Top News CMC Strategy Forum Japan 2023" held

Printable PDF

CMC*1Strategy Forum Japan 2023" hosted by CASSS (California Separation Science Society) was held at Tokyo Marriott Hotel (Shinagawa-ku, Tokyo) over two days from December 4 to 5, 2023. This was the first face-to-face meeting in four years since 2019, and approximately 100 participants registered from 11 countries in Asia, North America, and Europe, as well as Japan, and opinions were exchanged very actively.

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 U.S., the Forum has been held in Europe since 2007, Japan since 2012, Latin America since 2014, and the U.S. since 2021. The CMC Strategy Forum is a forum where experts from industry, academia, and regulatory agencies spend ample time discussing issues related to the research and development, manufacturing, and regulation of biopharmaceutical CMCs, in order to promote mutual understanding and problem-solving. The CMC Strategy Forum in Japan is a forum for companies, academia, and regulators to discuss issues related to biopharmaceutical CMC R&D, manufacturing, and regulation.

For the CMC Strategy Forum in Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) and the Pharmaceutical Manufacturers Association of Japan (PMAJ) organized a preparatory committee, which not only selected the themes and determined the direction of discussions, but also spent about a year preparing for the 2023 meeting, which will be the first time in four years that the meeting will be run only face-to-face.

The meeting was opened with Welcome and Introductory Comments by Mr. Wassim Nashabeh of Genentech, Fellow of CASSS and Chair of the CMC Forum Global Advisory Committee, and Mr. Hiroshi Suzuki, Director of PMDA's Review Center and Director of the Regulatory Science Center. After Introductory Comments, the following topics were discussed.

Session 1: Recent Trends in the Regulation of Biopharmaceutical Products

Session 1, moderated by Mr. Yoshiaki Maruyama, Director, Regenerative Medicine Products Review Division, PMDA, and Ms. Cecilia Tami, Genentech, covered a wide range of topics including the latest regulatory trends, especially for biopharmaceuticals, and lessons learned from the COVID-19 pandemic. PMDA

Mr. Yasuhiro Kishioka of the PMDA's Regenerative Medicine Products Review Department gave a presentation on the latest regulatory updates related to biopharmaceuticals in Japan, international activities of the MHLW/PMDA (International Conference on Harmonization of Pharmaceutical Regulations (ICH), ICMRA (International Coalition of Medicines Regulatory Authorities), and product-related topics (biosimilars, microbiomes, and exosomes).

Ingrid Markovic of the Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) presented the lessons learned from COVID-19 and efforts to improve access to medicines (IND Expanded Access, emergency use authorization, etc.), the contribution of the CMC Development and Readiness Pilot program to cellular/gene therapy for rare diseases, and efforts to streamline and modernize submission/review ( ICH M4Q (R2), PQ/CMC, KASA (Knowledge-aided Assessment & Structured Application), etc.

Mr. Hugo Hamel of Health Canada introduced Health Canada's international collaborative activities with ICMRA, World Health Organization (WHO), and others to support patients' access to medicines. He also discussed parallel reviews and work sharing with EMA, ACCESS, FDA, and Project ORBIS.

Mr. Brian Dooley of the European Medicines Agency (EMA) talked about global harmonization and collaboration, including ICH, PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme), ICMRA, OPEN (Opening He introduced the activities of ICH, PIC/S (Pharmaceutical Inspection Convention and Cooperative Scheme for Pharmaceutical Inspection), ICMRA, OPEN (Opening procedures at EMA to non-EU authorities), and IPRP (International Pharmaceutical Regulators Programme) as global harmonization and collaboration. He also explained the PRIME tool box guideline, which is a guidance to support quality data in PRIME.

Jiaqi Lu, Center for Drug Evaluation (CDE), China's State Administration for Drug Supervision, presented the regulatory framework for ATMP (Advanced Therapy Medical Products) development in China, recent trends in ATMP submissions and regulatory guidance for ATMPs.

Markus Goese of Roche explained the ICMRA PQKMS and the pilot program, and described Roche's experience with the pilot program. Roche proposed and was approved to participate in the pilot program and received approval from the EMA/FDA on the same day after an inter-regulatory review. He also mentioned that an ICMRA stakeholder workshop was held in July 2023, where several companies shared their experiences with the pilot program.

In the panel discussion, the panelists responded to many questions from the chairperson and general participants, and had a lively discussion on the lessons learned in the CMC area from the COVID-19 pandemic, regulatory issues related to the CMC area of biopharmaceuticals, and other topics.

Session 2: Stability of Biopharmaceutical Products: Topics about ICH Guidance Q1/Q5D Revision

The efficacy period of biopharmaceuticals, including antibody drugs, is set based on actual data obtained under actual storage temperature conditions in accordance with the Q5C guidelines, but in the process of rapid drug development, the setting of efficacy period is increasingly becoming the law of the land. Against this background, Akiko Ishii, Director, Biopharmaceuticals Division, National Institute of Health Sciences, and Markus Goese, Roche, moderated Session 2, and introduced the contents of the discussion in the revision of stability guideline Q1/Q5C on extrapolation of efficacy period using biopharmaceutical modeling. The content of the discussion was introduced.

Mr. Takashi Kameda of the PMDA's Vaccine and Other Drugs Review Department explained the status of the Q1/Q5C guideline revision. He also commented that since the revision work is being conducted in the direction of allowing extrapolation of efficacy periods for biopharmaceuticals through modeling, there is a need to discuss the necessary background knowledge on acceptable products and modeling methods, and to explore the possibility of implementation.

Hiroko Shibata of the Department of Biopharmaceuticals, National Institute of Health Sciences, Japan, explained the challenges of evaluating the stability of biopharmaceuticals in expedited review, the use of tools and models for predicting stability in biopharmaceutical development considering the complexity of degradation pathways, challenges, and future prospects.

Paula Russell of Health Canada spoke about the challenges of modeling biopharmaceuticals from a regulatory perspective, two case studies, and future perspectives.

Mitja Zidar of Novartis Pharma, based on a scientific report involving several international pharmaceutical companies, explained the modeling approach and the results and challenges of predicting stability and aggregate formation for antibody drugs using Arrhenius predictions. The panel discussion was held to discuss the results and challenges of the modeling method and the prediction results.

Kosuke Tamura of Daiichi Sankyo joined the panel discussion, answering questions from the chairperson and the audience. A lively discussion ensued on the use of modeling to predict the stability of biopharmaceuticals, including

Session 3: Challenges, Opportunities and Regulatory Expectations for CGT Product Comparability

In Session 3, Dr. Tamura discussed the importance of using modeling to predict the stability of biopharmaceuticals. In Session 3, Mr. Satoshi Yasuda, Director of Regenerative and Cellular Medicine, National Institute of Health Sciences, and Ms. Vandana Chauhon, Gilead Sciences, chaired the session and introduced the draft Comparability Guidelines for CGTPs in Japan and the United States, as well as their experiences in product development and post-marketing change management. The panel discussion was followed by a presentation by Mr. Vandana Chauhon, CGTPs. In the panel discussion that followed, the panelists discussed approaches to technical issues in the comparability assessment of CGTPs and the importance of dialogue with the regulatory authorities.

Dr. Yoji Sato, Director of the Pharmaceuticals Division of the National Institute of Health Sciences, introduced the technical challenges in searching for and evaluating critical quality characteristics of processed cell products, as well as the approaches taken before and after the development of evaluation methods and changes in manufacturing methods. He then explained the "Draft Guideline for Equivalence/Homogeneity Assessment of Human Cell Processed Products Following Changes in Manufacturing Processes.

Ingrid Markovic, FDA CBER, explained the Manufacturing Process Change and Comparability in CGTPs, based on the draft guidelines issued in July 2023. In particular, he showed the importance of risk management in manufacturing process changes and comparability studies, as well as consultation (pre-planning) and consensus building with the FDA throughout the lifecycle. He also introduced the concept of split source comparability.

Ms. Edyta Pawelczyk of Novartis Pharma, based on a case study of CAR-T product development, presented the issues in the early stages of development and points to be considered in comparability testing, such as evaluation in a process representative of actual manufacturing, as well as the concept according to the manufacturing process stage (for example, the use of heterogeneous raw materials such as autologous blood). In addition, he talked about the approach to be taken when conducting comparability testing using heterogeneous raw materials such as autologous blood (split apheresis approach), etc. He said that correct communication with the authorities is the key to solving problems, and that it is important to conduct risk assessment to determine whether quality affects product efficacy.

Using autologous cultured epidermis and autologous cultured cartilage as examples, Yukio Mori of Japan Tissue Engineering presented the concept of manufacturing method changes and comparability testing for product types in which the characteristics of the autologous cells used as raw materials have a relatively large impact on product quality. He also discussed the continuous approach to deliver optimal products to patients even after marketing, and explained the importance of conditions at the time of cell collection.

In the panel discussion, Mr. Akiyoshi Kunieda of PMDA's Regenerative Medicine Product Review Division and Mr. Yuki Miyatake of Bristol-Myers Squibb joined the panel to discuss the need for a thorough understanding of the product (understanding of the mechanism of action, characterization factors, and the need for reliable analytical methods from the early stages of development, etc.), and the need to ensure that the product is well characterized. ), the concept of risk assessment of the impact on product quality when increasing manufacturing capacity such as scale-out, etc., and the importance of early consultation and dialogue with the authorities regarding possible future changes.

Session 4: A Strategy for the Quality Control of Antibody-Drug Conjugates (ADCs) Throughout the Entire Life Cycle of the Product

Antibody-Drug Conjugate (ADC) is a complex molecule that combines an antibody with a drug via a specific linker, and is expected to be a promising therapeutic approach that offers a unique mechanism of action different from that of existing drugs. On the other hand, due to their complexity, ADCs require a different approach to quality control than other antibody products, and there are factors that directly affect product quality in terms of efficacy, pharmacology, toxicity, etc. Regulatory requirements are also complex, as they require quality control strategies from both a biopharmaceutical and small molecule perspective. Session 4, chaired by Dr. Shigenori Kidokoro of Daiichi Sankyo and Dr. Helen Louise Newton of MSD, will focus on quality control of ADCs, from pre-clinical to clinical development and commercial manufacturing. They discussed quality control strategies throughout the lifecycle of ADC products, from preclinical to clinical development and commercial manufacturing, issues in quality assessment items specific to ADCs, points to keep in mind when preparing CTD (Common Technical Document), and regulatory trends in each country.

Ayuki Nakano of the PMDA's Regenerative Medicine Product Review Department explained about ADC approval cases in Japan, guidelines to be referred to when applying for ADC approval, quality evaluation items to be focused on for ADC heterogeneity, the PMDA's review system, and points to keep in mind when preparing the CTD. Michihiko Aoyama of the National Institute of Health Sciences explained the assumed mechanism of off-target cytotoxicity caused by aggregates of ADCs, specifically that aggregates formed by agitation play an important role in internalization into non-target cells via the Fcγ receptor and may increase the risk of cytotoxicity. reported that they may increase the risk of cytotoxicity.

Yuki Shioiri, Daiichi Sankyo, explained the quality control strategy in the development of ADCs, which requires consideration of the quality characteristics of the antibody, drug linker (DL), drug substance, and drug product, respectively. The following are examples of ADC-specific quality characteristic evaluation items: distribution and variability of DAR (Drug-to-Antibody Ratio), purity and stability of DL, antigen binding of antibody, potency, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity (CDC), etc., and investigation of unintended mechanisms of action such as signal inhibition. He also pointed out the importance of setting equivalence endpoints according to the risk of impact on quality when changing the manufacturing process.

Dr. Vandana Chauhan of Gilead Sciences explained the regulatory trends of ADCs in each country and the use of the PACMP system for manufacturing process changes, noting that ADCs are a combination of macromolecules and small molecules and that cooperation between the two teams is necessary in both development and review, He also pointed out that ADCs are defined as biologics and that no specialized guidelines exist yet. He also pointed out that change management is also an issue, and that when changes are made to the manufacturing of antibodies for ADC products, depending on the degree of change, stability evaluation of the drug substance and formulation may also be required, which takes time. However, it was proposed that the time can be shortened by utilizing the Post-Approval Change Management Protocol (PACMP) system.

The panel discussion triggered many questions from the audience, which led to a lively exchange of ideas on the safety of aggregates in drug formulations, interpretation of data introduced by Dr. Aoyama, formulation design of ADCs, composition of CTD, active use of the PACMP system, and other topics.

Closing Remarks

This was the first time in four years that the forum was held face-to-face, and the panel discussions in each session were extremely active. In addition, the Networking Reception and Networking Break, which were held during the forum, provided a very good opportunity for participants from industry, academia, and government to communicate with each other, and we could fully feel the unique advantages of this forum.

After the four sessions, Jamie Moore, Vice President of CASSS Board of Directors, gave a summary of the forum and closed the meeting.

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 2024" is scheduled to be held on December 9-10, 2024.

(Biopharmaceuticals Committee: Yoshinori Kubodera, Teru Nonoyama, Mizuyo Shibata, Nao Nakamura, Akiko Ikeda, Tsutomu Sugihara )

Back to Newsletter Top

TOP