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Welcome to the CMC Strategy Forum Japan 2014

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 third meeting of the CMC Strategy Forum Japan

2014.

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 sponsorship by CASSS and the support from the United States Food and Drug

Administration, that we are continuing with the CMC Strategy Forum Japan 2014. 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, Health Canada, as well as Asian health authorities. The technical sessions

will include discussions on new technology of antibody engineering with focus on glycan engineering

and also bi-specific antibodies, CMC considerations in accelerated approval, life cycle approach to

process validation in biopharmaceuticals, as well as a session for regenerative medicines, bringing

together global and Japan specific case studies.

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: Astellas Pharma Inc.; Baxter Limited;

Biogen Idec; Chugai Pharmaceutical Co., Ltd.; Daiichi Sankyo Co., Ltd.; Eisai Co., Ltd.; F. Hoffmann-

La Roche Ltd.; Kissei Pharmaceutical Co., Ltd.; Kyowa Hakko Kirin Co., Ltd.; Nippon Kayaku Co.,

Ltd.; Sanwa Kagaku Kenkyusho Co., Ltd.; 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 Johnston from MJ Audio-Visual Productions. Their experience and

guidance in the preparation of this Forum has been invaluable.

ACKNOWLEDGEMENTS

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 Idec, USA

Anthony Mire-Sluis, Amgen Inc., USA

Wassim Nashabeh, F. Hoffmann-La Roche Ltd., Switzerland (Chair)

Ilona Reischl, BASG/AGES, Austria

Anthony Ridgway, Health Canada, Canada

Nadine Ritter, Global Biotech Experts, LLC, USA

Thomas Schreitmüller, F. Hoffmann-La Roche Ltd., Switzerland

Mark Schenerman, MedImmune, USA

Karin Sewerin, BioTech Development AB, Sweden

Japan Scientific Organizing Committee:

Ayako Enokida, Pharmaceuticals and Medical Devices Agency (PMDA)

Kimio Esumi, Pharmaceuticals and Medical Devices Agency (PMDA)

Futaba Honda, Pharmaceuticals and Medical Devices Agency (PMDA)

Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA)

Junichi Koga, Daiichi Sankyo Co., Ltd.

In Eui Lee, Chugai Pharmaceutical Co., Ltd.

Noriyuki Matsumoto, Japan Pharmaceutical Manufacturers Association (JPMA) (Secretariat)

Hisako Ohnishi, Japan Pharmaceutical Manufacturers Association (JPMA) (Secretariat)

Daisaku Sato, Pharmaceuticals and Medical Devices Agency (PMDA)

Yasushi Shikata, Eisai Co., Ltd.

Kazuhisa Uchida, Kyowa Hakko Kirin Co., Ltd.

Koji Usui, Pfizer Japan, Inc.

Toyohiko Yamamoto, Asahi Kasei Pharma Corporation

Reiko Yanagihara, Pharmaceuticals and Medical Devices Agency (PMDA)

The Scientific Organizing Committee gratefully acknowledges the pharmaceutical

and biotechnology industry for their generous support of the CMC Strategy Forum

Japan 2014.

SUSTAINING DIAMOND PROGRAM PARTNER

F. Hoffmann – La Roche Ltd.

SUSTAINING PLATINUM PROGRAM PARTNER

Biogen Idec

FORUM PROGRAM PARTNERS

Astellas Pharma Inc.

Baxter Limited

Chugai Pharmaceutical Co., Ltd.

Daiichi Sankyo Co., Ltd.

Eisai Co., Ltd.

Kissei Pharmaceutical Co., Ltd.

Kyowa Hakko Kirin Co., Ltd.

Nippon Kayaku Co., Ltd.

Sanwa Kagaku Kenkyusho Co., Ltd.

Sumitomo Dainippon Pharma Co., Ltd.

Takeda Pharmaceutical Company Limited

LEADING MEDIA PARTNERS

BioProcess International

International Pharmaceutical Quality

MEDIA PARTNERS

The Analytical Scientist

BioProcessing Journal

Genetic Engineering & Biotechnology News

The Medicine Maker

The Pathologist

separationsNOW.com

Technology Networks Limited

CMC Strategy Forum Japan 2014

Scientific Program Summary

Monday, 8 December 2014

06:30 – 08:15 Buffet Breakfast in Dining Café CAMELLIA (South Wing, 1st Floor)

06:30 – 10:00 Buffet Breakfast in Dining Café CAMELLIA (South Wing, 1st Floor) (for

accompanying guests)

07:15 – 09:00 Coffee Service in the Maple Room

07:15 – 17:00 Registration in the Orchard Foyer

08:15 – 08:45 CASSS Welcome and Introductory Comments in the Orchard Room

Wassim Nashabeh, Genentech, a Member of the Roche Group

CMC Strategy Forum Japan 2014 Welcome and Introductory Comments in

the Orchard Room

Takao Yamori, Pharmaceuticals and Medical Devices Agency (PMDA), Japan

Recent Trends in the Regulation of Biopharmaceutical Products in the Orchard Room

Session Chairs: Anthony Ridgway, Health Canada and Yoji Sato, National Institute of Health Sciences

08:45 – 09:15 PMDA Perspective: Recent Trends in the Regulation of Biopharmaceuticals

Daisaku Sato, Pharmaceuticals and Medical Devices Agency (PMDA), Japan

09:15 – 09:45 FDA Perspective: Recent Trends in the Regulation of Biopharmaceuticals

Marjorie Shapiro, CDER, FDA, USA

09:45 – 10:15 European Union Regulatory Updates and Recent Developments for

Biotechnology Products

Niklas Ekman, Finnish Medicines Agency, Finland

10:15 – 10:45 AM Break in the Maple Room

10:45 – 11:15 Malaysia Perspective: Recent Trends in the Regulation of

Biopharmaceuticals

Arpah Abas, Ministry of Health Malaysia (MHM), Malaysia

11:15 – 11:45 APEC Biotherapeutic Roadmap Activity: How to Work Together with

Global Initiatives

Jeewon Joung, Ministry of Food and Drug Safety (MFDS), Korea

Monday, 8 December continued…

11:45 – 12:15 Taiwan Regulatory Framework and CMC Requirements for Biotechnology

Products Churn-Shiouh Gau, Center for Drug Evaluation (CDE), Taiwan

12:15 – 13:30 Buffet Lunch in the Maple Room

13:30 – 14:45 Panel Discussion – Questions and Answers

Arpah Abas, Ministry of Health Malaysia (MHM), Malaysia


Churn-Shiouh Gau, Center for Drug Evaluation (CDE), Taiwan




14:45 – 15:15 PM Break in the Maple Room

Aspects of Quality Evaluation and Control Corresponding to the Type of Cell-based Products for

Regenerative Medicine in the Orchard Room

Session Chairs: Takao Hayakawa, Kinki University and Kazuhisa Uchida, Kyowa Hakko Kirin Co., Ltd.

15:15 – 15:25 Introduction

Takao Hayakawa, Kinki University, Japan

15:25 – 15:50 The European Landscape for Regenerative Medicine

Margarida Menezes Ferreira, INFARMED, National Authority of Medicines and

Health Products, Portugal

15:50 – 16:15 Case Study: Cell Therapy Using Accumulated Cells Launched in Japan Only

Kenichiro Hata, Japan Tissue Engineering Co., Ltd., Japan

16:15 – 16:40 Case Study: Examples Relating to the Quality Control of Cell-based

Products

Yuuki Miyatake, Teijin Pharma Limited, Japan

16:40 – 17:40 Panel Discussion - Questions and Answers

Margarida Menezes Ferreira, INFARMED, National Authority of Medicines and

Health Products, Portugal


Daisuke Maeda, Pharmaceuticals and Medical Devices Agency (PMDA), Japan


Yoji Sato, National Institute of Health Sciences, Japan

17:45 – 19:15 Networking Reception in the Maple Room

19:15 Adjourn Day One

Tuesday, 9 December 2014

06:30 – 08:30 Buffet Breakfast in Dining Café CAMELLIA (South Wing, 1st Floor)

06:30 – 10:00 Buffet Breakfast in Dining Café CAMELLIA (South Wing, 1st Floor) (for

accompanying guests)

07:15 – 09:00 Coffee Service in the Maple Room

07:15 – 17:00 Registration in the Orchard Foyer

Antibody Engineering Technologies and Products: Current Status and Future Prospects in the

Orchard Room

Session Chairs: Niklas Ekman, Finnish Medicines Agency and Nana Kawasaki, National Institute of

Health Sciences

08:15 – 08:40 Effective Engineered Antibody Formats

Izumi Kumagai, Tohoku University, Japan

08:40 – 09:05 Bispecific IgG Antibody against FIXa and FX to Treat Hemophilia A

Manabu Wada, Chugai Pharmaceutical Co., Ltd., Japan

09:05 – 09:30 GAZYVA® / GAZYVARO™ - The Success Story of a Glyco-engineered

Antibody Elisabeth Kirchisner, Roche Diagnostics GmbH, Germany

09:30 – 10:30 Panel Discussion - Questions and Answers


Futaba Honda, Pharmaceuticals and Medical Devices Agency (PMDA), Japan

Elisabeth Kirchisner, Roche Diagnostics GmbH, Germany



Teruhide Yamaguchi, Pharmaceuticals and Medical Devices Agency (PMDA),

Japan

10:30 – 11:00 AM Break in the Maple Room

Tuesday, 9 December continued…

Accelerated Developing Programs: Unique CMC Consideration in the Orchard Room

Session Chairs: Junichi Koga, Daiichi Sankyo Co., Ltd. and Wassim Nashabeh, F. Hoffmann-La Roche

Ltd.

11:00 – 11:10 Introduction

Junichi Koga, Daiichi Sankyo Co., Ltd., Japan

11:10 – 11:35 CMC Considerations and Challenges for Accelerated Programs

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

Japan

11:35 – 12:00 Challenges and Opportunities for Commercial Manufacturing Readiness and

Launch of Breakthrough Therapy Products

Earl Dye, Genentech, a Member of the Roche Group, USA

12:00 – 12:25 Risk-based Analytical Life Cycle Steps for Accelerated Products

Stephan Krause, AstraZeneca Biologics, USA


Brigitte Brake, Federal Institute for Drugs and Medical Devices, BfArM,

Germany


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

Japan



Kazuhisa Uchida, Kyowa Hakko Kirin Co., Ltd., Japan

13:30 – 14:45 Buffet Lunch in the Maple Room

Lifecycle Approach to Process Validation in the Orchard Room

Session Chairs: Kowid Ho, F. Hoffmann-La Roche Ltd. and Atsushi Matsumoto, Kyowa Hakko Kirin

Co., Ltd.

14:45 – 15:10 PMDA Perspective: Regulatory Updates on Process Validation Standard

Kazunobu Oyama, Pharmaceuticals and Medical Devices Agency (PMDA),

Japan

15:10 – 15:35 EMA Guidance Documents on Process Validation for Biotechnology-derived

Medicinal Products – A Regulatory Update Brigitte Brake, Federal Institute for Drugs and Medical Devices, BfArM,

Germany

Tuesday, 9 December 2014 continued…

15:35 – 16:00 The Lifecycle of Process Validation: An Industry Case Study on Continued

Process Verification Stefanie Pluschkell, Pfizer, Inc., USA

16:00 – 16:30 PM Break in the Maple Room


Brigitte Brake, Federal Institute for Drugs and Medical Devices, BfArM,

Germany


Atsushi Matsumoto, Kyowa Hakko Kirin Co., Ltd., Japan

Kazunobu Oyama, Pharmaceuticals and Medical Devices Agency (PMDA),

Japan

Stefanie Pluschkell, Pfizer, Inc., USA

17:30 – 18:00 CMC Strategy Forum Japan 2014 Recap

Nadine Ritter, Global Biotech Experts, LLC, USA

18:00 – 18:15 Closing Remarks

Wassim Nashabeh, Genentech, a Member of the Roche Group, USA

18:15 Adjournment

Welcome and Introductory Comments

Takao Yamori

Pharmaceuticals and Medical Devices Agency (PMDA), Japan

NOTES:

Recent Trends in the Regulation of Biopharmaceutical Products

Session Chairs: Anthony Ridgway, Health Canada and Yoji Sato, National Institute of Health Sciences

In this opening scientific session, an international group of regulators representing the US FDA, EMA,

MHM, MFDS, CDE and PMDA, will present their views on recent trends in the regulation of

biopharmaceutical products. Within this general category, presenters will be asked to include

information that will contribute to panel discussions covering three themes:

Innovative regulatory strategies for enabling the rapid development and the potential for early

marketing approval of highly promising new biotherapeutic products;

Areas of frequent consultations between industry and regulators, including, if applicable, cell and

gene therapy, and biosimilars;

International regulatory convergence and, in particular, how the picture for Asia might appear

different than the global picture.

NOTES:

Presenter’s Abstracts and Presentations

PMDA Perspective: Recent Trends in the Regulation of Biopharmaceuticals

Daisaku Sato

Pharmaceuticals and Medical Devices Agency, Japan

The Japanese regulation has improved its review performance over the last decade. In the current mid-

term plan starting from 2014, PMDA will further shorten its review period with increasing staff size. In

this presentation, we will discuss the current challenges of CMC review for biologics including post-

approval changes. In addition, biosimilars update will be also touched with a focus on the issues

surrounding global developments such as the choice of reference product and regional clinical data.

We will also outline Japanese new legislations for regenerative medicine (cellular and tissue-based

products) enacted on 25 November 2014. It enables early patient access to promising therapies, using

conditional and time-limited approval scheme in place for regenerative medical product review. At the

same time, for all pharmaceuticals including biopharmaceuticals, “Forerunner package strategy” has

been introduced to implement “accelerated approval” (including rolling submission). Such early access

schemes would raise the issues of quality evaluation and validation during the development, due to the

limited experience of batches and timeline for regulatory process. We will take an appropriate product

lifecycle approach in the post-approval changes and validation and will step further global collaboration

among regulators and with industries as well.

NOTES:

FDA Perspective: Recent Trends in the Regulation of Biopharmaceuticals

Marjorie Shapiro

CDER, FDA, Silver Spring, MD USA

Biopharmaceuticals are among the most successful drugs on the market and represent an increasing

proportion of drugs in development. The quality of these products is paramount and decisions should be

made with patient needs in mind. Initiatives such as the reorganization of quality review functions at

CDER, the development of biosimilar products, breakthrough designation, the lifecycle approach to

process validation and challenges in understanding the impact of antibody engineering will be presented.

NOTES:

European Union Regulatory Updates and Recent Developments for Biotechnology Products

Niklas Ekman

Finnish Medicines Agency, Finland

This presentation will provide an update on a number of topics which important for developing

biopharmaceuticals. The new clinical trial regulation published in the Official Journal of the European

Union in May 2014, will change the way clinical trials are authorized in the EU. The main goal of the

regulation is to harmonize the regulatory requirements, provide high standard for patient safety, and

create an environment that is favourable for conducting clinical trials. The new regulation will also

increase the transparency of clinical trial data. The principles of transparency in decision making will be

further strengthened by the recent decision from the EMA Management Board to publish clinical reports

starting from 1 January 2015. In addition to the discussion on the clinical trials regulation and the EU

transparency policy, the presentation will also summarize the current status of the EU pilot project on

adaptive licensing, as well as the future directions in the field of Advanced Therapy Medicinal Products

(ATMPs) based on the recent European Commission report on the ATMP regulation. Furthermore, the

main activities of the CHMP Biologicals Working Party (BWP) during 2014 will be reviewed.

NOTES:

Malaysia Perspective: Recent Trends in the Regulation of Biopharmaceuticals

Arpah Abas

Ministry of Health Malaysia (MHM), Malaysia

Biotechnology medicines hold some of the greatest promise for medical breakthroughs. There is a

growing interest in making biosimilars, which have the potential to lead to enormous cost-savings in

healthcare without reducing the level of care to patients.

Biosimilar regulatory pathway is a paradigm shift that requires demonstration of high similarity in terms

of quality, safety and efficacy to the reference product. However, worldwide situation shows that the

pathway is implemented rather non-homogenous particularly in developing countries. The World Health

Assembly in May 2014 passed a resolution to develop the necessary scientifically-based regulatory

frameworks that promote access to products that are affordable, safe, efficacious and quality, taking note

of the relevant of WHO guidelines on similar biotherapeutic products (SBPs).

The next wave of biosimilars are monoclonal antibodies (mAbs) that have great potential for clinical

use. As such there is much to learn and more challenges wait.

The field of cell and gene therapy products (CGTPs) is radically changing through the use of

biotechnology and products are moving towards licensure. Due to their unique, diverse and complex

manufacturing and the poor fit into the biologics pathway, a new framework is necessary to ensure

public safety but presents numerous challenges.

Malaysia had the draft CGTPs guideline completed and on circulation now for comments. Regulation of

CGTPs is still evolving, as befits a relatively young developing field. As reforms move forward,

worldwide regulatory convergence and sharing knowledge and experience will be vital to effective

regulation, since safety issues have no borders. The future success of biosimilars and CGTPs depends on

sound science and putting patients first. Science, even with broad-band, takes time and due diligence.

NOTES:

APEC Biotherapeutic Roadmap Activity: How to Work Together with Global Initiatives

Jeewon Joung

Ministry of Food and Drug Safety (MFDS), Korea

NOTES:

Taiwan Regulatory Framework and CMC Requirements for Biotechnology Products

Churn-Shiouh Gau

Center for Drug Evaluation (CDE), Taiwan

Abstract and slides were not available at the time of printing.

NOTES:

Recent Trends in the Regulation of Biopharmaceutical Products

Plenary Session

Panel Discussion – Questions and Answers Arpah Abas, Ministry of Health Malaysia (MHM), Malaysia


Churn-Shiouh Gau, Center for Drug Evaluation (CDE), Taiwan




The following questions will guide the panel discussion:

Theme 1) - Innovative regulatory strategies for enabling the rapid development and the potential for

early marketing approval of highly promising new biotherapeutic products:

What regulatory frameworks and pathways are available for the potential accelerated approval of

promising new products? What are the advantages and disadvantages of different approaches?

How will regulators in emerging markets address these concepts?

In some regulatory jurisdictions, evaluations of marketing applications may be streamlined if

approvals have been made in certain “benchmark” regulatory agencies. How will

“breakthrough”-type approaches and accelerated approval pathways, with their reliance on less

well-developed data be accommodated?

Theme 2) - Areas of frequent consultations between industry and regulators, including, if applicable: cell

and gene therapy and biosimilars:

What is the level of current activity and future landscape for cell and gene therapy products?

What is the level of current activity and future landscape for biosimilar products?

Theme 3) - International regulatory convergence and, in particular, how the picture for Asia might

appear different than the global picture:

Regarding regulatory convergence, what progress is being made at several discussion forums

(e.g., APEC, ASEAN, and APAC)?

What might be possible for regulatory convergence involving jurisdictions in Asia and the US

FDA and EU?

Are there any areas of regulatory convergence that might be Asia-specific, i.e., convergence

within Asia that does not necessarily include other major regulatory jurisdictions?

NOTES:

NOTES:

Aspects of Quality Evaluation and Control Corresponding to the

Type of Cell-based Products for Regenerative Medicine

Session Chairs: Takao Hayakawa, Kinki University and Kazuhisa Uchida, Kyowa Hakko Kirin Co., Ltd.

It is expected to accelerate the development of a variety of cell therapy products along with

establishment of the revised Pharmaceutical Affairs Law Including a two-step approval process to

ensure separately the safety and efficacy in Japan. Therefore, it should be a good opportunity to take up

this matter in CMC Strategy Forum Japan 2014.

These products are derived from the processing of human autologous or allogeneic somatic cells, human

autologous or allogeneic somatic stem cells, human autologous or allogeneic induced pluripotent cells

(hiPS cells) or hiPS-like cells and human embryonic stem cells by means of substantial manipulation

such as propagation, differentiation of a cell, activation of a cell by pharmaceutical or chemical

treatment, alteration of a biological characteristic, combination with a non-cellular component, and

manipulation by genetic engineering. There are a lot of issues to be solved with respect to evaluation and

quality control of these products because of variety of product type as well as potent significant

inconsistency of quality attributes among the same type of product manufactured through the same

procedures.

Therefore, it is necessary to discuss on general considerations and scientific principles/elements that

may apply commonly to all products for ensuring their quality and safety, as well as on points to

consider for specific product, taking into account source of cells, raw materials, cell banking ,

processing of cells, preparation of the final product, quality attributes and intended clinical use.

NOTES:


The European Landscape for Regenerative Medicine

Margarida Menezes Ferreira

INFARMED, National Authority of Medicines and Health Products, Portugal

Manipulation of tissues and cells beyond conventional transplantation as well as the development

of gene therapy determined the European Commission to establish a regulatory framework to cover

those extensively manipulated cells and gene based products as medicines and to regulate them centrally

through a Committee for Advanced Therapies (CAT) at the European Agency for Medicines (EMA).

Advanced therapies medicinal products are presently the most challenging and innovative products

being developed, in the highly accelerated moving field of regenerative medicine. Scientific journals are

flooded with new information on cells and their metabolism, differentiation and fate, on genes and

vectors that carry and deliver them in highly controlled manner and innovative materials and processes

to guide cells to generate engineered tissues. Yet, as usually happens with innovative approaches, while

multiple products are under development and in clinical trials, the path to market as a pharmaceutical

product has been rather slow. Their extreme intrinsic complexity in terms of substance and also their

dynamic mode of action, often require a complex program to ensure consistency, safety and efficacy.

The Regulation for the advanced therapy medicinal products (ATMP, established in 2007 and for

application in 2009) included several innovative provisions to support an effective development of these

important products. New regulatory approaches were foreseen for fuelling drug development without

jeopardizing public safety.

The first marketing authorization was granted in the EU to a tissue engineered product composed

of chondrocytes for cartilage repair, followed by the approval of another chondrocyte product for the

same indication. Successful long term results are expected with most these complex approaches that

combine consistent products and good surgical practices. Other cell based medicinal products have been

developed for quite some time e.g. cell based cancer immunotherapy is tried since the 90’s and it

represents presently the largest number of clinical trials in Europe. One cancer immunotherapy is

presently approved in the EU. Likewise, gene therapy medicinal products are getting into a mature phase

being used already in clinical trials with very promising results on gene repair mainly in monogenetic

diseases. The first gene therapy product was recently approved in Europe for an ultra orphan enzyme

deficiency.

The present talk will give an integrated view of the regulatory building blocks for the centralised

marketing authorisation of ATMPs in Europe, from the particular aspects in the legislation to the

relevant guidelines developed at EMA by a large group of experts from the EU member states.

Particularities such as specific GMP provisions, the risk based approach, long term safety and efficacy

follow-up will be addressed. The presentation will have a special focus on stem cell based medicinal

products in regenerative medicine.

Presently, after 5 years of ATMP Regulation implementation, intensive reflection have started to

prepare a revision of the regulatory framework, to further facilitate development without jeopardising

patient expectations and safety.

NOTES:

Case Study: Cell Therapy Using Accumulated Cells Launched in Japan Only

Kenichiro Hata

Japan Tissue Engineering Co., Ltd., Japan

Abstract and slides were not available at the time of printing.

NOTES:

Case Study: Examples Relating to the Quality Control of Cell-based Products

Yuuki Miyatake

Teijin Pharma Limited, Japan

In order to discuss the quality control regarding the cell-based products, I arranged a model case and

showed examples of quality control. Please keep in mind that these examples are not the official opinion

from JPMA but my personal opinion.

NOTES:

Aspects of Quality Evaluation and Control Corresponding to the

Type of Cell-based Products for Regenerative Medicine

Workshop Session

Panel Discussion - Questions and Answers

Margarida Menezes Ferreira, INFARMED, National Authority of Medicines and Health Products,

Portugal


Daisuke Maeda, Pharmaceuticals and Medical Devices Agency (PMDA), Japan


Yoji Sato, National Institute of Health Sciences, Japan


What type of cell-based products for regenerative medicine would be developed as commercial

products?

What strategy can be employed for evaluation and control of cell-based products for regenerative

medicine in terms of quality and safety? Identification of scientific concepts/principles and

technical elements that commonly applicable for any types of products.

Identification of points to consider for specific type of product, taking into account source of

cells, raw materials, cell banking , processing of cells, preparation of the final product, quality

attributes, intended clinical use etc. What is a role of specifications in the overall quality control

strategy of a specific product?

NOTES:

NOTES:

Antibody Engineering Technologies and Products:

Current Status and Future Prospects

Session Chairs: Niklas Ekman, Finnish Medicines Agency and Nana Kawasaki, National Institute of

Health Sciences

New strategies for antibody engineering have been developed in the biopharmaceutical field. In this

session, the current status of antibody engineering will be presented and issues related to, for example

sugar engineering and bispecific antibodies will be discussed. In addition, specific technologies and

challenges for the development of engineered antibodies will be highlighted.

NOTES:


Effective Engineered Antibody Formats

Izumi Kumagai

Tohoku University、Japan

In recent years, more than thirty monoclonal antibodies have been approved as biopharmaceutical

products in many threpeutic areas, including cancer and immune disorders. From the point of view in

protein tcchnology, the drastic and successful advances of antibody threpeutics have been achieved by

the recombination of protein folds and motives. Antibody engineering has developed various molecular

formats including IgG, smaller antibody fragments(Fab, Fv, scFv) and proteins fused with these formats,

by recombination of immunoglobulin folds as structural and functional units and then generated the

novel antibody functions. The engineered antibody formats and variants are now emerging as credible

alternatives and possess other unique and superior properties for therapeutic applications. The typical

example may be the development of bispecific antibodies.

We would focus on applications of molecular formats with bi-specificity consisting of two different

scFvs(diabody). One application of the molecule is targeting effector cells to tumor cell surfaces. We

previously reported the marked antitumor effects of a humanized bispecific diabody. The domains of

bispecific diabodies can be ordered in four different ways. We rearranged the domains of the bispecific

diabody to examine the influence of domain order on the function of bispecific diabodies. All three

rearranged bispecific diabodies inhibited cancer growth more effectively than did the original bispecific

diabody in which both components were in VH-VL domain order. The molecular spieces with the

highest effects had comparable antitumor effects to those of the tandem scFv format(BiTE type). Further

functional analyses of these formats are summarized .

NOTES:

Bispecific IgG Antibody against FIXa and FX to Treat Hemophilia A

Manabu Wada

Chugai Pharmaceutical Co., Ltd., Japan

Bispecific antibody is a promising technology for antibody engineering, because its potential as a

therapeutic exceeds that of combining two monospecific antibodies. ACE910, our asymmetric bispecific

human IgG antibody for treating hemophilia A, exemplifies this potential by mimicking the action of

coagulation factor VIII; namely, by binding to coagulation factor IXa with one arm and factor X with

another. However, reducing undesired products that have mis-paired arms is key when manufacturing an

asymmetric antibody. To manufacture ACE910 we have implemented several engineering technologies

— common light chain, pI modification, and CH3/CH3 interface engineering — that have enabled large

scale GMP production on a standard IgG production/purification platform.

NOTES:

GAZYVA®/ GAZYVARO™ - The Success Story of a Glyco-engineered Antibody

Elisabeth Kirchisner

Roche Diagnostics GmbH, Germany

GAZYVA

/ GAZYVARO (INN: obinutuzumab) is the first glycoengineered antibody which has been

approved for commercial use. Glycoengineering was obtained by GlycoMAbTM

technology. This

technology is based on the co-expression of the antibody with glycosylation-modifying enzymes during

cell culture which leads to a modified glycosylation pattern with reduced levels of core-fucosylation.

The increased level of afucosylation results in an increase in antibody-dependent cell-mediated

cytotoxicity (ADCC).

Obinutuzumab has shown increased ADCC and direct cell death activity as compared to rituximab and

ofatumumab. For treatment of CLL patients in clinical trials progression-free survival was significantly

longer when using obinutuzumab in combination with chlorambucil than rituximab in combination with

chlorambucil or chlorambucil alone. Based on these data obinutuzumab was approved by the FDA as

GAZYVA® on 1 November 2013 and as GAZYVARO™ by EMA and Swissmedic in 2014.

A full Quality by Design (QbD) approach was used for technical development of obinutuzumab. Critical

Quality Attributes (CQAs) and respective acceptance criteria were identified. During process

characterization and validation univariate and multivariate studies and worst-case linkage studies were

performed. Critical and non-critical process parameters (CPPs/ non-CPPs) and a process-wide Design

Space were identified. Based on how well CQAs are controlled by the process and how stable they are a

comprehensive testing strategy was set up. The resulting release specification for Drug Substance also

covers several glycostructures.

Benefits of using the QbD approach include enhanced product and process understanding, the ability to

meet international Health Authority expectations and enhanced process robustness.

NOTES:

Antibody Engineering Technologies and Products:

Current Status and Future Prospects

Workshop Session

Panel Discussion - Questions and Answers Niklas Ekman, Finnish Medicines Agency, Finland

Futaba Honda, Pharmaceuticals and Medical Devices Agency (PMDA), Japan

Elisabeth Kirchisner, Roche Diagnostics GmbH, Germany



Teruhide Yamaguchi, Pharmaceuticals and Medical Devices Agency (PMDA), Japan


• What are the biological and structural features characteristic to engineered antibodies?

• Are there any specific issues (e.g. with regard to technologies used) related to the development,

characterization, manufacture and control of engineered antibodies?

• Compared to conventional monoclonal antibodies, are there any additional CMC issues to be

considered for NDA approval of engineered antibodies?

• Current promises and future hopes; how do patients benefit from engineered antibodies?

NOTES:

NOTES:

Accelerated Developing Programs:

Unique CMC Considerations

Session Chairs: Junichi Koga, Daiichi Sankyo Co., Ltd. and Wassim Nashabeh, F. Hoffmann-La Roche

Ltd.

A breakthrough therapy approval and an adaptive licensing program have started in US and in EU,

respectively. More recently, in Japan, SAKIGAKE designation system has been introduced. These

initiatives encourage industries to deliver a better drug faster to patients. Meanwhile, industries are

required to collect sufficient data or rationale to set an appropriate control strategy within a short period

of time.

This session will discuss on the unique CMC considerations for more accelerated CMC developments in

each stage of prior to and post approvals, and share the lessons learned from the accelerated CMC

development or marketing authorization application review for the breakthrough therapy.

NOTES:


CMC Considerations and Challenges for Accelerated Programs

Yasuhiro Kishioka


NOTES:

Challenges & Opportunities for Commercial Manufacturing Readiness and Launch of

Breakthrough Drug Products

Earl Dye

Genentech, a Member of the Roche Group, USA

The Advancing Breakthrough Therapies for Patients Act was included as a component of the 2012 re-

authorization of the Prescription Drug User Fee Act to expedite development of new, potential

“breakthrough” therapies. 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. Upon

designation, the FDA and sponsor collaborate in a dynamic, multi-functional process to determine the

most efficient path forward. This expedited approach to the design of the clinical program could

potentially reduce development timelines from 7-10 years to 3-5 years, necessitating a different

approach to product and process development, and commercial readiness, launch and regulatory filings.

A cross functional team modeled accelerated timelines for large and small molecule products assuming a

typical clinical development program for a breakthrough product would be five years, including 1-2

years to generate sufficient preliminary clinical information to qualify for breakthrough therapy

designation, and an additional 2-3 years to complete the pivotal studies, file an application and launch

the product. To complete all the necessary activities within these accelerated time lines required front

loading certain product and process development activities earlier, truncating phase III process

optimization to focus on reliability of the phase l cell line process and formulation to ensure a reliable

supply of quality product at launch. Key considerations for success relied on leveraging prior knowledge

and platform data, use of comparability protocols, and flexible manufacturing arrangements for potential

launch from a clinical facility. This presentation will discuss the manufacturing development and launch

considerations for breakthrough therapies, together with the assumptions and considerations that went

into the design of the accelerated timelines.

NOTES:

Risk-based Analytical Life Cycle Steps for Accelerated Products

Stephan Krause

AstraZeneca Biologics, USA

Accuracy and reliability of analytical methods should be assured throughout the product life cycle.

Strategies for the analytical method lifecycle steps will be discussed with the intent to minimize the risk

of potential product development/approval delay. This presentation will cover risk-based processes for

analytical method qualification, transfer, and validation. The presentation will specifically focus on

opportunities to use prior experience (ex., analytical platform technology) to support accelerated product

development and process validation studies. The goal is to understand how analytical platform

technology and parallel (versus sequential) analytical method and specification lifecycle steps can

greatly support accelerated development programs.

NOTES:

Accelerated Developing Programs:

Unique CMC Considerations

Workshop Session

Panel Discussion – Questions and Answers

Brigitte Brake, Federal Institute for Drugs and Medical Devices, BfArM, Germany


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



Kazuhisa Uchida, Kyowa Hakko Kirin Co., Ltd., Japan


• What are the regulatory expectations on accelerated developing programs for CMC?

• What regulations are the most challenging for the accelerated CMC development? What is the

alternative approach to be considered?

• Among CMC development, which parts are having possibility to speed up?

• How do you set specifications for drug substance and drug product with limited information or

limited period, for instances, few of manufacturing data, low frequency of clinical trials, or the

results from scale-down study?

• How do you set the expiry date with the short-term stability test data using pilot runs?

NOTES:

NOTES:

Lifecycle Approach to Process Validation

Session Chairs: Kowid Ho, F. Hoffmann-La Roche Ltd. and Atsushi Matsumoto, Kyowa Hakko Kirin

Co., Ltd.

The product lifecycle concept was introduced in ICH Q8 and Q10 guidelines. The application of process

performance and product quality monitoring system throughout the product lifecycle is encouraged for

the assurance of product quality in ICH Q10 guideline.

To incorporate this concept, FDA guidance on process validation was revised in 2011. For the

harmonization with FDA guidance, MHLW revised the notices of GMP/QMS upon enforcement of the

Pharmaceutical Affairs Act in 2013. EMA revised the process validation guideline in 2014.

The purpose of this session is to discuss how this new concept should be applied to the process

validation for biopharmaceuticals and how the process validation strategy should be presented in

marketing application dossier.

NOTES:


PMDA Perspective: Regulatory Updates on Process Validation Standard

Kazunobu Oyama


NOTES:

EMA Guidance Documents on Process Validation for Biotechnology-derived Medicinal Products –

A Regulatory Update

Brigitte Brake

Federal Institute for Drugs and Medical Devices, BfArM, Germany

NOTES:

The Lifecycle of Process Validation: An Industry Case Study on Continued Process Verification

Stefanie Pluschkell

Pfizer Inc., USA (on behalf of BPOG)

This presentation reports on a cross-company collaboration on Continued Process Verification (CPV) in

response to the FDA’s 2011 process validation guidance (“Stage 3”). Created by representatives from 24

companies, with facilitation from the BioPhorum Operations Group (BPOG) (www.biophorum.com),

the presentation describes approaches to implementing CPV and offers specific recommendations on the

content of a CPV Plan. CPV encompasses a written plan for continued monitoring of a licensed

biopharmaceutical manufacturing process, providing a basis from which to assure maintenance of the

validated state, improve process understanding, the control strategy, and ultimately the robustness of the

manufacturing process itself. These recommendations are based on a typical cell culture production

process for making a fictitious monoclonal antibody drug substance, as described in the ‘A-Mab Case

Study’. Consequently, not all of the details are going to apply directly to actual products or processes.

However, the concepts and principles upon which the content of this case study was derived should help

with CPV implementation for a real product. The presentation will include concepts and examples of

how to apply quality risk management principles (ICHQ9) to generate an effective process monitoring

plan as well as a risk-based decision tree to determine if and to what extent observed trends should be

responded to. CPV execution may involve examination of already existing process control

measurements and/or the use of improved methodologies for data tracking and analysis. Enhanced

monitoring of process performance provides the opportunity to identify and control sources of variation

and hence improve process robustness, increasing the assurance of reliable product supply to the market.

The intent is to discuss some of the challenges and potential complications associated with the

implementation of CPV, and to increase understanding of region-specific perspectives on the value of

CPV in the context of a lifecycle approach to process validation.

NOTES:

http://www.biophorum.com/

Lifecycle Approach to Process Validation

Workshop Session

Panel Discussion – Questions and Answers

Brigitte Brake, Federal Institute for Drugs and Medical Devices, BfArM, Germany


Atsushi Matsumoto, Kyowa Hakko Kirin Co., Ltd., Japan

Kazunobu Oyama, Pharmaceuticals and Medical Devices Agency (PMDA), Japan

Stefanie Pluschkell, Pfizer, Inc., USA


What information and knowledge from product and process development needs to be collected

for the risk assessment together with the development of process validation (PV) strategy?

What are the issues that may cause difficulties with the implementation of the new PV concept

for biopharmaceuticals?

How do we present the rationale of PV strategy in dossier to efficiently share the PV strategy

with the review?

NOTES:

NOTES: