Welcome to the CMC Strategy Forum Europe 2015 We are pleased to welcome you to the CMC Strategy Forum Europe 2015. The purpose of the CMC Strategy Forum is to provide a venue for biotechnology/biological product discussion. The meetings focus on relevant CMC issues throughout the lifecycle of a product and thereby foster collaborative technical and regulatory interactions. The Forum strives to share information with the regulatory agencies to assist them in merging good scientific and regulatory practices. Outcomes of the Forum meetings are published in an appropriate peer-reviewed journal. The ninth annual CMC Strategy Forum Europe, organized by CASSS - An International Separation Science Society, 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; Product Development Acceleration Strategies; Tools and Enablers for Biosimilar Development; Practical Application of QbD-enabled Control Strategies; CMC Information and Link to Clinical Trials; Update on Medical Device/Combination Products; and Principles, Implications and Benefits of Applying QbD to Analytics. The success of the CMC Strategy Forum will depend on your active participation in discussing and raising issues pertaining to development of biologics. 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. We encourage you to participate wholeheartedly in the workshops that have been designed to stimulate exchange of ideas and information. We would like to thank the speakers who are giving generously of their time and resources, and to you, for your attendance. We acknowledge the generosity of our program partners: AbbVie, Inc., Amgen Inc., Biogen, Bristol-Myers Squibb Company, CMC Biologics, F. Hoffmann-La Roche Ltd., MedImmune, A member of the AstraZeneca Group, Merck & Co., Inc., Novo Nordisk A/S and UCB Biopharma sprl. We are grateful for the expert management from CASSS and the audio-visual expertise of Michael Johnstone from MJ Audio-Visual Productions. Their experience and guidance in the preparation of this Forum has been invaluable.

ACKNOWLEDGEMENTS CMC STRATEGY FORUM EUROPE SCIENTIFIC PROGRAM PLANNING COMMITTEE Forum Co-Chairs: Niklas Ekman, Finnish Medicines Agency, Finland Jason Hampson, Amgen Inc., USA Jolanda Westerlaken, UCB Biopharma sprl, Canada Scientific Organizing Committee: Brigitte Brake, BfArM - Federal Institute for Drugs and Medical Devices, Germany Emmanuelle Charton, EDQM – European Directorate for the Quality of Medicines, France John Dougherty, Eli Lilly and Company, USA Chana Fuchs, CDER, FDA, USA Ralf Gleixner, F. Hoffmann-La Roche Ltd., Switzerland Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland Brendan Hughes, Bristol-Myers Squibb Company, USA Ronald Imhoff, Janssen Biologics BV, Netherlands Alistair Kippen, MedImmune Limited, United Kingdom Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark Ingrid Markovic, CBER, FDA, USA Inger Mollerup, Novo Nordisk A/S, Denmark Ilona Reischl, AGES – Austrian Federal Office for Safety in Health Care, 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, BioPharmaLinx AB, Sweden Lance Smallshaw, UCB Biopharma sprl, Belgium CMC STRATEGY FORUM GLOBAL STEERING COMMITTEE Siddharth Advant, Kemwell Biopharma, USA 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 Marcelo Moreira, ANVISA - Brasilian National Health Surveillance Agency, Brasil Wassim Nashabeh, F. Hoffmann-La Roche Ltd., Switzerland Ilona Reischl, AGES - Austrian Agency for Health & Food Safety, Austria Anthony Ridgway, Health Canada, Canada Nadine Ritter, Global Biotech Experts, LLC, USA Daisaku Sato, PMDA – Pharmaceutical 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, BioPharma Linx AB, Sweden

The Scientific Organizing Committee gratefully acknowledges the program partners for their generous support of the CMC Strategy Forum Europe 2015.

SUSTAINING DIAMOND PROGRAM PARTNER

F. Hoffmann-La Roche Ltd. SUSTAINING PLATINUM PROGRAM PARTNERS

AbbVie, Inc. Biogen

MedImmune, A member of the AstraZeneca Group

GOLD PROGRAM PARTNER

Novo Nordisk A/S SILVER PROGRAM PARTNERS

Amgen Inc. CMC Biologics

BRONZE PROGRAM PARTNERS Bristol-Myers Squibb Company

UCB Biopharma sprl FRIEND of CASSS PROGRAM PARTNER

Merck & Co., Inc.

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 BioTech International

Genetic Engineering & Biotechnology News LCGC Europe

The Medicine Maker The Pathologist

RSC Advances (Analyst/Analytical Methods) separationsNOW.com Technology Networks

European Biopharmaceutical Enterprises (EBE) Satellite Session

Monday, 4 May 2015

07:30 – 12:00 Registration in the Foyer Scandinavian Ballroom 08:30 – 08:45 Welcome and Introduction to the European Biopharmaceutical Enterprises

(EBE) Ongoing Activities and Initiatives in the Markus Goese, F. Hoffmann-La Roche Ltd., Switzerland

Concept Paper - 2015 Update In the Finland / Norway Rooms

Session Chairs: Ronald Imhoff, Janssen Biologics BV and Karin Sewerin, BioPharmaLinx AB 08:45 – 09:15 A Risk-based Approach to Setting Sterile Filtration Bioburden Limits Stephen Chang, MedImmune, A member of the AstraZeneca Group, USA 09:15 – 10:00 Panel Discussion – Question and Answers Karoline Bechtold-Peters, F. Hoffmann-La Roche Ltd., Switzerland

Stephen Chang, MedImmune, A member of the AstraZeneca Group, USA Teresa Pepper, Amgen Limited, United Kingdom Harry Yang, MedImmune, A member of the AstraZeneca Group, USA 10:00 – 10:30 AM Break in the Foyer Scandinavian Ballroom

Use of Prior Knowledge for Biotech Products Workshop In the Finland / Norway Rooms

Session Chairs: Ronald Imhoff, Janssen Biologics BV and Karin Sewerin, BioPharmaLinx AB 10:30 – 10:45 Application of Prior Knowledge to Biotech Products Ranga Godavarti, Pfizer, Inc., USA 10:45 – 11:00 Mathematical Modelling as a Platform for API Process Development Ernst Broberg Hansen, Novo Nordisk A/S, Denmark

Monday, 4 May continued… 11:00 – 11:15 Knowledge Management Examples in CMC Development Kristopher Barnthouse, Janssen Pharmaceutical R&D, LLC, USA 11:15 – 12:00 Panel Discussion – Questions and Answers

Kristopher Barnthouse, Janssen Pharmaceutical R&D, LLC, USA Chana Fuchs, CDER, FDA, USA Ernst Broberg Hansen, Novo Nordisk A/S, Denmark Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland Godavarti Ranga, Pfizer, Inc., USA Mats Welin, Medical Products Agency, Sweden

12:00 – 12:15 Concluding Remarks Piers Allin, European Biopharmaceutical Enterprises (EBE), Belgium

Monday, 4 May continued…

CMC Strategy Forum Europe 2015 Scientific Program Summary

12:00 – 13:15 Buffet Lunch in Mama’s & Papa’s Restaurant 13:00 – 17:00 Registration in the Foyer Scandinavian Ballroom 13:15 – 13:30 CASSS Welcome and Introductory Comments in the Finland / Norway Rooms

Mark Schenerman, MedImmune, A member of the AstraZeneca Group, USA

Introduction / Welcome to the 9th European CMC Strategy Forum Jason Hampson, Amgen Inc., USA

Regulatory Updates from Around the World Plenary Session in the Finland / Norway Rooms

Session Chairs: Niklas Ekman, Finnish Medicines Agency and Jolanda Westerlaken, UCB Biopharma sprl

13:30 – 13:50 The Landscape of Drug Development and the Role of the Regulator Christian Schneider, Danish Health and Medicines Authority, Denmark 13:50 – 14:10 PMDA Regulatory Updates: Approach to Making Further Progress

Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan

14:10 – 14:30 EMA Update on Regulatory Developments Pascal Venneugues, European Medicines Agency (EMA), United Kingdom 14:30 – 15:45 Panel Discussion – Questions and Answers Ofra Axelrod, Israeli Ministry of Health, Israel Chana Fuchs, CDER, FDA, USA

Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan

Robin Levis, CBER, FDA, USA Christian Schneider, Danish Medicines Agency, Denmark

Pascal Venneugues, European Medicines Agency, United Kingdom 15:45 – 16:15 PM Break in the Foyer Scandinavian Ballroom

Update on Medical Device/Combination Products Plenary Session in the Finland / Norway Rooms

Session Chairs: Chana Fuchs, CDER, FDA and Karin Sewerin, BioPharmaLinx AB 16:15 – 16:30 Combination Products for Biopharmaceuticals in the EU and CMC Strategy

Forum North America January 2015 Recap Ilona Reischl, AGES – Austrian Federal Office for Safety in Health Care, Austria

Monday, 4 May continued… 16:30 – 16:45 Ensuring Fulfillment of the Essential Requirements: EMA versus Notified

Bodies Farzana Hussain, Novo Nordisk A/S, Denmark 16:45 – 17:00 The Role of Notified Bodies in Defining Risk Assessment for a Recombinant

Protein Used in a Medical Device – Case Study Karin Sewerin, BioPharmaLinx AB, Sweden 17:00 – 17:30 Panel Discussion – Questions and Answers 18:15 – 22:30 Welcome and Networking Event at Carlsberg Brewery Transportation will be provided

Tuesday, 5 May 2015 08:00 – 17:00 Registration in the Foyer Scandinavian Ballroom 08:45 – 09:00 Announcements by Jolanda Westerlaken, UCB Biopharma sprl

Tools and Enablers for Biosimilar Development Workshop Session One in the Finland / Norway Rooms

Session Chairs: Brigitte Brake, BfArM - Federal Institute for Drugs and Medical Devices and Martin Schiestl, Sandoz Biopharmaceuticals

09:00 – 09:05 Introduction 09:05 – 09:30 The Role of Statistics in the Evaluation of Biosimilarity Thomas Stangler, Sandoz Biopharmaceuticals, Austria 09:30 – 09:55 Critical Considerations for Analytical Tools in Biosimilar Development Jennifer Liu, Amgen Inc., USA 09:55 – 10:20 An Update on Regulatory Expectations for Biosimilars Seán Barry, Health Products Regulatory Authority (HPRA), Dublin, Ireland 10:20 – 10:50 AM Break in the Foyer Scandinavian Ballroom 10:50 – 11:50 Panel Discussion – Questions and Answers Seán Barry, Health Products Regulatory Authority (HPRA), Ireland

Emmanuelle Charton, EDQM – European Directorate for the Quality of Medicines, France Niklas Ekman, Finnish Medicines Agency, Finland Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan

Jennifer Liu, Amgen Inc., USA Christian Schneider, Danish Health and Medicines Authority, Denmark Thomas Stangler, Sandoz Biopharmaceuticals, Austria 12:00 – 13:15 Buffet Lunch in Mama’s & Papa’s Restaurant

Establishing a Link between the Quality Control Strategy & the Clinical Trials Experience Workshop Session Two in the Finland / Norway Rooms

Session Chairs: Inger Mollerup, Novo Nordisk A/S and Ilona Reischl, AGES - Austrian Federal Office for Safety in Health Care

13:15 – 13:20 Introduction 13:20 – 13:45 Linking IMPD Experience and Commercial Control Strategy: A Regulator’s

Perspective Mats Welin, Medical Products Agency (MPA), Sweden

Tuesday, 5 May continued… 13:45 – 14:10 A Pilot Study to Link CMC CQA Data to Clinical Experience John O’Hara, UCB Celltech, United Kingdom 14:10 – 14:35 Translating Clinical Experience into the Quality Control Strategy Romain Le Deun, Voisin Consulting Life Sciences, France 14:35 – 15:00 PM Break in the Foyer Scandinavian Ballroom 15:00 – 16:00 Panel Discussion – Questions and Answers

Brigitte Brake, BfArM, Federal Institute for Drugs and Medical Devices, Germany Michael Defelippis, Eli Lilly and Company, USA Romain Le Deun, Voisin Consulting Life Sciences, France Robin Levis, CBER, FDA, USA Karen Miller, Amgen Inc., USA John O’Hara, UCB Celltech, United Kingdom Mats Welin, Medical Products Agency (MPA), Sweden

16:00 – 16:30 Networking Break in the Foyer Scandinavian Ballroom

Principles, Implications and Benefits of Applying QbD to Analytics Workshop Session Three in the Finland / Norway Rooms

Session Chairs: Emmanuelle Charton, EDQM - European Directorate for the Quality of Medicines, Alistair Kippen, MedImmune Limited and Thomas Schreitmüller, F. Hoffmann-La Roche Ltd.

16:30 – 16:35 Introduction 16:35 – 17:00 QbD in Analytics – Enhancement of Method Development and Facilitation of

Change Management Christof Finkler, F. Hoffmann-La Roche Ltd., Switzerland 17:00 – 17:25 The Application of QbD Concepts to Analytical Methods: Enabling Efficient,

Rapid and Effective Bioprocess Development Brian Fahie, Biogen, USA 17:25 – 17:50 Analytical QbD Applied to Analytical Methods for Therapeutic Proteins –

Opportunities and Challenges Annick Gervais, UCB Biopharma sprl, Belgium 17: 50 – 18:15 Experimental Design and Modeling to Improve HPLC Method Performance

for Small Molecules John Kauffman, CDER, FDA, USA

Tuesday, 5 May continued… 18:15 – 19:15 Panel Discussion – Questions and Answers

Keith Chidwick, Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom Brian Fahie, Biogen, USA

Christof Finkler, F. Hoffmann-La Roche Ltd., Switzerland Annick Gervais, UCB Biopharma sprl, Belgium John Kauffman, CDER, FDA, USA

Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark

19:15 Adjourn

Wednesday, 6 May 2015 08:30 – 17:00 Registration in the Foyer Scandinavian Ballroom 09:00 – 09:15 Announcements by Jason Hampson, Amgen Inc.

Practical Application of QbD-enabled Control Strategies Workshop Session Four in the Finland / Norway Rooms

Session Chairs: Ralf Gleixner, F. Hoffmann-La Roche Ltd. and Jason Hampson, Amgen Inc. 09:15 – 09:20 Introduction 09:20 – 09:45 An Approach for Control Strategy from the MedImmune QbD Pilot

Program Timothy Schofield, MedImmune, A member of the AstraZeneca Group, USA 09:45– 10:10 Using QbD Principles to Optimize Lot Release and Stability Control Testing

Strategies Jay Higgins, Amgen Inc., USA

Karen Miller, Amgen Inc., USA 10:10 – 10:35 Regulatory View on the Application of Enhanced Pharmaceutical Quality

Systems for Establishing Real Time Release Mechanisms Steffen Gross, Paul-Ehrlich-Institut, Germany 10:35 – 11:00 AM Break in the Foyer Scandinavian Ballroom 11:00 – 12:00 Panel Discussion – Questions and Answers

Keith Chidwick, Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom Steffen Gross, Paul-Ehrlich-Institut, Germany Jay Higgins, Amgen Inc., USA Karen Miller, Amgen Inc., USA Dieter Schmalzing, Genentech, a Member of the Roche Group, USA Timothy Schofield, MedImmune, A member of the AstraZeneca Group, USA

12:00 – 13:15 Buffet Lunch Mama’s & Papa’s Restaurant

Product Development Acceleration Strategies Workshop Session Five in the Finland / Norway Rooms

Session Chairs: Brendan Hughes, Bristol-Myers Squibb Company and Ronald Imhoff, Janssen Biologics BV

13:15 – 13:20 Introduction 13:20 – 13:45 Regulatory Update and Considerations on the EU Adaptive Pathway Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark

Wednesday, 6 May continued… 13:45 – 14:10 Enabling Speed to Patient Starting in the Early Biologics Development Space Henrik Andersen, Bristol-Myers Squibb Company, USA 14:10 – 14:35 Manufacturing Readiness Considerations for Expedited Development

Programs Earl Dye, Genentech, a Member of the Roche Group, USA 14:35 – 15:00 Expedited Programs: US Regulatory and Quality Implications for

Biotechnology Product Development Chana Fuchs, CDER, FDA, USA 15:00 – 15:30 PM Break in the Foyer Scandinavian Ballroom 15:30 – 16:30 Panel Discussion – Questions and Answers

Henrik Andersen, Bristol-Myers Squibb Company, USA Earl Dye, Genentech, a Member of the Roche Group, USA Chana Fuchs, CDER, FDA, USA Markus Goese, F. Hoffmann-La Roche Ltd., Switzerland Jason Hampson, Amgen Inc., USA Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark

Rohin Mhatre, Biogen, USA 16:30 – 16:45 Closing Remarks and Invitation to CMC Strategy Forum Europe 2016 Jolanda Westerlaken, UCB Biopharma sprl 16:45 Adjournment

EBE Satellite Session Concept Papers – 2015 Update

A Risk-Based Approach to Setting Sterile Filtration Bioburden Limits Stephen Chang MedImmune, A member of the AstraZeneca Group, USA Microbial contamination control during the drug manufacturing process is critical for ensuring product quality and safety. For sterile biopharmaceutical drug products (finished dosage forms), manufacture typically incorporates a sterile filtration step followed by an aseptic fill-finish process, where control of the microbial load at the sterile filtration step is critical to the overall microbial control strategy. The EMA guideline (EMA/CHMP/BWP/534898/2008) states that, prior to sterile filtration, a bioburden limit of no more than 10 CFU/100 mL is considered acceptable in most situations, depending on the volume to be filtered in relation to the filter diameter. The EMA guideline further states that in the event of limited formulated product, a pre-filtration sample volume of less than 100 mL may be tested if justified. In this presentation, a risk-based approach is introduced to establish and scientifically justify alternative pre-filtration bioburden limits and test volumes. Quantitative relationships between bioburden risk, pre-filtration bioburden test limits, and sterile filtration process parameters, such as filtration volume, filter surface area, and microbial retention capacity of the sterilizing filter, were determined. Further, quantitative evaluation of the risk factors allows for rationale design of the sterile filtration step and associated control strategy. It is shown that pre-filtration bioburden test volumes and acceptance limits other than 10 CFU/100 mL may be justified, without compromise to sterility assurance. Use of this approach is illustrated through manufacturing process examples. NOTES:

Bioburden Limits Panel Discussion – Questions and Answers Karoline Bechtold-Peters, F. Hoffmann-La Roche Ltd., Switzerland Stephen Chang, MedImmune, A member of the AstraZeneca Group, USA Teresa Pepper, Amgen Limited, United Kingdom Harry Yang, MedImmune, A member of the AstraZeneca Group, USA NOTES:

NOTES:

Use of Prior Knowledge for Biotech Products Session Chairs: Ronald Imhoff, Janssen Biologics BV and Karin Sewerin, BioPharmaLinx AB The term “prior knowledge” has been frequently used for quite some time, e.g. in the discussions around QbD, new approaches for process validation, and in the development of platforms. The question still remains: What is “prior knowledge”? Is there a common understanding among biotech industry and regulators on the expectations of how the experience shall be generated? The topic “Definition and use of of Prior Knowledge” has been discussed between EBE and BWP as a potential topic for a future EMA expert workshop. The new initiatives for accelerated strategies (discussed at a separate session in the CMC Forum, e.g. EFPIA/ EBE initiative for MAPPs), will be including the assumption knowledge will be achieved from broader experience. “Knowledge management is a key basis for lifecycle management and facilitates continual improvement. The greater the knowledge, the greater the confidence” (Moheb Nasr). Another EMA workshop is scheduled for the topic of Life Cycle Management as a collaboration between Industry, QWP and BWP, in October 2015 to support the drafting process of the new ICH Q12 guideline; the understanding of the term prior knowledge and its application for biotech derived products is essential for success. NOTES:

Presenter’s Abstracts and Presentations Application of Prior Knowledge to Biotech Products Ranga Godavarti Pfizer, Inc., USA Use of prior knowledge has the potential to provide benefits to industry, regulators and patients by providing faster access to novel therapies. Prior knowledge can be from literature and/or based on company specific data. A few examples of how prior knowledge can be utilized will be provided. Specifically, application of prior knowledge in developing a modular viral clearance package for early phase clinical products will be discussed. Additional examples of use of prior knowledge in process characterization studies will also be provided. NOTES:

Mathematical Modelling as a Platform for API Process Development Ernst Broberg Hansen, Novo Nordisk A/S, Denmark The application of mathematical models for process development and optimization has been a topic of discussion in the Pharmaceutical industry for many years. Mathematical (mechanistic) models are considered as an alternative to a standard DoE type empiric approach. In our company we use mathematical models for the development of selected downstream process steps. Contrary to the general discussion of which approach is better, it is not a reduction in experimental resources or time consumption that drives us. It is the level of process understanding that we gain from using a model based approach compared to an empiric approach. Knowing what is going on we raise the bar for what is expected and what is unexpected. When the model describes the data well we are confident that the process is running as would be expected. This can include non-linear and counter intuitive behaviour. On the other hand when there is a systematic discrepancy between the model and the data we acknowledge that something unusual is going on and start looking for the unexpected phenomena. In this presentation we show two examples of how modelling is used during process development for design and troubleshooting purposes. NOTES:

Knowledge Management Examples in CMC Development Kristopher Barnthouse Janssen Pharmaceutical R&D, LLC, USA Abstract was not available at the time of printing. NOTES:

Use of Prior Knowledge for Biotech Products Workshop Session

Panel Discussion – Questions and Answers Kristopher Barnthouse, Janssen Pharmaceutical R&D, LLC, USA Chana Fuchs, CDER, FDA, USA Ernst Broberg Hansen, Novo Nordisk A/S, Denmark Kowid Ho, F. Hoffmann-La Roche Ltd., Switzerland Godavarti Ranga, Pfizer, Inc., USA Mats Welin, Medical Products Agency, Sweden The following questions will guide the discussion:

• Is prior knowledge limited to utilization of manufacturing platform procedures? • Is the knowledge product specific, company specific, or can reference be made to published

data? • How many products must be approved using the same process principle? Can data from

scientific experiments be sufficient to generate a knowledge base? E.g. demonstration of lack of effector function, using a model for several products.

• How can prior knowledge be used in the accelerated strategies for approval of new products? Can an initial validation program build on prior knowledge, with product specific data generated after approval?

• How can prior knowledge be used to determine shelf-life? • Knowledge management is one of the key components of the new ICH Q12 topic lifecycle

management, how can prior knowledge be effectively managed and leveraged to facilitate change approvals?

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Regulatory Updates from Around the World Session Chairs: Niklas Ekman, Finnish Medicines Agency and Jolanda Westerlaken, UCB Biopharma sprl In this session regulators from the host country, EU and non-EU agencies present recent developments and relevant information for the field. For the panel discussion, we will have additional global representation which will include Israel and the United States Food and Drug Administration. We have chosen three topics that we would like to start with and then open the discussion for questions from the audience. The topics for the panel discussion are listed below:

• Falsified medicines • Collaboration between agencies and industry • Collaboration between agencies

NOTES:

Presenter’s Abstracts and Presentations The Landscape of Drug Development and the Role of the Regulator Christian Schneider Danish Health and Medicines Authority, Denmark Abstract and slides were not available at the time of printing. NOTES:

NOTES:

PMDA Regulatory Updates: Approach to Making Further Progress Yasuhiro Kishioka Pharmaceuticals and Medical Devices Agency (PMDA), Japan PMDA has successfully improved its performance over the last decade. In the current mid-term plan starting from 2014, PMDA sets 4 major challenges and will further enhance its performance with increasing staff size. In this presentation, these challenges will be addressed with a focus on international activities. Our communications with industries, another key enabler for further progress, will also be introduced. Furthermore, this presentation will give the regulatory updates in Japan such as SAKIGAKE designation system (accelerated developing program) and biosimilars development. NOTES:

EMA Update on Regulatory Developments Pascal Venneugues European Medicines Agency, United Kingdom This presentation will provide a regulatory update on the current state of play on EMA international cooperation, lifecycle management and adaptive pathways in relation to CMC. The status of the BWP Process validation guideline will also be presented. Slides were not available at the time of printing. NOTES:

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Regulatory Updates from Around the World Panel Discussion

Panel Discussion – Questions and Answers Ofra Axelrod, Israeli Ministry of Health, Israel Chana Fuchs, CDER, FDA, USA Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Robin Levis, CBER, FDA, USA Christian Schneider, Danish Health and Medicines Authority, Denmark Pascal Venneugues, European Medicines Agency, United Kingdom The following questions will guide the discussion: Falsified medicines: How does your region/country deal with falsified medicines?

• Is falsified medicines considered an issue in your country/region? • What is your region doing to stop falsified medicines? • Do you have specific guidance or law enforcement in place to deal with falsified medicines?

Collaboration between agencies and industry: What kind of collaborations between agencies and industry does your agency support?

• Is there a mechanism for scientific discussions with industry (industry organization or individual companies) in your region

• How active is your agency in these kinds of discussions? • Most regions have a process for industry to provide comments on guidances, how is this process

in your region? • Do you find that comments from on industry on draft guidances are valuable? • Is there any particular topic that your agency will be focusing on for 2015-2016 in interactions

with Industry?

Collaboration between agencies: What kind of collaborations between agencies in other countries/regions do exist?

• How does your agency interact with other agencies and which pathways do assessors have to interact with assessors from other countries/regions?

• Are there regular interactions with other agencies, if so what are typical subjects/issues that are discussed at these meetings?

• Does your country/region have any mutual recognition procedures that could speed up approval process of MAA/BLA or variations? If so, which countries do you collaborate with?

• Does your country/region work with any other country in particular to discuss approvability issues on regulatory submissions?

• Is there any particular topic that your agency will be focusing on for 2015-2016 in interactions with other agencies?

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Update on Medical Device / Combination Products Session Chairs: Chana Fuchs, CDER, FDA and Karin Sewerin, BioPharmaLinx AB Combination products combine drugs, devices, and/or biological products. FDA and European regulations for combination products have been undergoing changes and have led to regulatory uncertainties for developers of these products. The FDA has recently implemented its final rule on cGMPs for combination products, and the European regulatory authorities are revising the EU medical device regulations. In this one hour session, updates on the evolving regulatory pathways for development of combination products will be addressed. NOTES:

Presenter’s Abstracts and Presentations Combination Products for Biopharmaceuticals in the EU and CMC Strategy Forum North America January 2015 Recap Ilona Reischl AGES - Austrian Federal Office for Safety in Health Care, Austria A summary of the January 2015 North America CMC Strategy Forum on "Combination Products for Biopharmaceuticals: Emerging Trends in Development, GMPs and Regulatory Expectations" will be provided and followed by a brief introductory overview on the regulatory framework for combination products in Europe with reference to the US framework. NOTES:

Ensuring Fulfillment of the Essential Requirements: EMA versus Notified Bodies Farzana Hussain Novo Nordisk A/S, Denmark Abstract was not available at the time of printing. NOTES:

The Role of a Notified Body in Defining Risk Assessment for a Recombinant Protein Used in a Medical Device – Case Study Karin Sewerin BioPharmaLinx AB, Sweden Abstract was not available at the time of printing. NOTES:

Update on Medical Device / Combination Products Discussion – Questions and Answers The following questions will guide the discussion:

• What is a combination product? • How are combination products regulated in the various regions? What are the similarities and what

are the differences? • What are the changes proposed for the revised EU medical device regulations? • Updated FDA cGMP regulations were recently implemented – what are the points of confusion as

related to new and legacy products? NOTES:

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Tools and Enablers for Biosimilar Development Session Chairs: Brigitte Brake, BfArM – Federal Institute for Drugs and Medical Devices and Martin Schiestl, Sandoz Biopharmaceuticals Looking back to the current experience with biosimilar products on the market and the huge interest in ongoing biosimilar development programs, this session will focus on enablers for development and on lessons learned with recent applications. We will look into the use of statistical tools when comparing quality attributes between the biosimilar candidate and its reference product, and the use of new analytical technologies. We will further discuss the residual uncertainty following analytical and biological characterization and to which extent quality data and product knowledge can substitute for clinical studies. On the regulatory side, we will discuss the evolving regulations and the level of harmonization of regulatory expectations between different regions, based on experiences from biosimilar developers. NOTES:

Presenter’s Abstracts and Presentations The Role of Statistics in the Evaluation of Biosimilarity Thomas Stangler Sandoz Biopharmaceuticals, Austria The analytical comparison of a biosimilar candidate to its reference product generates large amounts of data. With a sufficiently large number of batches of the reference product and biosimilar candidate, the data can be subjected to statistical evaluation. In the recent past, regulators and industry have intensified discussions on the suitability of different statistical approaches and how to integrate the statistical evaluation in the overall assessment of biosimilarity. Regulatory guidelines and reflection papers are under preparation. This talk presents recent experiences in Sandoz’ biosimilar development projects and regulatory interactions with respect to the use of statistics in the evaluation of biosimilarity. Benefits and limitations of statistical approaches will be discussed, in addition to how the statistical results fit into the overall evaluation of biosimilarity. Slides were not available at the time of printing. NOTES:

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Critical Considerations for Analytical Tools in Biosimilar Development Jennifer Liu Amgen Inc., USA The opportunities and challenges in biosimilar product development are the ability to establish pre-defined quality target product profiles based on the target reference product. Analytical tools capable of assessing critical quality attributes and serving as beacons to guide the biosimilar product and process development should be employed early and throughout all development stages. The effective development and registration of biosimilar products hinges on the use of analytical methods that are capable of informing decision making. These decisions include the selection of the cell line, the process design and development, formulation selection, and ultimately the demonstration of similarity in support of an approval decision. Biosimilar product should be demonstrated to match the reference product’s biological functions, and at the time of approval, meet the standard of being highly similar. The reliability, resolution, and relevance of the analytical tools used in biosimilar development are critical and should be demonstrated. The analytical results generated should provide high confidence for any conclusions that are drawn regarding the similarity of the reference product and proposed biosimilar. Some experts have suggested that certain highly sophisticated analytical technologies can provide fingerprinting-like profiles for large proteins. In some cases such techniques have been applied to the analysis of candidate biosmilar products. These techniques, in regards to their relative strengths and weaknesses, will be critically reviewed for their utility in biosimilar development. NOTES:

An Update on Regulatory Expectations for Biosimilars Seán Barry Health Products Regulatory Authority (HPRA), Ireland The regulatory expectations for the demonstration of biosimilarity at the quality level have been evolving over recent years. This has included recent updates to the EMA’s biosimilar scientific guidelines which have provided clarity to many aspects of the biosimilarity exercise. Notwithstanding this, regulatory understanding is constantly developing and many questions continue to challenge both regulators and industry. This presentation will deal with various aspects of the biosimilarity exercise and address several topics where there has been recent discussion and debate among regulators. The concept of ranking of quality attributes based on their relevance to biosimilarity is an emerging topic. Thus, some quality attributes can be considered of paramount importance which would preclude biosimilarity if found to be significantly different to the reference product, however other quality attributes can in fact be considered to have little or indeed no relevance to the demonstration of biosimilarity. The relative importance of quality attributes and how such ranking can influence the interpretation of biosimilarity ranges will be considered. An emerging area of interest for biosimilar developers and regulators is the possible presence of low level amino acid sequence variants in a biosimilar but not the originator. The advent of extremely sensitive techniques for protein sequence determination now facilitates detection of such variants which may arise due to mutations or errors in transcription/translation. The consequence of these variants for biosimilar development will be explored. Following the update to the biosimilar guidance, non-EEA authorised comparators can now be used in clinical and non-clinical studies; how these non-EEA authorised batches should be presented in Module 3 will be discussed. With the anticipated increase in biosimilar monoclonal antibodies (mAbs) over the coming years, the current data expectations for mAb glycosylation and effector function will be addressed. Finally, statistical analysis in biosimilarity assessment will be discussed. NOTES:

Tools and Enablers for Biosimilar Development Workshop Session

Panel Discussion – Questions and Answers Seán Barry, Health Products Regulatory Authority (HPRA), Ireland Emmanuelle Charton, EDQM – European Directorate for the Quality of Medicines, France Niklas Ekman, Finnish Medicines Agency, Finland Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Jennifer Liu, Amgen Inc., USA Christian Schneider, Danish Medicines Agency, Denmark Thomas Stangler, Sandoz Biopharmaceuticals, Austria The following questions will guide the discussion:

• What is the role of statistical tools? Can such tools facilitate the biosimilar evaluation? • What is the current status of analytical technologies and what can we expect from current progress

in this field? • To which extent can CMC data substitute for clinical study data? What is the residual uncertainty

after comparing the physicochemical and biological properties? How to explain this to clinicians? • How much are regulatory expectations harmonized on a global level? • What are the differences in written regulations between different jurisdictions? • Are there differences in advices and final opinions between different agencies? • What are the tools and enablers for further convergence of regulatory expectations on a global

level? NOTES:

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Establishing a Link between the Quality Control Strategy & the Clinical Trials Experience

Session Chairs: Inger Mollerup, Novo Nordisk A/S and Ilona Reischl, AGES – Austrian Federal Office for Safety in Health Care, Austria According to ICH Q6B, specifications are linked to numerous factors including the manufacturing process, stability data and considerations, analytical procedures as well as preclinical and clinical studies. The guideline states that “Specifications should be based on data obtained for lots used in pre-clinical and clinical studies. The quality of the material made at commercial scale should be representative of the lots used in preclinical and clinical studies.” In this session, we will explore strategies for ensuring this link between the commercial specification and the quality used in the clinical studies supporting the MAA while not forgetting manufacturability. Thus, the focus is on the methodology for ensuring the link, and neither on “setting specifications” or characterisation of impurities per se. NOTES:

Presenter’s Abstracts and Presentations Linking IMPD Experience and Commercial Control Strategy: A Regulator’s Perspective Mats Welin Medical Products Agency (MPA), Sweden A CQA is by default an attribute that may impact safety and/or efficacy if outside its limits. For this reason it is obvious that acceptance criteria for CQA´s need to be in line with what has been qualified in clinical studies or clinically qualified by other means. In addition it is important that the process is validated to consistently deliver a product that will fulfill these limits. It is agreed that Q6B in addition to results from clinical batches also adds normal process capability and stability results as factors to include in setting specification but it was very clear at the BWP-industry workshop on establishment of specifications held in 2011 that clinical justification is the most important aspect. Regardless if an attribute is tested at the Drug Substance or Drug product stage or assured through upstream in process testing or by other means, the criteria should be set such that a clinically qualified level is assured throughout the shelf life of the Drug Product. This means that the release requirements of the Drug substance and Drug product or IPC limits need to be stringent enough to allow for potential decrease during manufacture and storage. The experience up to now is that applicants often proposes acceptance criteria based on statistical calculations using all relevant batches at release, i.e. even those from which there are no clinical experience, without clinically justifying the proposed acceptance criteria. The control strategy evolves over the product life cycle and is different for products to be used in clinical trials and those for commercial production. In assessment of clinical trial the main focus is safety and as these trials are the stage when the actual levels of attributes are qualified, there are less stringent requirements applied since there is a clinical follow-up to capture any possible safety issues. This in contrast to commercial production where no such active follow-up is done and the control strategy needs to be robust to assure clinically qualified attribute levels. A common mistake is that the acceptance criteria for the material in the validation of commercial processes are set to meet the acceptance criteria used for the clinical batches and not the actual levels seen in the clinical trial batches which are the levels that are qualified. The talk will elaborate on regulator´s expectations on how this could be presented in the file and aspects to consider in linking the IMPD experience with commercial production. NOTES:

A Pilot Study to Link CMC CQA Data to Clinical Experience John O’Hara UCB Celltech, United Kingdom Historically, CMC and Clinical functions have developed autonomously. The ability to mine clinical data to support CMC understanding is often seen as difficult and low priority. Data is presented from an internal pilot study that determined the process and product related impurity levels used in clinical studies. The study aimed to assist in supporting scientific rationale for identifying Critical Quality Attributes, setting end-of-shelf life specifications and correlating Clinical events such as responders/non responders to CMC data. Slides were not available at the time of printing. NOTES:

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Translating Clinical Experience into the Quality Control Strategy Romain Le Deun Voisin Consulting Life Sciences, France The successful clinical development of a medicinal product ends up with the approval of a quality dossier related to the safety and efficacy profile the product demonstrated. The Quality Control Strategy validated through the final pivotal study sets up the baseline for the product lifecycle. The quality of biological or biotech products is however constantly evolving since the early Phase I until the Phase III pivotal study; and continues to evolve during its lifecycle. The difficulty faced by both the industry and assessors is to demonstrate that all the early safety and efficacy conclusions made on a product remain valid along its development and its lifecycle. A key element is to ensure the continued representativeness of former clinical lots compared to the most recent product versions. The following questions arise:

• How can we take into account the product ‘real life’ variability for the definition of its initial QCS? • What should be done to ensure that past conclusions on the product safety and efficacy can be

extrapolated to the next product generation? • How do we continually ensure that the product clinical profile remain the same along the inevitable

cascade of quality changes it will suffer?

This presentation will discuss different approaches that could be implemented to address these questions. In particular, we will cover the importance of implementing a solid set of analytical tools early on in the development and running a comparability program which supports the necessary quality bridges during clinical development. NOTES:

Establishing a Link between the Quality Control Strategy & the Clinical Trials Experience

Workshop Session Panel Discussion – Questions and Answers Brigitte Brake, BfArM, Federal Institute for Drugs and Medical Devices, Germany Michael Defelippis, Eli Lilly and Company, USA Romain Le Deun, Voisin Consulting Life Sciences, France Robin Levis, CBER, FDA, USA Karen Miller, Amgen Inc., USA John O’Hara, UCB Celltech, United Kingdom Mats Welin, Medical Products Agency (MPA), Sweden The following questions will guide the panel discussion:

• Typically only a limited number of batches are used in clinical trials, these will constitute what is “representative of lots used in preclinical and clinical studies”. How does on best ensure that they support the target specification?

• What considerations for use of the typically larger amount of data from all development batches vs. the smaller number of clinical batches could be applied?

• How can clinical data be used to support specification limits for specific impurities? • There will always be variability in production and thereby in the quality attributes included in the

specification. Which strategies can be applied to ensure a realistic variability during manufacture of clinical batches?

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Principles, Implications and Benefits of Applying QbD to Analytics Session Chairs: Emmanuelle Charton, EDQM – European Directorate for the Quality of Medicines, Alistair Kippen, MedImmune Limited and Thomas Schreitmüller, F. Hoffmann-La Roche Ltd. This session is intended to introduce the concept of QbD for Analytics. The concept will be discussed in terms of the Analytical Target Profile (ATP) for robust measurements throughout product lifecycle, development of analytical tools for control & measurement of CQAs, the Analytical design space to evaluate method performance criteria, incorporation of new technologies, and appropriate support of product specification setting. Real-life examples of QbD for Analytics as used within Industry to support product development will be presented to help define and demonstrate the potential benefits of QbD principals towards an effective and consistent Analytical control strategy. The session will encourage valuable discussions on QbD for Analytics, incorporating both regulatory & industry opinion and feedback. NOTES:

Presenter’s Abstracts and Presentations QbD in Analytics - Enhancement of Method Development and Facilitation of Change Management Christof Finkler F. Hoffmann-La Roche Ltd., Switzerland The goal Quality by Design (QbD) is the enhancement of pharmaceutical development through the design of product quality, its manufacturing process and controls to consistently deliver the intended performance of the product. The application of the principles described in ICHQ8(R2), “Pharmaceutical Development”,ICHQ9 “Quality Risk Management” and ICHQ11 “Development and Manufacture of Drug Substances” are leading to an increased product and process understanding. Product lifecycle management and continual improvement as outlined ICH Q10 “Pharmaceutical Quality System” are important elements to ensure product quality and supply to patients. QbD in analytics transfers these elements into analytical development and contributes to the precise, accurate and robust control of critical quality attributes. The presentation will give an overview on QbD in Analytics, presents elements of the enhanced method development and provides examples of the application of QbD principles on method development for biopharmaceuticals. Opportunities for post approval change management considering the regulatory frame work will be discussed. Slides were not available at the time of printing. NOTES:

The Application of QbD Concepts to Analytical Methods: Enabling Efficient, Rapid and Effective Bioprocess Development Brian Fahie Biogen, USA One perceived value that drove the QbD approach for process development was to provide regulatory flexibility where greater scientific understanding of the pharmaceutical and manufacturing sciences was demonstrated. Imbedded within this approach was the hope that industry could adapt a process over a lifecycle, while still ensuring a quality, safe and efficacious product. The extent of the regulatory relief over the past few years could be described as limited given the high expectations and enthusiasm of our industry just a few short years ago. The application of QbD concepts including Design Space to analytical method development may provide an opportunity to facilitate QbD approaches for bioprocess development. Specifically, having in place sufficient product understanding and adequate analytical tools is a particular challenge when applying QbD concepts for process development of complex products like biotechnology products. At a minimum, improved product understanding and analytical tools will decrease the possibility that important product quality attributes will go unrecognized during a QbD approach to process development. In addition, we propose an alternative cultural approach to QbD that reduces the emphasis on the regulatory relief value propositions (although this remains highly desirable), but rather justifies the effort and the outcomes by simply focusing on improved quality through effective and efficient control strategies. In this approach, we embrace the concept of “Right Analytics at the Right Time” and use QbD concepts applied to analytical methods as part of an integrated approach to QbD to mitigate product quality risks throughout development and product lifecycle management. We start with QbD for analytical method development first and demonstrate its value to, and link with:

• QbD for Process Development • Product Quality • Advanced Process Control • Laboratory Efficiency

Slides were not available at the time of printing. NOTES:

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Analytical QbD Applied to Analytical Methods for Therapeutic Proteins - Opportunities and Challenges Annick Gervais UCB Biopharma sprl, Belgium Benefits of applying QbD principles to analytical methods are clearly seen in terms of enhancing method robustness to produce consistent and reliable data throughout the method lifecycle. Examples of elements of QbD applied to development of analytical methods for biologicals will be presented covering the three stages of lifecycle management of analytical procedures:

• Method Design: use of design of experiments to define the method ranges • Method Performance Qualification: use of predictive approach rather than descriptive approach • Continued Method Verification: control strategy via the use of control charts

Despite the clear benefits, implementing analytical QbD to biologicals also represent challenges due to protein complexity (micro-heterogeneity) and to the potential criticality of the quality attributes. Amongst those, we would like to raise a few questions:

• Definition of the analytical target profile and link to specifications: can it be technology

independent? • Are DoE applicable to bioassays without automatisation for randomisation? • Control Strategy: how can we ensure a long term control given the criticality of key reagents

(antibodies, columns, etc…) that can add sources of variability? Slides were not available at the time of printing. NOTES:

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Experimental Design and Modeling to Improve HPLC Method Performance for Small Molecules John Kauffman CDER, FDA, USA Abstract and slides were not available at the time of printing. NOTES:

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Principles, Implications and Benefits of Applying QbD to Analytics Workshop Session

Panel Discussion – Questions and Answers Keith Chidwick, Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom Brian Fahie, Biogen, USA Christof Finkler, F. Hoffmann-La Roche Ltd., Switzerland Annick Gervais, UCB BioPharma sprl, Belgium John Kauffman, CDER, FDA, USA Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan Nanna Aaby Kruse, Danish Health and Medicines Authority, Denmark The following questions will guide the discussion:

• What should be key elements of the enhanced approach to the development and utilization of analytical procedures?

• What may be considered the benefits of applying an enhanced approach to the development and utilization of analytical methods from a regulatory and industry perspective?

• What are the implications of applying an enhanced approach from a regulatory and an industry perspective? – As above?

• Is the implementation of QbD for Analytics consistent across industry and in line with regulatory interpretation?

• Does this approach to Analytical testing strategy enhance support of product specification setting? • Is the enhanced approach restricted to any analytical technology? • Can/should the enhanced approach be applied retrospectively to traditionally develop analytical

methods? • What is the expectation of a company’s quality system to support the enhanced approach? • What could be the ultimate vision for this approach?

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Practical Application of QbD-enabled Control Strategies Session Chairs: Ralf Gleixner, F. Hoffmann-La Roche Ltd. and Jason Hampson, Amgen Inc. In order to realize the potential benefits of Quality by Design principles as articulated in ICH guidance, many companies have been investing significant resources to develop an enhanced understanding of their products and the potential impact of the process on critical quality attributes. This enhanced product and process knowledge is enabling the re-design of control strategies, where product quality is assured via a complementary combination of process controls, testing controls such as raw material controls, in-process testing, drug substance and drug product release and stability testing. Such control strategies have also enabled a reduction in unnecessary, duplicative and non-value adding testing. As companies begin to implement such control strategies, it is necessary to submit these proposals to regulatory agencies around the world for approval. These regulatory submissions necessitate the concise communication of a significant amount of data regarding risk assessments, small scale experimentation, and Quality Management Systems, which historically have not been included in Module 3 of the Marketing Application. In this session, two companies will present their experiences in developing and filing such control strategies, and the regulatory agency responses to such filing applications. A regulatory agency will also present their experiences in reviewing such applications. NOTES:

Presenter’s Abstracts and Presentations An Approach for Control Strategy from the MedImmune QbD Pilot Program Timothy Schofield MedImmune, A member of the AstraZeneca Group, USA MedImmune has had an ongoing dialogue about control strategy with the US FDA as a participant in the Quality by Design Pilot Program. While still in progress, the intent has been to obtain concurrence on some novel approaches for addressing process and analytical control. Those approaches are founded on the use of development studies to craft the control strategy as a forecast of manufacturing variability and product stability, with the intention of verifying the forecasts as sufficient data on manufacturing history and stability performance has been accrued. Agency response to the proposals has been both collegial and informative, and speaks to the value of regulatory interactions during adoption of QbD. This talk will describe the framework for the proposed MedImmune QbD control strategy, including the inter-relationships among the process, formulation and analytical controls, comparability, and a vision for continued process verification. Some examples of the use of in vitro and in vivo studies to inform specifications will be included. The talk will also examine the challenges associated with introducing new paradigms into biopharmaceutical development and manufacturing control. Slides were not available at the time of printing. NOTES:

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Using QbD Principles to Optimize Lot Release and Stability Control Testing Strategies Jay Higgins and Karen Miller Amgen, Inc., USA Specifications, as a group of tests and associated limits, are intended to be only one of a set of controls that ensure product quality. When applying Quality by Design concepts, the attributes of the product and their criticality should first be identified. Then, there is the need to understand how the process impacts those quality attributes, from raw materials to the final container and through storage. Thus, lot release specifications become a subset of the overall control strategy which includes raw material controls, in process controls, prior knowledge, process characterization and other sources of information that ensure product quality. Using the principles of QbD, an understanding of criticality of quality attributes, orthogonality of various lot release methods, control of the attribute within the process etc. enables a re-examination how specifications are set (e.g. validating out DNA and HCP testing, moving pH testing in line etc.). In the case of stability studies, knowledge and characterization of the degradation pathways of the molecule will enable refinement of testing protocols, where the validated container/closure system and appropriate storage conditions is affirmed as the primary mechanism to assure product quality, and only those attributes shown to degrade over time need to be tested. This presentation will not only cover the concepts of creating specifications using QbD but provide real examples of how commercial products can change their control strategy away from multiple lot release and stability tests. Regulatory Agency feedback on the proposed changes will also be presented. NOTES:

Regulatory View on the Application of Enhanced Pharmaceutical Quality Systems for Establishing Real Time Release Mechanisms Steffen Gross Paul-Ehrlich-Institut, Germany Global understanding of QbD has progressed since the Science- and Risk-based approach described in ICH Q8-Q11 guidelines was endorsed by industry and regulators and number of QbD submissions were meanwhile evaluated and approved. The principles of QbD were primarily focused on enhanced process development and validation information. There are new or revised guidance documents with a clear impact control strategies which will be discussed from the regulators point of view such as real-time release testing approaches based on data gained during the manufacture of medicinal products. NOTES:

Practical Application of QbD- enabled Control Strategies Workshop Session

Panel Discussion – Questions and Answers Keith Chidwick, Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom Steffen Gross, Paul-Ehrlich-Institut, Germany Jay Higgins, Amgen Inc., USA Karen Miller, Amgen Inc., USA Dieter Schmalzing, Genentech, a Member of the Roche Group, USA Timothy Schofield, MedImmune, A member of the AstraZeneca Group, USA The following questions will guide the discussion:

• Is QbD still considered optional? • Is there sufficient Return on investment? What are the benefits to industry: a) “regulatory

flexibility”; b) process and product understanding & platform knowledge • How much information do regulators need (want?) regarding all the supporting risk assessments

and small scale studies? What is the best mechanism for concisely communicating this? • How much information on the QMS is needed/wanted? How much assurance does the QMS

provide to reviewers that controls are in place? How do (will) reviewers and inspectors work together to ensure the part of the control strategy which operates within the GMP space is appropriately audited? Will EU reviewers begin to routinely attend inspections?

• What is definition of design space? Could apply to a single manufacturing step, or series of steps, but alternatively a holistic control strategy could be viewed as a type of Design Space

• Just because Industry can do something (eg testing), is it necessary for patient safety? Do all potential risks need to be mitigated by “just in case” testing?

• Challenges of implementation in a Global non-harmonized regulatory framework – what potential solutions exist?

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Product Development Acceleration Strategies Session Chairs: Brendan Hughes, Bristol-Myers Squibb Company and Ronald Imhoff, Janssen Biologics BV Recent advances in the understanding of disease biology and possible clinical interventions, particularly in oncology have resulted in a surge in clinical studies designed to test new candidates. Concurrently, regulatory processes in several major regions are being adapted (‘Breakthrough’ Status, ‘Adaptive Pathway’) and developed to support and enable early clinical testing and accelerated approval for promising candidates. Multiple, small proof-of-concept studies are planned with novel candidates with a focus on speed from lab to clinic. This has resulted in changes to the CMC development cycle and regulatory approval pathway as the clinical development pathway establishes pivotal studies earlier in the development cycle. Activities which were planned for completion during the traditional phase 3 clinical phases may now need to be complete before the commencement of phase IIB often bringing CMC on the critical path or addressed by risk mitigation or late stage comparability strategies. Regulators are inviting early dialogue and there are suggestions of more flexible approaches to data availability. This session will explore the opportunities and challenges posed by this changing environment and consider some of the responses which the CMC community can make to accelerate the availability of important novel medicines to patients.

Presenter’s Abstracts and Presentations Regulatory Update and Considerations on the EU Adaptive Pathway Nanna Aaby Kruse Danish Health and Medicines Authority, Denmark On 19th March 2014, the European Medicines Agency (EMA) published on their website an announcement on the launch of the Adaptive Licensing Pilot Project. Several applications have already been received by EMA indicating a huge interest and need for such a pathway. The process has since December 2014 been referred to as Adaptive Pathway. This talk will illustrate some of the issues that will is expected to be up for discussion in the Module 3 Quality / CMC part of a dossier for a medicinal product following the Adaptive Pathway. Some perspectives on the balance between available information/documentation for the product and the process in relation to the fact that “Adaptive Pathway builds upon regulatory processes already in place within the existing EU legal framework” will be presented. Some scenarios on which data that may be considered by the Authorities as “a must” and which may be considered for “negotiation” will be discussed. Finally, current guidelines and guidelines under development, which may be of use in the Adaptive Pathway process, will be discussed. NOTES:

Enabling Speed to Patients Starting in the Early Biologics Development Space Henrik Andersen Bristol-Myers Squibb Company, USA Abstract and slides were not available at the time of printing. NOTES:

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Manufacturing Readiness Considerations for Expedited Development Programs Earl Dye Genentech, a Member of the Roche Group, USA In July 2012, Congress passed the Advancing Breakthrough Therapies for Patients Act as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). This legislation specifies that a new drug may be designated as a Breakthrough Therapy if it is intended to treat a serious or life-threatening disease, and preliminary clinical evidence suggests that it provides a substantial improvement over existing therapies. In March 2014, the EMA launched an Adaptive Licensing Pilot to bring stakeholders together to address challenges and opportunities for making innovative medicines available to patients sooner. The objective of these expedited programs is to accelerate design and review of clinical development programs so that trials are as efficient as possible. As a consequence, traditional clinical development programs could be reduced by several years. Shorter clinical development programs will have significant impact on traditional product and process development timelines, requiring manufacturers to undertake new approaches for manufacturing readiness to ensure an adequate supply of quality product at the time of approval. This presentation will explore options manufacturers have for front-loading certain critical product and process characterization activities earlier, and working together with health authorities to identify risk based approaches to mitigate the potential risk of less, non-critical CMC data at the time of launch versus the benefit of having these innovative new products available to patients sooner. NOTES:

Expedited Programs: US Regulatory and Quality Implications for Biotechnology Product Development Chana Fuchs CDER, FDA, USA Abstract and slides were not available at the time of printing. NOTES:

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Product Development Acceleration Strategies Workshop Session

Panel Discussion – Questions and Answers Henrik Andersen, Bristol-Myers Squibb Company, USA Earl Dye, Genentech, a Member of the Roche Group, USA Chana Fuchs, CDER, FDA, USA Markus Goese, F. Hoffmann-La Roche Ltd., Switzerland Jason Hampson, Amgen Inc., USA Nanna Aaby Kruse, Danish Medicines Agency, Denmark Rohin Mhatre, Biogen, USA The following questions will guide the discussion:

• Are applicants seeing any flexibility from Regulators on CMC issues when they achieve Breakthrough (or regional equivalent)?

• Are companies changing their platform or other business process to adapt to the new dynamics imposed by pipeline acceleration and regulatory change?

• Are there technical/scientific strategies that companies might adopt that would enable and support rapid movement from exploratory to pivotal studies?

• How do companies manage mixed portfolios of molecules following a regular path and accelerating pathways?

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