“CMC Strategy Forum Japan 2025” Held

The “CMC*1 Strategy Forum Japan 2025,” organized by CASSS (California Separation Science Society), was held over two days, December 8–9, 2025, at the Tokyo Marriott Hotel (Shinagawa Ward, Tokyo).Approximately 100 participants registered from 14 countries, including not only Japan but also Asia, North America, and Europe, and a very lively exchange of opinions took place.

Background on the “CMC Strategy Forum Japan”

Session 1: Recent Trends in the Regulation of Biopharmaceutical Products

Chair: Alexey Khrenov, Takeda Pharmaceutical Company Limited
PMDARyosuke Kuribayashi, Department of Review for Regenerative Medicine Products, etc.

Session 1 covered a wide range of topics, including the latest trends in regulatory affairs focused on biopharmaceuticals and regenerative medicine products, the status of international joint reviews, and explanations of guidance on new technologies.

Mr. Ryosuke Kuribayashi, Regenerative Medicine Products Evaluation Department, PMDA

Regarding the latest regulatory trends in Japan related to biopharmaceuticals, the presentation covered the procedures for moderate changes, for which a pilot program has begun; review experience with regenerative medicine products; the approach to applying moderate changes to biopharmaceuticals; and the importance of prior consultation regarding eligibility for moderate changes.
A published paper analyzing trends in new drug approvals was introduced, explaining that biopharmaceuticals, such as antibody drugs, account for approximately two-thirds of newly approved products in Japan and that this trend is expected to continue.Furthermore, a published paper on biosimilars indicated that only 6% of cases where differences in quality characteristics from the reference product were justified by equivalence studies, and highlighted that biosimilar development remains at an early stage.
Progress was shared regarding the development of guidelines and approaches to ensuring quality and safety for diversifying modalities, such as regenerative medicine products.

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

Regarding the implementation of the ICH Q12 (Life Cycle Management of Medicinal Products) guideline in Japan, explanations focused on Established Conditions (ECs) for manufacturing and control, the Post-Approval Change Management Plan (PACMP), and Product Life Cycle Management (PLCM) documentation.By utilizing the elements included in ICH Q12, more efficient lifecycle management is expected.
Additionally, regarding ICH M4Q [CTD (Common Technical Document)]Explanation of the latest status of discussions within the working group, covering the background of the revision, the roadmap, key features—including the new structure of CTD M3 and M2.3 in ICH M4Q(R2)—and the published examples (mockups).It was explained that ICH M4Q(R2) aims to further improve lifecycle management and knowledge management.

European Medicines Agency (EMA): Mr. Nino Mihokovic

Presentations were given on the newly established guidelines, revisions to existing guidelines for regulatory changes, and the International Cooperation on Medicines Regulatory Authorities (ICMRA) Joint Review Pilot Program.The Guidelines on Regulatory Changes were revised on September 22, 2025, based on experience gained in Europe to date and scientific and technological advances, with the aim of improving review efficiency while ensuring public health within the European Union.The revised guidelines for regulatory changes, which will take effect on January 15, 2026, incorporate numerous streamlining measures—including the downgrading of change categories from their previous classifications, particularly for biopharmaceuticals—and are expected to improve efficiency.In addition, regarding the ICMRA Joint Review Pilot Program, results demonstrating improved review efficiency were shared, along with past case studies.

Irish Regulatory Authority (HPRA), Mr. Kevin O’Donnell

Mr. O’Donnell, a GMP inspector, gave a presentation on the interpretation of regulatory requirements from a GMP perspective.Regarding change management, the effectiveness of the Pharmaceutical Quality System (PQS) is positioned in ICH Q12 as a core requirement for the flexible application of regulations, and the management of manufacturing changes across the entire supply chain can be said to be a critical part of the change management system throughout the product lifecycle.The joint reflection paper by the International Cooperation on Medicines Regulatory Authorities (ICMRA) also mentions risk-based single-change submissions; this is not a new concept but is consistent with what is described in the Q10 Appendix. Therefore, by properly demonstrating justification through an appropriate PQS, it may be possible to secure inspection waivers or facilitate post-approval changes smoothly.

Panel Discussion

A panel discussion was held with the participation of Ms. Jayda Siggers from Health Canada and Mr. Marcel Hoefnagel from the Dutch regulatory authority (MEB).
First, Health Canada—which had not made a presentation earlier—provided an overview of the latest regulatory developments in Canada. They shared their initiatives regarding ICH Q12 and new modalities, and indicated that their policy moving forward is to advance implementation while accumulating case studies.During the subsequent Q&A session, discussions focused on joint reviews such as those conducted by ICMRA and ACCESS, platform applications, and challenges related to the implementation of ICH M4Q and Q12.Regarding the progress of joint reviews, it was noted that while immediate harmonization is difficult due to differences in regulatory requirements among countries, the decision-making process can be streamlined by building on the accumulated experience of each regulatory authority and deepening collaboration both within and between regulatory agencies.It was also emphasized that, regarding platform applications, the authorities are still exploring the best approach; therefore, it is important for companies to clearly demonstrate their understanding of the process and to proceed while maintaining communication with the authorities.

Session 1

Session 2: Advancements in AAV Technology: Quality Considerations, Analytics, and Manufacturing Strategies

In this session, experts from academia, industry, and regulatory agencies delivered presentations and participated in a panel discussion on the latest findings and challenges regarding the manufacturing and quality assessment of adeno-associated virus (AAV) vectors. AAV is a major platform for gene therapy, and its quality control is directly linked to ensuring patient safety and product reliability.
This session emphasized that AAV is inherently a heterogeneous particle population (with varying fill states—empty, partial, or full—and containing associated impurities) and that, given this complexity, it is essential to design the definition, characterization, and control strategies for Critical Quality Attributes (CQAs) as an integrated approach.Furthermore, it was demonstrated that advances in analytical techniques—particularly multi-tiered analysis centered on mass spectrometry (MS)—enable more quantitative and multifaceted evaluation of AAV fill status, capsid proteins (including PTMs),host cell-derived proteins (HCPs), among other factors, can now be evaluated in a more quantitative and multifaceted manner, and it was demonstrated that this directly contributes to the understanding and control of manufacturing and purification processes.Furthermore, since the selection of the manufacturing platform (cell line, gene delivery method, and purification method) significantly affects yield and quality, it was agreed that integrated optimization across the entire manufacturing process is crucial from both a cost and safety perspective.From a regulatory perspective, key review points include the management of the fill rate (empty/partial) of therapeutic genes within the AAV capsid, impurity control,genomic integrity and titer, and the establishment of specifications based on the validation of analytical methods; in addition, process consistency, raw material risks, and equivalence during manufacturing changes were identified as key review issues, highlighting the need to establish highly reliable control strategies throughout the entire product lifecycle.

Professor Susumu Uchiyama, Graduate School of Engineering, Osaka University

We provided a comprehensive overview of AAV heterogeneity and associated impurities, and introduced a series of analytical methods for evaluating both purified and unpurified vectors to identify critical quality attributes (CQAs).In addition, we presented detailed characterization data for AAV produced using HAT cells—a newly developed human-derived production cell line—and explained how the production cell platform can influence particle populations and quality profiles.

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

Highly specialized insights regarding AAV characterization techniques were shared. The effectiveness of a multi-step MS workflow was demonstrated in addressing challenges such as the complexity of AAV analysis and limited sample volumes.First, in addition to the identification of empty, partial, and full particles using native MS and charge-detection MS (CDMS), a method was introduced that combines pH-gradient anion-exchange chromatography with these MS techniques to evaluate the packing state on a chromatographic timescale.Furthermore, the characterization of capsid proteins using LC-MS and microchip electrophoresis (MCE)-MS was presented, along with the use of top-down MS/MS to complement cases where post-translational modifications (PTMs) are difficult to attribute due to sequence homology (redundancy).Finally, as an example of HCP clearance evaluation using high-performance MS such as the Orbitrap Astral MS, a lab-scale study including AAVx affinity purification and empty/full separation processes was presented.

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

Practical challenges in AAV manufacturing through the culture and purification processes were addressed, emphasizing that productivity, yield, and quality are key factors directly linked to cost reduction and patient safety.In addition, the presentation summarized the impact of platform selection—such as cell lines, culture formats, and scale-up systems—as well as purification strategies (including affinity, ion exchange, size exclusion, and ultracentrifugation) on yield and API quality.Furthermore, examples were presented showing that even with the same gene of interest (GOI) (e.g., CMV-GFP), vector genomic titer can vary depending on design differences. Finally, an outlook was presented for more robust and efficient AAV manufacturing in the future.

Kenichiro Maeda, Department of Review of Regenerative Medicine Products, etc., PMDA

From a regulatory perspective, key issues in the quality evaluation of AAV vector products and frequently cited considerations during reviews were summarized.Specifically, these included the characterization and control of empty and partially filled capsids; the management of product- and process-derived impurities; the evaluation of genomic integrity and potency; and the validation of analytical methods supporting specification setting.Furthermore, the presentation addressed ensuring process consistency—a frequent challenge in regulatory submissions—the appropriate assessment of raw material risks, and the adequacy of equivalence/homogeneity data following manufacturing changes. It expressed the expectation that specifications be established with clinical significance in mind and that reliable control strategies be established throughout the entire product lifecycle.

Panel Discussion

The panel discussion, featuring four speakers and moderated by Mr. Srinivasan Kellathur of Roche Singapore, focused on practical issues and challenges related to AAV manufacturing and control strategies.Participants exchanged views on how the AAV manufacturing process can vary due to inter-batch variations and differences in product characteristics, and questions were raised regarding(ID) testing, and whether the use of in-process control (IPC) could reduce the number of release tests in quality control (QC).In addition, discussions were held on strategies for addressing unknown impurities and overall characterization approaches. From the perspective of immunogenicity, the nature of empty capsids, the importance of reducing empty capsids (including cell line selection),and the emergence of cell lines showing a high “Full” ratio—85–90% “Full” in AAV9—were highlighted. The PMDA expressed the view that empty capsids should be minimized as much as possible to reduce immunogenicity risks.Other topics included virus filtration during the purification process, evaluation of containers related to stability, strategies to reduce manufacturing costs by enhancing cell line development, and the application of AI (particularly optimization using the Design of Experiments (DOE) methodology).

Session 2

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

Chair: Ms. Akiko Ishii, Director, Department of Biopharmaceuticals, National Institute of Health Sciences ( NIHS )
　　　　AmgenAndrew Lennard

The ICH Q1 draft guideline, which reached Step 2b in April 2025, aims to consolidate the multiple existing guidelines on stability testing, introduce science- and risk-based stability evaluation, and address new modalities such as advanced therapy products.In this session, an explanation of the draft ICH Q1 guideline was provided, and the impact of this revision on the stability evaluation of biopharmaceuticals was discussed.

PMDA, Division of Vaccine and Related Products Review, Mr. Takashi Kameda

In addition to an overview of the draft ICH Q1 (Stability Testing) guideline, the outlook for the stability evaluation of biopharmaceuticals from the regulatory authorities’ perspective was presented.The new draft guideline consolidates six guidelines on stability testing and Q1F, resulting in a comprehensive framework for risk-based stability evaluation. Furthermore, the scope of application for biopharmaceuticals has been significantly expanded and is expected to include therapeutic proteins, vaccines, allergen products, and advanced therapy medicinal products (ATMPs).While the principle of relying primarily on long-term storage test data will be maintained, it was suggested that the setting of retest intervals and the use of extrapolation—which have traditionally been considered difficult for biopharmaceuticals—may be applied on a limited basis, provided that the active pharmaceutical ingredient (API) is frozen and its stability profile is fully understood.

Genentech: Mr. Boris Zimmermann

A “Risk-to-Knowledge Framework” was proposed to optimize the level of rigor in stability evaluation methods in line with the growing body of knowledge on product stability accumulated throughout the product lifecycle.Furthermore, a case study on shelf-life extrapolation for biopharmaceuticals was presented, highlighting how combining limited stability data with existing platform knowledge enables extrapolation based on scientific validity, thereby achieving a reasonable shelf-life setting at the time of initial approval.

Mr. Andrew Lennard, Amgen

Focusing on the difference between the standard approach to stability testing outlined in the draft ICH Q1 guideline and the alternative approach—which rationally optimizes stability testing plans based on science and risk—it was emphasized that the alternative approach carries the same weight as the standard approach.It was explained that the introduction of alternative approaches aims to shorten development timelines through the use of modeling and prior knowledge, thereby enabling rapid patient access.

Ms. Hiroko Shibata, Department of Biopharmaceuticals, National Institute of Health Sciences (NIHS)

Based on recently published papers on modeling the stability behavior of biopharmaceutical quality attributes, the feasibility of setting retest intervals and shelf life through extrapolation for biopharmaceuticals was presented.In addition, it was reported that a research group on the stability prediction of biopharmaceuticals has been established in collaboration with several domestic pharmaceutical companies, and efforts are underway to promote discussion on this topic within Japan.

Panel Discussion

Points of discussion included differences in the acceptance of alternative approaches across regions such as Japan, the U.S., and the EU; a cautious stance toward unknown factors and risks; responses to process changes and the addition of manufacturing sites in product lifecycle management; and the acceptability of extrapolation for frozen and lyophilized products.
Overall, the draft ICH Q1 guideline is expected to serve as a “key to transformation” that accelerates science- and risk-based stability assessments. By allowing for a more flexible, case-by-case approach to stability evaluation, it is expected to balance patient access to medicines with development efficiency.Global harmonization through collaboration between regulatory authorities and the industry is essential for implementing the guideline, and it was emphasized that a standard approach is not the only option, and that alternative approaches can enable rapid product supply while ensuring quality and safety.

Session 3

Session 4: Innovative Approaches in Biopharmaceutical Manufacturing: Advanced Manufacturing, Dx, and AI/ML

In this session, the latest insights were shared on the themes of Advanced Manufacturing, Dx, and AI/ML as innovative technologies in biopharmaceutical manufacturing and quality control. In addition to perspectives on innovation from the regulatory authorities’ standpoint, the latest case studies were shared regarding automation, process optimization, advanced quality control, real-time monitoring, and the use of AI during the development phase.
Furthermore, there was a lively discussion regarding the current status, benefits, limitations, and future prospects of AI utilization by regulatory authorities and the industry from the perspectives of regulatory compliance and data integrity.

F. Hoffmann-La Roche: Mr. Gert Thurau

This presentation consisted of two main parts. The first half began with an overview of artificial intelligence (AI), followed by case studies on the use of AI in pharmaceutical development, illustrating the specific scenarios in which AI could be implemented.The second half focused on the regulatory environment for the use of AI in pharmaceutical development and manufacturing, discussing the content of draft guidance documents published in 2025 by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), respectively, and providing an explanation of the current status, including regulatory challenges.It was noted that, centered on the FDA and EMA, active discussions continue between regulatory authorities and stakeholders regarding the regulatory environment surrounding AI. The view was expressed that in rapidly evolving technological fields such as AI, it is extremely important to strike the right balance between ensuring safe use and promoting innovation.

MSD K.K. — Mr. Kenichiro Furuki

Batch manufacturing at large-scale facilities alone cannot fully accommodate the production of small quantities of a wide variety of products.It was demonstrated that achieving decentralized manufacturing using small-scale, identical facilities increases the likelihood of supplying cell-based therapeutics to patients in various countries at the appropriate time. MSD is advancing the continuous production of biopharmaceuticals, and by combining this with POD (Portable-on-demand) facilities, a more flexible supply system is expected.
In relation to this technology, the use of process analytical technology (PAT) and the concept of lots based on residence time distribution models were presented. Furthermore, a presentation was given on the development of a digital twin to address the reduction in permeate flow rate during the concentration process through the introduction of soft sensors.

Health Canada (HC), Ms. Jayda Siggers

In this presentation, Health Canada’s review perspective regarding the use of AI and models in pharmaceutical development and manufacturing was outlined.It was explained that in model reviews, the focus is on whether the model is appropriate for its intended use. Models are classified into “Primary Models,” which are used as the basis for critical decisions and data, and “Supporting Models,” which provide supplementary information and data; the level of review rigor is then determined based on the intended use.Furthermore, when submitting an application using a model, it was recommended to explain the model’s overview in a manner that is easy for regulatory authorities to understand and to engage in discussions from an early stage. It was also suggested as an important future direction to publicly disclose the approaches and strategies used in the application to help establish best practices in the future.

Mr. Marcel Hoefnagel, Dutch Regulatory Authority (MEB)

A presentation was given on the EMA Quality Innovation Group (QIG)’s activities to support pharmaceutical manufacturing. The QIG includes experts in chemical products, biologics, ATMPs, and GMP, who provide advice on technical and regulatory matters as well as international collaboration.It was noted that the “Listen & Learn Focus Groups” began operations in 2023 and are driving innovation by facilitating discussions among experts from industry, academia, and government on topics related to advanced manufacturing—including the use of AI, digitalization, automation, and continuous manufacturing.It was explained that QIG avoids establishing detailed guidelines and prioritizes identifying best practices, viewing the harmonization of expectations among national authorities and the definition of AI as challenges for the future.

Panel Discussion

With the participation of Mr. Kevin O’Donnell of the Irish regulatory authority (HPRA), Mr. Yo Sakurai of the PMDA, and Mr. Kimiaki Takenaka of TAKEDA PHARMACEUTICAL COMPANY LIMITED, the discussion focused on the current extent of AI tool utilization and how their effectiveness is evaluated.It was noted that while both regulatory authorities and companies have already begun introducing AI on a pilot or limited basis, full-scale implementation in the review process itself or for high-risk decision-making has not yet been achieved, and its use is currently concentrated in relatively low-risk areas.While there is a possibility that the use of AI will gradually expand over the next one to two years for simple reviews and process streamlining, the “black box” nature of AI models, the need to explain their validity, risk management, and the nature of audits and inspections were cited as continuing major challenges.Furthermore, it was recognized that there are no fundamental differences between active pharmaceutical ingredients (APIs) and finished dosage forms regarding the application of AI; rather, AI should be evaluated based on what it determines and what risks its errors could directly entail.In particular, it was emphasized that early and ongoing communication between manufacturing and regulatory affairs departments within companies, as well as between companies and regulatory authorities, is essential for the successful implementation of AI. A common understanding was reached that AI is not intended to replace humans; rather, it should be used in a complementary manner while carefully assessing the balance between risks and benefits.
Regarding continuous manufacturing, it was noted that the production of biopharmaceuticals via continuous manufacturing inevitably carries higher quality risks, and that further discussion and consideration are needed regarding the equivalence and homogeneity of such products compared to those produced via batch manufacturing.

Session 4

In Conclusion

Following the 2024 event, this year’s forum was held in person, and the panel discussions in each session featured very lively exchanges.In addition, the Networking Reception and Networking Breaks held during the forum provided excellent opportunities for participants from industry, academia, and government—both domestic and international—to interact with one another, allowing us to fully appreciate the unique strengths of this forum.
Following the conclusion of the four sessions, Mr. Jamie Moore, Vice President of the CASSS Board of Directors, delivered a summary of the forum, bringing the event to a close.
As the JPMA, we intend to continue our support so that this global conference will be held regularly in Japan going forward and contribute to promoting biopharmaceutical research and development and revitalizing the CMC field.We appreciate your continued support.
The next “CMC Strategy Forum Japan 2026” is scheduled to take place on December 7–8, 2026.

(Biopharmaceutical Committee: Mizuyo Shibata, Nao Nakamura, Makoto Sadamitsu, Hideyuki Yoshiyama, Kenji Hayamizu, Hiroaki Ito)

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