CMC Strategy Forum Japan 2025

The CMC*1 Strategy Forum Japan 2025, hosted by CASSS (California Separation Science Society), was held at the Tokyo Marriott Hotel (Shinagawa-ku, Tokyo) on December 8-9, 2025. Approximately 100 participants registered from 14 countries in Asia, North America, and Europe, as well as Japan, and a very active exchange of opinions took place.

Background of CMC Strategy Forum Japan

Session 1: Recent Trends in the Regulation of Biopharmaceutical Products

Chairperson: Takeda Pharmaceutical Company Limited: Mr. Alexey Khrenov
PMDAMr. Ryosuke Kuribayashi, Regenerative Medicine Products Review Department

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

Mr. Ryosuke Tanaka, PMDA, Regenerative Medicine Products Review Dept.

As the latest regulatory trend related to biopharmaceuticals in Japan, he explained about the procedures for Moderate Change Matters, which have been started on a trial basis, the experience in reviewing regenerative medical products, etc., and the concept of applying Moderate Change Matters to biopharmaceuticals and the importance of prior consultation regarding the applicability of Moderate Change Matters.

He introduced a published paper on trend analysis of new drug approvals and explained that biopharmaceuticals such as antibody drugs account for approximately two-thirds of all new drug approvals in Japan, and this number is expected to increase in the future. In addition, as published papers on biosimilars, only 6% of the differences in quality characteristics between biosimilars and their predecessors could be justified by efficacy equivalence studies, and the development of biosimilars is not progressing well.

Progress in the development of guidelines and the concept of ensuring quality and safety for diversified modalities, such as regenerative medicine products, were shared.

Mr. Keisuke Tanaka, Regenerative Medicine Products Review Department, PMDA

The implementation of ICH Q12 (Life Cycle Management of Pharmaceuticals) guidelines in Japan was explained, focusing on the Establish Condition (ECs), Post Approval Change Management Plan (PACMP), and Product Life Cycle Management (PLCM) documents for manufacturing and control. By utilizing the elements included in ICH Q12, more efficient lifecycle management is expected.

The latest status of discussions in the working group for the revision of ICH M4Q [Common Technical Document (CTD)] guideline was also explained, including the background of the guideline revision, roadmap, features including the new structure of CTD M3 and M2.3 in ICH M4Q (R2), and the published description examples (mock-ups). Explanation was given that ICH M4Q(R2) aims to further improve lifecycle management and knowledge management.

Mr. Nino Mihokovic, European Medicines Agency (EMA)

He explained the new guidelines, revisions to the existing regulatory change guidelines, and the International Cooperation of Medicines Regulatory Authorities (ICMRA) Joint Review Pilot Program. The revised guidelines, which will enter into force on January 15, 2026, will specifically biopharmaceuticals, incorporates a number of streamlining measures, including the downgrading of the change category from the previous one, which is expected to improve efficiency. In addition, the ICMRA Joint Review Pilot Program was shared, along with past examples of how it has improved review efficiency.

Kevin O'Donnell, Irish Regulatory Authority (HPRA)

Mr. O'Donnell, a GMP inspector, gave a presentation on the interpretation of pharmaceutical requirements from a GMP perspective. The effectiveness of the Pharmaceutical Quality System (PQS) with respect to change management has been identified in ICH Q12 as a core requirement for flexible use of regulations, and the management of manufacturing changes throughout the supply chain is an important part of a change management system across the life cycle. The International Collaboration of Medicinal Regulatory Authorities (ICMRA) Joint Reflection Paper also mentions risk-based single change submission, which is not a new concept but the same one described in the Q10 Appendix. Therefore, with proper rationale provided in the appropriate PQS, it may be possible to facilitate a waiver of inspections or post-approval modification.

Panel Discussion

Jayda Siggers of Health Canada and Marcel Hoefnagel of the Netherlands Regulatory Authority (MEB) joined the panel discussion.

First, Health Canada, which did not present, explained the latest regulatory developments in Canada, and shared their initiatives for ICH Q12 and new modalities, indicating that they intend to operationalize them as they accumulate examples. During the Q&A session that followed, the participants discussed issues related to the joint review of ICMRA and ACCESS, platform applications, and implementation of ICH M4Q and Q12. Regarding the progress of the joint review, although immediate harmonization is difficult due to differences in regulatory requirements in each country, it was noted that the decision-making process should be made more efficient by building on the experience of each regulatory authority and by deepening cooperation within and between regulatory authorities. The regulators are also exploring platform applications, and it was emphasized that it is important for companies to demonstrate a clear understanding of the process and to communicate with the regulators as they move forward. Session 1

Session 2: Advancements in AAV technology: Quality Considerations, Analytics and Manufacturing Strategies
Chairperson: Dr. Yasuhiro Kishioka, PMDA
Regenerative Medicine Products Review Division 　　　　Roche Singapore Mr. Srinivasan Kellathur

In this session, experts from academia, industry, and regulatory authorities gave lectures and participated in a panel discussion on the latest findings and issues related to the manufacturing and quality assessment of adeno-associated virus (AAV) vectors. directly related to ensuring patient safety and product reliability.

The session emphasized that AAVs are inherently heterogeneous particle populations (including Empty/Partial/Full and associated impurities), and given their complexity, it is essential to design an integrated Critical Quality Attributes (CQAs) definition, characterization, and management strategy. The complexity of the CQAs is a prerequisite for the integrated design of a CQA definition, characterization, and management strategy. In addition, the advancement of analytical techniques (especially multilayer analysis centered on mass spectrometry (MS)) has enabled more quantitative and multifaceted evaluation of AAV packing, capsid proteins (including PTMs), and host cell-derived proteins (HCPs), which is directly related to understanding and managing the manufacturing and purification process. This is directly related to the understanding and management of the manufacturing and purification process. Furthermore, it was shared that the choice of manufacturing platform (cell line, transgene delivery method, and purification method) has a significant impact on yield and quality, and therefore, integrated optimization throughout the entire manufacturing process is important from both a cost and safety perspective. On the regulatory side, in addition to control of the fill rate (empty/partial) of therapeutic genes in AAV capsids, impurity control, genomic integrity and titer, and specification setting based on the validity of analytical methods, process consistency, raw material risk, and equivalence during manufacturing changes are key issues in the review, and a reliable control strategy must be established throughout the product life cycle. The need to establish a reliable control strategy throughout the product lifecycle was also highlighted.

Prof. Susumu Uchiyama, Graduate School of Engineering, Osaka University

He provided a comprehensive overview of AAV heterogeneity and associated impurities, and introduced a series of analytical methods to evaluate both purified and unpurified vectors to determine critical quality attributes (CQAs). In addition, he presented detailed characterization data on AAVs produced in HAT cells, a newly developed human-derived production cell line, and explained how the production cell platform can affect particle population and quality profiles.

Mr. Jonathan Bones, National Bioprocessing Research and Training Institute, Ireland

Highly specialized insights on AAV characterization techniques were shared, demonstrating the effectiveness of a multilayered MS workflow in addressing the challenges of complexity and limited sample volume in AAV analysis. First, in addition to determining Empty/Partial/Full particles by native MS and charge detection MS (CDMS), the combination of these MS with pH gradient anion exchange chromatography was introduced to assess packing status on the chromatographic time scale. The presentation also included a discussion on LC-MS and microfluidics. The use of LC-MS and microchip electrophoresis (MCE)-MS to characterize capsid proteins was also presented, as well as the use of top-down MS/MS to complement cases where sequence homology (condensation) makes attribution of post-translational modifications (PTM) difficult. Finally, as an example of HCP clearance evaluation using high performance MS such as Orbitrap Astral MS, a lab-scale study including AAVx affinity purification and Empty/Full separation process was introduced.

Mr. Takashi Sakurai, Cell & Gene Therapy Research, Astellas Pharma Inc.

He addressed the practical challenges of AAV manufacturing through the culture and purification processes, emphasizing that productivity, recovery rate, and quality are the main factors directly related to cost reduction and patient safety. He also summarized the impact of platform selection, such as cell line, culture form, and culture expansion system, as well as purification strategies such as affinity, ion exchange, size exclusion, and ultracentrifugation, on yield and drug substance quality. In addition, examples of how vector genomic titer can vary due to differences in design, even for the same transgene (GOI) (e.g., CMV-GFP), were presented. Finally, he presented a vision for more robust and efficient future AAV production.

Mr. Kenichiro Maeda, PMDA Regulatory Affairs Division

From a regulatory perspective, he summarized key issues in the quality assessment of AAV vector products and points to be considered frequently in the review process. Specifically, he discussed the characterization and control of Empty/Partially Filled capsid, control of product-derived and process-derived impurities, evaluation of genomic integrity and titer, and validity of analytical methods to support specification setting. In addition, the committee noted process consistency, appropriate assessment of raw material risk, and sufficiency of equivalence/identicality data after manufacturing changes, which is often a challenge in regulatory submissions, and expressed the hope that specification setting will be based on clinical relevance and establish a reliable control strategy throughout the product lifecycle. The committee also discussed the following issues

Panel Discussion

A panel discussion among the four speakers, facilitated by the chair, Mr. Srinivasan Kellathur of Roche Singapore, focused on practical issues and challenges related to AAV manufacturing and control strategies. Participants discussed how lot-to-lot differences and product characteristics can alter the AAV manufacturing process, and questioned the use of polymerase chain reaction (PCR) for identification (ID) testing and whether in-process controls (IPC) can be used to reduce the number of shipping tests in quality control (QC), The question was raised on these points. In addition, there was discussion on the use of unknown impurities and the overall characterization approach. From the viewpoint of immunogenicity, the nature of Empty Capsid, the importance of Empty reduction (including cell line selection), and the emergence of cell lines with a high Full ratio (85-90% Full in AAV9) were discussed. The PMDA has stated that Empty capsid should be minimized as much as possible in order to reduce immunogenic risk. Other topics discussed included viral filtration in the purification process, container considerations related to stability, strategies to reduce manufacturing costs through enhanced cell line construction, and the application of AI, particularly optimization through Design of Experiments (DOE). Session 2

Session 3: Advancing Stability Testing: Modernisation and Expansion of the ICH Q1 Guideline with Science- and Risk-Based Approaches

Chairperson: Dr. Akiko Ishii, Director, Division of Biopharmaceuticals, National Institute of Health Sciences ( NIHS )
　　　　AmgenMr. Andrew Lennard, Astellas Pharma Inc.

The ICH Q1 draft guideline, which reached Step 2b in April 2025, is intended to integrate multiple existing guidelines on stability studies, introduce science and risk-based stability assessment, and address new modalities such as advanced medical products. In this session, an overview of the ICH Q1 Draft Guideline was explained and the impact of this revision on the stability assessment of biopharmaceuticals was discussed.

Dr. Takashi Kameda, Vaccine Evaluation Division, PMDA

In addition to an overview of the ICH Q1 (Stability Studies) Draft Guideline, he introduced the prospects for stability assessment of biopharmaceuticals from a regulatory perspective. The new draft guideline integrates the six guidelines on stability testing and Q1F, and the concept of risk-based stability assessment has been enriched. In addition, the scope of biopharmaceuticals will be greatly expanded to include therapeutic proteins, vaccines, allergenic products, and advanced medical treatments (ATMPs). While the principle of basing the application on long-term preservation study data will be maintained, it is suggested that retest period setting and the use of extrapolation for biopharmaceuticals, which have traditionally been considered difficult, may be applied on a limited basis only to APIs that have been cryopreserved and whose stability profiles are well understood.

Boris Zimmermann, Genentech

A "risk-to-knowledge framework" was proposed to optimize the degree of rigor in how stability assessments are performed as knowledge about product stability increases throughout the product lifecycle. A case study of efficacy extrapolation for a biopharmaceutical product was also presented, in which the combination of limited stability data and existing platform knowledge enabled extrapolation based on scientific validity, resulting in a reasonable efficacy setting at the time of initial approval.

Mr. Andrew Lennard, Amgen Inc.

Focusing on the difference between the standard approach to stability testing as presented in the ICH Q1 Draft Guidelines and the alternative approach to rationally optimize stability testing study plans based on science and risk, it was emphasized that the alternative approach carries equal weight with the standard approach. The introduction of the alternative approach was introduced with the goal of shortening development time and achieving rapid access to patients through modeling and the use of Prior Knowledge.

Hiroko Shibata, National Institute of Health Sciences (NIHS), Biopharmaceuticals Division

Based on recently published papers on modeling the stability behavior of biopharmaceutical quality characteristics, the feasibility of setting retest periods and validity periods using extrapolation for biopharmaceuticals was introduced. He also introduced a research group on biopharmaceutical stability prediction that has been established in cooperation with several Japanese pharmaceutical companies, and is working to promote the discussion in Japan.

Panel Discussion

Differences in acceptance of alternative approaches among regions such as Japan, the U.S., and the EU, a cautious attitude toward unknown elements and risks, responses to changes in manufacturing methods and addition of manufacturing sites in product life cycle management, and the acceptability of extrapolation in frozen and lyophilized products were discussed as issues. Overall, the ICH Q1 Draft Guidelines are expected to be a "key to change" in accelerating science- and risk-based stability assessment, allowing a more flexible approach to stability assessment on a case-by-case basis, thereby balancing access to patients and development efficiency for pharmaceutical products. Global harmonization through collaboration between regulators and industry for guideline implementation is essential, and it was emphasized that the standard approach is not the only way, and that alternative approaches will enable rapid product availability while ensuring quality and safety.

Session 3

Session 4: Innovative Approaches in Biopharmaceutical Manufacturing: Advanced Manufacturing, Dx, and AI/ML
Chair: Alexey Khrenov, Takeda Pharmaceutical Company Limited Mr. Yosuke Watanabe, CHUGAI PHARMACEUTICAL CO., LTD.

In this session, the latest findings were shared on the topics of Advanced Manufacturing, Dx, and AI/ML as innovative technologies in biopharmaceutical manufacturing and quality control. In addition to the regulatory perspective on innovation, the latest case studies on automation, process optimization, advanced quality control, real-time monitoring, and the use of AI in the development phase were shared. There was also a lively discussion on the current status, benefits and limitations, and future prospects of AI utilization by regulators and industry from the perspective of regulatory compliance and data integrity.

Gert Thurau, F. Hoffmann-La Roche

The first half of the lecture consisted of two major parts. In the first half, following an overview of artificial intelligence (AI), examples of AI applications in drug development were presented, showing in what situations AI could actually be introduced. The second half of the presentation focused on the regulatory environment for the use of AI in the development and manufacture of pharmaceuticals, with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) each issuing draft guidance in 2025, Explanation of the current status, including regulatory issues, surrounding AI, He expressed his belief that in a rapidly evolving technology field such as AI, it is extremely important to maintain an appropriate balance between ensuring safe use and promoting innovation.

Kenichiro Furuki, MSD K.K.

Batch manufacturing in large facilities alone is not sufficient for small-quantity, high-mix production. By combining this with a POD facility (Portable-on-demand), MSD is promoting the continuous production of biopharmaceuticals, which is expected to enable a small-volume, high-mix supply. MSD is currently working on continuous production of biopharmaceuticals, and by combining this with POD facilities (Portable-on-demand), it is expected to provide a more flexible supply. In relation to this technology, the use of process analysis technology (PAT) and the concept of lot size based on a residence time distribution model were also presented. He also introduced the construction of a digital twin to cope with the reduction of permeate flow velocity in the concentration process by introducing a soft sensor.

Ms. Jayda Siggers, Health Canada (HC)

In this presentation, the perspective of the Health Canada review regarding the use of AI and models in drug development and manufacturing was presented. In the review of models, the emphasis is on whether the model is appropriate for the intended use, and the degree of rigor of the review is determined based on the intended use, classifying models into two categories: primary models used as the basis for important decisions and data, and supporting models that provide supplementary information and data. He explained that the degree of rigor of screening is determined based on the purpose of use. It was also suggested that an important direction for the future would be to provide an overview of the models in a form that is easily understood by regulators and to discuss them at an early stage of the application process, as well as to disclose the approaches and strategies used in the application and establish best practices in the future. The GMP inspector, Mr. O. O. Kato, was also invited to participate in the meeting.

Mr. Marcel Hoefnagel, Dutch Regulatory Authority (MEB)

He introduced the activities of the EMA Quality Innovation Group (QIG) in support of pharmaceutical manufacturing, which includes experts in ATMP and GMP in addition to chemical synthesis and biologics, and advises on technical, regulatory, and international collaborations. Among them, the Listen & Learn Focus Groups have been active since 2023 and are discussing advanced manufacturing topics, including AI utilization, digitalization, automation, and continuous production, with experts from industry, academia, and government to boost innovation. He explained that the QIG has avoided formulating detailed guidelines and prioritized finding best practices, and that homogenization of expectations of national authorities and definitions of AI are issues that need to be addressed in the future.

Panel Discussion

Mr. Kevin O'Donnell of the Irish Regulatory Authority (HPRA), Mr. Yo Sakurai of PMDA, and Mr. Kosuke Takenaka of TAKEDA PHARMACEUTICAL COMPANY LIMITED joined the discussion, which focused on the extent to which AI tools are being used at this point and how their effectiveness is being evaluated. It was shared that although both regulators and companies have already introduced AI on a trial or limited basis, it has yet to be fully utilized in the examination itself or in high-risk decision making, and is mainly used in relatively low-risk areas. While there is a possibility that over the next year or two, the use of AI will gradually advance in simple examinations and process streamlining, the black box of AI models, explanation of validity, risk management, and the nature of audits and inspections were still cited as major issues to be addressed. It was also recognized that in the application of AI, there is no essential difference between APIs and formulations, and that evaluation should be based on what the AI determines and what risks are directly associated with such errors. In particular, it was emphasized that early and continuous communication between manufacturing and regulatory affairs within a company, as well as between the company and regulatory authorities, is essential for the successful implementation of AI. The participants reached a common understanding that AI should not be used to replace people, but should be used in a complementary manner and proceed by determining the balance between risks and benefits. With regard to continuous production, it was agreed that the production of biopharmaceuticals through continuous production inevitably entails higher risks to quality, and that further discussion and consideration are needed regarding the equivalence/quality of the product with batch-type products.

Session 4

Lastly, Mr. Kenichiro Furuki, MSD Corporation

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 from Japan and abroad to communicate with each other, and we could fully feel the unique advantages of this forum.

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

JPMA hopes that this global conference will continue to be held in Japan in the future and that it will help promote biopharmaceutical research and development and revitalize the CMC field. We look forward to your continued support.

TOP