Welcome to CMC Strategy Forum Japan 2018 On behalf of the CASSS Board of Directors and the CMC Strategy Forum Global Steering Committee, we would like to extend to you a warm welcome to the second meeting of the CMC Strategy Forum Japan 2018. We are very pleased that with the strong support from the Pharmaceuticals and Medical Devices Agency (PMDA Japan), as well as the Japan Pharmaceutical Manufacturers Association (JPMA), and with the continued organization by CASSS and the support from the United States Food and Drug Administration, that we are continuing with the CMC Strategy Forum Japan 2018. The Forum will follow the established model of the CMC Forum series with focus on topics and regulatory updates relevant for Japan and Asia and will feature an opening regulatory session that will include presentations from PMDA, FDA, EMA, as well as Asian health authorities. The technical sessions will include discussions on new trends for quality control of biopharmaceutical products; new trends in manufacturing of biologics: technologies involved in continuous manufacturing and regulatory perspectives; and CMC development of regenerative medicines regulations and mandatory quality control of products, raw materials and cell substrates. The success of the CMC Strategy Forum Japan will depend on your active participation in discussing and raising issues pertaining to the development of biologics. We encourage you to participate whole-heartedly in the panel discussions that have been designed to stimulate exchange of ideas and information. We would like to thank the speakers and the panel members who are giving generously of their time and resources and to you for your attendance. We would also like to acknowledge the generosity of our program partners for the continued support of the Forum series: Biogen; Chugai Pharmaceutical Co., Ltd.; Daiichi Sankyo Co., Ltd. F. Hoffmann-La Roche Ltd.; Kissei Pharmaceutical Co., Ltd.; Kyowa Hakko Kirin Co., Ltd.; MedImmune, a Member of the AstraZeneca Group; Novo Nordisk A/S; Sumitomo Dainippon Pharma Co., Ltd.; and Takeda Pharmaceutical Company Limited. 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 JAPAN SCIENTIFIC ORGANIZING COMMITTEE: Ayako Enokida, PMDA-Pharmaceuticals and Medical Devices Agency Futaba Honda, PMDA-Pharmaceuticals and Medical Devices Agency Yasushi Jotatsu, PMDA-Pharmaceuticals and Medical Devices Agency Yasuhiro Kishioka, PMDA-Pharmaceuticals and Medical Devices Agency Junichi Koga, Daiichi Sankyo Co., Ltd. Noriyuki Matsumoto, JPMA-Japan Pharmaceutical Manufacturers Association (Secretariat) Nao Nakamura, Sumitomo Dainippon Pharma Co., Ltd. Kei Nishimura, UCB Japan Co., Ltd. Hisako Ohnishi, JPMA-Japan Pharmaceutical Manufacturers Association (Secretariat) Yutaka Osawa, Asahi Kasei Pharma Kyoko Sakurai, PMDA-Pharmaceuticals and Medical Devices Agency Kazuhisa Uchida, Kyowa Hakko Kirin Co., Ltd. Masatoshi Yamada, Nippon Kayaku Co., Ltd. Takeshi Yoshino, Chugai Pharmaceutical Co., Ltd. CMC STRATEGY FORUM GLOBAL STEERING COMMITTEE Siddharth Advant, Celgene Corporation, USA Daniela Cerqueira, ANVISA-Brasilian National Health Surveillance Agency, Brasil Yasuhiro Kishioka, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Steven Kozlowski, CDER, FDA, USA Junichi Koga, Daiichi Sankyo Co., Ltd., Japan Rohin Mhatre, Biogen, USA Anthony Mire-Sluis, AstraZeneca, USA Wassim Nashabeh, Genentech, a Member of the Roche Group, USA (Chair) Ilona Reischl, BASG-Federal Office for Safety in Health Care, Austria Anthony Ridgway, Health Canada, Canada Nadine Ritter, Global Biotech Experts, LLC, USA Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland Mark Schenerman, CMC Biotech-MAS Consulting, USA Karin Sewerin, BioTech Development AB, Sweden Chikako Torigoe, CBER, FDA, USA CASSS STAFF Noelle Atkins, Administrative Coordinator Karen A. Bertani, CMP, Director, Global Engagement and Knowledge Sharing, (CMC Forum Manager) Stephanie L. Flores, CAE, Executive Director Julia Fowle, Program Planning and Event Specialist Anna Lingel, CMP, Exhibitor Relations and Technology Specialist Renee Olson, Senior Program Manager Catherine Stewart, Finance Manager AUDIO VISUAL Michael Johnstone, MJ Audio Visual Productions

The Scientific Organizing Committee gratefully acknowledges the pharmaceutical and biotechnology industry for their generous support of the CMC Strategy Forum

Japan 2018.

STRATEGIC DIAMOND PROGRAM PARTNER

F. Hoffmann – La Roche Ltd. Genentech, a Member of the Roche Group

STRATEGIC PLATINUM PROGRAM PARTNER

Biogen MedImmune, A member of the AstraZeneca Group

STRATEGIC GOLD PROGRAM PARTNER

Novo Nordisk A/S FORUM PROGRAM PARTNERS

Chugai Pharmaceutical Co., Ltd.

Daiichi Sankyo Co., Ltd.

Kissei Pharmaceutical Co., Ltd.

Kyowa Hakko Kirin Co., Ltd.

Nippon Kayaku Co., Ltd.

Sumitomo Dainippon Pharma Co., Ltd.

Takeda Pharmaceutical Company Limited

The Scientific Organizing Committee gratefully acknowledges the following media for their promotional consideration of the CMC Strategy Forum Japan 2018.

LEADING MEDIA PARTNERS

BioProcess International

International Pharmaceutical Quality MEDIA PARTNERS

The Analytical Scientist

BioProcessing Journal

Genetic Engineering & Biotechnology News

LC/GC

The Pathologist

Technology Networks

CASSS Mobile App

Does the printed program look a little bit thinner this year? That’s because we’re going mobile. This year, we are pleased to once again offer the CASSS

Mobile App for the CMC Strategy Forum Japan 2018! Top Six Reasons You Need to Have the App:

o Connect and network with fellow attendees, speakers, and exhibitors o View the schedule and create a personalized agenda o Download speaker abstracts and handouts o Take notes during the presentations and export later o Receive all the latest information on schedule changes or updates o Have all your questions answered during sessions through the activity feed

Log on and be a part of the CMC Japan Community! STEP 1 OPTION 1: On your mobile phone, go to the App Store (Apple App Store, Google Play Store) and search "CASSS 365 OPTION 2: Use a QR code reader to scan the QR code on this page. OPTION 3: To use the HTML version of the app on a laptop, go to the internet browser on your mobile phone, tablet, or computer and go to the link www.tripbuildermedia.com/apps/casss365 STEP 2 Follow store instructions to download the CASSS 365 mobile app. STEP 3 Open the app. It will ask for your username and password. THIS IS THE SAME INFORMATION YOU USE TO REGISTER FOR A CASSS MEETING. STEP 4

Go to Events and select "CMC Strategy Forum Japan" from the list. Enter your username and password again. This is the same username and password used in step three.

You now have access to the entire schedule, session abstracts, speaker handouts and bios – as well as the ability to connect with your fellow attendees.

Need Help? Still not sure how to sign in and get the most out of the mobile app? Contact CASSS Technology Specialist Anna Lingel (alingel@casss.org) or stop by the registration desk.

CMC Strategy Forum Japan 2018 Scientific Program Summary

Monday, 3 December 2018

06:30 – 08:45 Buffet Breakfast for all CMC registered guests of the Tokyo Marriott Hotel in

the Dining Grill (Lobby Level) 07:30 – 09:30 Coffee Service in the South Ballroom Foyer 07:30 – 17:00 Registration in the Oak Room 08:30 – 09:00 CASSS Welcome and Introductory Comments in the South Ballroom Wassim Nashabeh, F. Hoffmann-La Roche Ltd., USA CMC Strategy Forum Japan 2018 Welcome and Introductory Comments in

the South Ballroom Takao Yamori, PMDA-Pharmaceuticals and Medical Devices Agency, Japan

Recent Trends in the Regulation of Biopharmaceutical Products Plenary Session in the South Ballroom

Session Chairs: Yasuhiro Kishioka, PMDA-Pharmaceuticals and Medical Devices Agency and Ingrid Markovic, Genentech, a Member of the Roche Group

09:00 – 09:30 PMDA Perspective: Recent Trends in the Regulation of Biopharmaceuticals

Ayako Enokida, PMDA-Pharmaceuticals and Medical Devices Agency, Japan 09:30 – 10:00 Recent Trends in the Regulation of Biopharmaceuticals – A Korean

Perspective Gi Hyun Kim, MFDS-Ministry of Food and Drug Safety, Republic of Korea 10:00 – 10:30 A China Perspective: China NMPA Drug Regulatory Framework Reform Meng Yang, Center for Drug Evaluation, National Medical Products

Administration (NMPA), China 10:30 – 11:00 AM Break in the South Ballroom Foyer 11:00 – 11:30 US FDA Update: Recent Trends in the Regulation of Biopharmaceuticals William Hallett, CDER, FDA, USA 11:30 – 12:00 CBER Regulatory Updates: Initiatives for Product Review and Licensure Robin Levis, CBER, FDA, USA 12:00 – 12:30 Current Hotspots during CMC Evaluation – A European Regulatory

Perspective Steffen Gross, Paul-Ehrlich-Institut, Germany

Monday, 3 December continued… 12:30 – 13:45 Buffet Lunch in the North Ballroom 13:45 – 15:00 Panel Discussion – Questions and Answers

Ayako Enokida, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Steffen Gross, Paul-Ehrlich-Institut, Germany

William Hallett, CDER, FDA, USA Gi Hyun Kim, MFDS-Ministry of Food and Drug Safety, Republic of Korea Robin Levis, CBER, FDA, USA Meng Yang, Center for Drug Evaluation, National Medical Products

Administration (NMPA), China 15:00 – 15:30 PM Break in the South Ballroom Foyer

New Trends for Quality Control of Biopharmaceutical Products Workshop Session in the South Ballroom

Session Chairs: Robin Levis, CBER, FDA and Kazuhisa Uchida, Kyowa Hakko Kirin Co., Ltd. 15:30 – 15:55 Evaluation of Protein Aggregates/Subvisible Particles in Therapeutic Protein

Injections Hiroko Shibata, National Institute of Health Sciences, Japan 15:55 – 16:20 Novel Virus Clearance and Virus Detection Technologies and Applications

Qi Chen, Genentech, a Member of the Roche Group, USA 16:20 – 16:45 Multi-attribute Method by Mass Spectrometry: Current and Future State

Jette Wypych, Amgen Inc., USA 16:45 – 18:00 Panel Discussion - Questions and Answers

Qi Chen, Genentech, a Member of the Roche Group, USA Niklas Ekman, Finnish Medicines Agency, Finland

William Hallett, CDER, FDA, USA Yasuhiro Kishioka, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Chunming Rao, National Institute for Food and Drug Control, National Medical Products Administration (NMPA), China Hiroko Shibata, National Institute of Health Sciences, Japan Jette Wypych, Amgen Inc., USA

18:00 – 19:30 Networking Reception in the North Ballroom 19:30 Adjourn Day One

Tuesday, 4 December 2018 06:30 – 08:45 Buffet Breakfast for all CMC registered guests of the Tokyo Marriott Hotel in

the Dining Grill (Lobby Level) 07:30 – 09:30 Coffee Service in the South Ballroom Foyer 08:00 – 17:00 Registration in the Oak Room

New Trends in Manufacturing of Biologics: Technologies Involved in Continuous Manufacturing and Regulatory Perspectives

Workshop Session in the South Ballroom Session Chairs: Akiko Ishii-Watabe, National Institute of Health Sciences and Wassim Nashabeh,

F. Hoffmann–La Roche Ltd. 08:45 – 08:50 Introduction 08:50 – 09:15 Tne Landscape of Continuous Manufacturing in Japan Kyoko Sakurai, PMDA-Pharmaceuticals and Medical Devices Agency, Japan 09:15 – 09:40 Continuous Biomanufacturing: Relevant Experiences with Development,

Hybrid Implementation and Emerging Opportunities Erik Fouts, BioMarin Pharmaceutical Inc., USA 09:40 – 10:05 Back Pack Medicine: A Real Possibility? Michael Abernathy, Amgen Inc., USA 10:05 – 10:30 Chugai Next Generation Factory Concept: Implementation of Continuous

Manufacturing Technologies to Biopharmaceutical DS Manufacturing Yasufumi Ueda, Chugai Pharmaceutical Co., Ltd., Japan 10:30 – 11:00 AM Break in the South Ballroom Foyer 11:00 – 12:15 Panel Discussion - Questions and Answers Michael Abernathy, Amgen Inc., USA Erik Fouts, BioMarin Pharmaceutical Inc., USA Steffen Gross, Paul-Ehrlich-Institut, Germany Ingrid Markovic, Genentech, a Member of the Roche Group, USA

Kyoko Sakurai, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Yasufumi Ueda, Chugai Pharmaceutical Co., Ltd., Japan 12:15 – 13:30 Buffet Lunch in the North Ballroom

Tuesday, 4 December continued…

CMC Development of Regenerative Medicines: Regulations and Mandatory Quality Control of Products, Raw Materials and Cell Substrates

Workshop Session in the South Ballroom Session Chairs: Niklas Ekman, Finnish Medicines Agency and Yoji Sato, National Institute of Health

Sciences 13:30 – 13:55 Perspectives from the CASSS CGTP 2018 Conference: Manufacturing,

Quality and Regulatory Considerations Andrew Weiskopf, Biogen, USA 13:55 – 14:20 Considerations on Chemistry, Manufacturing and Control of Cell Therapy

Products Wei Wei, Center for Drug Evaluation, National Medical Products Administration (NMPA), China

14:20 – 14:45 CMC Consideration for the Development of Regenerative Medical Products

Kazunobu Oyama, PMDA-Pharmaceuticals and Medical Devices Agency, Japan 14:45 – 15:10 Regenerative Medicines Regulation and Quality Control in the EU Christiane Niederlaender, MHRA-Medicines and Healthcare Products Regulatory

Agency, United Kingdom 15:15 – 15:45 PM Break in the South Ballroom Foyer 15:45 – 16:10 Quality Control Strategy for Regenerative Medicine in CMC Development Kiwamu Imagawa, JCR Pharmaceuticals Co., Ltd., Japan 16:15 – 17:30 Panel Discussion – Questions and Answers Kiwamu Imagawa, JCR Pharmaceuticals Co., Ltd., Japan

Shigemi Kitagawa, Novartis K.K., Japan Ingrid Markovic, Genentech, a Member of the Roche Group, USA

Christiane Niederlaender, MHRA-Medicines and Healthcare Products Regulatory Agency, United Kingdom Kazunobu Oyama, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Wei Wei, Center for Drug Evaluation, National Medical Products Administration (NMPA), China Andrew Weiskopf, Biogen, USA

17:30 – 17:45 Closing Remarks Wassim Nashabeh, Genentech, a Member of the Roche Group, USA 17:45 Adjournment

Welcome and Introductory Comments

Wassim Nashabeh F. Hoffmann-La Roche Ltd., USA AND Takao Yamori PMDA-Pharmaceuticals and Medical Devices Agency, Japan NOTES:

Recent Trends in the Regulation of Biopharmaceutical Products Session Chairs: Yasuhiro Kishioka, PMDA-Pharmaceuticals and Medical Devices Agency and Ingrid Markovic, Genentech, a Member of the Roche Group Biopharmaceutical industry has experienced a considerable transformation in the recent years due to advancement of new therapeutic modalities such as Cell & Gene Therapies, Tissue Engineering, Anybody-Drug Conjugates or Bispecific Antibodies, which have explored new therapeutic targets or identified more sophisticated ways to address existing ones. Such therapies are often customized to the patient with the intent to match the patient specific genetic make-up achieving the desired therapeutic effect while minimizing the undesired outcomes. As these complex therapies have evolved, so have the processes to manufacture them in a consistent manner with accompanying analytics assuring that products meet the desired quality criteria. In that regard, the manufacturing environment seems to be moving away from the labor and resource-intensive batch manufacturing towards processes where given unit operations can be integrated, or in some cases, fully continuous process can be realized. Alongside with modern manufacturing, the analytics are becoming more sophisticated moving toward a multi-attribute continuous monitoring where multiple Critical Product Quality Attributes can be monitored and adjusted as needed in real-time. The innovative technological approaches are enabled by modern facility designs with smaller footprint, modular units and reliance on single-use systems with smaller batch size ensuring an agile and flexible manufacturing environment. In this regard, the regulatory landscape has become even more challenging in ensuring the quality of these products and the safety of the patients that use them. With this in mind, the strong incentive to increase the competition by boosting the biosimilars market, to accomplish an accelerated development and approval timelines (e.g., Breakthrough/Prime/Sakigake designation), both the regulators and industry, may have to continually adapt to address these challenges in order to assure continuous supply of safe and effective medicines to the patients. Because there is a greater demand for manufacturing efficiency and productivity, and an increased incentive to bring biosimilars to the market, questions were developed for the panelists to start the discussion. NOTES:

Presenter’s Abstracts PMDA Perspective: Recent Trends in the Regulation of Biopharmaceuticals Ayako Enokida PMDA-Pharmaceuticals and Medical Devices Agency, Japan Recent trends of the Japanese regulation and activities of MHLW and PMDA for drugs including biopharmaceuticals will be introduced, especially CMC topics. In addition, update information on biopharmaceuticals including biosimilars will be introduced. NOTES:

Recent Trends in the Regulation of Biopharmaceuticals – A Korean Perspective Gi Hyun Kim MFDS-Ministry of Food and Drug Safety, Republic of Korea The Ministry of Food & Drug Safety has six bureaus for ensuring the safety of foods, drugs, cosmetics, and herbal medicines and medical devices. NIFDS conducted to the science-based risk assessment, testing/analysis, review/approval of foods and drug. Biopharmaceuticals and Herbal Medicine Evaluation Department has six Division. The Recombinant Protein Products Division is belonged to that. Regulatory changes of MFDS aimed to expand the therapeutic opportunities for patient-centered drug use, to ensure safety of the patients and to prepare the 4th industrial revolution era. They reinforced the patient’s accessibility to medicine for the treatment of life-threatening disease etc. by expanding the accelerating review. Since 2015 the implementation of Risk Management Plan has been expanded step by step, all NDA drugs with different route of administration were applied in July 2017. MFDS has approved twelve biosimilar products, and nine of these products were developed in Korea until 2018. Twenty-two Biosimilar candidates were being tested. As a chair of IPRF biosimilar working group, MFDS was prepared the reflection paper on extrapolation indications in authorization of biosimilar products. NOTES:

A China Perspective: China NMPA Drug Regulatory Framework Reform Yang Meng Center for Drug Evaluation, National Medical Products Administration (NMPA), China China’s pharmaceutical market has been undergoing rapid growth in recent years to become the world’s second largest. However, China’s pharmaceutical market has historically been dominated by generic products. It was clear that to stimulate innovation by the research-based domestic drug industry and improve Chinese patients’ access to high-quality drugs, China’s regulatory system had to be reformed. In recognition of these issues, the Chinese government is promoting innovation through ongoing efforts to improve drug quality, streamline regulatory processes and cultivate an innovation-oriented environment. The past three years have witnessed that the reform has already worked, meanwhile, the Chinese pharmaceutical industry need to continuously adapt and restructure in this rapidly changing R&D landscape. NOTES:

US FDA Update: Recent Trends in the Regulation of Biopharmaceuticals William Hallett CDER, FDA, USA This presentation will cover three topics related to the review of biologics from the US FDA. The first topic includes an overview of the CDER Office of Pharmaceutical Quality and OPQ’s Strategic Priorities for the next five years. The second part of the presentation includes updates to the Biosimilars program including updates to guidance documents and approvals of biosimilars in 2018. Finally, this presentation will discuss updates and experiences with the FDA expedited programs including challenges and lessons learned. NOTES:

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

Current Hotspots during CMC Evaluation – A European Regulatory Perspective Steffen Gross Paul-Ehrlich-Institut, Germany Biopharmaceuticals have become a significant importance for treatment of human diseases. Beside the recombinant DNA-derived proteins an increasing percentage of gene therapy and genetically engineered cellular medicinal products are developed. Numerous changes to the manufacturing process are being introduced by companies in order to satisfy the increasing demands of their products. Fast but reliable procedures are necessary to having these processes accepted and approved by regulatory agencies. This talk will explore practical guidance for the CMC teams to develop an acceptable, risk-based CMC regulatory compliance strategy from early clinical stage development through market authorization taking recent, ongoing and future GMP, EMA and ICH guidance into account. It is noted that the interface between GMP and regulatory requirements with focus on marketing authorization gains more importance and an interaction between GMP inspectors and scientific assessors will be essential in order to apply certain approaches, e.g. established conditions as defined in the current draft ICHQ12 guideline. NOTES:

Recent Trends in the Regulation of Biopharmaceutical Products Workshop Session One

Panel Members: Ayako Enokida, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Steffen Gross, Paul-Ehrlich-Institut, Germany William Hallett, CDER, FDA, USA Gi Hyun Kim, MFDS-Ministry of Food and Drug Safety, Republic of Korea Robin Levis, CBER, FDA, USA Meng Yang, Center for Drug Evaluation, National Medical Products Administration (NMPA), China The following questions will guide the discussion:

1. What do you perceive as the most urgent regulatory challenges today? 2. How can those challenges be addressed? 3. How can regulatory harmonization/convergence be achieved? 4. Is global regulatory environment ready to adopt ICH Q12 and Established Conditions? 5. If not, what steps need to be taken to implement Established conditions in your region? 6. Can you share examples and strategies used in your region to accelerate CMC development

through Breakthrough/PRIME/Sakigake pathway (e.g., process validation, control strategy, stability, etc)?

7. Regional review updates/initiatives shared by panelists for each region? o E.g. An update on the FDA/CDER KASA initiative for US

8. Can you share what regulatory pathways are used in your region to approve and implement innovative technologies (e.g., Next generation Sequencing, RTRT, etc.)? o Do you have Examples to share? o Can you comment on reviewers’ readiness to review such applications in your region?

9. Regional updates on Biosimilars entry to market and time of uptake NOTES:

NOTES:

New Trends for Quality Control of Biopharmaceutical Products

Session Chairs: Robin Levis, CBER, FDA and Kazuhisa Uchida, Kyowa Hakko Kirin Co., Ltd. Evolutions and new applications of existing analytical technologies, such as mass spectrometry, and developments of novel technologies, such as next generation sequencer, enable more rapid and efficient analyses as well as analyses of new characteristics of biopharmaceutical products. Ultimately, some of such new technologies and applications may potentially change paradigm of quality control of the biotherapeutics. For example, LC-MS (LC-MS/MS) technologies that can measure multiple quality attributes (e.g., deamidation, oxidation, degradation, and protein impurities) in one method with rapid turnaround, can potentially be used as process analytical technologies (PAT) for continuous manufacturing and, subsequently, may change the paradigm from traditional lot release testing of final products towards more real-time release with the in-process results. In parallel with the evolutions of the analytical technologies, there are several attempts to compare and standardize various technologies for same purposes (e.g., aggregate analysis), to develop uniform test methods which could ultimately be added to the compendias. In this session, such new technologies and efforts for the standardization will be introduced and the predicted future trend of quality control of the biopharmaceutical products will be discussed. NOTES:

Presenter’s Abstracts Evaluation of Protein Aggregates/Subvisible Particles in Therapeutic Protein Injections Hiroko Shibata National Institute of Health Sciences, Japan Since protein aggregates/subvisible particles may relate to immunogenicity, the quantification and characterization of subvisible particles are important for ensuring the quality and safety of therapeutic protein injections. However, there are some issues for the evaluation of protein aggregates/subvisible particles. In this presentation, I will outline the current challenges as well as the emerged technologies for evaluation of protein aggregates/subvisible particles. One of the issues would be a standardization of flow imaging method. To date, the flow imaging (FI) method has emerged as a powerful tool instead of light obscuration (LO) due to the fact that (1) protein aggregates/subvisible proteins contain highly transparent particles and thereby escape detection by LO, and (2) FI provides detailed morphological characteristics of subvisible particles. However, the FI method has not yet been standardized nor listed in any compendium. Therefore, we recently conducted a collaborative study to assess the feasibility of the standardization of the FI method. Our recent achievement of the collaborative study and challenges for the future will be introduced in this presentation. NOTES:

Novel Virus Clearance and Virus Detection Technologies and Applications Qi Chen Genentech, a Member of the Roche Group, USA Virus clearance is a key component to establish virus safety of cell line derived protein therapeutics. Since the publication of ICH Q5A in 1998, significant progress has been made in virus clearance unit operations, virus quantification methods and virus clearance validation approaches. This presentation will discuss current industry knowledge of virus inactivation by eco friendly detergents, virus removal by small virus retentive filtration and chromatography steps, as well as Next Generation Sequencing for virus detection. In addition, a review of recent advances in understanding of CHO cell line virus infection risks from CHO genome sequencing and industry trend in virus clearance during continuous processing will be presented. NOTES:

Multi-attribute Method by Mass Spectrometry: Current and Future State Jette Wypych Amgen Inc., USA Historically, control strategies have typically relied on a comprehensive set of lot release tests for the drug substance and drug product. Often many of the conventional release methods lack specificity, and frequently purity methods rely on peak profiles without measuring specific attributes in scenarios where “the process defines the product” and quality is tested into the product. An integrated attribute focused product development strategy based on quality by design (QbD) principles with a defined quality target profile (TPP) and quality target product profile (QTPP) profits from innovative analytical approaches. In this presentation, we will share progress in the development and application of a mass spectrometry based multi-attribute method, which provides direct product attribute measurements and supports design of optimized quality into therapeutic protein product. Today MAM has advanced as a QC release method for clinical programs; MAM can be envisioned as a process analytical technology “on the floor method” with potential for advancing real time release testing. NOTES:

New Trends for Quality Control of Biopharmaceutical Products

Workshop Session Two Panel Members: Qi Chen, Genentech, a Member of the Roche Group, USA Niklas Ekman, Finnish Medicines Agency, Finland William Hallett, CDER, FDA, USA Yasuhiro Kishioka, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Chunming Rao, National Institute for Food and Drug Control, National Medical Products Administration (NMPA), China Hiroko Shibata, National Institute of Health Sciences, Japan Jette Wypych, Amgen Inc., USA The following questions will guide the discussion:

1. What kind of novel analytical technologies and applications are being developed and being implemented in in-process and/or release testing?

2. What are best practices of implementations of novel technologies for continuous improvements? How we can catch up with, select and implement advanced technologies?

3. How can we generate uniform/standardized testing methods out of multiple technologies being developed?

4. How should we react (report/control) when a new attribute is identified with new technologies? 5. How will the quality control paradigm evolve in near future?

NOTES:

NOTES:

New Trends in Manufacturing of Biologics: Technologies Involved in Continuous Manufacturing and Regulatory Perspectives

Session Chairs: Akiko Ishii-Watabe, National Institute of Health Sciences and Wassim Nashabeh, F. Hoffmann-La Roche Ltd. Continuous manufacturing of pharmaceutical products has been a hot topic for recent years and finally selected as a new ICH topic, ICH-Q13, because of its potential to increase manufacturing efficiency (higher productivity and reduction of manufacturing time etc). While the continuous perfusion culture itself is not a new technology and has been used for manufacturing of commercial biopharmaceuticals since 1990s, other novel technologies further supporting the continuous manufacturing, such as single-use technologies (disposable bioreactors and tubing systems (including valves, connectors, etc.)), modular manufacturing designs and continuous downstream processing equipment, are being developed and being installed to actual manufacturing facilities. These new technologies and equipment could benefit pharmaceutical companies by enabling i) more efficient production with smaller equipment in smaller facilities, ii) easier scale-up of the process and iii) facility for multiple product manufacturing without a risk of cross contamination, all of which will considerably reduce an investment for launch of new facilities and lines. On the other hand, such new technologies will require a new set of rules to regulate and control quality risks associated with such new manufacturing schemes. For example, in the continuous manufacturing setting, how is a batch defined, what kind of in-process monitoring, and feedback loop should be built-in to the process to avoid “continuous” failures, what portion should be rejected upon out-of-specification, what change control assessment will be required for switch from conventional manufacturing, and so on. While, for low molecular drugs, rules and actual example of marketing approvals, are gradually developed recently (e.g., “Points to Consider Regarding Continuous Manufacturing” guideline has been released in Japan by AMED research group), similarity and differences between the low molecules and biologics must be analyzed. In this session, an overview of new technologies being implemented to facilities, purposes and applications of the technologies (e.g., easy scale-up and capability for multi-product manufacturing to accelerate development with use of the single-use equipment, use of smaller tanks to scale down facility by implementing perfusion) and regulatory insight to the new manufacturing scheme will be introduced.

Presenter’s Abstracts The Landscape of Continuous Manufacturing in Japan Kyoko Sakurai PMDA-Pharmaceuticals and Medical Devices Agency, Japan Continuous Manufacturing (CM) is a manufacturing method in which row materials or their blended materials are entered continuously in the manufacturing process throughout the duration of the process, and products are produced continuously through the manufacturing. The CM technique is expected to address issues of agility, flexibility, cost and robustness in the development of pharmaceutical manufacturing. This presentation will provide recent activities for CMC in Japan. NOTES:

Continuous Biomanufacturing: Relevant Experiences with Development, Hybrid Implementation and Emerging Opportunities Erik Fouts BioMarin Pharmaceutical Inc., USA The benefits of continuous manufacturing (CM) have been demonstrated for decades in industries as diverse as food, electronics, and petrochemical manufacturing. CM has the similar potential to improve agility, flexibility, robustness, quality, and reduce cost in the manufacture of pharmaceuticals. These benefits have driven many pharmaceutical manufactures to adopt CM processes for synthetic molecule products. However, the adoption of CM in the biomanufacturing space has been limited, and exists primarily is in the form of a hybrid CM/batch process format. Moreover, the implementation of CM technologies has been predominantly associated with upstream processes. Today, small and pilot scale CM systems are offered by several equipment manufacturers. These tools enable the development of integrated continuous upstream and downstream processes. However, significant challenges do remain for complex biologics manufacturing, such as on-line or at-line analytical capability that allows for real time assessment of critical quality attributes spanning the operation and supporting real-time release. Another challenge is the limited understanding of the key scientific and regulatory concepts of emerging CM technology. Key to resolving this issue is a working partnership between the regulatory authorities and industry committed to creating a clear path for CM implementation. The ICH has recently formed an expert working group (EWG) to develop a technical and scientific guideline on CM for pharmaceuticals. The intent of the new ICH guidance (Q13), will be to describe key scientific and regulatory considerations, provide general guidance to regulatory agencies and industry for developing and assessing CM technologies, and promote the adoption of flexible approaches for CM implementation for a variety of modalities. Progress made by the EWG on ICH Q13 will be discussed along with examples CM implementation and development for complex biologics manufacturing to illustrate the current state, success factors, challenges, and future directions. NOTES:

Back Pack Medicine: A Real Possibility? Michael Abernathy Amgen Inc., USA The recent, and unprecedented growth of the biotechnology sector have led to a broad and diverse portfolio of innovative modalities providing hope for patients around the globe who are inflicted with grievous illnesses. Next generation biotherapeutic advancements are forging our industry ahead at an unprecedented pace paving the path towards increasingly personalized medicines. This evolution requires us to leverage technological advancements, including flexible and modular manufacturing, innovative treatment paradigms and emerging in-line, at-line and on-line Process Analytics Technologies (PAT). With recent advancements we have the capability to fit product modality to manufacturing model, while continuously monitoring and quantifying product quality attributes with increased specificity, linking attribute relevance to safety and efficacy indicators. Next generation advancements have the potential to benefit the patient, the pharmaceutical and biotherapeutic industry, and the overall health care sector driving down costs associated with shorter process and product development timelines, flexible modular and regional manufacturing models, and method optimization for in-process, release and stability testing. All of which have the potential to minimize the life-cycle management burden providing global regulatory relief. However, for us to reach our aspirational objectives and future paradigm of integrated bioprocessing and testing from “vial to device”, we require wider and more rapid global acceptance of these emerging technologies. In order for our industry to keep up with unprecedented growth and provide sustenance for personalized medicine, we must work together. Industry firms with academia and regulators must strive to develop, educate, implement and accept these more advanced, modality independent manufacturing and analytical technologies, at a more rapid pace, and by more efficient and effective means. Ultimately, the drive towards “Back Pack Medicine” will enhance the patient experience, drive down manufacturing costs, improve safety and efficacy profiles linking critical quality attributes to in vivo molecular function and clinical performance. NOTES:

Chugai Next Generation Factory Concept: Implementation of Continuous Manufacturing Technologies to Biopharmaceutical DS Manufacturing Yasufumi Ueda Chugai Pharmaceutical Co., Ltd., Japan Recently, continuous manufacturing technologies are recognized as the upcoming technologies for Pharmaceutical DS manufacturing facilities for Biologics that enables speedy, lean, down-sizing, low cost, and demand-flexible manufacturing. Chugai is trying to implement continuous manufacturing technologies to the next generation factory concept. During the internal discussion, we pointed out some technical and regulatory hurdles need to manage. In this presentation, I would like to introduce Chugai next generation factory concept and then, summarize the continuous manufacturing technologies that are under discussion in Chugai next generation factory concept and share some preliminary data of USP and DSP technologies and finally, propose the topics we considered as the hurdle needs to overcome. NOTES:

New Trends in Manufacturing of Biologics: Technologies Involved in Continuous Manufacturing and Regulatory Perspectives

Workshop Session Three Panel Members: Michael Abernathy, Amgen Inc., USA Erik Fouts, BioMarin Pharmaceutical Inc., USA Steffen Gross, Paul-Ehrlich-Institut, Germany Ingrid Markovic, Genentech, a Member of the Roche Group, USA Kyoko Sakurai, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Yasufumi Ueda, Chugai Pharmaceutical Co., Ltd., Japan The following questions will guide the discussion:

1. What are the novel technologies and equipment being installed in/evaluated for manufacturing of biologics?

• Upstream: Perfusion, single-use etc • Downstream: continuous chromatography system, virus clearance evaluation

2. What are benefits of such new technologies and equipment? 3. What are best practices of implementation of the new technologies? How is a facility set up and

validated? How should change control be made with maintaining product quality? 4. How is the new manufacturing scheme, in particular the continuous manufacturing, regulated?

How similar and/or different from the continuous manufacturing of low molecular drugs? 5. Any progress in ICH-Q13 development?

NOTES:

NOTES:

CMC Development of Regenerative Medicines: Regulations and Mandatory Quality Control of Products,

Raw Materials and Cell Substrates Session Chairs: Niklas Ekman, Finnish Medicines Agency and Yoji Sato, National Institute of Health Sciences The quality attributes of cell-based products, which should be tested, monitored and controlled, vary product by product. Several kinds of background factors, such as property of starting materials, origin and quality of raw materials, and/or complex manufacturing process, could cause the variations of the critical quality attributes amongst the cell-based products. The recent progress in cell-based medicinal products developments could provide accumulated knowledge about several challenges commonly observed over multiple cell-based products. For example, required quality of raw material are not always achievable, under circumstances where high quality ingredients such as pharmaceutical grade are not available. In this session, current regulatory requirements and/or considerations against these common issues in the cell-based medicinal product developments, especially regarding quality control and raw materials, will be discussed, with overviews of case studies and/or lessons learned from actual developments. NOTES:

Presenter’s Abstracts Perspectives from the CASSS CGTP 2018 Conference: Manufacturing, Quality and Regulatory Considerations Andrew Weiskopf Biogen, USA This past July near Washington, DC, CASSS hosted its first annual conference devoted to CMC topics in cell and gene therapy product development. With over 200 attendees from fifteen different countries, the inaugural CGTP meeting provided both industry representatives and regulators a forum to discuss emerging issues in manufacturing, analysis, and commercialization of these novel products. A summary of key messages from this year’s CGTP conference speakers will be presented. NOTES:

Considerations on Chemistry, Manufacturing and Control of Cell Therapy Products Wei Wei Center for Drug Evaluation, National Medical Products Administration (NMPA), China Cell therapy has emerged as a promising new treatment in medicine, which is expected to be able to cure diseases by repairing, replacing, and regenerating tissues, as well as immune-modulation. However, challenges remain in ensuring consistent quality, clinical efficacy and safety profiles because of the diversity of cell types and clinical indications for cell therapy products (CTPs), as well as different and complex manufacturing process. Therefore, scientific consensus and regulatory measurements are urgently warranted to promote the translation of the latest scientific advances and innovative manufacturing technologies into clinical application. This presentation aims to propose perspectives on the manufacturing, quality study and quality control of CTPs and provide considerations and opinions in the regulation of CTPs. NOTES:

CMC Consideration for the Development of Regenerative Medical Products Kazunobu Oyama PMDA-Pharmaceuticals and Medical Devices Agency, Japan Regenerative medical products have more complicated properties. Therefore, there are various challenges in CMC development of regenerative medical products. Dealing with such properties pose various challenges to strategy of CMC development for regenerative medical products. This presentation will provide the common-discussion points and regulatory perspectives about quality and CMC development, encountered in our recent experience on reviews and consultations of regenerative medical products. NOTES:

Regenerative Medicines Regulation and Quality Control in the EU Christiane Niederlaender MHRA-Medicines and Healthcare Products Regulatory Agency, United Kingdom The ATMP Regulation 1394/2007 has been in force for just over 10 years and the Committee for Advanced Therapies (CAT) has gained considerable expertise in regulating these products within the centralised system. Applying a risk-based approach, either formalised of non-formalised, helps formulating a pragmatic approach to the challenges of stating and raw materials control and product release. Examples of addressing problems associated with patient variability, raw materials qualification and short shelf-life of the finished product are addressed. NOTES:

Quality Control Strategy for Regenerative Medicine in CMC Development Kiwamu Imagawa JCR Pharmaceuticals Co., Ltd., Japan Cell Therapy Products (CTPs) consist of live cells and present a variation come from raw materials as well as in starting cells, the manufacturing processes and test methods. Manufacturing and quality controls for CTPs need to be established in consideration of their unique attributes and clinical effects. The specifications of materials and release criteria of final products will set based on product life cycle. Basic principle to control the quality is the same between Cells and Biological products. But it’s difficult to cover all of the quality of CTPs only setting quality criteria. The materials used in a manufacturing process for CTPs directly affect the quality of the final product, especially by starting materials. In addition that, during CMC development, the grade, research or pharmaceutical for materials and test methods are also important for quality control. Test methods are still not established at an early stage of CMC development. These are the cause of further variations. In the case of ordinary medicines, once the specifications are decided, it is possible to put materials into the validated manufacturing process, and then manufacture a product of a certain quality. But CTPs will not go the same way. Under such circumstances, we have already launched TEMCELL® HS inj, first allogeneic cell-based products in Japan and has been manufactured as CTPs according to agreed quality criteria. This presentation will show points to consider to establish and control the quality of materials and final product during CMC development through the case of TEMCELL® HS inj and development pipeline for another CTPs. NOTES:

CMC Development of Regenerative Medicines: Regulations and Mandatory Quality Control of Products,

Raw Materials and Cell Substrates Workshop Session Four

Panel Members: Kiwamu Imagawa, JCR Pharmaceuticals Co., Ltd., Japan Shigemi Kitagawa, Novartis K.K., Japan Ingrid Markovic, Genentech, a Member of the Roche Group, USA Christiane Niederlaender, MHRA-Medicines and Healthcare Products Regulatory Agency,

United Kingdom Kazunobu Oyama, PMDA-Pharmaceuticals and Medical Devices Agency, Japan Wei Wei, Center for Drug Evaluation, National Medical Products Administration (NMPA), China Andrew Weiskopf, Biogen, USA The following questions will guide the discussion:

1. Points to consider for quality control strategy of cell- and/or gene-therapy medicinal products; 2. Required quality grade for raw materials including ancillary materials; 3. Approach to risk assessment for strategic CMC development; 4. Considerations of consistency and comparability during CMC development; 5. Approach to process-verification and process-validation; 6. Differences in the regulatory requirements between the regions.

NOTES:

NOTES: