CMC Japan 2022

09:00 – 09:15
CASSS Welcome and Introductory Comments
Wassim Nashabeh, F. Hoffmann-La Roche Ltd., United States

09:15 – 09:30        
Welcome to the CMC Strategy Forum Japan 2022          
Hiroshi Suzuki, PMDA-Pharmaceuticals and Medical Devices Agency, Japan

Every regulatory agency around the world has been addressing the emergent issues for the last two years and they may evolve through the lessons learned from the unprecedent situation. In this opening scientific session, an international group of regulators will provide the recent regulatory updates and future perspective on the regulation of biopharmaceutical products. The presentations will include information that will contribute to, and be further explored in, panel discussions covering several themes, including:
Preliminary Key Questions:
1. Regulatory update on biopharmaceutical products.
2. Hot topics of CMC review / GMP inspection on biopharmaceutical products.
3. Lessons learned from COVID-19 pandemic and future initiatives.
4. Operation status and points to consider for accelerated approval program.
5. Prospect and possibility for further international collaboration in CMC department.
6. Global procurement risks of raw materials for biopharmaceutical products and accompanying regulatory treatment

Session Speakers:
09:35 - 10:00
Regulatory Updates and a Perspective on Biopharmaceuticals in Japan
Yasuhiro Kishioka, PMDA-Pharmaceuticals and Medical Devices Agency, Japan

10:00 - 10:25
China's Regulatory Framework for Biological Products and the Latest Trend
Min Li, Center for Drug Evaluation (CDE) of NMPA, China

10:40 - 11:05
Regulatory Considerations for Moving from Emergency Use Authorization to Biological License Application for U.S. Products
Robin Levis, CBER, FDA, United States

11:05 - 11:30
FDA Perspective on Opportunities for Modernization of Regulatory Submissions
Ingrid Markovic, CBER, FDA, United States

11:30 - 11:55
EMA’s Support to Innovation – A Status Update
Veronika Jekerle, European Medicines Agency, Netherlands

ICH guideline Q1A is a stability guideline that reached Step 4 in 1993 and was established as one of the first guidelines finalized by the ICH. ICH guideline Q5C is a stability guideline for biopharmaceuticals that reached Step 4 in 1995.
Since the establishment of the guidelines, various experiences on stability have been accumulated by both industry and regulatory authorities, and concepts such as control strategy (ICH Q8/11), quality risk management (ICH Q9), and life cycle approach (ICH Q10/12) have been proposed. Against these backgrounds, Q1/Q5C revision is required to harmonize the existing stability guidelines Q1/Q5C by incorporating science- and risk-based approaches and establishing a single integrated guideline. In addition, stability modeling is considered to be one of the ways to enable early patient access to medicines by predicting retest date and shelf-life.
In this session, the draft concept paper on the revision of ICH guideline Q1/Q5C will be explained and case studies on stability modeling for biopharmaceuticals will be presented.

Key Questions:
1. Is there any expectation to ICH Q1/Q5C revision in terms of stability study programs, retest date and shelf-life from the viewpoint of regulator and industry?
2. What are the challenges and expectation to predict stability profile, set retest date and shelf-life by using stability modeling?
3. Are there any cases where different shelf-lives are approved for different countries, though the same stability data package is provided?
4. Are there any cases of approved products with stability testing or shelf-life utilizing prior/platform knowledge?
5. In accelerated and early access programs (e.g., Sakigake Designation, FDA BTD, EMA PRIME), what approaches can be used for stability testing and shelf-life setting?

Session Speakers:
14:05 - 14:25
Topics Regarding Revisions of ICH Q1/Q5C Guidelines: Focus on Biological Products
Takashi Kameda, PMDA-Pharmaceuticals and Medical Devices Agency, Japan

14:25 - 14:45
Targeted Revision of ICH Q1s/Q5C - Opportunities with Science and Risk-based Approaches
Boris Zimmermann, Genentech, a Member of the Roche Group, United States 

14:45 - 15:05
Using Stability Prior-knowledge from 'Like-molecules' to Determine Shelf-life
Andrew Lennard, Amgen Limited, United Kingdom

Visible particle control is an important part of the control strategy for biological products. Visible particles testing is required for release and stability testing of biological drug products (Injections). Particles may originate from many sources and can be foreign to the manufacturing process (extrinsic particles), related to the manufacturing process (intrinsic) or known to be a specific for a certain product formulation in its primary container closure system (inherent). Beside measures implemented to reduce the ingress of visible particles, the 100% visual control has the goal to identify any container with intrinsic or extrinsic particles. Each container with a particle needs to be discarded. The AQL test verifies the effectiveness of the 100 % visual control. The visual inspection is probabilistic and and the detection probability depends on many factors (e.g. nature of the particles). In case where particles are observed in an on-going stability study their nature has to be explored. This may inform route cause analysis, further use of the material or the need for any regulatory interaction. 

In recent years, new type of root courses of intrinsic particles formation in biological products attract industry/regulatory attention, e.g. excipients degradation and/or visible particle formation related to residual host cell proteins. Advances in analytical techniques enabled the investigation of these new particle phenomena and contributed to the route cause understanding. This session will introduce the mechanism of intrinsic particles formation in biological products, then the control strategy will be discussed from industry/regulatory point of views. 

Preliminary Key Questions:
- How to set a suitable approach for characterization of visible particles, and to select suitable analytical methods?
- What is known about the mechanism of visible particle formation?
- Which approaches can be taken to mitigate risk of visible particle formation and strengthen the control strategy: e.g. control of raw material and manufacturing process, release and stability testing
- How to set suitable acceptance criteria for visible particles specification of biological products?
- Acceptance criteria of visible particles: Are there differences to implement “Practical free from particle” among JP, USP and Ph.Eur.?

Session Speakers:
16:05 - 16:25
Perspective on Visible Particles in Biopharmaceuticals
Yukiko Shirahata, PMDA-Pharmaceuticals and Medical Devices Agency, Japan

16:25 - 16:45
Proteinaceous Visible Particle in Liquid Monoclonal Antibody Formulations
Satoshi Saito, Chugai Pharmaceutical Co., Ltd., Japan

16:45 - 17:15
Industry Perspective on Polysorbate Degradation and Control Strategy for Biopharmaceutical Products - A view of EFPIA Working Group 
Karoline Bechtold-Peters, Novartis Pharma AG, Switzerland and Klaus Wuchner, Cilag AG, Switzerland

The ICH Q5A guideline considers testing and evaluation of the viral safety of biotechnology products derived from characterized cell lines of human or animal origin. Since the Q5A(R1) was finalized in 1999, the manufacturing technology, product types, analytical methodology, and strategies for virus clearance have emerged and evolved over the past 20 years. The R1 guideline is still referred to actively and considered quite useful. However, it was recognized that a revision of the Q5A guideline was necessary to reflect the current scientific knowledge and biotechnology advances.

This year, the Q5A(R2) draft guideline reached Step 2 of the ICH process and has been published on the ICH Website for public consultation. The draft guideline reflects current scientific knowledge and biotechnology advances, for example, new product types in scope, new analytical methodologies and alternative testing approaches to align with the 3Rs principles, points to consider about viral safety for continuous manufacturing, the scientific principles to allow flexible strategies of testing and/or virus clearance including risk-based approach and applying prior knowledge. 

In this session, key points of the revised guideline will be explained, and the expected benefits or challenges in the virus clearance strategies and better viral safety supporting data will be discussed, from perspectives of regulator and industry including CROs with viral testing and virus clearance evaluation, in terms of both product types of emerging and with extensive manufacturing experiences. 

Key Questions:
-Concerning Q5A(R2) guideline, what kind of benefits and challenges are expected in virus clearance strategies or validation approach?
-Are there any challenges or expectation in terms of virus clearance strategy of emerging product type/class which will be scope of revised guideline, such as AAV?
-In terms of product type with extensive experiences of manufacturing such as Mab, are there any challenges or expectations concerning flexible and alternative approach of virus clearance and validation including prior knowledge?
-Are there any challenges or expectations to implement alternative virus detection method as replacement/supplement of existing assay?
-Are there any desirable suggestion or challenges concerning virus clearance strategies of continuous manufacturing process?

Session Speakers:
09:05 - 09:30
Concept of the ICH-Q5A Second Revision
Akira Sakurai, PMDA-Pharmaceuticals and Medical Devices Agency, Japan

09:30 - 09:55
An Industry Perspective on CHO Cell Product Virus Safety
Shohei Kobayashi, Chugai Pharmaceutical Co., Ltd., Japan

10:05 - 10:30
ICH Q5A (R2) Expansion of Scope to Include Viral Vectors: Application of Prior Knowledge for Adenovirus-Vectored Vaccines
Gilles Chénard, Janssen Vaccines & Prevention B.V., Netherlands

10:30 - 10:45
ICH-Q5A Update and Possible Impact on Approach to Virus Clearance Study
Munehisa Masuda, Merck Life Science

10:45 - 11:00
Progress of Blazar Platform with the Background of ICHQ5A R2
Huixing Feng, Merck Life Science

Recently, as the number of approved Regenerative Medical Products (RMPs) in Japan has been rising, companies are expected to face a number of challenges specific to the Cell Therapy and/or Gene Therapy Products. Meanwhile, the collaborations between industry, government, and academia to resolve these challenges are drawing the spotlights, such as the framework to consider the laws and regulations related to the RMPs among regulatory authorities and industries.  
In this session, current regulatory considerations on the unique/specific challenges of RMPs through the product life cycle from development to post-marketing stages, such as regulatory affair, change control, manufacturing, technical transfer, quality control, Japanese Standards for Biological Ingredients, raw material procurements, or logistics, will be discussed, with overviews of case studies and lessons learned from actual developments.
As a part of initiatives to resolve the unique/specific challenges of RMPs through the product life cycle, the developing/draft guidance for the preparation of quality section of the application file for RMPs will be shared by PMDA to exchange views on that.
Furthermore, the current Japanese and European operations of the Law/Act concerning Cartagena Protocol on Biosafety for the development of gene therapy products will be shared, and the differences in the regulatory consideration, such as scope, criteria, and approaches of review process through the development of gene therapy products, will be discussed.        

Key Questions:
• What are the challenges in the development of cell therapy products or gene therapy products unique to Japan?
• What are the differences in the operation of Cartagena Act between Japan and EU to develop gene therapy products? Are there any desired improvement or streamline efforts in the operation of Cartagena Act for the clinical development of the gene therapy products in Japan?
• What are the desirable suggestions regarding the developing/draft guidance for the preparation of quality section of the application file for RMPs, from Industry perspective? Or, what are the unique/specific challenges in RMPs to prepare the quality part of application dossiers?
• Are there any desirable improvement/updating of regulation to encourage the development of RMPs in Japan?
• Are there any differences and/or challenges in review/evaluation process concerning the cell/gene therapy products compared to those of Drugs?
• Compared GMP compliance inspection for Drugs, are there any differences and/or challenges in GCTP compliance inspection concerning cell/gene therapy products?
• At present, there is no region nor country which has signed mutual recognition agreements with Japan concerning GCTP inspections and batch certification of RMPs. What kinds of challenges would be expected to achieve the MRAs for cell/gene therapy products? Are there any expectation/request from Industry concerning the MRAs for the cell/gene therapy products?
• Compared to Drugs, the amount of analytical sampling could significantly impact on the yield, due to its smaller lot size. At present, the importer countries are required to conduct the batch release testing of the imported RMPs in some countries including Japan, and the impact of the amount of analytical sampling on the yield could be substantial. Regarding the imported cell/gene therapy products, are there any differences in the regulatory requirement concerning batch release testing in the importer countries or the status of waiving re-testing upon importation based on product type or country/territories? Are there any challenges or desirable streamlining from perspectives of regulator, industry, or patients? Are there any expectations to mitigate the impact of batch release testing or re-testing in the importer countries from regulatory or industry?
• Compared to the PQS of Drugs, are there any differences or challenges in the quality system for cell/gene therapy products?
• Compared to Drugs, are there any specific challenges concerning supply chain including a case for storage/transportation at ultra-low temperature condition, and a case for a product requiring rapid delivery?

Session Speakers:
14:05 - 14:30
Global Regulatory Considerations of Allogeneic Cell Therapies
Yoko Momonoi, Takeda Pharmaceutical Company Limited, United States

14:30 - 14:55
Points to Consider and Challenges in CMC for Regenerative Medical Products
Mitsuo Kitada and Naoyuki Hanada, Novartis Pharma K.K., Japan

14:55 - 15:20
Composition of the Application Material on Quality for the Marketing Authorization Application of Regenerative Medical Products
Atsushi Nishikawa, PMDA-Pharmaceuticals and Medical Devices Agency, Japan

15:35 - 16:00
Current Status of GMO Regulation in Japan
Seiichi Kanzaki, PMDA-Pharmaceuticals and Medical Devices Agency, Japan

16:00 - 16:25
Differences in Regulations on Gene Modified Organisms Between the Europe, Japan, and the United States
Gentaro Tajima, Pfizer R&D Japan G.K., Japan

Julia Edwards, Genentech, a Member of the Roche Group