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CMC Strategy Forum Japan 2019, hosted by CASSS (California Separation Science Society), was held at the Tokyo Marriott Hotel (Shinagawa, Tokyo) on December 11 and 12, 2019. A total of 110 participants from Japan as well as Asia, North America, and European countries took part in lively discussions.

Background of CMC Strategy Forum Japan

The CMC Strategy Forum was spun off from the Well Characterized Biotechnology Pharmaceutical (WCBP) Symposium in 2002, and after the first meeting in the United States, the Forum has been held in Europe since 2007, Japan since 2012, and Latin America since 2014. At the CMC Strategy Forum, experts from industry, academia, and regulatory agencies meet to discuss issues related to the research, development, manufacturing, and regulation of biopharmaceutical CMC (Chemistry, Manufacturing and Control)*1. The CMC Strategy Forum in Japan is a forum for companies, academia, and regulators to discuss issues related to research and development, manufacturing, and regulation of biopharmaceuticals.

The CMC Strategy Forum in Japan was organized by the Pharmaceuticals and Medical Devices Agency (PMDA) and the Pharmaceutical Manufacturers Association of Japan (PMAJ) as a preparatory committee, and took about a year to select discussion topics and the direction of the discussions.

After welcome comments from Wassim Nashabeh of Genentech (Roche Group), the representative of CASSS, and Hiroyoshi Arai, Director of PMDA's Review Center, the following themes were actively discussed at the meeting.

Session 1: Recent Trends in the Regulation of Biopharmaceutical Products

Session 1 was moderated by Mr. Shinichi Okudaira of PMDA's Regenerative Medicine Product Review Division and Mr. Markus Goese of Roche, with regulatory officials from various countries introducing a wide range of recent regulatory developments, particularly for biopharmaceuticals.

Session 1 moderators Mr. Markus Goese and Mr. Shinichi Okudaira

Ms. Ayako Enoda of PMDA's Regenerative Medicine Products Review Department introduced the three pillars of the revision of the Law Concerning Quality, Efficacy and Safety Assurance of Pharmaceuticals, Medical Devices and Other Products (Pharmaceutical Affairs Agency Law), progress of the Pioneer Review Designation System, consultation and application status of gene therapy products, efforts in Japan related to ICH Q12, and current status of biosimilars The following information was introduced.

Ms. Jina Kim of the Ministry of Food and Drug Safety (MFDS), Korea (via teleconference system), presented the status of applications in recent years, the addition of new organizations, additional regulations on the safety of advanced regenerative medicine products and biopharmaceuticals, and the CMC She introduced biosimilars and stability testing requirements.

Anthony Ridgway, Health Canada, introduced Health Canada's policies on timely drug launches and regulatory harmonization, challenges in the new review rules (Sandbox) for advanced products, and the definition of biosimilar substitution and switching. The presentation included an introduction of the U.S. Food and Drug Administration (FDA).

Christopher Downey, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA) (via teleconference system), presented on the team-based review system to Cassandra Overking, CBER (Center for Biologics Evaluation and Research), gave a presentation on CBER's (Center for Biologics Evaluation and Research) CBER pilot program to promote and expedite awareness, expedite review and progress on biosimilars and the Established Condition (EC) pilot program. Ms. Overking, Center for Biologics Evaluation and Research (CBER), presented CBER's four priority review strategies (Priority Review, Accelerated Approval, Fast Track, and Breakthrough Therapy designation), its regenerative medicine product and advanced technology initiatives, and its biosimilars and biosimilars pilot program in Established Condition. The presentation included an overview of the work on regenerative medicine products and advanced technologies, as well as the challenges in evaluating products with novel technologies.

Steffen Gross of the German regulatory authority (Paul-Ehrlich-Institut (PEI)) presented on the European Medicines Agency's (EMA) Brexit response, the status of expedited review, the impact on biosimilars of the listing of biopharmaceuticals in the European Medicines Agency's (EMA) regulatory framework, and the impact on new biosimilars. He also introduced the challenges in granting indications to new biosimilars, Traceability, Interchangeability, Switching, and Substitution.

During the panel discussion, there was a lively debate on CMC data harmonization, promotion of harmonization in each region, ICH Q12 pilot program, biopharmaceuticals on the regulatory market, and the EC, in addition to questions to the regulators.

Panel discussion in Session 1

Session 2: ASEAN Regulatory Updates

In Session 2, which continued from Session 1, Mr. Okudaira of PMDA and Ms. Sannie Chong of Roche Singapore moderated a session in which regulatory officials from the Association of Southeast Asian Nations (ASEAN) introduced their countries' responses to biopharmaceuticals.

Noraisyah binti Mohd Sani of the National Pharmaceutical Regulatory Agency, Ministry of Health, Malaysia (NPRA), gave an introduction to the NPRA in Malaysia, and discussed the safety and He also introduced the policies of the NPRA based on the assurance of safety and efficacy and the development of the industry, as well as the management of pharmaceutical products to ensure their timely use, the strengthening of the framework in accordance with the Stringent Regulatory Authority (SRA), and the promotion of priority review, conditional registration, and approval processes. The meeting also included a presentation on the Food and Drug Administration of the Royal Thai Ministry of Health (FDMA).

Dr. Wittawat Viriyabancha of the Food and Drug Administration, Thailand (Thailand FDA) introduced the Medical Hub policy of the Thai government, which focuses on promoting R&D, and the Thai FDA, He introduced the new regulations that incorporate the upgrading and modernization of regulatory science (law revision in April 2019, effective in February 2020), and the promotion of collaboration with regulatory authorities in other countries (introduction of Regulatory Sandbox, etc.).

Mr. Wittawat Viriyabancha, FDA, Thailand

Mr. Togi Junice Hutadjulu, National Agency for Drug and Food Control, Republic of Indonesia, introduced the efforts to comply with the World Health Organization (WHO) system, the review He also introduced the introduction of online screening and electronic signatures to prevent counterfeit drugs, as well as the strengthening of infrastructure for self-reliance and support for the development of the industry.

In the panel discussion, in addition to questions to the regulators, there were active discussions on CMC quality assurance, ASEAN standardization, ICH Q12 post-approval change management, and biopharmaceuticals' response to listing on the Japanese Pharmacopoeia.

Session 3: Technologies Related to Viral Safety and Topics about the ICH Q5A Revision

Session 3 was moderated by Kazuhisa Uchida of Kyowa Kirin and Steffen Gross of PEI, and included presentations and discussions on the latest trends in virus analysis technology related to the revision of ICH Q5A guidelines and strategies for more flexible virus clearance.

Mr. Steffen Gross and Mr. Kazuhisa Uchida, moderators of Session 3

At the beginning of the meeting, Dr. Yo Sakurai of PMDA's Vaccine and Other Products Review Department introduced the background of the ICH Q5A guideline revision, the activities of the Expert Working Group at the most recent Singapore meeting, and the concept paper. Issues to be considered for the guideline revision include: applicable advanced biotechnological products, more flexible viral clearance approach strategies, general principles for applying new viral analysis methods, viral clearance and risk reduction strategies in advanced manufacturing technologies such as continuous production and reflection of viral clearance technologies that have evolved since the 1999 revision of ICH Q5A (R1), among others.

Dr. Arifa Khan of FDA CBER then discussed the need for new virus analysis methods against the backdrop of the diversification of modalities and cellular substrates for biotechnology-applied drugs, the potential of next-generation sequencing (NGS) as an analytical technology capable of detecting a wide range of viruses with high sensitivity, and the technical issues involved in its utilization. He also introduced the next-generation sequencer (NGS), which is expected to be an analytical technology capable of detecting a wide range of viruses with high sensitivity. He explained CBER's approach to issues such as standardization of sample preparation and measurement methods, validation of analytical methods, and the importance of model viruses and highly reliable databases for analysis.

Dr. Keisuke Yusa of Kobe University introduced the identification of three genes involved in the formation of non-infectious retrovirus-like particles (RVLPs) in CHO (Chinese Hamster Ovary) cell lines and the establishment of CHO cell lines that do not form RVLPs by knocking out these endogenous retrovirus genes. He also introduced the research on the establishment of CHO cell lines that do not form RVLPs by knockout of these endogenous retrovirus genes. He also introduced a cell line characterization technique using NGS. He explained that this technology can reduce the risk of false positives by utilizing cell line-specific databases and subtracting background signals such as endogenous retroviruses, which are constant in each cell line, and that it can be used to evaluate the safety of a wide range of biotechnology-applied drugs such as gene therapy products and cellular drugs. The possibility of using this method for viral safety evaluation of a wide range of biotechnological drugs, such as gene therapy products and cellular drugs, was demonstrated.

Finally, Dr. Qi Chen of Genentech, from the standpoint of a development company, presented the results of their CHO cell-derived products, including studies showing that the number of resin cycles does not affect the viral clearance performance of the process as a process characteristic related to viral clearance, and data showing that different products do not necessarily require different flow rates, pressures, etc., to correlate with viral clearance performance. He also presented data showing that flow rate, pressure, and other conditions do not necessarily correlate with the performance of virus removal filters, and expressed his hope and suggestion to enable the selection of flexible virus clearance strategies, such as modular validation, that effectively utilize the knowledge already available (Prior Knowledge). The presentation also included expectations and suggestions for flexible virus clearance strategies, such as modular validation, that effectively utilize already acquired knowledge (Prior Knowledge). He also explained the concept of facility design in accordance with the progress of virus clearance strategies in continuous production and manufacturing facilities such as closed systems.

After the presentations, speakers were joined by Koichi Yamamoto of Kyowa Kirin and Anthony Ridgway of Health Canada for a panel discussion. Among the issues discussed were the suitability of NGS for cell bank characterization and other uses, and the importance of standard viruses and reliable databases. Regarding the modular validation approach, the panel discussed expectations and challenges for future Q5A revisions, including the possibility of inter-company collaboration to share Prior Knowledge and the approach to review.

Panel discussion in Session 3

Session 4: New Trends in Advanced-type Antibody Products including Antibody Drug Conjugates and Bi-specific Antibodies

Session 4, moderated by Masayuki Yabuta of Daiichi Sankyo and Wassim Nashabeh of Genentech, focused on the development of advanced antibodies and discussed the latest technologies, quality control, and regulatory considerations.

After an introduction by Dr. Yabuta, the chairperson of the session, Mr. Masato Amano, also from Daiichi Sankyo, gave a presentation on the overview and advantages of advanced antibodies, considerations in the development of antibody-drug conjugates (ADCs) developed by the company as an example, developability, and quality risk management of advanced antibodies. As an advantage of ADCs, he explained that the synergistic effect of drug efficacy can be expected compared to that of an antibody and a small-molecule drug alone, using the analogy of a marriage. As for developability, it is important to evaluate the potential for development from the early stages of development, and not to develop low-potential products. Furthermore, he explained that it is important to manage the quality of advanced antibodies based on an understanding of the characteristics of the molecule, rather than mechanically applying the conventional standard setting.

Session 4 speaker Mr. Masato Amano and moderator Mr. Masayuki Yabuta

Next, Mr. Nobuyuki Tanaka of Chugai Pharmaceutical gave a presentation on a case study of manufacturing method development, using the company's bispecific antibody (BiAb) as an example. First, as the three key points in the development, he mentioned that the molecular design was devised with an awareness of manufacturability, a single-use in-house plant was constructed, and the company's first Quality by Design (QbD) application was filed. He explained that the selection of cell lines that were easy to develop from the cell line construction stage gave the company an advantage in subsequent development, and that the company was able to overcome the difficulty of clogged virus filters that arose during the development of the manufacturing process, He also explained the challenges unique to single-use systems.

In addition, Art Hewig of Amgen presented process development and future prospects for advanced antibodies, including BiAb, which is already marketed as a drug, but the development of new types of drugs based on this concept continues to evolve. He noted that the increasing complexity of molecular structures poses various challenges for process development and quality control, but that these challenges can be mitigated through focused optimization. He likened the company's drug development for treating various diseases to Tokyo's rail network (each line is combined to reach its destination), and explained that applying the modular platform to drug development allows for a fast, flexible, and efficient development strategy with limited resources.

Finally, Benedicte Lebreton of Genentech gave a presentation titled "Lessons Learned and Insights from the Development of Advanced Therapeutic Antibodies from a Global and Regulatory Perspective. Advanced antibodies such as those discussed in this session have the potential to meet the medical needs of diseases for which no cure has yet been found. He explained that the Post-Approval Change Management Protocol (PACMP) and early discussions between companies and regulatory authorities regarding the submission materials will build mutual trust and support innovation as keywords to accelerate global development. He also explained that the use of the Post-Approval Change Management Protocol (PACMP) and early discussions between companies and authorities regarding application materials build mutual trust and support innovation. In addition, he stated that drug regulations are in place to support drug development, and that appropriate utilization of these regulations while paying attention to the differences among countries will accelerate development.

After the presentations by the four speakers, a panel discussion was held with two additional speakers, Kyoko Sakurai of the PMDA's Regenerative Medicine Product Review Division and Steffen Gross of PEI. Almost all speakers explained the difficulties in the development of advanced antibodies, but some suggested that discussions with authorities from the early stages of development could reduce the difficulties. Regarding the sufficiency of existing guidelines for new modalities, there is room for improvement of ICH Q5A, but it is not necessary to cover all modalities in the guidelines.

Lively panel discussion in Session 4

Summary

This year's CMC Strategy Forum Japan 2019 was also a very impressive conference, with active discussions in each session involving not only panelists but also audience members, as well as communication including networking during the relatively long breaks. after the four sessions were over, After the four sessions, Nadine Ritter of Global Biotech Experts, LLC gave a summary of the forum and Wassim Nashabeh gave closing remarks (slides of the day's presentations are available on the CMC Strategy Forum (Slides from the day's presentations are available on the CMC Strategy Forum Japan 2019 website).

The Pharmaceutical Manufacturers Association of Japan (PMAJ) will continue to support this global conference so that it will continue to be held in Japan in the future and help promote biopharmaceutical R&D and revitalize the CMC field. We look forward to your continued support.

The next CMC Strategy Forum Japan 2020 is scheduled to be held on December 7 and 8, 2020.

Questions from the floor during the panel discussion

(Biopharmaceuticals Committee: Masatoshi Yamada, Takeshi Yoshino, Nao Nakamura, Tetsushi Ito )

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