 13:45 14:00 CASSS Welcome and Introductory Comments in Wintertuin Nadine Ritter, Global Biotech Experts LLC Introduction / Welcome to the 12 th European CMC Strategy Forum Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland 14:00 14:15 Good Medicines Used Better Martijn van der Plas, Medicines Evaluation Board, Netherlands Regulatory Updates from the Around the World: Part One Plenary Session in Wintertuin Session Chairs: Niklas Ekman, Finnish Medicines Agency and Kowid Ho, F. Hoffmann-La Roche Ltd. 14:15 14:30 Ghana FDA and Harmonization of Medicines/Biologics in the ECOWAS Region Eric Karikari-Boateng, Food and Drugs Authority, Ghana 14:30 14:45 An Overview of the Regulation of Biotechnological and Biosimilar Products in Peru Ana Maria Chura Tito, DIGEMID-General Directorate of Medicines, Supplies and Drugs, Peru 14:45 15:00 The Highest Priorities for ANVISA in 2018 Kalinka de Melo Carrijo, ANVISA-Brazilian Health Regulatory Agency, Brazil 15:00 15:45 Panel Discussion Questions and Answers Kalinka de Melo Carrijo, ANVISA-Brazilian Health Regulatory Agency, Brazil Ana Maria Chura Tito, DIGEMID-General Directorate of Medicines, Supplies and Drugs, Peru Chana Fuchs, CDER, FDA, USA Veronika Jekerle, European Medicines Agency (EMA), United Kingdom Eric Karikari-Boateng, Food and Drugs Authority, Ghana Patrick Owusu-Danso, Food and Drugs Authority, Ghana Martijn van der Plas, Medicines Evaluation Board, Netherlands 15:45 16:15 Networking Break in the Wintertuin Foyer

8 Monday, 14 May continued Regulatory Updates from the Around the World: Part Two Plenary Session in Wintertuin Session Chairs: Niklas Ekman, Finnish Medicines Agency and Kowid Ho, F. Hoffmann-La Roche Ltd. 16:15 16:30 Between Biosimilars and PRIME: EMA s Report on Regulatory Trends and Priorities for Biopharmaceutical Products Veronika Jekerle, European Medicines Agency (EMA), United Kingdom 16:30 16:45 PMDA Update Takahiro Nakamura, PMDA-Pharmaceuticals and Medical Devices Agency, Japan 16:45 17:00 Regulatory Updates: CBER and OVRR Robin Levis, CBER, FDA, USA 17:00 18:00 Panel Discussion Questions and Answers Kalinka de Melo Carrijo, ANVISA-Brazilian Health Regulatory Agency, Brazil Veronika Jekerle, European Medicines Agency (EMA), United Kingdom Robin Levis, CBER, FDA, USA Takahiro Nakamura, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Martijn van der Plas, Medicines Evaluation Board, Netherlands 18:00 19:00 Networking Reception in the Wintertuin Foyer 19:00 Adjourn Day One

9 Tuesday, 15 May :30 10:30 Breakfast in Oriento Restaurant (Breakfast is included in the CMC Strategy Forum group sleeping room rate; other attendees / guests can pay individually for breakfast if they are not included in the group room rate) 08:00 17:00 Registration in the Wintertuin Foyer Adding to the Complexity Combining Drugs and Devices Workshop Session One in Wintertuin Session Chairs: Chana Fuchs, CDER, FDA and Ilona Reischl, AGES-Austrian Agency for Health and Food Safety 09:00 09:10 Introduction 09:10 09:35 Global Regulator and Industry Activities on Drug-Device Combination Products Focus on Europe Janine Jamieson, IPQ Publications, Sweden 09:35 10:00 Drug Device Products and the Impact of MDR Mark Chipperfield, Corvus Device Limited, United Kingdom 10:00 10:25 ISO 20069: Assessment & Evaluation of Changes to Drug Delivery Systems Paul Jansen, Board Member & Senior Advisor, Haselmeier; Board Member, Subcuject; and Chair Elect ISO TC84, USA 10:25 10:50 Experience with Notified Body Interactions for Drug Device Combination Products Tine Juul Zachariasen, Novo Nordisk A/S, Denmark 10:50 11:20 Networking Break in the Wintertuin Foyer 11:20 12:20 Panel Discussion Questions and Answers Elizabeth Baker, MHRA-Medicines and Healthcare Products Regulatory Agency, United Kingdom Mark Chipperfield, Corvus Device Limited, United Kingdom Janine Jamieson, JCombinations AB, Sweden Ann Jans, FAMPS-Federal Agency for Medicines and Health Products, Belgium Paul Jansen, Board Member & Senior Advisor, Haselmeier; Board Member, Subcuject; and Chair Elect ISO TC84, USA Peter Jongen, Medicines Evaluation Board, Netherlands Stephanie Horn, F. Hoffmann-La Roche Ltd., Switzerland Tine Juul Zachariasen, Novo Nordisk A/S, Denmark 12:30 14:00 Buffet Lunch in Oriento Restaurant

10 Tuesday, 15 May continued Clinical Relevance of Specifications Workshop Session Two in Wintertuin Session Chairs: Michael Abernathy, Amgen Inc. and Mark Schenerman, CMC Biotech-MAS Consulting 14:00 14:10 Introduction 14:10 14:35 Clinical Qualification of Specifications: A Regulator s View Mats Welin, Medical Products Agency, Sweden 14:35 15:00 The Yin and the Yang of Pre-clinical antigenicity and Immunogenicity Assessment Campbell Bunce, Abzena, United Kingdom 15:00 15:25 Studies on the Potential Immunogenicity of Attributes of Protein Aggregates Linda Narhi, Amgen Inc., USA 15:25 15:50 Immunogenicity of Protein Aggregates: Does Size Matter? Wim Jiskoot, Leiden University, Netherlands 15:50 16:20 Networking Break in the Wintertuin Foyer 16:20 17:20 Panel Discussion Questions and Answers Campbell Bunce, Abzena, United Kingdom Wim Jiskoot, Leiden University, Netherlands Robin Levis, CBER, FDA, USA Linda Narhi, Amgen Inc., USA Birgit Schmauser, BfArM- Federal Institute for Drugs and Medical Devices, Germany Jan Stracke, F. Hoffmann-La Roche Ltd., Switzerland Mats Welin, Medical Products Agency, Sweden 17:30 Adjourn Day Two 18:30 22:30 Off Property Networking Reception and Dinner Within walking distance from the hotel. Gallery Klooster Chapel and Church at Sea 18:30 19:30 Arrival / Reception 19:30 22:30 Dinner

11 Wednesday, 16 May :30 08:45 Breakfast in Oriento Restaurant (Breakfast is included in the CMC Strategy Forum group sleeping room rate; other attendees / guests can pay individually for breakfast if they are not included in the group room rate) 08:30 17:00 Registration in the Wintertuin Foyer Current and Future Approaches to Enhance Development, QbD and Design Spaces Workshop Session Three in Wintertuin Session Chairs: Brendan Hughes, Bristol-Myers Squibb Company and Martijn van der Plas, CBG- MEB 09:00 09:10 Introduction 09:10 09:35 Integrating Product and Process Knowledge and Control in Developing Vaccine Products Marta Germano, Janssen Vaccines, Netherlands 09:35 10:00 QbD for Biologics: Design Space, Testing Strategy and Lessons Learned Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland 10:00 10:25 From QbD to Control Strategy Mairead Looby, Bristol-Myers Squibb Company, Ireland 10:30 11:00 Networking Break in the Wintertuin Foyer 11:00 12:00 Panel Discussion Questions and Answers Koenraad Brusselmans, Scientific Institute of Public Health, Belgium Marta Germano, Janssen Vaccines, Netherlands Steffen Gross, Paul-Ehrlich-Institut, Germany Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland Veronika Jekerle, European Medicines Agency (EMA), United Kingdom Mairead Looby, Bristol-Myers Squibb Company, Ireland 12:00 13:30 Buffet Lunch in Beachclub O Restaurant

12 Wednesday, 16 May continued Prior Knowledge in CMC Submissions Moving the Conversation Forward Workshop Session Four in Wintertuin Session Chairs: Seán Barry, HPRA-Health Products Regulatory Authority and Ronald Imhoff, Janssen Biologics BV 13:30 13:40 Introduction 13:40 14:20 Summary of the 2017 EMA Workshop on Prior Knowledge and Its Use in Regulatory Applications Markus Goese, F. Hoffmann-La Roche Ltd., Switzerland Mats Welin, Medical Products Agency, Sweden 14:20 14:45 Modular Retrovirus Clearance in Support of Clinical Development Marie Murphy, Eli Lilly Kinsale Limited, Ireland 14:45 15:10 Use of Prior Knowledge in Shelf-life Setting for Vaccines in Clinical Development Jolanta Zamelczyk, Janssen Vaccines, Netherlands 15:15 15:45 Networking Break in the Wintertuin Foyer 15:45 16:45 Panel Discussion Questions and Answers Emmanuelle Charton, EDQM-Council of Europe, France Chana Fuchs, CDER, FDA, USA Brian Dooley, EMA-European Medicines Agency, United Kingdom Markus Goese, F. Hoffmann-La Roche Ltd., Switzerland Marie Murphy, Eli Lilly Kinsale Limited, Ireland Mats Welin, Medical Products Agency, Sweden Jolanta Zamelczyk, Janssen Vaccines, Netherlands 16:45 17:15 Forum Summary Nadine Ritter, Global Biotech Experts, LLC, USA 17:15 17:30 Closing Remarks and Invitation to CMC Strategy Forum Europe 2019 Ronald Imhoff, Janssen Biologics BV 17:30 Adjournment

13 EBE Satellite Session: Concept Paper 2018 Updates and CAR-T Cell Therapy Workshop EBE (European Biopharmaceutical Enterprises) of EFPIA has published a number of position papers and is currently progressing industry consensus activities on other key topics. The EBE session will initially reflect upon all of the concept/position papers that have been published to date and the value of these published papers. The benefit seen by companies in not only the use of the published papers but also participation in cross industry teams in the development of an Industry position on key topics. The contribution of these papers to prior knowledge concept will also be explored. An update will also be given on the position papers that have recently been published Drug Device Combination Products / A Biopharmaceutical Industry Perspective on the Control of Visible Particles in Biotechnology-Derived Injectable Drug Products and ongoing papers Quality Aspects of Antibody Drug Conjugate. Furthermore EBE also led a team focused on Industry feedback on the EMA guideline" Reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development. The session will include a presentation on the key aspects of the public consultation process and key outcomes of the joint EMA/Industry workshop of 3-4th May A subsequent session comprising of short presentations followed by a panel discussion will be dedicated to Chimeric Antigen Receptor-T (CAR-T) Cell Therapy. In recent years we have seen a rapidly emerging immunotherapy approach called Adoptive Cell Transfer (ACT) involving collection and use of patients own immune cells to treat cancer. There are several types of ACT but CAR-T cell therapy is the one that has advanced the furthest with the first commercial product approval in Initially Dr Marcel Hoefnagel of the Dutch National Agency will present on CAR-T cell therapy from regulator s perspective in EU with a particular focus on bioassay challenges associated with CAR-T products and a recent publication on this topic. Novartis will showcase their CAR-T platform and the recent Kymriah approval. EUFETS will talk on manufacturing challenges associated with CAR-T products from an SME perspective. The presentations will be followed by a panel discussion.

14 Concept Paper 2018 Updates Presenter s Abstracts Session Chairs: Fionnuala O Driscoll, Eli Lilly Kinsale Limited and Saroj Ramdas, GlaxoSmithKline EBE s Approach to Development of Concept / Position Papers Saroj Ramdas GlaxoSmithKline, USA Concept/position papers are intended to capture industry s perspective regarding key topics of interest. This session will introduce definitions of papers established by EBE and the step wise approach used to introduce a topic of interest and progression towards a published paper. A survey of current members regarding their experience with this process will be presented. The benefits seen by companies include the various uses of the published papers and participation in cross industry teams in the development of an Industry position on key topics. Going forward, how can industry utilize these papers to further engagement with regulators and the contribution of these papers to leverage prior/platform knowledge?

15 An Overview of EBE Advocacy Work on Drug/Biologics-Device Combination Products Serge Mathonet Sanofi R&D, France Industry is getting highly concerned about the impact of the entry into force in May 2020 of the new EU Medical Device Regulation (MDR), especially on the requirement for a Notified Body (NB) conformity assessment report for the device constituent of a drug-device combination (DDC) product. With the continued absence of any MDR implementing acts or guidance related to DDC products, understanding the proposed involvement of a NB remains a critical issue for manufacturers; having a defined scope, process and timing of such assessment is extremely important as it could have significant impact on the MAA review and approval timelines. Furthermore, NB re-accreditation is taking more time than originally expected, the very first date for the re-accreditation seems to be end July 2019 and only a limited of NB have applied for re-accreditation raising the concern of workload and availability for the few re-accredited NB S. In that context EBE published in January 2018 a broad reflection paper on Medicinal product incorporating a drug delivery device component: An Industry Perspective on the EU marketing application technical requirements, regulatory review process and post-approval device related change assessment and is finalizing a focused position paper to be entitled An Industry Perspective on Article 117 of the EU Medical Device Regulation and the Impact on how Medicines are assessed. Aside regulatory matters, EBE has also a technical focus and is developing a new position paper to be entitled An Industry Perspective on developing an efficient, End To End, Control Strategy aimed to be a companion piece to the broader reflection paper published in January 2018 which addressed Module 3 dossier content strategy for a DDC case study. The presentation will give a brief overview of key EBE proposals and asks reflected on those position papers.

16 Position Paper in Preparation: EBE Position Paper on Regulatory Control of Antibody Drug Conjugates Karoline Bechtold-Peters Novartis Pharma AG, Switzerland (on behalf of EBE Industry Consortium) Antibody drug conjugates are more complex in comparison to unconjugated therapeutic antibodies and require additional analytical characterization. In addition, the process chain consists of several components and intermediates, the naked antibody, a bifunctional linker, the toxin, the toxin-linker construct, which must also be suitably analyzed and characterized. However, it is important to define the respective analytical methods based on scientific understanding in order to avoid redundant or irrelevant measurements. Similarly, progress in conjugation technology should be taken into account, such as sitespecific conjugation compared to stochastic conjugation. Finally, a distinction should be made between characterization methods for process development and those for the release. At this point, the authors note that regulatory authorities sometimes expect such redundant analyzes or even specifications on nonrelevant parameters, such as specifying traces of non-conjugated antibodies. Another ADC unique consideration is the format of the dossier. There is no international uniform, where the information on the naked antibody, toxin and linker is to be placed within module 3. Furthermore, the views obviously differ between FDA and EMA, whether all information should be submitted in one file or in several files. This makes it difficult for the sponsors to create a globally suitable document. Instead the authors would like to propose to continue to allow flexibility in order to choose the most appropriate approach, be it one file or several files dependent on the specific situation. Finally changes in the small molecule parts of the ADC can be quite cumbersome in case the remaining processes downstream have to be addressed as well. Also, the authors would like to propose a risk-based approach regarding comparability assessment and the focus on the very part changed only. A case-study will illustrate the approach.

17 EMA Draft Reflection Paper on Statistical Methodology for the Comparative Assessment of Quality Attributes in Drug Development Richard Keane Biogen Idec Limited, United Kingdom This presentation will primarily describe the EBE biomanufacturing working party topic group activities to support the industry response to the EMA Draft Reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development (EMA/CHMP/138502/2017). This will include the steps taken to get a broad industry group together to comment on the paper as well as support the trade association attendance and case studies for the EMA workshop on this topic which took place 3 rd & 4 th May 2018.

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19 CAR-T Cell Therapy Workshop Presenter s Abstracts Session Chairs: Fionnuala O Driscoll, Eli Lilly Kinsale Limited and Karoline Bechtold Peters, Novartis Pharma AG Regulatory Aspects of CAR-T Cell Therapy Marcel Hoefnagel Medicines Evaluation Board, Netherlands In recent years there has been a rapid development in the field of genetically modified T cell products, with CAR-T cell therapy attracting most attention. As for all cell-based medicinal products the regulatory aspects are challenging, e.g. due to the inherent variability in the autologous starting material which makes control of manufacturing processes much more complex. The variability in starting material also leads to variability in final products. Therefore, quality control requires a full understanding of the impact of the different manufacturing steps on the phenotype and function of the cells in the final product. Thus, proper characterisation is imperative and should include the development of an appropriate potency (i.e. functionality) test. In vitro potency assay(s) for release of T cell medicinal products should reflect one or more of the cells relevant in vivo functions. However, developing an in vitro assay that is sufficiently representative of the mode of action is not always straightforward. In this presentation CMC-related regulatory aspects of genetically modified T cell products will be discussed with a focus on considerations for the development of potency assay for (CAR-)T cell products.

20 Manufacturing Challenge of CAR-T Andrea Schilz BioNTech Innovative Manufacturing Services, Germany The potential of CAR-T cell/gene therapy has generated considerable excitement in the last years due to the rates and duration of complete remission observed in patients with relapsed or refractory disease who had previously received multiple lines of treatment. As a consequence of the clinical successes, a number of CAR-T cell products have received breakthrough therapy designation from the FDA and some have already received approval. Meanwhile; CAR-T therapies are under investigation not only for hematological diseases but also for several solid tumor types. Each autologous CAR therapy is a cellular biologic that combines CAR gene constructs with an individual patient s T-cells. For off-the-shelf CAR-T cell therapies, the endogenous T-cell receptor needs to be knocked-out, putting even more complexity to the cell sourcing and manufacturing. A T-cell therapy manufacturing process presents economic, logistical, quality and safety issues that have to be fully addressed during process development. Moving from an academic-stage to a commercially viable manufacturing process means that high-quality cellular products must be consistently produced at reasonable cost of goods to meet demand over the commercial life of the product. This talk will focus on the different critical decision points during the establishment of a scientifically sound T-cell manufacturing process for CAR-T therapy.

21 Autologous Cell Therapy Challenges and Opportunities in Manufacturing Sam Yaghmour Amgen Inc., USA CAR-T cell therapy has resulted in remarkable responses in patients and offer the promise to revolutionize medicine. Yet, many challenges pertaining to manufacturing and product characterization remain to be overcome in order to achieve broad usage and commercialization of this therapeutic modality. The talk will summarize manufacturing challenges and consideration to ensure manufacturing reliably, safety, potency and cost-effectively of this promising therapy.

22 Potency Assessment of Kymriah Cell Therapy Product Erik Rutjens Novartis Pharmaceuticals Corporation, USA CTL019 cells are engineered T cells containing a chimeric antigen receptor (CAR) that recognizes cluster of differentiation 19 (CD19) which is a protein found exclusively on B cells. The extracellular domain of the CAR is linked to an intracellular signaling domain comprised of the T cell receptor CD3ζ signaling chain and a co-stimulatory domain derived from 4-1BB for optimal T cell activation. T-cells equipped with this CAR are capable of specifically recognizing CD19 expressing (tumor) cells, resulting in a T-cell response, involving cytokine secretion, proliferation and cytolysis of the CD19 expressing cells. As part of clinical development, several approaches to assess potency of the product were evaluated, leading to a variety of assays with different degrees of variability, as the active ingredient in our product are cells, which have intrinsic biological variability. Increasing experience and learnings about the product and assay have led to a robust release assay for commercial use as well as characterization data from other bioassays to support understanding of the product s mode of action. The commercial release assay was fully validated and contains numerous system suitability parameters to allow for continuous evaluation and control throughout the scale up of the numbers of products being tested, as well as increase in trained analysts, which can influence the performance of complex bioassays. Due to the vast variability of product, originating from patient-to patient differences in T-cell quality, broad ranges of results have been obtained in the clinical development stage, which made setting of specifications based on historical experience a challenging exercise. Despite the vast heterogeneity in regard to key product attributes such as T cell composition, activity and functional response, the product resulted in high rates of tumor remissions in both Pediatric ALL as well as in the adult DLBCL population.

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24 Regulatory Updates from Around the World: Part One Session Chairs: Niklas Ekman, Finnish Medicines Agency and Kowid Ho, F. Hoffmann-La Roche Ltd. This session will provide updates on regulatory trends for biotherapeutic products from regulators around the world. The first part of the journey will discuss regulatory trends and priorities in different regions of the globe, related to reliance and convergence.

25 Presenter s Abstracts Good Medicines Used Better Martijn van der Plas Medicines Evaluation Board, Netherlands Abstract was not available at the time of printing.

26 Ghana FDA and Harmonization of Medicines/Biologics in the ECOWAS Region Eric Karikari-Boateng Ghana Food and Drugs Authority (GFDA), Ghana Legislation, standards, policies and guidelines for the regulation of biologics in most African countries in general and in Sub-Sahara Africa in particular are either evolving or are yet to be established. The Ghana Food and Drugs Authority (GFDA) is the agency in Ghana mandated to regulate the safety, quality and efficacy of Medicines including Biologics as enshrined in the Public Health Act (581) In the last twenty (20) years, the GFDA has developed and implemented policies, standards and guidelines for the regulation of new biological products, biosimilars, vaccines, blood and blood products to assure their quality, safety and efficacy. Pathways for the registration, granting of market authorization and regulations for, inspections, market surveillance, conduct of clinical trials and pharmacovigilance have been defined and approved for new biological products, biosimilars, vaccines, blood and blood products. The GFDA has also been actively involved and continually supported the vision for the harmonization of the regulation of biologics in the Economic Community of West African States (ECOWAS) in the last five years. Currently, the Terms of Reference for the Steering Committee, Expert Working Groups and Governance Framework for the West African Medicines Regulatory Harmonization Programme has been documented, approved and accepted by all 15-member states in the region. The goal of this harmonization programme is to have harmonized and functioning medicines/biologics regulatory systems within the region in accordance with national and internationally recognized policies and standards and to encourage mutual recognition agreements among member states.

27 An Overview of the Regulation of Biotechnological and Biosimilar Products in Peru Ana Maria Chura Tito DIGEMID-General Directorate of Medicines, Supplies and Drugs, Peru The Ministry of Health of Peru is an entity of the Peruvian government responsible for the healthcare sector. The General Directorate of Medicines, Supplies and Drugs (DIGEMID) is a line agency of the Vice-ministerial Office of Public Health. It has four main direction, among them is the Directorate of Pharmaceutical Products, with the functions of authorizing the registration, re-registration, modification and cancellation of marketing authorization of pharmaceutical products. DIGEMID is a legal-technical institution whose main objective is to ensure that the population has access to safe, effective and quality medicines promoting its rational use. The Law of Pharmaceutical Products, Medical Devices and Sanitary Products N 29459, published in November 2009, guides the regulations of these products, establishing requisites to apply for the marketing authorization of pharmaceutical products that are necessary to guarantee their efficacy, safety and quality. The term pharmaceutical products includes Biological products. The regulation about Registration, Control and Health Surveillance of Pharmaceutical Products, Medical Devices and Health Products issued by Supreme Decree SA came into effect on January 23, This regulation defines specific aspects of Law N 29459; describes general requirements for marketing authorization of biological products: full data of quality, efficacy and safety; establishes classification for biological products and describes general requirements to submit and evaluate similar biological product based in WHO s recommendations. The Article 103 of Supreme Decree SA classifies biological products as follows: Immunological: Vaccines, Allergens and Serums; Blood and Plasma-derived Products; Biotechnological Product; and Other Biological Products The specific aspects of quality, preclinical and clinical studies requirements of biological products that opt for similarity pathway is established in Supreme Decree Nº SA, which is taking into account the progress of science and WHO recommendations. Currently, there are 478 biological products with marketing authorization. This regulation considers the following countries as authorities of high sanitary surveillance: France, Netherlands, United Kingdom, United States of America, Canada, Japan, Switzerland, Germany, Spain, Australia, Denmark, Italy, Norway, Belgium, Sweden, Republic of Korea, Portugal and Ireland.

28 The Highest Priorities for ANVISA in 2018 Kalinka de Melo Carrijo ANVISA-Brazilian Health Regulatory Agency, Brazil In 2010 Brazilian Health, Regulatory Agency - Anvisa published a new regulation for biological and biosimilar products RDC 55/2010. According this regulation there are two classes of biotherapeutic products: new biological products and biological products. New biological products are defined as innovative biological drugs, and biological products are the copy biological drugs or non-innovative biological products. The approval of new biological products follows the classical regulatory pathway and is based on a full registration dossier including a complete physical-chemical and biological characterization and non-clinical and clinical data. Otherwise, biological products can be licensed by the comparative regulatory pathway (biosimilar approach) or by the stand-alone approach. The comparative regulatory pathway requires a head-to-head comparison at the levels of quality, safety and efficacy to demonstrate that the product and the comparator biological (reference biological product) have similar profiles, proving that there are no significant differences between them. The comparative analysis comprises quality, non-clinical and reduced clinical data, and may allow extrapolation to other indications. A product licensed by the comparative pathway is called biosimilar. In the stand-alone approach the applicant needs to present complete data regarding quality issues but these data do not have to be comparative. For the license by the stand-alone pathway, the comparative Phase III study with the innovator biological product is mandatory. Extrapolation of indications is not accepted in the stand-alone approach. Brazilian regulation for biological and biosimilar products is aligned with WHO guidelines. Regardless of the regulatory pathway chosen to license a biological product in Brazil, RDC 55/2010 requires proof of quality, safety and efficacy of all products. At the end of 2017, Anvisa has launched some regulation to speed up the analyses and easier the access of the Brazilian population to biological products. Since 2015, Anvisa is a Regulatory Member of ICH, and the highest priority for the coming years is improving harmonization of the Regulation with The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

29 Regulatory Updates from Around the World: Part One Panel Discussion Panel Members: Kalinka de Melo Carrijo, ANVISA-Brazilian Health Regulatory Agency, Brazil Ana Maria Chura Tito, DIGEMID-General Directorate of Medicines, Supplies and Drugs, Peru Chana Fuchs, CDER, FDA, USA Veronika Jekerle, European Medicines Agency (EMA), United Kingdom Eric Karikari-Boateng, Food and Drugs Authority, Ghana Patrick Owusu-Danso, Food and Drugs Authority, Ghana Martijn van der Plas, Medicines Evaluation Board, Netherlands The following questions will guide the discussion: Reliance and a Regulatory Pathway: o Opportunities for regulatory convergence related to biologic products? o Opportunities for accelerate approval and/or access of new therapies? o What activities are planned in terms of new guidelines development or implementation of existing ones (e.g. ICH, WHO ) o Status regarding putlication and implementation of variation of guidelines? Timelines? Agencies concerns, issues, priorities, goals and projects for 2020?

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31 Regulatory Updates from Around the World: Part Two Session Chairs: Niklas Ekman, Finnish Medicines Agency and Kowid Ho, F. Hoffmann-La Roche Ltd. This session will provide updates on regulatory trends for biotherapeutic products from regulators around the world. The second part will focus on the current regulatory trends in the US, Japan and EU.

32 Presenter s Abstracts Between Biosimilars and PRIME: EMA s Report on Regulatory Trends and Priorities for Biopharmaceutical Products Veronika Jekerle European Medicines Agency (EMA), United Kingdom In Europe, Biotechnologically-derived products and their Biosimilars, which fall within the mandatory scope of the centralized procedure (according to Annex of Regulation 726/2004) are reviewed by CHMP s specialist working party on Biologicals, the Biological Working Party (BWP). This includes ATMPs and Vaccines obtained from recombinant DNA technology. In this presentation the experience of the BWP representative of the Agency s current trends in early development, scientific advice and marketing authorisation across biological products is discussed. Current trends such as PRIME, Biosimilars or antibody-drug conjugates are reviewed, and examples illustrated. Innovative approaches to accelerated development of candidate products such as flexibility around process validation, prior knowledge or extrapolation on stability are explored. In addition, the perspective on scientific trends, challenges and priorities in the development and manufacture of biopharmaceuticals is discussed with close reference to the BWP workplan. Opportunities for stakeholder interactions with the BWP are highlighted. Finally, the Agency s involvement in regulatory convergence and global harmonisation including ICH Q12 and others (international pharmaceutical regulator s forum) are mentioned.

33 PMDA Update Takahiro Nakamura PMDA-Pharmaceuticals and Medical Devices Agency, Japan Topics of this presentation are as follows: New Guideline for Post-approval CMC Changes When the marketing authorization holder changes the description in the Application Form, the legally binding document regarding indication, dosage and administration, process, specifications etc., the postapproval regulatory procedure is required. For appropriate changes of approved matters as well as facilitating transparency and flexibility in terms of post-approval process changes, new guidelin for postapproval CMC changes has been released. In this topic, the overview of this guideline will be presented. Biosimilars Brief introduction and updates on approved biosimilars in Japan will be provided in this topic. Accelerated Programs Since 2017, a new accelerated program, conditional early approved system, has been executed in order to facilitate development of pharmaceuticals targeting serious and life-time threatening diseases. In this topic, the framework of this system will be provided. Furthermore, the overview of other accelerated programs, priority review and Sakigake designation system, as well as the update of product designated product under Sakigake will be also presented.

34 Regulatory Updates: CBER and OVRR Robin Levis CBER, FDA, USA The Center for Biologics Evaluation and Research has a wide variety of regulatory responsibilities for a diverse number of biological products. Review and support of these products is performed within eight Offices located within the Center. Each Office makes a distinct and critical contribution to the review of FDA regulated biological products. In addition to review activities associated with the development (IND) and licensure (BLA) of biological products, the Center engages in many domestic and global public health and regulatory activities. This presentation will include highlights of Center-wide regulatory initiatives and will review specific CMC related activities in the Office of Vaccines Research and Review.

35 Regulatory Updates from Around the World: Part Two Panel Discussion Panel Members: Kalinka de Melo Carrijo, ANVISA-Brazilian Health Regulatory Agency, Brazil Veronika Jekerle, European Medicines Agency (EMA), United Kingdom Robin Levis, CBER, FDA, USA Takahiro Nakamura, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Martijn van der Plas, Medicines Evaluation Board, Netherlands The following questions will guide the discussion: Agencies concerns, issues, priorities, goals and projects for 2020? Update on Brexit Update on ICH activities and topics? Q12 update?

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37 Adding to the Complexity Combining Drugs and Devices Workshop Session One Session Chairs: Chana Fuchs, CDER, FDA and Ilona Reischl, AGES-Austrian Agency for Health and Food Safety In Europe, different legal frameworks regulate the path to market for medicinal products and medical devices. Challenges exist for development and regulatory control when both regulatory frameworks need to be considered for products that combine medicinal product and medical device aspects. While the term combination product is anchored in the US legislation, this is not the case in Europe, where the principal mechanism of action determines the path to the market. Equally, there is a more complex approach for the development of products that need to combine the use of medicinal products and medical devices, for example in the case of companion diagnostics. While the Clinical Trials Regulation (REG/2014/536/EC) has been published for some time, the practical application is still awaiting the finalization of programming of the EU portal to facilitate submission. A similar portal is foreseen for the recently published Medical Device and In-vitro-diagnostics Regulations (REG/2017/745/EC and REG/2017/746/EC respectively). Developers and regulatory agencies have 3 years to implement the new requirements which include new modes of interaction for competent authorities and notified bodies. This session will provide insight into the new requirements and ongoing discussions and will explore the pending procedure in the context of biologics. Case studies, best practices and pitfalls, and regulatory expectations for products combining drug and device aspects will be presented.

38 Presenter s Abstracts Global Regulator and Industry Activities on Drug-Device Combination Products Focus on Europe Janine Jamieson IPQ Publications, Sweden As the number and complexity of medicinal products incorporating integral delivery device components increases in particular for biological products the regulatory focus on these combination products is also increasing. Demonstration of appropriate design and controls for safety and performance of the device component is expected, in addition to information on compatibility with the drug component and accuracy of dosing. This presentation will explain the background to the evolution of drug/device combination product (DDCP) regulations in different jurisdictions, including the US, where there is a legal definition for combination products and the FDA Office of Combination Products has published a number rules and guidances over recent years. In Europe, where such combination products are regulated either as medicines or as medical devices in quite distinct regulatory pathways, assessment of often quite complex device components is currently within the remit of medicines Competent Authorities. The EMA Quality Working Party and Biologics Working Party communicated in a recent concept paper their intent to develop a guideline on quality aspects of dossier requirements for DDC products to show that they have been appropriately designed and controlled and can be used correctly in the intended use situations. At the same time, the new Medical Device Regulation (MDR) coming into force in May 2020 will amend EU medicines legislation to require review of integral device components by third party conformity assessment Notified Bodies. The background to, and significant impact of, Article 117 of the MDR will be discussed as an introduction to the following presentations. Whilst guidance on EMA expectations and the new procedure for NB review is awaited, a collaborative group of interested parties led by the European Biopharmaceutical Enterprises (EBE) working group on DDCs is developing proposals based on current EU guidance, industry best practice and their collective experience of interactions with regulatory bodies. The EBE DDG working group published a reflection paper with thematic mirroring of the scope of the EMA concept paper, and also covering the Medical Devices Regulation, in an effort to encourage discussion between industry and regulatory bodies on the identified issues. The reflection paper will be presented in the EBE satellite session and discussed further in this presentation, including proposals for how the review by Notified Body could work in practice, within an MAA procedure.

39 Drug Device Products and the Impact of MDR Mark Chipperfield Corvus Device Limited, United Kingdom A brief look at the complex set of configurations making up drug-device combinations. The integration of the different development concepts at play in drug and device development will be highlighted, before a closer look at some of the areas needing consideration when applying the MDR.

40 ISO 20069: Assessment & Evaluation of Changes to Drug Delivery Systems Paul Jansen Board Member & Senior Advisor, Haselmeier; Board Member, Subcuject; and Chair Elect ISO TC84, USA In practice there is a considerable and significant variability as to how companies manage changes to drug delivery systems. Existing tools and processes including risk management do not appear to be informing decision making. ISO when published will provide guidance to assess and evaluate changes to drug delivery systems throughout their lifecycles. In particular, it focuses on changes to the drug delivery system from entry into pivotal or registration clinical studies through the end of commercial supply. The core of the document is the process flow, which guides an organization through a risk-based evaluation based on primary sources of change to the drug delivery system design, manufacturing process and the labelling & user interface. Changes are evaluated through the risk assessment of how the change could impact system form, fit and function (including medicinal product flow paths) such that users are not negatively impacted in terms of quality, safety and effectiveness, or use of the drug delivery system. Given that a single change may affect more than one of the primary change types (e.g., a material change may also drive a process change), all change types should be comprehensively assessed and evaluated. The process can be applied to multiple product lifecycle stages, including design and development, production, storage and distribution, installation, servicing and final decommissioning/disposal of the drug delivery system or associated activities (e.g. up-dating of software). It can also be used by an organization's suppliers and external parties (e.g. raw materials, components, subassemblies, medical devices, sterilization services, calibration services, distribution services, maintenance services). ISO provides guidance on the how and what. This standard works well with ICH Q12 which provides guidance on what to submit (or if to submit) to regulatory agencies.

41 Experience with Notified Body Interactions for Drug Device Combination Products Tine Juul Zachariasen Novo Nordisk A/S, Denmark Under the current legislation, if the device and the medicinal product form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single product shall be governed by Directive 2001/83/EC. The relevant essential requirements of Annex I of the Medical Device Directive shall however apply as far as safety and performance-related device features are concerned. It is the responsibility of the Competent Authority/ European Medicines Agency to review information and data relating to the device constituent part of single integral product (e.g. prefilled pens) as part of the medicinal application. With the new EU Medical Device Regulation 2017/745 (article 117) an important amendment is introduced to the medicinal legislation (Directive 2001/83/EC). This amendment introduces the requirement for a notified body opinion for the device constituent part of drug-device combination products to be part of the drug registration file. In Novo Nordisk A/S the Quality Management System fulfils the requirements for both drug cgmp and Annex II of the Medical Device directive. For devices, the quality management system covers both the development of stand-alone devices and the device constituent part of a drug-device combination product to ensure that products comply to Annex I. Novo Nordisk has for a number of years engaged with a notified body for a third party review of the relevant safety and performance requirement of Annex I in relation to the device constituent part of the Drug-device combination product. This presentation will give an insight into the process for the interaction with the notified body, the reporting of the review and how the assessment result have been implemented in the drug registration file.