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
Niklas Ekman, Finnish Medicines Agency, Finland
Churn-Shiouh Gau, Center for Drug Evaluation (CDE), Taiwan
Jeewon Joung, Ministry of Food and Drug Safety (MFDS), Korea
Daisaku Sato, Pharmaceuticals and Medical Devices Agency (PMDA), Japan
Marjorie Shapiro, CDER, FDA, USA
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
Kenichiro Hata, Japan Tissue Engineering Co., Ltd., Japan
Daisuke Maeda, Pharmaceuticals and Medical Devices Agency (PMDA), Japan
Yuuki Miyatake, Teijin Pharma Limited, 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
Niklas Ekman, Finnish Medicines Agency, Finland
Futaba Honda, Pharmaceuticals and Medical Devices Agency (PMDA), Japan
Elisabeth Kirchisner, Roche Diagnostics GmbH, Germany
Izumi Kumagai, Tohoku University, Japan
Manabu Wada, Chugai Pharmaceutical Co., Ltd., Japan
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
12:25 – 13:25 Panel Discussion – Questions and Answers
Brigitte Brake, Federal Institute for Drugs and Medical Devices, BfArM,
Germany
Earl Dye, Genentech, a Member of the Roche Group, USA
Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA),
Japan
Stephan Krause, AstraZeneca Biologics, USA
Marjorie Shapiro, CDER, FDA, USA
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
16:30 – 17:30 Panel Discussion – Questions and Answers
Brigitte Brake, Federal Institute for Drugs and Medical Devices, BfArM,
Germany
Jeewon Joung, Ministry of Food and Drug Safety (MFDS), Korea
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
Niklas Ekman, Finnish Medicines Agency, Finland
Churn-Shiouh Gau, Center for Drug Evaluation (CDE), Taiwan
Jeewon Joung, Ministry of Food and Drug Safety (MFDS), Korea
Daisaku Sato, Pharmaceuticals and Medical Devices Agency (PMDA), Japan
Marjorie Shapiro, CDER, FDA, USA
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:
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:
Presenter’s Abstracts and Presentations
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
Kenichiro Hata, Japan Tissue Engineering Co., Ltd., Japan
Daisuke Maeda, Pharmaceuticals and Medical Devices Agency (PMDA), Japan
Yuuki Miyatake, Teijin Pharma Limited, Japan
Yoji Sato, National Institute of Health Sciences, Japan
The following questions will guide the panel discussion:
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:
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:
Presenter’s Abstracts and Presentations
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
Izumi Kumagai, Tohoku University, Japan
Manabu Wada, Chugai Pharmaceutical Co., Ltd., Japan
Teruhide Yamaguchi, Pharmaceuticals and Medical Devices Agency (PMDA), Japan
The following questions will guide the panel discussion:
• 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:
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:
Presenter’s Abstracts and Presentations
CMC Considerations and Challenges for Accelerated Programs
Yasuhiro Kishioka
Pharmaceuticals and Medical Devices Agency (PMDA), Japan
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
Earl Dye, Genentech, a Member of the Roche Group, USA
Yasuhiro Kishioka, Pharmaceuticals and Medical Devices Agency (PMDA), Japan
Stephan Krause, AstraZeneca Biologics, USA
Marjorie Shapiro, CDER, FDA, USA
Kazuhisa Uchida, Kyowa Hakko Kirin Co., Ltd., Japan
The following questions will guide the panel discussion:
• 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:
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:
Presenter’s Abstracts and Presentations
PMDA Perspective: Regulatory Updates on Process Validation Standard
Kazunobu Oyama
Pharmaceuticals and Medical Devices Agency (PMDA), Japan
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:
Lifecycle Approach to Process Validation
Workshop Session
Panel Discussion – Questions and Answers
Brigitte Brake, Federal Institute for Drugs and Medical Devices, BfArM, Germany
Jeewon Joung, Ministry of Food and Drug Safety (MFDS), Korea
Atsushi Matsumoto, Kyowa Hakko Kirin Co., Ltd., Japan
Kazunobu Oyama, Pharmaceuticals and Medical Devices Agency (PMDA), Japan
Stefanie Pluschkell, Pfizer, Inc., USA
The following questions will guide the panel discussion:
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: