Welcome to the CMC Strategy Forum Europe 2016 The 10th annual CMC Strategy Forum Europe, organized by CASSS, will explore a number of 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; ICH Q12 Update: Established Conditions / Approved Matters; The Evolution of Post-approval Change Protocols in Biopharmaceutical Lifecycle Management; Innovative Approaches: Tools and Technology; Regulatory and Scientific Challenges of Combination Product Development and Leveraging Continuous Process Verification to Facilitate Faster Patient Access. The EBE session will present updates on the following concept papers: Antibody Drug Conjugates; Management and Control of Raw Materials; Drug Device Combination Products, as well as the workshop topic Medicines Adaptive Pathways to Patients Initiative. 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: AbbVie, Inc.; Amgen Inc.; Biogen, Bristol-Myers Squibb Company; Eli Lilly and Company; F. Hoffmann-La Roche Ltd.; IPSEN Biopharm; MedImmune, A member of the AstraZeneca Group; Merck & Co., Inc.; Novo Nordisk A/S, Pfizer, Inc. and Sanofi Pasteur. 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.

ACKNOWLEDGEMENTS CMC STRATEGY FORM EUROPE SCIENTIFIC ORGANIZING COMMITTEE Brigitte Brake, Federal Institute for Drugs and Medical Devices (BfArM), Germany Emmanuelle Charton, EDQM, Council of Europe, France Brian Corrigan, Pfizer Ireland Pharmaceuticals Limited, Ireland John Dougherty, Eli Lilly and Company, USA Niklas Ekman, Finnish Medicines Agency, Finland Chana Fuchs, CDER, FDA, USA Ralf Gleixner, Ares Trading SA, An affiliate of Merck Serono, Switzerland Jason Hampson, Amgen Inc., USA Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland Brendan Hughes, Bristol-Myers Squibb Company, USA Ronald Imhoff, Janssen Biologics BV, The Netherlands Alistair Kippen, IPSEN Biopharm Ltd., United Kingdom (Co-chair) Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark (Co-chair) Ingrid Markovic, CBER, FDA, USA Serge Mathonet, Sanofi Pasteur, France Jens Bjørn Nielsen, Novo Nordisk A/S, Denmark Ilona Reischl, AGES-Austrian Agency for Health and Food Safety, Austria Mark Schenerman, MedImmune, A member of the AstraZeneca Group, USA Martin Schiestl, Sandoz Biopharmaceuticals, Austria Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Karin Sewerin, BioTech Development AB, Sweden Lance Smallshaw, UCB Biopharma sprl, Belgium Jolanda Westerlaken, UCB Pharma SA, Canada (Co-chair) Pierrette Zorzi, Consultant, France CMC STRATEGY FORUM GLOBAL STEERING COMMITTEE Siddharth Advant, KemWell Biopharma, USA Daniela Cerqueria, ANVISA-Brasilian National Health Surveillance Agency, Brasil John Dougherty, Eli Lilly and Company, USA Steven Kozlowski, CDER, FDA, USA Junichi Koga, Daiichi Sankyo Co., Ltd., Japan Rohin Mhatre, Biogen, USA Anthony Mire-Sluis, Amgen Inc., 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 Daisaku Sato, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Mark Schenerman, MedImmune, A member of the AstraZeneca Group, USA Karin Sewerin, BioTech Development AB, Sweden

The Scientific Organizing Committee gratefully acknowledges the program partners for their generous support of the CMC Strategy Forum Europe 2016:

SUSTAINING DIAMOND PROGRAM PARTNER F. Hoffmann-La Roche Ltd. SUSTAINING PLATINUM PROGRAM PARTNERS AbbVie, Inc. Biogen MedImmune, A member of the AstraZeneca Group SUSTAINING GOLD PROGRAM PARTNERS Novo Nordisk A/S Pfizer, Inc. SUSTAINING SILVER PROGRAM PARTNER Merck & Co., Inc. GOLD PROGRAM PARTNER Sanofi Pasteur SILVER PROGRAM PARTNERS Amgen Inc. Eli Lilly and Company BRONZE PROGRAM PARTNERS Bristol-Myers Squibb Company IPSEN Biopharm Ltd.

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

The Analytical Scientist BioProcessing Journal Chemical Communications Chemical Society / Chemical Society Reviews Genetic Engineering & Biotechnology News The Medicine Maker The Pathologist separationsNOW.com Technology Networks

European Biopharmaceutical Enterprises (EBE) Satellite Session Monday, 9 May 2016 06:30 – 08:30

Breakfast in R’Yves 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 Forum Foyer, Level 1

08:30 – 08:45

Welcome and Introduction to the European Biopharmaceutical Enterprises (EBE) Ongoing Activities and Initiatives in the Forum Rooms E-J Markus Goese, F. Hoffmann-La Roche Ltd., Switzerland

Concept Paper 2016 Update: New Initiatives In the Forum Rooms E-J Session Chairs: Ronald Imhoff, Janssen Biologics BV and Karin Sewerin, MedImmune Limited (consultant) 08:45 – 09:00

Antibody Drug Conjugates Fred Jacobson, Genentech, a Member of the Roche Group, USA

09:00 – 09:15

Management and Control of Raw Materials Annick Gervais, UCB Pharma sprl, Belgium

09:15 – 09:30

Learnings from EBE Cross-industry Informational Sharing Session on Development and Licensing of Biologics/Device Combination Products Serge Mathonet, Sanofi R&D, France

Medicines Adaptive Pathways to Patients (MAPPs) Initiative Workshop In the Forum Rooms E-J Session Chairs: Ronald Imhoff, Janssen Biologics BV and Karin Sewerin, MedImmune Limited (consultant) 09:30 – 09:45

Introduction to CMC Challenges and Opportunities for MAPPs / Accelerated Pathways Ronald Imhoff, Janssen Biologics BV, The Netherlands

09:45 – 10:00

Use of Prior Knowledge in Applications Mats Welin, Medical Products Agency, Sweden

10:00 – 10:30

Networking Break in the Forum Foyer, Level 1

Monday, 9 May continued… Use of Prior Knowledge Panel Presentations and Discussion In the Forum Rooms E-J Session Chairs: Ronald Imhoff, Janssen Biologics BV and Karin Sewerin, MedImmune Limited (consultant) 10:30 – 11:45

Panel Discussion – Questions and Answers Ciro Cottini, Chiesi Pharmaceutici S.p.A., Italy Earl Dye, Genentech, a Member of the Roche Group, USA Chana Fuchs, CDER, FDA, USA Alistair Kippen, IPSEN Biopharm Ltd., United Kingdom Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Scott Tobler, Merck & Co., Inc., USA Mats Welin, Medical Products Agency, Sweden

10:30 – 10:55

Prior Knowledge in Drug Substance Process Validation Earl Dye, Genentech, a Member of the Roche Group, USA

10:55 – 11:20

Prior Knowledge in Establishing Control Strategy Alistair Kippen, IPSEN Biopharm Ltd., United Kingdom

11:20 – 11:45

Drug Product Modeling in Scale-up and Transfer of Lyophilization Processes Ciro Cottini, Chiesi Pharmaceutici S.p.A., Italy

11:45 – 12:00

Concluding Remarks Barbara Freischem, European Biopharmaceutical Enterprises (EBE), Belgium

Monday, 9 May continued… CMC Strategy Forum Europe 2016 Scientific Program Summary 12:00 – 13:30

Buffet Lunch in Loft AD, Third Floor

13:00 – 17:00

Registration in the Forum Foyer, Level 1

13:30 – 13:45

CASSS Welcome and Introductory Comments in the Forum Rooms E-J Wassim Nashabeh, F. Hoffmann-La Roche Ltd., Switzerland Introduction / Welcome to the 10th European CMC Strategy Forum Jolanda Westerlaken, UCB Pharma SA, Canada Opening / Keynote Plenary Session in the Forum Rooms E-J Session Chair: Serge Mathonet, Sanofi R&D

13:45 – 14:30

France’s Attractiveness for the Biopharma Industry: Global Ecosystem Competitiveness Clusters Claude-Alain Cudennec, AFSSI Life Sciences, France Manuel Gea, ADEBIOTECH and Bio-Modeling Systems, France

14:30 – 14:35

Transition

Regulatory Updates from Around the World Plenary Session in the Forum Rooms E-J Session Chairs: Nanna Aaby Kruse, Danish Health and Medicines Authority and Jolanda Westerlaken, UCB Pharma SA 14:35 – 15:00

Regulatory Updates from the EU Seán Barry, Health Products Regulatory Authority (HPRA), Ireland

15:00 – 15:25

PMDA Updates: Approach to Making much Further Progress Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan

15:25 – 15:50

Regulatory Updates for Biopharmaceutical Products: FDA Perspective Sarah Kennett, CDER, FDA, USA

15:50 – 16:15

Networking Break in the Forum Foyer, Level 1

Monday, 9 May continued… 16:15 – 17:30

Panel Discussion – Questions and Answers Seán Barry, Health Products Regulatory Authority (HPRA), Ireland Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Sarah Kennett, CDER, FDA, USA Robin Levis, CBER, FDA, USA Anthony Ridgway, Health Canada, Canada Pascal Venneugues, European Medicines Agency (EMA), United Kingdom

17:30 – 18:00

Networking Break

Leveraging Continuous Process Verification to Facilitate Faster Patient Access Update Session in the Forum Rooms E-J Session Chairs: Ralf Gleixner, Ares Trading SA, An affiliate of Merck Serono and Jason Hampson, Amgen Inc. 18:00 – 18:05

Introduction

18:05 – 18:25

PPQ-to-Filing Timelines - Acceleration Approaches at BMS Marcus Boyer, Bristol-Myers Squibb Company, USA

18:25 – 18:45

Continuous Process Verification of Next Generation Processes Utilizing Advanced Process Control (APC) Rohin Mhatre, Biogen, USA

18:45 – 19:05

Process Validation and Adaptive Pathways Martijn van der Plas, Medicines Evaluation Board (MEB), The Netherlands

19:05 – 19:35

Panel Discussion – Questions and Answers Marcus Boyer, Bristol-Myers Squibb Company, USA Niklas Ekman, Finnish Medicines Agency, Finland Rohin Mhatre, Biogen, USA Martijn van der Plas, Medicines Evaluation Board (MEB), The Netherlands

19:35

Adjourn Day One Participants on their own

Tuesday, 10 May 2016 06:30 – 08:45

Breakfast in R’Yves 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 Forum Foyer, Level 1

08:45 – 09:00

Announcements by Jolanda Westerlaken, UCB Pharma SA

09:00 – 09:15

ICH Q12 – Challenges, Opportunities…and More Challenges Anthony Ridgway, Health Canada, Canada

ICH Q12 Update: Established Conditions / Approved Matters Workshop Session One in the Forum Rooms E-J Session Chairs: Brian Corrigan, Pfizer Ireland Pharmaceuticals Limited and Ronald Imhoff, Janssen Biologics BV 09:15 – 09:40

Established Conditions - Concepts and Updates from Expert Working Group Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark

9:40 – 10:05

Industry Perspective on ICH Q12 Progress and Direction Frank Montgomery, Astra Zeneca, United Kingdom

10:05 – 10:30

Filing Established Conditions and Life-cycle Management of a Bioprocess Christine Mitchell-Logean, UCB Pharma sprl, Belgium

10:30 – 10:55

Preparing Implementation of Established Conditions Principles: Regulatory Approach Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland

11:00 – 11:30

Networking Break in the Forum Foyer, Level 1

11:30 – 12:45

Panel Discussion – Questions and Answers Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland Sarah Kennett, CDER, FDA, USA Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark Christine Mitchell-Logean, UCB Pharma sprl, Belgium Frank Montgomery, AstraZeneca, United Kingdom Anthony Ridgway, Health Canada, Canada

12:45 – 14:15

Buffet Lunch in Loft AD, Third Floor

Tuesday, 10 May continued… The Evolution of Post-approval Change Protocols in Biopharmaceutical Lifecycle Management Workshop Session Two in the Forum Rooms E-J Session Chairs: John Dougherty, Eli Lilly and Company and Anthony Ridgway, Health Canada 14:15 – 14:40

The Use of Comparability Protocols for Biologics: An Effective Tool to Manage Post-approval Changes Robin Levis, CBER, FDA, USA

14:40 – 15:05

Post-approval Safety Surveillance Studies to Support Biopharmaceutical Changes John Ayres, Eli Lilly and Company, USA

15:05 – 15:30

Experience of Post-approval Change Management Protocols in the EU Mats Welin, Medical Products Agency, Sweden

15:30 – 15:55

Improving Post-approval Change Processes as a Way to Ensure Technical Innovation and Drug Product Availability Anders Vinther, Sanofi Pasteur, USA

16:00 – 16:30

Networking Break in the Forum Foyer, Level 1

16:30 – 17:45

Panel Discussion – Questions and Answers John Ayres, Eli Lilly and Company, USA Mairead Duke, BioMarin Europe Ltd., United Kingdom Markus Goese, F. Hoffmann-La Roche Ltd., Switzerland Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Robin Levis, CBER, FDA, USA Anders Vinther, Sanofi Pasteur, USA Mats Welin, Medical Products Agency, Sweden

17:45

Adjourn Day Two

18:30 – 23:00

Dinner Cruise on the River Seine ‘PAVILLON SEINE’, Escale Trocadéro Debilly, Paris The boat will leave the port at 19:30; please be there in time for departure. Included in the registration fee; an additional fee is required for guests and one-day registrants.

Wednesday, 1 May 2016 06:30 – 08:45

Breakfast in R’Yves 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 Forum Foyer, Level 1

08:45 – 09:00

Announcements by Alistair Kippen, IPSEN Biopharm Ltd.

Regulatory and Scientific Challenges of Combination Product Development Workshop Session Three in the Forum Rooms E-J Session Chairs: Chana Fuchs, CDER, FDA and Ilona Reischl, AGES-Austrian Agency for Health and Food Safety 09:00 – 09:05

Introduction

09:05 – 09:30

Regulatory Challenges of Drug Device Combination Products in the EU Janine Jamieson, Medicines & Healthcare Products Regulatory Agency (MHRA), United Kingdom

09:30 – 09:55

Regulatory Challenges of Developing a Combination Product in a Globalised World – An Industry Perspective Tim Chesworth, AstraZeneca, United Kingdom

09:55 – 10:20

Considerations for Control Strategies for mAb/mAB Combination Therapies - An Industry Perspective Dieter Schmalzing, Genentech, a Member of the Roche Group, USA

10:20 – 10:45

Science-based Development & Licensing of Combination Products – Focus on High Concentration Monoclonal Antibody Solutions in Prefilled Syringes or Prefilled Pens Deborah (Debbie) Thomas, Sanofi Pasteur, USA

10:45 – 11:15

Networking Break in the Forum Foyer, Level 1

11:15 – 12:30

Panel Discussion – Questions and Answers Tim Chesworth, AstraZeneca, United Kingdom Janine Jamieson, Medicines & Healthcare Products Regulatory Agency (MHRA), United Kingdom Dieter Schmalzing, Genentech, a Member of the Roche Group, USA Deborah (Debbie) Thomas, Sanofi Pasteur, USA Shayesteh Fürst Ladani, SFL Regulatory Affairs & Scientific Communication Ltd., Switzerland

Wednesday, 11 May continued… 12:30 – 14:00

Buffet Lunch in Loft AD, Third Floor

Innovative Approaches: Tools and Technology Workshop Session Four in the Forum Rooms E-J Session Chairs: Emmanuelle Charton, EDQM, Council of Europe and Alistair Kippen, IPSEN Biopharm Ltd. 14:00 – 14:05

Introduction

14:05 – 14:30

Viral Safety Testing of Vaccines and Other Biological Products: A Change of Paradigm Laurent Mallet, Sanofi Pasteur, France

14:30 – 14:55

Benefits of an Innovative Multi‐attribute Method in Attribute Focused Process and Product Development Jette Wypych, Amgen Inc., USA

14:55 – 15:20

The Power of Data to Accelerate Development of Robust, Scalable Manufacturing Processes Susan Abu-Absi, Bristol-Myers Squibb Company, USA

15:20 – 15:45

A Regulatory Assessor’s Perspective on Novel Analytical Techniques Peter Jongen, Medicines Evaluation Board (MEB), The Netherlands

15:45 – 16:15

Networking Break in the Forum Foyer, Level 1

16:15 – 17:30

Panel Discussion – Questions and Answers Susan Abu-Absi, Bristol-Myers Squibb Company, USA Brigitte Brake, Federal Institute for Drugs and Medical Devices (BfArM), Germany Peter Jongen, Medicines Evaluation Board (MEB), The Netherlands Robin Levis, CBER, FDA, USA Laurent Mallet, Sanofi Pasteur, France Jette Wypych, Amgen Inc., USA

17:30 – 17:45

Closing Remarks and Invitation to CMC Strategy Forum Europe 2017 Alistair Kippen, IPSEN Biopharm Ltd.

17:45

Adjournment

EBE Satellite Session: Concept Paper 2016 Update: New Initiatives Medicines Adaptive Pathways to Patients (MAPPs) Initiative Use of Prior Knowledge Session Chairs: Ronald Imhoff, Janssen Biologics BV and Karin Sewerin, MedImmune Limited (consultant) CMC Challenges and Opportunities In order for CMC not to be on the critical path for early access and adaptations to the traditional approach to development and manufacturing may be required. 1. Aspects associated with commercializing a new product more typical of a late stage investigational medicinal product than a full-blown commercial product:  More focus on testing, verification and concurrent validation;  Commensurate with the conditions and controls used for the manufacture of late stage clinical trial materials;  Possibly launching from an R&D pilot plant facility;  Maybe limited in manufacturing flexibility;  May utilize controlled distribution to allow a shorter shelf life to be used initially;  May leverage knowledge that the manufacturer has from similar products and processes to accelerate decisions and support proposals for manufacture and control; 2. Commitment, timescale and assessment of an ongoing rolling submission of data, if required: Early access may often entail a reduced level of CMC information at submission and include a plan for making additional information available during review, before launch or at a later defined time point. As a consequence, the CMC data/documentation package will most likely need to evolve over the life-cycle of the product. For example:  Provisional specifications upgraded to full specifications;  Provision of longer term stability data at a later stage  Provision of stability data from Commercial site at a later stage;  Scale –up activities to a Commercial site;  Control strategy evolving over time ( periodic or skip testing; relatively wide (safety based) initial acceptance criteria; which may allow some flexibility beyond ICH limits (based on risk benefit);  Concurrent validation. NOTES:

Short Bios Ciro Cottini Chiesi Pharmaceutici S.p.A. Earl Dye Genentech, a Member of the Roche Group Chana Fuchs CDER, FDA Annick Gervais UCB Pharma sprl Chemical engineer by education and doctor from University Louis Pasteur (Strasbourg, France) specialised in mass spectrometry, I have now acquired 20 years’ experience and expertise on biotech products working in analytical and process development of recombinant proteins first in Switzerland (Serono) for 11 years and currently in Belgium (UCB) for the last 9 years. I am currently director of physico-chemical method development in analytical sciences for biologicals in UCB Pharma (Braine L’Alleud, Belgium) dealing with development, validation, transfer of methods and process support from early phase to life cycle management for therapeutic proteins and monoclonal antibodies in the field of immunology. I am also representing UCB in European Biopharmaceutical Enterprises (EBE) BioManufacturing working group since 2012. Ronald Imhoff Janssen Biologics BV Ronald Imhoff is senior director of global regulatory affairs - CMC at Janssen based in Leiden, The Netherlands and is responsible for leading a global team of regulatory affairs-CMC professionals. His team provides strategy for multiple biological products at all stages of development supporting worldwide regions. Ronald is co-founder and currently vice-chair of the EBE BioManufacturing Working Group, member of the EFPIA Technical Development Expert Group and member of the EFPIA/EBE ICHQ12 support team. He is also an associate director of CASSS and member of the organizing committee for the CMC Strategy Forum Europe. Ronald received his masters of science degree in chemical technology from the Technical University Eindhoven, The Netherlands Fred Jacobson Genentech, a Member of the Roche Group Alistair Kippen IPSEN Biopharm Ltd. Alistair joined IPSEN in Jan 2016, leading CMC development of novel biopharmaceuticals including process, formulation, analytical development groups, product specification, supply & regulatory documentation, to manufacturing & commercial lifecycle support. Previously, he was director & global head of analytical sciences at MedImmune, the biologics division of AstraZeneca (March 2009 –

Short Bio’s continued December 2015), including product characterisation, potency, stability, in-process/residuals & quality control (QC) groups as part of biopharmaceutical development (BPD). He was also BPD lead for cardiovascular & metabolic diseases therapies, CMC project leader and lead for various European biotechnology industry/regulatory forums. Alistair gained his PhD from Cambridge University and held various previous academic & industrial positions: (1) University Medical Centre in Geneva as a research scientist on the behaviour and fate of insulin-proteins in collaboration with GSK Biologics & Serono; (2) PolyMASC Pharmaceuticals in London; and (3) Covance in Harrogate as associate director of biotechnology-protein and immunochemistry, with responsibility for product-specific analytical method development, validation, cGMP batch release/stability testing and PK/TK & immunogenicity assessment, gaining extensive experience of drug development for a wide range of biotherapeutics from pre-clinical to commercial release. Yasuhiro Kishioka Pharmaceuticals and Medical Devices Agency (PMDA) Dr. Kishioka is a principal reviewer in the Office of Cellular and Tissue-based Products of the Japanese regulatory agency, Pharmaceuticals and Medical Devices Agency (PMDA). Since joining PMDA in 2008, his main work is the pharmaceutical quality review of biotechnological/biological products. His areas of expertise also include biosimilars and he has been assigned as the ICH Q12 topic leader of Japanese regulatory authorities. He holds a PhD from Hokkaido University in meat science with emphasis in molecular biology. Serge Mathonet Sanofi R&Dr Serge is a global regulatory affairs group leader with more than 12 years of regulatory affairs experience in chemistry, manufacturing and controls (CMC), focusing on biologics and biologics/device development, licensing and launch/life cycle management activities. Prior to joining global regulatory affairs, Serge has held various positions in Sanofi Industrial Operations in API Regulatory Compliance activities either at the corporate or industrial site level. Serge is a member of EBE BioManufacturing group, co-chair of LEEM Bioproduction group and member of EU CMC Strategy forum 2016 scientific organization committee. As member of EBE BioManufacturing group, Serge is leading the visible particle and biologics/device combination product topic groups. Scott Tobler Merck & Co., Inc. Scott Tobler is a principal scientist in the global vaccines and biologics commercialization group at Merck and Co., Inc. in New Jersey, USA. In this group, he focuses on the commercialization of drug substance manufacturing processes for therapeutic proteins, including process characterization, process validation, and preparation of regulatory submissions. Prior to Merck, Scott worked in the protein purification development group at Wyeth BioPharma in Massachusetts, USA. In this group, he focused

Short Bio’s continued on early and late stage process development for monoclonal antibodies and other therapeutic proteins. Scott holds a BS in chemical engineering from Tufts University and a PhD in chemical engineering from the University of Virginia. Mats Welin Medical Products Agency Mats Welin holds a position as senior expert at the Medical Products Agency in Sweden, working with quality assessment of human and veterinary biologics and normative work within this field with a focus on vaccines and monoclonal antibodies. He is a pharmacist by training and has been employed at the agency since 1988. Since 1996, he is the Swedish delegate of CHMPs sub group on biologics, the Biologics working party (BWP). He is also a member of EMEA PAT team dealing with QbD related topics since 2003 as one of the BWP representatives to cover biological aspects in the field. He was a delegate of the quality implementation working group (Q-IWG) of the ICH during its existence to work with introduction of the Q8-Q10 concepts. He is a frequent speaker at conferences on Quality by Design, process validation, setting of specifications and on general aspects in relation to biological medicinal products. He has attended all the CMC Strategy Forum Europe meetings.

Presenter’s Abstracts Antibody Drug Conjugates Fred Jacobson Genentech, a Member of the Roche Group, USA Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

NOTES:

Management and Control of Raw Materials Annick Gervais UCB Pharma sprl, Belgium There are many challenges related to raw materials for the production of biological/biotechnological, cell based and gene therapy products. These challenges are related to: -

the large number of materials, the large number of suppliers, the variability of source material, the traceability of source material, the testing

A white paper on management and control of raw materials is being developed by members of EBE BioManufacturing Working Group with the aim to provide a framework to facilitate, guide and raise awareness to manufacturers on the critical aspects of the management of RM across the product lifecycle. This white paper will present some current practices from Industry and propose guidance and methodology for the management of raw materials using a risk-based approach by phase of development. It also aims at seizing opportunities to anticipate and implement some principles of ICHQ12. The presentation here will provide an outline for this new EBE initiative. NOTES:

Learnings from EBE Cross-industry Informational Sharing Session on Development and Licensing of Biologics/Device Combination Products Serge Mathonet Sanofi R&D, France First pass marketing approval of subcutaneous antibody therapy requiring chronic administration at high dosing (several mg/kg) and therefore high concentration, when coupled with prefilled syringe and autoinjector device for at-home administration, is dependent on overcoming a number of technical and regulatory challenges in delivering a complete Module 3. To address these challenges, EBE organized a cross industry informational sharing session held in Basel Switzerland on Novartis campus, April 30 2015. Topics addressed during the one-day meeting span from device development, to how to achieve compliance with 21 CFR Part 4, setting control strategies, specifications and shelf life from components to the combined product, dossier strategy , dossier content associated with design verification and process validation studies. The presentation will highlight learnings from this meeting and the work plan defined for EBE Biologics Device combination product topic group. Slides were not available at the time of printing. NOTES:

NOTES:

Introduction to CMC Challenges and Opportunities for MAPPs / Accelerated Pathways Ronald Imhoff Janssen Biologics BV, The Netherlands Abstract was not available at the time of printing. NOTES:

Use of Prior Knowledge in Applications Mats Welin Medical Products Agency, Sweden Prior knowledge has always been an indispensable tool both in designing a manufacturing process and establishing criticality of attributes but has in the past years gained even more focus in guidelines etc. This is also recognized in the recent EU guideline on process validation for biotech drug substances. The talk will discuss regulatory expectations on documentation of prior knowledge. Manufacturing platforms will simplify development of similar molecules but it is unlikely that the process will be identical and any extrapolation from data from other molecules needs to be carefully justified. Level of documentation will differ with stage of development- early stages may not need detailed description, while later studies aimed at establishing outer boundaries of a process and justify predictability of small scale results to represent the commercial scale performance will. Q11 is not crystal clear in its expectations, it is stated that the drug substance manufacturing process should be appropriately validated at the time of the marketing authorization. This would normally be considered to include product specific data both in small scale studies to set the outer boundaries of the process and the full scale verification runs but the wording opens for supported alternative options. Experience from platforms etc may under all circumstance be useful in supporting that small scale studies are representative for commercial production. Prior knowledge can also be used in establishing criticality of attributes. For some attributes the criticality is common to different products but in many cases criticality will depend on type of products, posology, indication and will still require product specific studies. NOTES:

Prior Knowledge in Drug Substance Process Validation Earl Dye Genentech, a Member of the Roche Group, USA Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

NOTES:

Prior Knowledge in Establishing Control Strategy Alistair Kippen IPSEN Biopharm Ltd., United Kingdom Improving the incorporation of prior knowledge into biologics process control strategies could allow more efficient product development and enhanced flexibility throughout lifecycle management. Can linking prior knowledge with product control reduce final product testing requirements & qualifications, implementation of real time release testing, and how much data would be required to justify a more effective approach to biopharmaceutical development? NOTES:

Drug Product Modeling in Scale-up and Transfer of Lyophilization Processes Ciro Cottini Chiesi Pharmaceutici S.p.A., Italy Abstract was not available at the time of printing. NOTES:

CMC Strategy Forum Europe 2016: Regulatory Updates from Around the World Session Chairs: Nanna Aaby Kruse, Danish Health and Medicines Authority and Jolanda Westerlaken, UCB Pharma SA This session will provide a high level regulatory update from around the world. The session starts with three/four short presentations that will provide us with an overview of changes/updates in their respective areas and after the presentation we will have a panel discussion. The panel discussion will include more Health Authorities from around the world and during this time questions from the audience will be discussed, as well as questions pre-planned for discussion. NOTES:

Short Bio’s Seán Barry Health Products Regulatory Authority (HPRA) Manuel Gea ADEBIOTECH and Bio-Modeling Systems Manuel Gea is co-founder, CEO and vice president R&D IT of Bio-Modeling Systems, the world's first “Mechanisms-based Medicine” company, dedicated to the discovery of cost effective new therapeutic, diagnostic and preventive solutions. This platform addresses two major life science issues:  the complexity of life’s mechanisms with its “Architectural Principle”;  the significant unreliability of scientific and clinical publications through its “Negative Selection Principle” He is chairman of the independent trans-discipline biotech “think tank” Adebiotech, and the cofounder and chairman of Centrale-Santé, the French health think tank, gathering 2500 professional members involved in sector innovations and creating value for patients. Manuel Gea is a serial entrepreneur and business angel, developing disruptive innovations (technologies, novel therapies and business models) in the life sciences, IT, digital, healthcare and cosmetics sectors to propose disruptive integrated solutions adapted to each segment. Manuel Gea graduated from Ecole Centrale Paris, and has a sociology of organizations degree from Paris IX Dauphine University. Yasuhiro Kishioka Pharmaceuticals and Medical Devices Agency (PMDA) Dr. Kishioka is a principal reviewer in the Office of Cellular and Tissue-based Products of the Japanese regulatory agency, Pharmaceuticals and Medical Devices Agency (PMDA). Since joining PMDA in 2008, his main work is the pharmaceutical quality review of biotechnological/biological products. His areas of expertise also include biosimilars and he has been assigned as the ICH Q12 topic leader of Japanese regulatory authorities. He holds a PhD from Hokkaido University in meat science with emphasis in molecular biology. Sarah Kennett CDER, FDA Sarah obtained her PhD in molecular cancer biology at Duke University and followed that with postdoctoral training in the Laboratory of Molecular Carcinogenesis at the National Institutes of Health (NIH).

Short Bio’s continued Sarah joined FDA in 2005 as an interagency oncology task force fellow in the Office of Cellular, Tissue, and Gene Therapies in the Center for Biologics Evaluation and Research (CBER). She joined the Center for Drug Evaluation and Research (CDER), Office of Biotechnology Products (OBP), Division of Monoclonal Antibodies in 2007 and was the division’s review chief when OBP was reorganized. She is currently the review chief for OBP’s Division of Biotechnology Review and Research I. Robin Levis CBER, FDA Dr. Levis received her PhD in the department of microbiology and immunology at Washington University School of Medicine. She conducted two postdoctoral fellowships; first at the National Cancer Institute in the laboratory of tumor biology and second at the Uniformed Services University of Health Sciences in the department of pathology. Dr. Levis began working in the Laboratory of Vector Borne Virus Disease in the Division of Viral Products at CBER/FDA in 1995. Her initial laboratory studies related to dengue virus replication. She then transitioned to become the primary reviewer for all licensed rabies vaccine products and for rabies vaccines and related products under development. In 2002, Dr. Levis became the regulatory coordinator for the Division of Viral Products and in 2006 she became the deputy director of the Division of Viral Products. In this position, she has continued to be involved in the review and regulation of viral vaccine products. Anthony Ridgway Health Canada Dr. Ridgway completed his PhD at McGill University in Montreal, and then proceeded to post-doctoral studies followed by an assistant professorship in the Cancer Research Laboratory and Department of Microbiology and Immunology at the University of Western Ontario. Academic research activities included work on the structure and expression of oncogenes, retroviral and HIV regulatory elements and inducible expression vectors. He has been with Health Canada since 1991 and in 1999, became manager of the biotherapeutics division, with responsibility for regulation of a wide range of products. In 2004, he guided the separation of his former division into three new divisions and became the senior regulatory scientist in the office of the director in the newly formed Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics, BGTD. He holds a range of advisory and supervisory responsibilities that includes retaining managerial responsibility for the evaluation of product quality for radiopharmaceuticals and gene therapy products. He has been active with the ICH* since 1993, serving on Expert Working Groups addressing the quality of biotechnology products and is currently with Q12. He has been active on consecutive US Pharmacopoeia Committees of Experts, since June 2000. Dr. Ridgway has been extensively involved in the Canadian approach to subsequent-entry biologics (biosimilars), and the drafting and dissemination of Canadian guidance. *International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

Pascal Venneugues European Medicines Agency (EMA) Pascal Venneugues qualified as a pharmacist from the University of Paris, with a doctorate in the field of molecular genetics. He also holds masters’ degrees in health economics and in European regulatory affairs. From 2001 to 2003, he worked in the pharmaceutical industry. In 2003, he joined the Human Medicines Evaluation Division at the European Medicines Agency. He works as principal scientist in Quality of Medicines with a focus on biologics.

Presenter’s Abstracts France’s Attractiveness for the Biopharma Industry: Global Ecosystem Competitiveness Clusters Manuel Gea ADEBIOTECH and Bio-Modeling Systems, France ADEBIOTECH is France’s independent, multi-disciplinary biotechnology “think-tank” and promotes interactions between the industrial world and academic centers in the field of biotechnology. The goal is to foster and support sustainable innovations. Slides were not available at the time of printing. NOTES:

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Regulatory Updates from the EU Seán Barry Health Products Regulatory Authority (HPRA) The regulatory landscape in the EU has seen some exciting changes in recent times. Earlier this year saw the launch of the PRIority MEdicines (PRIME) scheme which will see earlier and closer interaction between regulators and applicants for medicines where there is an unmet clinical need. The Adaptive Pathway allows for a tailored approach to development approval in stages, firstly in a more restricted patient population with progressive gathering of evidence through real life data. These new approaches bring their own unique challenges to the CMC/quality part of regulatory submissions. For example, full formal process validation may not have been completed at the time of submission, limited batch data may be available to leverage for setting specifications. The CMC challenges and possible solutions to these questions will be discussed during the presentation. The guideline on process validation of biotechnology-derived active substances has recently been published which further develops the concepts of continuous, concurrent and ongoing process verification. The implications for standard and accelerated submissions will be discussed. Finally, the trends in quality/CMC Day 80 review questions for centralised dossiers submitted to the EMA will be examined and areas where there are common issues will be discussed in further detail. Slides were not available at the time of printing. NOTES:

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PMDA Updates: Approach to Making much Further Progress Yasuhiro Kishioka Pharmaceuticals and Medical Devices Agency (PMDA), Japan Pharmaceuticals and Medical Devices Agency (PMDA) has succeeded in shortening the review period for medical products to the world’s top standard through its 1st and 2nd Mid-term Plan Periods (FY 2004 to 2013). PMDA has been highly evaluated internationally for this and other achievements, and now positioned to contribute more to the world. In this presentation, our new strategic plan titled “PMDA International Strategic Plan 2015” launched on June 26, 2015 will be introduced. This presentation will also include the latest information on SAKIGAKE designation system and Biosimilars. The SAKIGAKE designation system, also known as “Forerunner review assignment system”, is the accelerated developing program in Japan. As of April 1, 2016, 6 pharmaceuticals, 2 medical devices and 2 regenerative medicines have been designated. CMC considerations for accelerated programs will be discussed. Regarding Biosimilars, new Questions and Answers (Q&As) to the Japanese guideline was published in December 2015. These Q&As aim to clarify our current expectations on quality, non-clinical and clinical studies in the comparability exercise based on experience gained from our review and consultation. Furthermore, this talk will provide a current perspective on post-approval changes in Japan in connection with ICH Q12. NOTES:

Regulatory Updates for Biopharmaceutical Products: FDA Perspective Sarah Kennett CDER, FDA, USA Biopharmaceutical products have experienced a significant amount of success, which has led to enhanced interest and investment in the development of these products. Increased knowledge of biopharmaceutical products and their manufacturing processes, the development of new technologies, and communication among manufacturers and regulatory authorities have led to the advancement and increased use of new or improved mechanisms for managing the products throughout their lifecycles. The FDA has published the “Draft Guidance for Industry: Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products” ahead of the proposed ICH document for pharmaceutical lifecycle management (ICH Q12). This draft guidance is intended to provide FDA’s current thinking regarding the topic of established conditions, including the reporting of and changes to established conditions in BLA, NDA, or ANDA submissions. One mechanism for making post-approval changes to established conditions involves the use of comparability protocols; in recent years, the Agency has seen numerous such protocols submitted to BLAs. The increased understanding of biopharmaceutical products and processes, combined with advanced analytical techniques and approaches, has also supported the development of biosimilar products and biopharmaceutical “breakthrough therapy” products. A brief introduction to these lifecycle management topics will be presented. NOTES:

Regulatory Updates from Around the World Panel Discussion Panel Discussion – Questions and Answers Seán Barry, Health Products Regulatory Authority (HPRA), Ireland Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Sarah Kennett, CDER, FDA, USA Robin Levis, CBER, FDA, USA Anthony Ridgway, Health Canada, Canada Pascal Venneugues, European Medicines Agency (EMA), United Kingdom The following questions will guide the discussion:   

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How is your region/country involved in ICHQ12 discussions? If not directly involved is your region/country intending to follow the guidance given in ICHQ12 with respect to established condition or use of post approval change protocols? The goal of pharmaceutical companies and HA is to give access of medicines to patient as quick as possible. With the new accelerated clinical pathways CMC development might become rate limiting. What is being done in your region/HA to keep CMC development of the critical path i.e. initiatives for accepting continues process validation or new technologies? How does your region/country assess innovative approaches with regards to tools and technologies, are there specific pathways to get early feedback on this (do you have a specific group within your agency that deals with this)? Does your agency have a group within the agency that specifies in combination products/devices or are the quality assessments done by the more CMC focused quality asessors? Are there any issues that you are aware off that arise when using two products combined (combination products) in a clinical trial?

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CMC Strategy Forum Europe 2016: Leveraging Continuous Process Verification to Facilitate Faster Patient Access Session Chairs: Ralf Gleixner, Ares Trading SA, An affiliate of Merck Serono and Jason Hampson, Amgen Inc. This session will focus on the possibilities of Continuous Process Verification as described in the EMA 2014 guidance (EMA/CHMP/CVMP/BWP/70278/2012-Rev1) to accelerate the availability of important new medicines to patients. Currently, many worldwide regulators including EU typically require biotech manufacturers to complete full production scale process validation (PV) studies and present the resulting data in the initial Marketing Application (MAA). The completion of process validation studies is one of the last manufacturing activities, and is often on the critical path to MAA Module 3 completion. Sometimes the material manufactured during the PV campaign cannot be utilized in clinical trials, and may expire prior to Marketing Authorization approval, resulting in unnecessary scrap of high quality medicinal product. An alternative and continuous approach to PV, as described in the EMA guidance, would be to leverage platform process knowledge, process characterization data to develop a “continuous verification validation scheme” in a science and risk-based real-time approach to verify and demonstrate that a process that operates within the predefined specified parameters consistently produces material which meets all its critical quality attributes (CQAs) and control strategy requirements. In order to enable continuous process verification, companies would perform, as relevant, extensive in-line, on-line or at-line controls and monitor process performance and product quality on each batch. Relevant data on quality attributes of incoming materials or components, in-process material and finished products would be collected. This should include the verification of attributes, parameters and end points, and assessment of CQA and critical process parameter (CPP) trends. Process analytical technology (PAT) applications, and Multivariate Statistical Process Control (MSPC) can be viewed as enablers for continuous process verification. This approach would provide regulators with the necessary assurance that the process was robust and consistently yielded high quality product, and would enable MAA submission on the basis of a Continuous Verification Validation Scheme with data being available on site for inspection. Hence patient access to innovative medicines would be 3-6m earlier. It would also mitigate the risk of unnecessary scrap. Industry presenters will be asked to present case studies which describe the outcome of PV studies, compared to their prospectively defined PV protocols, and present proposals on how continuous verification validation schemes could look in practice. Regulatory agency representative(s) will be invited to present their perspectives on how the concepts of this alternative to traditional PV could be introduced into practice and their expectations of what a continuous process verification validation scheme, submitted in the MAA dossier, should contain. NOTES:

Short Bio’s Marcus Boyer Bristol-Myers Squibb Company Dr. Marcus E. Boyer is an associate director of process life-cycle management at Bristol-Myers Squibb in Syracuse, NY, USA. Having spent four years at BMS, he leads a group of drug substance process champions, scientists and engineers who act as overall drug substance process owners and are responsible to develop, align and execute the franchise strategy throughout the lifecycle of the company’s licensed biologic pharmaceuticals. Life-cycle activities include process monitoring, tech transfers, process changes, next-gen process development, initial and subsequent regulatory filings, and other regulatory interactions. Before assuming group leadership, Dr. Boyer served as the drug substance process champion for BMS’s immuno-oncology drug, Yervoy. He also represents BMS on the continued process verification workstream of the BioPhorum Operations Group (BPOG), an industrywide collaboration effort. Dr. Boyer received his PhD in chemical engineering from Stanford University in 2007, after which he worked for five years at Merck, in Pennsylvania, USA. At Merck, he led a group that provided direct technical support to upstream, downstream, and adjuvant operations as part of recombinant vaccine manufacturing. Niklas Ekman Finnish Medicines Agency Dr. Niklas Ekman has a background in molecular cell and cancer biology. Before joining the Finnish Medicines Agency in late 2006, he worked as a post-doc researcher in the cell cycle and cancer cell circuitry laboratory at the University of Helsinki, Finland. Currently, Dr. Ekman holds a position as a senior researcher and quality assessor for biological medicinal products at the Finnish Medicines Agency. His main activities and responsibilities include assessment of European Medicines Agency (EMA) centralised marketing authorisation applications, scientific advices, as well as national clinical trial applications. At EMA, Dr. Ekman is a nominated member of the Biosimilar Medicinal Products Working Party (BMWP) and the Finnish alternate member of the Biologics Working Party (BWP). Rohin Mhatre Biogen Rohin Mhatre is the vice president of global CMC regulatory affairs at Biogen. He joined Biogen in 1996 and has held various positions ranging from the head of analytical development, CMC portfolio management and head of biologics DS, DP and device development. Prior to Biogen, Rohin managed the applications development department at Perseptive Biosystems (now Applied Biosystems). He graduated from Northeastern University with a PhD in analytical chemistry. Rohin has been involved with CASSS for the past 20 years serving on the organizing committee of WCBP and the steering committee of the CMC Strategy Forum and the Mass Spec Pharma meeting.

Short Bio’s continued Martijn van der Plas Medicines Evaluation Board (MEB) Dr R. M. (“Martijn’) van der Plas is assessor for biological products at the Medicines Evaluation Board, and previously RIVM where he started working as assessor in 2000. His fields of attention include biosimilars, monoclonal antibodies and recombinant proteins and plasma-derived products in general. He obtained a PhD degree in 1999 with the thesis ‘Structure and Function of Human von Willebrand Factor’. He obtained a ‘doctorandus’ (MSc) degree in 1994 with a major in molecular pharmacology.

Presenter’s Abstracts PPQ-to-filing Timelines – Acceleration Approaches at BMS Marcus Boyer Bristol-Myers Squibb Company, USA One of the key aims of both pharmaceutical companies and regulators is to make innovative, highquality medicines that address unmet medical needs available to patients as quickly as possible. In biologics manufacturing, the ability to speed drugs to market can be limited by conservative approaches and associated long timelines required for full-scale process qualification and stability data collection. Increasingly, the reliance on a large amount of full-scale data to justify process qualification is being replaced by risk-based data collection coupled with other scientific rational and rigorous ongoing monitoring of the process. Here we share approaches taken in recent regulatory applications by BristolMyers Squibb to shorten the time between initiation of process qualification and readiness of the CMC file sections. The examples include proactive consideration of manufacturing expansion with regulatory agencies, equipment grouping and equivalency data packages, and risk-based stability requirements. Each illustration represents a relatively modest departure from conservative approaches used in the past, but can result in meaningful acceleration. Also presented are suggestions for further compression of timelines by extending the approaches discussed here. Extending risk-based acceleration begins to approach the continuous process validation paradigm. NOTES:

Continuous Process Verification of Next Generation Processes Utilizing Advanced Process Control (APC) Rohin Mhatre Biogen, USA The current state of monoclonal antibody process platforms and process understanding has enabled us to develop robust processes that yield consistent product quality. Biogen’s investment in process technology has resulted in high output processes with a good understanding of levers that control product quality. Our next-generation drug substance manufacturing processes utilize predictive product quality models along with automated and adaptive controls. This presentation will provide an overview of our next generation manufacturing processes utilizing APC enabling technologies, the new validation paradigm, and post-approval lifecycle management strategy. Slides were not available at the time of printing. NOTES:

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Process Validation and Adaptive Pathways Martijn van der Plas College Medicines Evaluation Board (MEB) The relation between adaptive pathways for approval on one hand and concepts related to process validation (e.g. continuous process verification, concurrent validation) will be explored from a regulator’s point of view. Slides were not available at the time of printing. NOTES:

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Leveraging Continuous Process Verification to Facilitate Faster Patient Access Update Session Panel Discussion – Questions and Answers Marcus Boyer, Bristol-Myers Squibb Company, USA Niklas Ekman, Finnish Medicines Agency, Finland Rohin Mhatre, Biogen, USA Martijn van der Plas, Medicines Evaluation Board (MEB), The Netherlands The following questions will guide the discussion: 

Approval of small molecule marketing applications based on a process validation protocol has been well established for many years. Given the significant technological advances in process understanding and analytical characterization for certain biologics, is a continuous process verification approach now a feasible option?

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What pre-conditions in terms of process- and product knowledge seem reasonable to be eligible for Continuous Verification?

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How can the concept of a Continuous Process Verification Schemes be translated into practice?

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CMC Strategy Forum Europe 2016 ICH Q12 Update: Established Conditions / Approved Matters Session Chairs: Brian Corrigan, Pfizer Ireland Pharmaceuticals Limited and Ronald Imhoff, Janssen Biologics BV The draft ICH guideline Q12 on lifecycle management introduces the concept of Established Conditions within the dossier that would delineate the compliance information intended for assessment from other informational content. This session will provide an update on current progress of the ICH discussions, with participation of ICH IWG topic contributors. In addition, the session will include industry case studies to explore the practical integration of an Established Conditions approach to the presentation and interpretation of content in key sections of the application dossier, such as the manufacturing description and control strategy. NOTES:

Short Bio’s Kowid Ho F. Hoffmann-La Roche Ltd. Kowid Ho has been working at F. Hoffmann-La Roche Ltd.’s Global Pharma Technical (CMC) Regulatory Policy in Basel, Switzerland for two years. He was previously a quality assessor for biological products at Agence nationale de sécurité du médicament et des produits santé (ANSM, formely AFSSaPS) for >10 years. He has authored many European assessment reports and scientific advices on biotech, vaccines, blood and advanced therapy products, and has participated to several product related inspections. He was a member of European Medicines Agency (EMA) Biologics Working Party (BWP), Biosimilar Working Party (BMWP), PAT team and BWP QbD core group. He was rapporteur for several quality guidelines for EMA (process validation for biological, biosimilar quality aspects, monoclonal antibody). He also participated in the drafting of other European and international guidelines (EDQM HCP general chapter, ICH Q11, revision of WHO guideline for product prepared from rDNA technology). Sarah Kennett CDER, FDA Sarah obtained her PhD in molecular cancer biology at Duke University and followed that with postdoctoral training in the Laboratory of Molecular Carcinogenesis at the National Institutes of Health (NIH). Sarah joined FDA in 2005 as an interagency oncology task force fellow in the Office of Cellular, Tissue, and Gene Therapies in the Center for Biologics Evaluation and Research (CBER). She joined the Center for Drug Evaluation and Research (CDER), Office of Biotechnology Products (OBP), Division of Monoclonal Antibodies in 2007 and was the division’s review chief when OBP was reorganized. She is currently the review chief for OBP’s Division of Biotechnology Review and Research I. Yasuhiro Kishioka Pharmaceuticals and Medical Devices Agency (PMDA) Dr. Kishioka is a principal reviewer in the Office of Cellular and Tissue-based Products of the Japanese regulatory agency, Pharmaceuticals and Medical Devices Agency (PMDA). Since joining PMDA in 2008, his main work is the pharmaceutical quality review of biotechnological/biological products. His areas of expertise also include biosimilars and he has been assigned as the ICH Q12 topic leader of Japanese regulatory authorities. He holds a PhD from Hokkaido University in meat science with emphasis in molecular biology.

Short Bio’s continued Nanna Aaby Kruse Danish Health and Medicines Authority Nanna Kruse holds a master of science in pharmacy. She has worked since 1995 at the Danish Medicines Agency. Currently she is in the licensing division where she is the lead assessor for biologics/biotech products in the centralised procedure. Nanna Kruse is vice-chair of CHMPs Biologics Working Party (BWP) and she is the Danish representative in the Committee for Advanced Therapies (CAT). In addition, she is member of Biosimilar Working Party (BMWP) and the EMA PAT-team. Finally, she is representing BWP in ICHs Expert Working Group for ICH Q12. Christine Mitchell-Logean UCB Biopharma sprl After obtaining a PhD in chemical & biochemical engineering from the University of Iowa, Dr. Mitchell-Logean spent three years at Bristol-Myers Squibb, heading-up the cell culture development group in Syracuse, NY. She then moved back to Switzerland and worked at Serono and then Merck Serono for ten years where she held several positions in cell culture, manufacturing support, as a lean sigma black belt and in project management. Christine is currently at UCB working as a CMC development lead on a late stage project, on QBD and process excellence. Frank Montgomery AstraZeneca Anthony Ridgway Health Canada Dr. Ridgway completed his PhD at McGill University in Montreal, and then proceeded to post-doctoral studies followed by an assistant professorship in the Cancer Research Laboratory and Department of Microbiology and Immunology at the University of Western Ontario. Academic research activities included work on the structure and expression of oncogenes, retroviral and HIV regulatory elements and inducible expression vectors. He has been with Health Canada since 1991 and in 1999, became manager of the biotherapeutics division, with responsibility for regulation of a wide range of products. In 2004, he guided the separation of his former division into three new divisions and became the senior regulatory scientist in the office of the director in the newly formed Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics, BGTD. He holds a range of advisory and supervisory responsibilities that includes retaining managerial responsibility for the evaluation of product quality for radiopharmaceuticals and gene therapy products. He has been active with the ICH* since 1993, serving on Expert Working Groups addressing the quality of biotechnology products and is currently with Q12. He has been active on consecutive US Pharmacopoeia Committees of Experts, since June 2000. Dr. Ridgway has been extensively involved in the Canadian approach to subsequent-entry biologics (biosimilars), and the drafting and dissemination of Canadian guidance. *International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

Presenter’s Abstracts ICH Q12 – Challenges, Opportunities…and More Challenges Anthony Ridgway Health Canada, Canada A perspective will be provided on the aspirations, issues, challenges and opportunities associated with development of the ICH Q12 guideline that is specifically intended to provoke discussion. Elements will include: the enduring value of risk-rationalized categorization of manufacturing changes requiring communication with the regulator; “Regulatory Commitments” or “Established Conditions” and their potential for leveraging “regulatory relief”; a possible new life for Post-Approval Change Management Protocols; and the potential for Q12 to have significant value beyond current ICH jurisdictions through “ICH-independent” harmonization and regulatory convergence. NOTES:

Established Conditions – Concepts and Updates from Expert Working Group Nanna Aaby Kruse Danish Health and Medicines Authority, Denmark The aim is that the new CMC guideline from ICH, ICH Q12, will facilitate the management of postapproval Chemistry, Manufacturing and Controls (CMC) changes in a more predictable and efficient manner across the product lifecycle. It is the hope that this new ICH Guideline will promote innovation and continual improvement, and strengthen quality assurance and reliable supply of product, including proactive planning of supply chain adjustments. In April 2016, a sub-group of the ICH Expert Working Group met in London to discuss one of the enablers in ICHQ12, the Established Conditions. This presentation will illustrate this new concept and provide insight to the latest EWG discussions on Established Conditions. NOTES:

Industry Perspective on ICH Q12 Progress and Direction Frank Montgomery AstraZeneca, United Kingdom Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

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Filing Established Conditions and Life-cycle Management of a Bioprocess Case Study Christine Mitchell-Logean UCB Biopharma sprl, Belgium The information given in a new Biologics License Application is critical to get the product approved, but also critical for the life cycle management of the product after getting the marketing authorization. If the binding information given in the filing is too tight and put too many constrains on the manufacturer, it may be difficult to release batches in compliance with the filing. On the contrary, if too little information is given or too much room is allowed, the product may not be approved or there may be risks that the product may vary from batch to batch. This case study will present, using a concrete bioprocess step, examples of how the various CMC sections could be filed with information that is binding and non-binding and the implications for life cycle management. NOTES:

Implementation of Established Conditions Principles: Regulatory Approach Kowid Ho F. Hoffmann-La Roche Ltd., Switzerland The concept of “Established Conditions” (EC), introduced in FDA draft guideline and further discussed in the ongoing ICH Q12, opens great perspective for change management by clarifying the regulatory binding information in the submission. This presentation will present some of the regulatory elements considered when preparing the implementation of the concept. This includes elements such as linking the product and process understanding to the level of details included in EC, leveraging protocols to frontload information, or using risk management plans to support post approval changes of non-EC. NOTES:

ICH Q12 Update: Established Conditions / Approved Matters Workshop Session One Panel Discussion – Questions and Answers Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland Sarah Kennett, CDER, FDA, USA Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark Christine Mitchell-Logean, UCB Biopharma sprl, Belgium Frank Montgomery, AstraZeneca, United Kingdom Anthony Ridgway, Health Canada, Canada Questions were not available at the time of printing. NOTES:

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CMC Strategy Forum Europe 2016 The Evolution of Post-approval Change Protocols in Biopharmaceutical Lifecycle Management Session Chairs: John Dougherty, Eli Lilly and Company and Anthony Ridgway, Health Canada Post-approval change management protocols (PACMPs) are one of the focal points of the ongoing development of ICH Q12. A PACMP is a regulatory tool that enables prospective planning of a future CMC change(s) including the assessment of impact on product quality. Regulatory approval of a PACMP is typically accompanied by a reduction in the reporting of the executed change enabling faster implementation which serves to maintain the uninterrupted supply of life saving medicines. This session will start with the overview of the current ICH Q12 activity on PACMP, followed by case studies describing recent advances and perspectives of PACMPs to biopharmaceutical manufacturing changes. The case studies will provide the framework for the subsequent and engaging discussion on the vision for PACMPs in the context of ICH Q12 and the global lifecycle management of biopharmaceuticals. NOTES:

Short Bio’s John Ayres Eli Lilly and Company Dr. John Ayres received his undergraduate degree in chemistry from Butler University in 1979 then received his doctor of medicine degree from Indiana University School of Medicine in 1983. He completed his residency at the Indiana University Medical Center and is Board Certified in Internal Medicine. Subsequently, Dr. Ayres obtained a law degree from Indiana University Bloomington in 1993 and was admitted as member of the Indiana and Federal bar before returning to the Indiana University School of Medicine as a faculty member. In addition to his clinical duties, Dr. Ayres established a risk management department and served on the Medical Center's Institutional Review Board (IRB). He has had clinical practices in both internal medicine and occupational and environmental medicine and has served in various consultative roles to both industry and government agencies. He currently serves on the USP Visual Inspection of Parenteral Expert Panel. For the past 13 years, Dr. Ayres has served as the health hazard evaluation physician for Eli Lilly and Company and senior medical fellow for product safety assessments. In this role, he works closely with product development, manufacturing, quality, and pharmacovigilance to evaluate the human safety risk potentially associated with critical quality attributes (CQAs), manufacturing and environmental excursions, linked to product complaints, or related to counterfeit medication issues including surveillance, risk assessment and management, and regulatory-compliance functions. Mairead Duke BioMarin Europe Ltd. Markus Goese F. Hoffmann-La Roche Ltd. Markus Goese holds a PhD in biochemistry/organic chemistry from the TU München, Germany. He has more than 15 years industry experience in various companies (Roche, DSM, Novartis) in pharmaceuticals and fine chemicals research, development and commercialization. For the last ten years, Dr. Goese has been working in CMC regulatory affairs, initially on biopharmaceutical products in early and late-stage development and then took on the responsibility as key liaison to EMA & EU regulatory agencies for CMC regulatory policy projects for Roche Pharma Global Technical Operations in early 2011. Markus is based in Basel, Switzerland. He is currently the chair of EBE’s Biomanufacturing Working Group and the EFPIA deputy topic lead for ICH Q12 (Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management).

Short Bio’s Yasuhiro Kishioka Pharmaceuticals and Medical Devices Agency (PMDA) Dr. Kishioka is a principal reviewer in the Office of Cellular and Tissue-based Products of the Japanese regulatory agency, Pharmaceuticals and Medical Devices Agency (PMDA). Since joining PMDA in 2008, his main work is the pharmaceutical quality review of biotechnological/biological products. His areas of expertise also include biosimilars and he has been assigned as the ICH Q12 topic leader of Japanese regulatory authorities. He holds a PhD from Hokkaido University in meat science with emphasis in molecular biology. Robin Levis CBER, FDA Dr. Levis received her PhD in the department of microbiology and immunology at Washington University School of Medicine. She conducted two postdoctoral fellowships; first at the National Cancer Institute in the laboratory of tumor biology and second at the Uniformed Services University of Health Sciences in the department of pathology. Dr. Levis began working in the Laboratory of Vector Borne Virus Disease in the Division of Viral Products at CBER/FDA in 1995. Her initial laboratory studies related to dengue virus replication. She then transitioned to become the primary reviewer for all licensed rabies vaccine products and for rabies vaccines and related products under development. In 2002, Dr. Levis became the regulatory coordinator for the Division of Viral Products and in 2006 she became the deputy director of the Division of Viral Products. In this position, she has continued to be involved in the review and regulation of viral vaccine products. Anders Vinther Sanofi Pasteur Anders Vinther is chief quality officer at the vaccine company Sanofi Pasteur. He has an MSc and PhD in chemical engineering from the Technical University of Denmark. Anders has worked in many different cultures and has experience from both small and large companies. He was the co-founder of the contract manufacturing organization CMC Biologics, vice president of quality in Novo Nordisk, and most recently before joining Sanofi Pasteur, he was vice president of quality for Genentech and Roche biologics product operations. Anders is the past chairman of Parenteral Drug Association (PDA), and is a quality thought leader currently working on the Living Quality Ecosystem, as well as ways to achieve sustainable quality. Outside his work in the pharma industry, Anders is the owner and winemaker at Flying Suitcase Wines. Mats Welin Medical Products Agency Mats Welin holds a position as senior expert at the Medical Products Agency in Sweden, working with quality assessment of human and veterinary biologics and normative work within this field with a focus on vaccines and monoclonal antibodies. He is a pharmacist by training and has been employed at the

agency since 1988. Since 1996, he is the Swedish delegate of CHMPs sub group on biologics, the Biologics working party (BWP). He is also a member of EMEA PAT team dealing with QbD related topics since 2003 as one of the BWP representatives to cover biological aspects in the field. He was a delegate of the quality implementation working group (Q-IWG) of the ICH during its existence to work with introduction of the Q8-Q10 concepts. He is a frequent speaker at conferences on Quality by Design, process validation, setting of specifications and on general aspects in relation to biological medicinal products. He has attended all the CMC Strategy Forum Europe meetings.

Presenter’s Abstracts The Use of Comparability Protocols for Biologics: An Effective Tool to Manage Post-approval Changes Robin Levis CBER, FDA, USA One of the key elements of managing CMC related post-approval changes is the establishment of a welldefined, validated manufacturing process that will serve as the basis for product comparability assessments post-licensure. This is done during the product and clinical development phases by defining the critical quality attributes that are essential for the production of a safe and efficacious vaccine. The impact of any post-approval changes on the product can then be linked to or compared with data from the product prior to the introduction of changes with the expectations that the product will behave similarly with regards to safety and efficacy. This presentation will introduce the essential role that product comparability plays in supporting post-approval changes and will introduce the use of comparability protocols as a tool to manage post-approval changes. NOTES:

Post-approval Safety Surveillance Studies to Support Biopharmaceutical Changes John D. Ayres Eli Lilly and Company, USA The biopharmaceutical products and device delivery systems used to administer them are prescribed by physicians and either administered by a health care provider, a care giver, or the patient. But how do we monitor the safe and effective use of these products? And do those that monitor recognize when changes have been introduced into the sourcing of materials, manufacture of the drug substance or drug product, or modifications to the delivery system? While many changes adopted might seem innocuous…“what we don’t know, we don’t know” concerning potential patient impact as the changes are introduced in some circumstances could play out differently. On-going surveillance programs, re-evaluation of Risk Management Plans, change control notifications and periodic safety management team meetings are essential to evaluate current and proposed changes in product attributes, analytical methods or process control strategies and assess their potential clinical impact. This presentation will focus on the benefits of integrating comprehensive pharmacovigilance systems into the product lifecycle. And a challenge to both industry and regulatory authorities to more fully incorporate clinicians into the development and manufacturing environment. NOTES:

Experience of Post approval Change Management Protocols in EU Mats Welin Medical Products Agency, Sweden Post approval change management plans (PACMPs) were introduced in the EU legislation in 2010 as an option for a faster and more predictable implementation of changes post-approval. It uses a step wise approach starting with an evaluation of the strategy for the change followed by a separate evaluation of the data produced based on the agreed strategy. It applies to all medicinal products regardless if a traditional or an enhanced QbD approach has been used for product development. The option has mainly been used for biotech products since many variations which are classified as type IIs for biologicals are IB´s for small molecules and there is less incentive for such products to use a procedure starting with a type II variation by default. It may still be very useful for all products due to the predictability- if the protocol is approved and the results as expected; a quick approval can be foreseen with no requests for further data- validation batches can be commercialized. For biotech products the approval is faster once the variation is ready for implementation compared to submission of a normal type II variation. The talk will give examples of the kind of PACMPs applications which have been received, which are the normal deficiencies we see in the applications and what may be foreseen for the future. NOTES:

Improving Post-approval Change Processes as a Way to Ensure Technical Innovation and Drug Product Availability Anders Vinther Sanofi Pasteur, USA The ICH Q10 objective of continual improvement including innovation seems to be happening at a slower pace than what many companies would prefer for various reasons. Variations in regulatory processes vary between various countries in terms of requirements and timelines, which leads to a logistics challenge for companies having to manage several product versions at the same time. This is turn increases risk to product availability. If we continue and expand the dialog between industry and regulators we have an opportunity to facilitate more innovation and improve drug product availability. The solution includes reduced regulatory filing submission burden and a strong science and risk based approach to post approval changes. NOTES:

The Evolution of Post-approval Change Protocols in Biopharmaceutical Lifecycle Management Workshop Session Two Panel Discussion – Questions and Answers John Ayres, Eli Lilly and Company, USA Mairead Duke, BioMarin Europe Ltd., United Kingdom Markus Goese, F. Hoffmann-La Roche Ltd., Switzerland Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Robin Levis, CBER, FDA, USA Anders Vinther, Sanofi Pasteur, USA Mats Welin, Medical Products Agency, Sweden The following questions will guide the panel discussion: 1. What are regulatory and industry experiences with the scope of comparability protocols? a. One specific change, e.g. transfer a biologic from site X to site Y b. Apply to future changes, e.g. transfer a biologic to another, undetermined site c. Apply across a platform, e.g., transfer a biologic to additional sites 2. What are some of the requirements/considerations for larger scope protocols? 3. How do protocols complement the concept of established conditions? 4. The EU GVPs require that “a Risk Management Plan (RMP) or an update may need to be submitted at any time during a product’s life-cycle” together with a summary of the RMP for changes related to the manufacturing process of a biotechnologically-derived product a. Is that for any and all changes? Only ‘major’ changes? b. Should RMP updates be included in protocols? 5. What is the biggest hurdle to incorporating clinical input into the CM&C space? 6. What do you see as the biggest challenge for timely innovation of the pharma industry? 7. How would you know is the Quality System of a company is effective? NOTES:

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CMC Strategy Forum Europe 2016 Regulatory and Scientific Challenges of Combination Product Development Session Chairs: Chana Fuchs, CDER, FDA and Ilona Reischl, AGES-Austrian Agency for Health and Food Safety Recent years have seen an increase in novel therapeutic approaches that include co-formulation of drug products or combinations that blur the lines between the medicinal product and the medical device sectors. These combinations have an impact on the developmental pathway of the product, including regulatory expectations. The benefit of combining multiple products in a single administration is being explored through different scenarios, such as co-formulation and combinations into a single infusion bag. This session will include discussion on the combination of biologics, in particular the combination of antibodies to different targets. The analytical and regulatory requisites that arise from combining multiple biologic products for a single administration will be explored. The combinations of drugs and devices is very heterogeneous with regards to complexity and requires diverse regulatory paths to market in the various global jurisdictions. In Europe, the pathways include different regulatory authorities which depends on the main mechanism of action of the product. The session will include discussions on products classified as medicinal products which are combined with a medical device, and will include case studies. Key issues and data necessitated by the combination product will be addressed. NOTES:

Short Bio’s Tim Chesworth AstraZeneca Tim joined AstraZeneca in 2007 to lead a team responsible for developing delivery devices for AZ’s new drug portfolio. This encompassed all dosage forms and had a significant focus on inhalation and injection devices. Tim’s current role is to lead the expansion of regulatory capability in relation to combination product development. This is required to respond to the needs of AstraZeneca’s rapidly expanding new product portfolio. He is also responsible for providing regulatory input into a number of combination product development projects across conventional pharmaceuticals and biologics. Tim is an active member of a number of combination product groups and associations including the Combination Products Coalition and TOPRA MedTec SPIN. Before joining AstraZeneca, Tim lead the regulatory affairs group at Valois Pharma (Part of the Aptar Group – a Manufacturer of Drug Delivery Devices) Tim was responsible for Valois’ regulatory strategy and provided technical & regulatory input to new product development. Janine Jamieson Medicines & Healthcare Products Regulatory Agency (MHRA) Janine is a pharmacist with a PhD from King’s College, London in targeted drug delivery to the colon. Janine joined MHRA (then MCA) in 1997 as a pharmaceutical assessor for licensing of new and abridged medicinal products. In 2001, she became involved in assessment of the quality of drug substance aspects of medical devices incorporating ancillary medicinal substances and has built up experience and knowledge in the area of Notified Body Consultations and medical device regulation over the following years. She is now one of the main MHRA contacts for drug-device combination products, including Notified Body Consultations involving communicating directly with the major Notified Bodies in Europe; also advising on drug-device borderline and combination issues for the internal MHRA Borderlines group, MHRA Innovation Office and EU Innovation Office Network, EMA Innovation Task Force, and via devices colleagues, the Medical Devices Expert Group on Borderline and Classification. Currently involved in MHRA Devices-led Human Factors Working Group with UK stakeholders including NICE, Clinicians and Notified Bodies, Academics and Industry representatives, on guidance due to be published June 2016. Actively involved in developing an internal, cross-agency Drug-Device Combination Products Working Group, which will be launching internal guidance on DDCPs in May 2016, commenting on FDA Guidance for Human Factors Testing for Combination Products and contributing to development of EU guidance on DDCPs.

Short Bio’s continued Janine is an active member in the TOPRA MedTech Special Interest Network steering group, o organising and chairing the 2015 Symposium joint pharma/medical devices session, writing articles on borderlines and combination products for TOPRA Regulatory Rapporteur, Journal of Medical Device Regulation and two book chapters and regular speaker at Informa Drug-Device Combination Products; also presented at Medtech and Pharma Platform: Innovation at the Interface inaugral meeting 2014 and IPAC-RS/ISAM Workshop on Inhalation Delivery Devices 2015, contributing to a subsequent publication. Dieter Schmalzing Genentech, a Member of the Roche Group Deborah (Debbie) Thomas Sanofi Pasteur Shayesteh Fürst Ladani SFL Regulatory Affairs & Scientific Communication Ltd.

Presenter’s Abstracts Regulatory Challenges of Drug Device Combination Products in the EU Janine Jamieson Medicines & Healthcare Products Regulatory Agency (MHRA), United Kingdom This presentation will discuss: 1. Brief background to medical devices regulation 2. Challenges for combination products 

Classification

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Dossier information

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Convergence

3. Current initiatives in EU NOTES:

Regulatory Challenges of Developing a Combination Product in a Globalised World – An Industry Perspective Tim Chesworth AstraZeneca, United Kingdom 1. How can we achieve a consistent approach to combination product development in an inconsistent and changing world? 2. New drug–device combinations are becoming increasingly complex – how will they be efficiently and effectively reviewed and approved? 3. Experience of industry and regulatory agency collaboration: Combination Products Coalition & FDA Office of Combination Products NOTES:

Considerations for Control Strategies for mAb/mAB Combination Therapies – An Industry Perspective Dieter Schmalzing Genentech, a Member of the Roche Group, USA Combination therapies, where two or more drugs (e.g. mAb/ mAb) are combined to combat multifactorial diseases more effectively, are increasingly clinically evaluated earlier for complex lifethreatening diseases. This presentation will focus on CMC challenges associated with these combination therapies, such as selection of suitable analytical tools and setting of meaningful acceptance criteria for product- and process-related impurities. Risk-based approaches that can meet these challenges will be illustrated using case examples. NOTES:

Science-based Development & Licensing of Combination Products – Focus on High Concentration Monoclonal Antibody Solutions in Prefilled Syringes or Prefilled Pens Deborah (Debbie) Thomas Sanofi Pasteur, USA From a regulatory perspective, the review process for combination products can be complex and therefore challenging. There is complexity in the drug/device combination product itself. There are many lessons learned from prefilled syringe/prefilled pen development and licensing for high concentration monoclonal antibodies. In the U.S., there are typically multiple FDA centers involved in the review process, in addition to addressing EMA/CHMP and PMDA requirements. Success factors include working collaboratively with the regulatory Agency using transparency as a guide, focusing on safety and efficacy, effective and robust quality systems, utilizing science-based decision making processes, innovative technology, and effective communication to name a few. Today and tomorrow are exciting times as evolving technology affords the opportunity for drug delivery systems to progress from healthcare providers to patients and caregivers; professional health care facilities and home use. Slides were not available at the time of printing. NOTES:

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Regulatory and Scientific Challenges of Combination Product Development Workshop Session Three Panel Discussion – Questions and Answers Tim Chesworth, AstraZeneca, United Kingdom Janine Jamieson, Medicines & Healthcare Products Regulatory Agency (MHRA), United Kingdom Dieter Schmalzing, Genentech, a Member of the Roche Group, USA Deborah (Debbie) Thomas, Sanofi, USA Shayesteh Fürst Ladani, SFL Regulatory Affairs & Scientific Communication Ltd., Switzerland The following questions will guide the panel discussion: 1. What are the current and anticipated CMC and regulatory challenges arising due to product combinations? Are the issues the same between the different jurisdictions? 2. What are the anticipated changes in requirements, if any, due to the new medical device (and IVD) regulations in the EU? 3. How much information on an integral medical device is needed in the dossier for a combined medicinal product to document suitability and adequate standards? How do you support a device-change? 4. Do you draw a strict line between drug and device data, if so, where? Where is the potential overlap? 5. Is the need for the generation of medicinal product specific data in the context of integral medical devices comparable between the jurisdictions? NOTES:

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CMC Strategy Forum Europe 2016 Innovative Approaches: Tools and Technology Session Chairs: Emmanuelle Charton, EDQM, Council of Europe and Alistair Kippen, IPSEN Biopharm Ltd. The advances in analytical technology which enabled ‘Well-characterized products’ have continued. New analytical strategies, tools and methodologies are enabling further advances in analysis, characterization comparability and control strategies. These technologies are now being complemented by advances in informatics, data modelling and statistical tools. This session will explore how these technological advances are enabling new approaches to biopharmaceutical product development increasing speed to patient and managing risk during process development. The application of these technologies to innovative and biosimilar products will be discussed. NOTES:

Short Bio’s Susan Abu-Absi Bristol-Myers Squibb Company Susan Abu-Absi, PhD is director of the global manufacturing sciences & technology organization at Bristol-Myers Squibb in Devens, MA, USA. She has over 15 years of experience in biologics process development and manufacturing. Her current organization provides strategic technical leadership from process validation through the commercial life of biologics drug substance processes manufactured across the BMS network. In addition, her team is accountable for continued process verification for the commercial portfolio. Previously, Susan led the cell culture group in manufacturing sciences & technology at the Bristol-Myers Squibb facility in Syracuse, NY, USA. As a leader at BMS, Susan has contributed to the successful development and manufacture of several immunoscience and immunooncology products, including the launches of Opdivo®, Empliciti™, Yervoy®, and Nulojix®. Prior to joining BMS, she was a member of the process development organization at Bayer Healthcare in Berkeley, CA, USA. Susan has authored more than a dozen peer-reviewed publications on the topics of tissue engineering and cell culture process development, and was among the first to demonstrate the application of Quality by Design principles to mammalian cell culture process development. Susan earned a PhD in chemical engineering from the University of Minnesota (Minneapolis, MN USA) in the laboratory of Professor Wei-Shou Hu and a BS in chemical engineering from the University of Toledo (Toledo, OH USA). Brigitte Brake Federal Institute for Drugs and Medical Devices (BfArM) Peter Jongen Medicines Evaluation Board (MEB) Mr. Peter Jongen obtained his degree in pharmacy from Utrecht University in the Netherlands. He has more than 25 years’ experience in regulatory assessment and quality control of medicinal products in particular biologicals. He has worked with the National Institute of Public Health and the Environment (1991-2015) and is currently working with the Medicines Evaluation Board (2011 onwards) as senior assessor biopharmaceuticals. Mr. Jongen is chair of the European Pharmacopoeia expert group 6 ‘biological substances’ and he is a member of the Dutch delegation to the European Pharmacopoeia Commission. Since its establishment, he took part in several advisory groups of the European Network of Official Medicines Control Laboratories. Robin Levis CBER, FDA Dr. Levis received her PhD in the department of microbiology and immunology at Washington University School of Medicine. She conducted two postdoctoral fellowships; first at the National Cancer Institute in the laboratory of tumor biology and second at the Uniformed Services University of Health Sciences in the department of pathology. Dr. Levis began working in the Laboratory of Vector Borne Virus Disease in the Division of Viral Products at CBER/FDA in 1995. Her initial laboratory studies

related to dengue virus replication. She then transitioned to become the primary reviewer for all licensed rabies vaccine products and for rabies vaccines and related products under development. In 2002, Dr. Levis became the regulatory coordinator for the Division of Viral Products and in 2006 she became the deputy director of the Division of Viral Products. In this position, she has continued to be involved in the review and regulation of viral vaccine products. Laurent Mallet Sanofi Pasteur Dr. Laurent Mallet obtained his master degree of science in biochemistry from Claude Bernard Lyon University in France. He completed his PhD work in virology and molecular biology under the codirection of Pr. Michèle Aymard (National Reference Center for Enterovirus, Lyon, France) and Dr. François Pelloquin (Sanofi Pasteur, formerly Pasteur Mérieux Connaught). He obtained his PhD in 1996. After several positions within Sanofi Pasteur in France and Canada, he is currently head of analytical R&D Europe. He is also a member of several expert committees, Group 15 “Sera and Vaccines” at European Pharmacopoeia and part of the French Pharmacopoeia Committee “Biological Products and Innovative Therapies”. Recently, he has been involved in several WHO working groups (e.g. IPV, dengue and yellow fever vaccines) including the WHO study group on cell substrates and the associated adventitious agent sub-group. Jette Wypych Amgen Inc. Jette Wypych is a scientific director in attribute sciences in the p rocess development organization at Amgen. With more than 25 years of experience in biotechnology, Jette has been responsible for key discoveries in the area of cytokine and hematopoietic research. For the past decade, she has dedicated her time to aspects of process and product development. She has contributed to the development of several programs and been responsible for the analytical characterization and formulation development of pipeline molecules and been responsible for content in the chemistry, manufacturing and control (CMC) sections of numerous regulatory filings. Jette was responsible for elements of the process and product development of Prolia®, XGEVA® and Repatha®, antibody therapies for metabolic and cardiovascular disease, respectively. At Amgen, Jette has made a broad range of contributions in the areas of discovery research, analytical method and process developments, product characterization including IgG2 disulfide heterogeneity and linking chemical modification to certain types of aggregates. Her work has resulted in more than 40 publications.

Presenter’s Abstracts Viral Safety Testing of Vaccines and Other Biological Products: A Change of Paradigm Laurent Mallet Sanofi Pasteur, France Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

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Benefits of an Innovative Multi-attribute Method in Attribute Focused Process and Product Development Jette Wypych Amgen Inc., USA Historically, compliance with release specifications has typically been established by performing a comprehensive set of lot release tests of the drug substance and drug product. Often many of the release methods lacked specificity, and frequently purity methods relied on peak profiles without measuring specific attributes in scenarios where quality was tested into the product. An integrated attribute focused product development strategy based on quality by design (QbD) principles with defined quality target profile (TPP) and quality target product profile (QTPP) profits from innovative analytical approaches. In this presentation, we will share case studies and progress in the application of QTPP and the introduction of an innovative mass spectrometry based multi‐attribute method, which provides direct product attribute measurements and supports design of optimized quality into product. Slides were not available at the time of printing. NOTES:

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The Power of Data to Accelerate Development of Robust, Scalable Manufacturing Processes Susan Abu-Absi Bristol-Myers Squibb Company, USA Speed to patient is an important commitment of biopharmaceutical companies. To ensure rapid initiation of Phase I studies, we have embraced platform processes and leverage knowledge and data across products. Following the publication of ICH Q8, the benefits of an enhanced Quality by Design approach to product development have been realized, including improved process understanding and reduced regulatory burden. We increasingly utilize high throughput laboratory screening systems, coupled with advanced DoEs and multivariate analysis to develop and characterize processes. Thousands of discrete and continuous data points are generated and collected for each experiment and manufacturing batch. A few examples will be presented to illustrate the tools that can be leveraged to aggregate and analyze large, complex datasets, and the benefits of creating knowledge from data, including improved robustness at launch and continuous improvement during the lifecycle of the product. NOTES:

A Regulatory Assessor’s Perspective on Novel Analytical Techniques Peter Jongen Medicines Evaluation Board (MEB), The Netherlands Abstract was not available at the time of printing. Slides were not available at the time of printing. NOTES:

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Innovative Approaches: Tools and Technology Workshop Session Four Panel Discussion – Questions and Answers Susan Abu-Absi, Bristol-Myers Squibb Company, USA Brigitte Brake, Federal Institute for Drugs and Medical Devices (BfArM), Germany Peter Jongen, Medicines Evaluation Board (MEB), The Netherlands Robin Levis, CBER, FDA, USA Laurent Mallet, Sanofi Pasteur, France Jette Wypych, Amgen Inc., USA The following questions will guide the panel discussion: 1. What are we doing today that was viewed as innovative 20 years ago (control strategies, QC approaches) 2. What does industry want to achieve with innovation (speed, lower cost of development, lower cost of production, new modalities?) 3. How do Regulators assess innovation? (Risk-based, proportional to beneficial impact?) 4. How does industry and the regulators create an environment to share future innovation directions? Can this dialogue improve the speed and acceptance of innovation? 5. Are there good models to pilot new technology (clinical phases?) NOTES:

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