CMC Strategy Forum Japan 2024" will be held

CMC* Strategy Forum Japan 2024" hosted by CASSS (California Separation Science Society) was held at Tokyo Marriott Hotel (Shinagawa-ku, Tokyo) on December 9-10, 2024. Approximately 100 participants from 9 countries including Japan, Asia, North America, and Europe registered for the forum and had a very active exchange of opinions.

Background of CMC Strategy Forum Japan

Session 1 - Recent Trend in the Regulation of Biopharmaceutical Products.

Chairperson: Dr. Yasuhiro Kishioka, PMDA Regenerative Medicine Products Review Division
　　　Mr. Andrew Chang, Novo Nordisk

In Session 1, a wide range of topics were introduced, including the latest regulatory trends, examples of international collaborative review, and guidance for new technologies, with a focus on biopharmaceuticals and regenerative medicine products.

Dr. Yo Sakurai, Regenerative Medicine Products Review Division, PMDA

As an update on pharmaceutical regulations related to biopharmaceuticals in Japan, he explained the "Enforcement of Introduction of Change Procedures for Moderately Modified Matters" and the "Timing of Product Switchover after Approval for Partial Change of Manufacturing Method, etc." notices. From the latest technologies that may become drugs in the future, he explained about microbiomes, preparations using extracellular vesicles (EVs) including exosomes, and products for in vivo gene therapy with target-directed properties.

Dr. Stelios Tsinontides, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA)

Background on the International Collaboration of Medicinal Regulatory Authorities (ICMRA) Joint Review and Joint Inspection pilot program was provided, as well as feedback from the joint reviews and joint inspections conducted to date.

Mr. Ingrid Markovic, Center for Biologics Evaluation and Research (CBER), FDA

The status of the Post Approval Change Management Practice Plan (PACMP) use in the U.S., the draft guidance on platform technology issued in September 2024, the CDPR Program, and the pilot program for international regulatory convergence in cell and gene therapy (CoGenT Global) were explained. The presentation included the following

Mr. Brian Dooley, European Medicines Agency (EMA)

He explained the three-year plan for 2025-2027 in the CMC area (development of guidance on mRNA vaccine quality, phage therapy, etc.; guidance on review of post-marketing change control categories; and collaboration with ICMRA and other external organizations).

Dr. Dongchen Jia, Center for Drug Evaluation (CDE), State Administration for Drug Supervision, China

He explained the ICH Q6 guideline, which is currently under revision, focusing on the considerations for introducing the guideline to China.

Dr. Subin Sankarankutty, Health Sciences Authority (HSA), Singapore

He explained the latest trends in Singapore's pharmaceutical administration, the status of international joint audits in which Singapore participates (ACCESS, Orbis, HAS-NPRA work sharing, and Asean joint audits), and the status of implementation of ICH and ASEAN guidelines.

Mr. Prasad Narayanan, National Pharmaceuticals Regulatory Agency (NPRA), Malaysia

The latest trend of Malaysian pharmaceutical administration and the status of ASEAN Joint Review in which Malaysia participates were explained.

Panel Discussion

A lively discussion was held on points to consider and expectations for future implementation of the various international joint examinations that are being conducted as pilot programs.

Session 1 Group photo

Session 2 - CTD Quality part of Biopharmaceutical Products: Topics about ICH Guideline M4Q Revision and Structured Application

Chairperson: Dr. Ingrid Markovic, FDA CBER
　　　Mr. Takao Kojima, AbbVie LLC

In the Common Technical Document (CTD), the quality sections (Module 2.3 and Module 3) that contain CMC information have been harmonized by ICH Guideline M4Q (R1) since its structure and format were introduced in 2002, and a concept paper for the revision of the guideline was published in 2021. A concept paper for the guideline revision was published in 2021. The concept paper identified the drivers for guideline revision as alignment with modern quality guidelines ICH Q8-Q14 and other relevant guidelines, support for complex products and technologies (e.g., ADCs, vaccines, regenerative medicine products and serial manufacturing technologies), and the use of digital tools. Session 2, chaired by Ingrid Markovic, FDA CBER, and Takao Kojima, AbbVie LLC, provided an update on the discussions in the ICH M4Q(R2) EWG toward guideline revision and expectations for ICH M4Q(R2) from pharmaceutical companies.

Mr. Yasuhiro Kishioka, PMDA Regenerative Medicine Products Review Division

He explained the background of the guideline revision, the objectives of ICH M4Q(R2), the current thinking of the EWG, and the future prospects of ICH M4Q(R2). He also indicated that ICH M4Q(R2) will also play a role toward digitalization. He also explained the new concepts currently being considered by the EWG, such as Core Quality Information (CQI) and Development Summary and Justification (DSJ), along with examples, and explained the basic structure of CTD M3 and M2.3, including The presentation also explained the Description, Manufacture, Control, Storage (DMCS) model of CTD M3 and M2.3 as the basic structure of CTD M3 and M2.3.

Mr. Yuji Otsuka, Bayer Yakuhin K.K.

The benefits of ICH M4Q(R2), expectations for ICH M4Q(R2) based on the mission of pharmaceutical companies, and considerations for ICH M4Q(R2) as a pharmaceutical company were explained. The expectations of pharmaceutical companies for ICH M4Q(R2) were discussed in light of their missions: (1) Global unification of CMC submission materials, (2) risk-based preparation of materials focusing on important points, (3) efficiency of change management after approval, and (4) support for new modalities and new technologies. The study examined each of the four points in the context of a pharmaceutical company's mission.

Panel Discussion

Andrew Chang of Novo Nordisk Inc. and Stelios Tsinontides of FDA CDER and Stephan Roenninger of Amgen (Europe) GmbH joined us to discuss ICH M4Q(R2)'s contribution to joint reviews such as ICMRA, Harmonization of ICH M4Q(R2) with concepts in ICH Q12 such as EC, modalities covered by ICH M4Q(R2), etc. were actively discussed.

Panel Discussion

Session 3 - Expectation for ICH Q6 Revision: Case Study of Commercial Specification Setting.

Chair: Dr. Akiko Ishii, Director, Division of Biopharmaceuticals, National Institutes of Health (NIHS)
　　　Dr. Andrew Chang, Novo Nordisk

The ICH Q6 Guideline for the Establishment of Specifications and Test Methods for Pharmaceutical Products has been in discussion at the ICH Q6A(R1) EWG for revision against the background of advances in manufacturing and analytical technologies, diversification of modalities, and consistency with the new ICH quality guidelines, etc. Session 3 Akiko Ishii, Director, Division of Biopharmaceuticals, National Institute of Health Sciences, and Andrew Chang, Novo Nordisk, moderated the session and introduced the background, objectives, and challenges of the ICH Q6 revision. The background, objectives, and issues to be addressed in the revision of ICH Q6 were introduced.

Mr. Ingrid Markovic, Regulatory Chair, ICH Q6(R1) EWG / US-FDA CBER

In addition to the background and purpose of the revision of ICH Q6, the expected effects of the revised guideline, such as streamlining the approval process and promoting global development through international harmonization of science and risk-based standard setting concepts, and accelerating patient access to high-quality, safe, and effective pharmaceutical products, were presented. He also explained the issues and policies to be addressed for the guideline revision, including consistency with ICH Q8-Q14 guidelines, Prior Knowledge, science and risk-based standard setting, and considerations in life cycle management.

Dr. Yu Chanfei, China National Institute of Food and Drug Certification (NIFDC)

He introduced the requirements of official regulations such as the Chinese Pharmacopoeia and the standard-setting approach based on batch data and process capabilities, using antibody drug products as an example. He also explained the importance of standard setting based on product and process understanding and clinical relevance, and expressed his expectations for the revised guidelines.

Dr. Hiroko Shibata, National Institute of Health Sciences (NIHS)

He explained the relationship between ICH Q6 and ICH Q2(R2)/Q14 guidelines in terms of analytical method development and life cycle management. In particular, the target analytical profile (ATP) presented in ICH Q14 consists of the purpose of using analytical methods and the performance criteria that analytical method barameters must meet, etc. The Critical Quality Attributes (CQAs) and related ATPs, etc. will deepen the systematic understanding of robustness and management strategies of analytical methods and will also help to improve the quality of pharmaceutical products as part of management strategies. He stated that CQAs and associated ATPs are expected to improve the robustness of analytical methods and the systematic understanding of management strategies, and to increase flexibility in drug lifecycle management with respect to specifications and test methods as part of the management strategy.

Ms. Kumi Mizuguchi, Chugai Pharmaceutical Co.

He introduced the approach to establishing a control strategy using the QbD methodology with an example of an antibody drug product, and contrasted the considerations in setting standards with problems in commercial production, showing the difficulties of aligning analytical method performance standards at multiple manufacturing sites and setting standards based on limited batch data. The presentation also included examples of the difficulties of aligning analytical method performance standards at multiple manufacturing sites and setting standards based on limited batch data. He also showed expectations for the revised Q6(R1) guideline, including consistency with the revised ICH Q1/Q5C, examples of standard-setting approaches that utilize Prior Knowledge, and the importance of international harmonization of science- and risk-based standard-setting approaches.

ICH Q6(R1) EWG Topic Leader / Asahi Kasei Pharma Corporation Mr. Takahiro Yamaguchi

In addition to the background of the Q6 revision, he explained the standard-setting issues in the current Q6B guidelines and the expected effects of the revised guidelines using a case study approach. While it is expected that the variability will be larger in commercial production compared to the limited manufacturing results during development, it is not easy to expand the standard width after obtaining approval. While narrow specification ranges based on small batch data during development may increase the risk of lot failure and manufacturing management costs, and supply management may be complicated by regional differences in approved specifications negotiated with regulatory authorities, the acceptance of appropriate specifications based on clinical relevance will ensure continued supply of the product. While there may be cases in which the acceptance of specifications may increase the risk of lot defects and manufacturing management costs, and cases in which supply management may be complicated by regional differences in approval specifications negotiated with regulatory authorities, the acceptance of appropriate specifications based on clinical relevance is expected to increase flexibility for continuous process improvement and improve the stable supply and patient access to medicines in global markets. He also introduced issues to be addressed for the revision of the Q6(R1) guideline, including the establishment of a science- and risk-based management strategy and the concept of standard setting as part of that strategy, promotion of continuous improvement of manufacturing technologies and analytical methods through drug lifecycle management, and response to the diversification of modalities.

Panel Discussion

ICH Cell and Gene Therapy Discussion Group rapporteur Kathleen Francissen of Genentech, Yukiko Shirahata of PMDA, and Daisuke Tsuchida of Kyowa Kirin Company, Ltd. joined us to discuss Key Questions and audience The discussion was focused on the expectations for the revised Q6(R1) guideline, such as the possibility of international harmonization of pharmacopoeias and the concept of setting standards and expanding standards in the clinical context, as well as the difficulties in setting standards for regenerative medicine products and the systematic understanding of analytical methods and control strategies based on more advanced development approaches (ICH Q8-Q14) and the development of standards for pharmaceutical products. The discussion was also focused on the systematic understanding of the life cycle management of standards and the positioning of moderately modified items, which were introduced on a trial basis, in the change management.

Session 3 Group photo

Session4 - Key Strategies and Harmonization Efforts on Raw Material Managements of Cell Therapies -What for CAR-T

Chair: Dr. Satoshi Yasuda, Director, Regenerative and Cellular Medicine Products, National Institute for Health Sciences (NIHS)
　　　Ms. Kathleen Francissen, Genentech

With the increasing number of cell and gene therapy products being developed and launched globally in recent years, international harmonization of science-based regulatory frameworks is becoming increasingly important in clarifying development requirements for these Advanced Therapy Medicinal Products (ATMPs). The importance of international harmonization of science-based regulatory frameworks is growing.

In Session 4, moderated by Satoshi Yasuda, Director of Regenerative and Cellular Products, NIHS, and Kathleen Francissen, Genentech, the four speakers will first discuss the development of CAR-T products as an example, with a particular focus on the management of raw materials and starting materials, namely leukocyte apheresis, and the associated regulatory The speakers gave oral presentations from either a regulatory or industry perspective on the relevant regulations and approaches to addressing the differences, with a particular focus on raw material and starting material leukocyte apheresis management. A panel discussion followed with the addition of one new panelist to provide an in-depth exchange of ideas and discussion.

Dr. Kathleen Francissen, ICH Cell and Gene Therapy Discussion Group Reporter / Genentech, Inc.

Kathleen Francissen, a reporter for the ICH Cell and Gene Therapies Discussion Group (ICH CGT DG), which was established in October 2023 to provide a forum for technical discussion of issues in ATMP development, provided an overview of the DG's activities The DG is reviewing existing ICH guidelines in the context of their application to ATMP development, identifying areas for harmonization, and ultimately developing a comprehensive roadmap prioritizing areas of particular need for harmonization. The DG plans to develop a comprehensive roadmap that prioritizes areas of particular need for harmonization, and to make recommendations on revisions to existing ICH guidelines or the development of new guidelines. The scope of the DG includes both ex vivo cellular therapies, such as autologous and allogeneic CAR-T cells, and in vivo viral vector-based gene therapies.

Dr. Ingrid Markovic, Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA)

He spoke on the basis of the US-FDA's January 2024 Guidance on CMCs, Nonclinical and Clinical Development of CAR-T Cell Products (Guidelines for the Development of CAR-T Cell Products). The guidance includes recommendations for equivalence evaluations that take into account variations among donors of starting materials during the product lifecycle, and the presentation also recommended the use of split studies, where one batch of the same starting material is divided into two batches, one processed by the old process and the other by the new process, and the resulting drug batches are compared. In the lecture, the use of split study was recommended. In this case, it is essential to use paired statistical tests for evaluation.

Mr. Atsushi Nishikawa, Regenerative Medicine Products Review Division, PMDA

Using the manufacturing process of a typical CAR-T product as an example, a detailed explanation was given on the quality control requirements for raw materials and the applicable scope (e.g., the concept of primary and secondary raw materials) based on domestic regulations centered on the criteria for biologically-derived raw materials. The presentation also touched on the management of raw materials related to CAR-T products using the piggy-BAC method of gene transfer and genome editing technology, which do not use viral vectors, in addition to the use of gene transfer via viral vectors, which are commonly used for existing products.

Mr. Shigeki Yagyu, A-SEEDS

He introduced the latest findings in the company's CAR-T products using the piggy-BAC method and demonstrated the importance of quality control and safety evaluation in CAR-T therapy. In particular, he presented detailed data on the impact of T cell composition on the drug efficacy and long-term effectiveness of the final product, and suggested the importance of quality control of raw material cells and optimization of product characteristics and manufacturing processes, also from a clinical perspective. Citing the latest literature, he also discussed cases of secondary cancer development in CAR-T therapy and presented challenges in evaluating the efficacy and long-term safety of CAR-T products based on criteria such as raw material cell characteristics, vector insertion site, and copy number.

Panel Discussion

Yuki Miyatake of Bristol-Myers Squibb Company joined the session, and focused on questions from the audience and key questions, including the differences in regulatory requirements and responses in each country regarding test items and testing methods for donor qualification in global development, the assessment of secondary cancer risk in CAR-T therapy, and quality control and manufacturing management, including raw material management. The importance of selecting appropriate raw materials from the early stages of CMC development with the clinical situation in mind, the concept of ensuring consistency in the characterization of starting materials and manufacturing processes, and the various apheresis procedures for each product were also discussed. In addition, there was a lively exchange of views on expectations for international harmonization of standards and regulatory requirements for the development of regenerative medicine products, including the supply system for raw material cells, collection of starting materials, quality control, and evaluation of equivalence and homogeneity of products using these materials, in anticipation of the development of other products.

Session 4 Group photo

Concluding Remarks

This year's forum was held face-to-face, as in 2024, and the panel discussions in each session were very active. In addition, the Networking Reception and Networking Break, which were set up during the forum, provided a very good opportunity for participants from industry, academia, and government in Japan and abroad to communicate with each other.

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 2025 is scheduled to be held on December 8-9, 2025.

(Mizuyo Shibata, Nao Nakamura, Mika Yoshimatsu, Chikako Suzuki, Hiroaki Ito, Biopharmaceutical Committee)

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