Department of Pharmaceutical Regulatory Affairs, Anand Pharmacy College Opposite to Town Hall, Anand-388001, Gujarat, India.
Human cells and tissue products belong to a relatively new class of medical products. The products were classified as human cells, tissue, and cellular and tissue-based products (HCT/Ps) in the US, advanced therapy medicinal products (ATMPs) in the EU, and cell/tissue-engineered products in Japan. The Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) are the key regulatory authorities overseeing these products. The Pharmaceutical and Medical Device Act, Japan 2013 Chapter 9: Section 6 Handling of Cellular and Tissue-based Products (Articles 65-2 to 65-6) categorized these products as biologics and medical device. The regulatory requirements for human cell and tissue products in Japan are robust and stringent, ensuring a high level of safety and quality.. Japan adheres to the Act on the Safety of Regenerative Medicine, which divides cell and tissue products into three risk categories (low risk, moderate risk and high risk). The regulatory procedure differs depending on the risk category, with higher-risk goods need more thorough review and clinical data. In compliance with Good Gene, Cellular, and Tissue-based Products Manufacturing Practices (GCTP) principles, manufacturers must undergo extensive testing, including safety and effectiveness assessments. Furthermore, clinical studies must follow Good Clinical Practices (GCP) guidelines which requires maintaining meticulous records of donor information, distribution protocols, and processing phases. Adverse incidents must be quickly reported to relevant regulatory authorities.
The creation of novel pharmaceutical goods, chemicals, and technologies has been significantly impacted by the significant changes that have occurred in Japan since 1997. The regulatory organization itself has evolved. International norms are currently followed when conducting clinical trials. Some clinical data generated in one area are accepted in other parts of the world through a bridging process that is thought to be merely temporary. International clinical trials and concurrent submission to key regulatory agencies are key components of the future of medication and device development. A number of reasons have contributed to the change in pharmaceutical regulation, but the International Conference on Harmonization of Technical Requirements' harmonization process is one of the most significant. The three primary regulatory agencies of the US, Europe, and Japan, as well as the three equivalent associations of pharmaceutical makers, make up the majority of the six parties that make up ICH. It makes sense that the ICH's recommendations would have an international focus and goal. The "quiet law" rules that the ICH creates are not legally enforceable. In light of this, ICH was successful in combining the rules from several domains into a single set that was universally accepted. Japan consented to the adjustments required to get to a consensus. Japan continues to have one of the largest clinical device markets in the world. Japan is a vital export market for American medicines and the world's third-largest pharmaceutical market. Since 2013, the Government of Japan (GOJ) has pushed the healthcare industry as a key growth engine as part of the country's economic revival and growth strategy. Recently, there has been a renewed focus on Japan's healthcare and medical device industries. The COVID-19 pandemic, which highlighted the importance of innovative healthcare goods, is one factor contributing to the heightened attention being paid to Japan's healthcare sector. Another important element influencing the increased interest in Japan's healthcare sector is the rise of the country's digital health sector.
1.1 Regulatory Agency of Japan
The Ministry of Health, Labor, and Welfare (MHLW) and the Pharmaceutical and Medical Device Agency (PMDA). Established in 2004, PMDA, an autonomous administrative agency with non-civil service status, collaborates with MHLW to deliver safer and more efficient medications and medical equipment as quickly as possible. While MHLW safeguards people and their lives both now and in the future, PMDA keeps enhancing our country's public health and safety by evaluating applications for marketing approval of pharmaceuticals and medical devices, implementing safety precautions, and offering assistance to those who have experienced adverse drug reactions. MHLW creates health policy and works on other government initiatives to protect people's lives. (1) For new drug products, drug substances, and medical devices, PMDA serves as a consulting, regulatory review, various compliance assessments, inspection standard creation, and health-related relief service supplier. A group of skilled and informed individuals with backgrounds in pharmaceutical science, medicine, veterinary medicine, physical science, biostatistics, or other fields assess the specific drug product under review's quality, pharmacology, pharmacokinetics, toxicology, clinical implications, and biostatistics. To make sure the product being reviewed is safe and effective, the reviewer committee talks about the test parameters and outcomes. (2)
Medical Technology Association of Japan (MTJAPAN): Under the motto "Never disrupt healthcare," the Medical Technology Association of Japan (MTJAPAN), formerly known as the Japan Medical Devices Manufacturers Association (JMED), was renamed in 2013 and strives to guarantee a steady supply of medical devices. They support the timely delivery of cutting-edge, safe medical technologies. promoting the growth of the medical device technology sector and better medical quality. (3)
1.2 History Of PMDA
Figure 2. Logos of PMDA and MHLW
After the Reorganization and Rationalization Plan for Special Public Corporations (RRSPC) was authorized in a Cabinet meeting in 2001, PMDA was founded in 2004. Prior to that, the Fund for Adverse Drug Reactions Suffering Relief was established in October 1979 in response to lessons learned from cases of drug-induced health harm, including Subacute Myelo-Optical Neuropathy (SMON) and thalidomide-induced prenatal deformities. This was carried out in accordance with the Adverse Drug Reaction Suffering Relief Fund Act's stipulations. In 1987, the Fund, then known as "The Fund for Adverse Drug Reaction Relief and R&D Promotion," began to promote R&D. In order to carry out bioequivalence evaluations of generic medications, this fund was restructured in 1994 as the Organization for Pharmaceutical Safety and Research (OPSR). Consequently, this institution started providing guidelines about clinical trials and performing GCP/GLP inspections as part of the process for assessing new drug applications in 1997. (4)
The National Institute of Health Sciences (NIHS) created the Pharmaceuticals and Medical Devices Evaluation Centre (PMDEC) in 1997 with the goal of creating a thorough regulatory review system and raising the level of review process sophistication. The Center will carry out reviews in collaboration with specialists in the pharmaceutical and medical sciences, biostatistics, and other relevant domains. Furthermore, in 1995, the Japan Association for the Advancement of Medical Equipment (JAAME) was established under the Pharmaceutical Affairs Act as an investigative organization with the responsibility of carrying out equivalency studies of medical equipment. From 121 in 1996 to 241 in 1999, the number of workers engaged in product evaluation and post-marketing safety measures at the former Ministry of Health and Welfare and the three institutions mentioned above increased steadily and significantly. However, because they were governmental institutions, they were limited in how many employees and structures they could add. The Special Service Agency Restructuring Plan was approved by the Cabinet in December 2001 notwithstanding these conditions. In order to further enhance post marketing safety procedures and reviews, it was decided to disband the OPSR and create the Pharmaceuticals and Medical Devices Agency (PMDA) by combining the responsibilities of PMDEC, the OPSR, and JAAME. A measure for the Pharmaceuticals and Medical Devices Agency (PMDA) was examined and approved during the Diet's 155th extraordinary session in 2002. In compliance with the Pharmaceuticals and Medical Devices Agency Act (Act No. 192 of 2002), the PMDA was founded on April 1, 2004. (5) However, in order for PMDA to concentrate solely on reviews, safety measures, and relief services for harm caused by adverse events related to the use of healthcare products, the Regulatory Division and the Research Promotion Division were separated, and in April 2005, services for the promotion of R&D were transferred to the National Institute of Biomedical Innovation, which has since been renamed the National Institutes of Biomedical Innovation, Health, and Nutrition (NIBIOHN).(6)
1.3. Japanese Pharmaceutical Market
According to data from Japan's Ministry of Health, Labor, and Welfare (MHLW), the country's medical equipment market was valued at $38 billion in 2020. The percentage of the Japanese medical equipment market that is made up of U.S. imports is much larger than what is shown in official figures, according to research done by CS Japan. CS Japan claims that up to 60% of the Japanese medical device market may be made up of imports from the US, including those produced in Japan by US businesses. (7) Larger U.S. medical device companies having subsidiaries in Japan include GE Healthcare, Johnson & Johnson, Abbott, Edwards Lifesciences, Medtronic, Stryker, Zimmer, and 3M. The American Medical Devices and Diagnostics Manufacturers' group (AMDD), an industry group for Japanese subsidiaries of U.S.-based firms that produce and market medical devices and in-vitro diagnostics, now has over 60 Japanese companies as members.
Furthermore, many American medical gadgets are sold by Japanese importers and wholesalers. Innovative new medical technology and therapies that reduce pain, restore lost functions, and enhance quality of life are available in Japan. Minimally invasive medical devices, medical technologies, and diagnostics utilizing Internet of Things ("IoT") and Artificial Intelligence ("AI") technology are among the specific medical gadgets that are anticipated to enjoy significant sales potential. The markets for medical equipment related to telemedicine, in-home care, self-care, and preventative care will probably grow as well. (8) The Pharmaceutical and Medical Device Act also heavily regulates the medical device business in Japan. To market a medical device in the United States, a Japanese importer must get a manufacturing/marketing license. By efficiently managing the devices' manufacturing and quality control, postmarketing surveillance operations, and other procedures, the importer with this license—a Marketing Authorization Holder (MAH)—manages the safety and quality of devices entering the Japanese market. Therefore, while choosing new medical equipment, Japanese importers are cautious and usually seek out those that significantly improve clinical results, lower healthcare expenses, have capabilities that are visibly different, and are generally cost-effective. (9)
Figure 1. Leading Pharmaceutical Company Market Share (%), 2023(51)
Companies covered in above graph: Takeda Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Chugai Pharmaceutical Co. Ltd., Astellas Pharma Inc., Otsuka Pharmaceutical Co. Ltd., Eisai Co. Ltd., Shionogi & Co. Ltd., Kyowa Kirin Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co. Ltd., and others. The Japan Pharmaceutical Market Size is Anticipated to Reach USD 65.11 Billion by 2033, Growing at a CAGR of 6.48% from 2023 to 2033Medical Technology Association of Japan (MTJAPAN):(10)(11) Under the motto "Never disrupt healthcare," the Medical Technology Association of Japan (MTJAPAN), formerly known as the Japan Medical Devices Manufacturers Association (JMED), was renamed in 2013 and strives to guarantee a steady supply of medical devices. They support the timely delivery of cutting-edge, safe medical technologies. promoting the growth of the medical device technology sector and better medical quality.
2 Cellular and Tissue-Based Products in Japan
Products made from human tissue and cells are a relatively new category of medical goods. The items were categorized as advanced therapy medical products (ATMPs) in the EU, human cells, tissue, and cellular and tissue-based products (HCT/Ps) in the US, and cell/tissue-engineered products in Japan. From burns and wounds to cancer and genetic diseases, these items have the potential to treat a wide range of medical conditions. These goods were classified as regenerative medicines as cell/tissue-engineered products under the Pharmaceutical and Medical Device Act of 2013 and the Safety and Regenerative Medicine Act (RM Act) of 2013. The primary regulatory bodies in charge of these items are the Pharmaceuticals and Medical Devices Agency (PMDA) and the Ministry of Health, Labour, and Welfare (MHLW). These goods were classified as biologics and medical devices under the Pharmaceutical and Medical Device Act, Japan 2013 Chapter 9: Section 6: Handling of Cellular and Tissue-based Products (Articles 65-2 to 65-6).(12,13)
Pharmaceutical administration in Japan is based on various laws and regulations, consisting mainly of:
The "Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics" (abbreviated as the PMD Act) replaced the Japanese Pharmaceutical Affairs Law (also known as PAL) after it was amended on November 25, 2014. The PMD Act establishes the legislative foundation for the regulation of pharmaceuticals, cosmetics, medical devices, in vitro diagnostic reagents, and products related to cellular and regenerative therapies in the Japanese market. Japan's Ministry of Health, Labor, and Welfare (MHLW) is in charge of administering and supervising the PMD Act legal framework. The Japanese regulatory body that collaborates with MHLW is the Pharmaceuticals and Medical Devices Agency (PMDA). It monitors the post-marketing safety of drugs and medical devices and performs scientific evaluations of their marketing applications. There are 91 articles and 17 chapters in the updated Pharmaceutical and Medical Device Act.
There are three Pillars of “PMD Act” (as per revised Pharmaceutical Affairs Act)
Safety Measures: Package inserts
Medical Devices
According to this legislation, medical devices are those that are mentioned in the PMD legislation Cabinet Order and are used for diagnosis, treatment, or prevention. A further addition to the 2019 Amendment is the introduction of the 'AI' medical device category. Generally speaking, AI medical devices must update data needed for proper medical assessment.
2.1 The Sakigake Strategy
The SAKIGAKE strategy (Lead the world in the practical implementation of new medical products) was launched in the most recent 2019 version. The establishment of a "priority examination designation system," which would cut the approval examination period prior to commercialization in half (from 12 months to 6 months) for medications determined to be likely to be remarkably effective during the early clinical trial phase, is one of the measures the government will support. By taking these steps, the government hopes to make sure that Japan is the world leader in the commercialization of cutting-edge medications, medical equipment, regenerative medicine products, and other goods that target deadly illnesses (such as orphan cancers, incurable diseases, and other severe conditions) for which there are currently no effective treatments. (13)(14)
Designation Criteria for medical products for diseases in dire need of innovative therapy and satisfies the following two conditions:
Figure 7. The Sakigake strategy (52)
2.2 Classification of Cellular and Tissue-Based Products
The ISO/TC210 GMDN project's medical device names are used to establish Japanese Medical Device Nomenclature (JMDN) codes and generic names for medical devices made, imported, and/or sold in Japan. The Global Harmonization Task Force's (GHTF) categorization guidelines were used to determine these classifications. In accordance with the Global Medical Device Nomenclature (GMDN), generic names and codes are established using the PMDA's Japan Medical Device Nomenclature (JMDN) system, which is comparable to the US FDA's product code categorization. Based on the device's possible risk, these generic names are then categorized under one of four medical device classes, ranging from Class I to Class III. The registration procedure varies significantly depending on the type of gadget. (15)(16)
In Japan, the Ministry of Health, Labor, and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) are in charge of classifying and regulating cellular and tissue-based products (CTPs). The Pharmaceuticals, Medical Devices and Other Therapeutic Products Act, also referred to as the PMD Act, regulates the approval and marketing authorization process for CTPs, which fall under the category of regenerative medicine products.
CTPs are divided into three groups under the PMD Act according to the level of processing and risk involved:
Before authorizing CTPs for sale, the PMDA assesses them for efficacy, safety, and quality. In order to encourage the creation and marketing of regenerative medicine products, such as CTPs, Japan also passed the Regenerative Medicine Products Act (RMPA) in 2014. For severe and life-threatening illnesses, the RMPA offers a framework for restricted and time-limited licensing of regenerative medicine products, facilitating quicker access to cutting-edge treatments while maintaining patient safety.
Scope of Regenerative Medical Technology (17)
Medical technologies other than the medical technologies listed below among those that satisfy the requirement of purpose and that use cell products.
1.Blood transfusion that uses processed cells (excludes those that use gene-transferred blood cell constituents or blood cell constituents manufactured from iPS cells etc.)
2.Hematopoietic stem cell transplantation (excludes those that use gene-transferred hematopoietic stem cells or hematopoietic stem cells manufactured from iPS cells etc.)
3.Assisted reproductive technology: Medical technology that uses processed (e.g., cultured) cells of human sperm or unfertilized eggs (excludes those that use embryotic stem cells established from human sperm or unfertilized eggs collected from humans or processed (e.g., cultured) cells of such embryotic stem cells)(18–20)
2.3 Risk Classification of Class I, Class II and Class III Regenerative Medical Technology
Figure 9. Risk classification of Class I, Class II and Class III (53)
Article 2, Paragraph 4 of the Act
According to this Act, "processed cells" are defined as human or animal cells that have undergone processing (such as culturing); "specific processed cells" are defined as processed cells used in regenerative medicine that are not regenerative medical products; "manufacturing" refers to the processing (such as culturing) of human or animal cells; and "cell culturing and processing facility" refers to a facility that manufactures specific processed cells.
Definition of processing
“Processing” stipulated in Article 2, Paragraph 4 of the Act refers to chemical treatment, biological property modification, combination of non-cell constituents, modification by gene engineering means, etc. carried out for the purpose of artificial multiplication/differentiation of cells or tissues, establishment of cells, activation of cells, etc. Separation of tissues, morcellation of tissues, separation of cells, isolation of specific cells (excludes isolation through biological or chemical treatment using chemicals etc.), treatment by antibiotics, cleaning, sterilization by gamma rays etc., refrigeration, thawing, etc. are not regarded as “processing” (this may not apply to procedures that are carried out for the purpose of developing structures or functions that are different from that of original cells).(21)
Manager Notification Ministerial Ordinance, Article 3, Item 3 related
(Definition of homologous use)
“Homologous use” refers to an administration method where the collected cells have the same function as that of cells at the relevant location of the recipient of regenerative medicine. For instance, while collection of fat cells from the abdominal region, separation of adipose derived stem cells from the relevant cells and administration of the stem cells to the affected part of breast cancer therapy for the purpose of reconstruction of the breast falls under the category of homologous use, transvenous administration of the adipose-derived stem cells for the purpose of diabetes treatment does not fall under the category of homologous use because the purpose is not reconstruction. Additionally, regarding medical technologies where centrifuged peripheral blood is used without culturing, for instance, administration to the skin or inside the mouth falls under the category of homologous use, while administration to tissues with poor blood flow (e.g. articular cavity) does not fall under the category of homologous use.(22)
Article 2, Paragraph 8 of the Act
“Specific processed cells manufacturer” refers to an entity who received license/approval of manufacturing specific processed cells or an entity who submitted a notification on manufacture of specified processed cells. 9
When manufacturing in places other than medical institutions etc. in Japan: License
When manufacturing outside Japan: Approval
When manufacturing in medical institutions etc. in Japan: Notification (23)
Standards of structure and equipment (Article 42 of the Act)
Structure and equipment of cell processing facilities must conform to the standards of structure and equipment (24)
Standards of manufacture management, quality control, etc. (Article 44 of the Act)
Specified cell product manufacturers must observe the standards of manufacture management, quality control, etc. (Contents of the Standards) Method of manufacturing and quality control of cell products, implementation method of testing and inspection, method of storage, etc.
2.5 Market Size of Cellular and Tissue-Based Products (25)
The market for cell therapy in Asia Pacific was estimated to be worth USD 959.8 million in 2020, and it is projected to increase at a 14.9% compound annual growth rate (CAGR) between 2021 and 2028. In 2020, Japan held the greatest revenue share of 17.1% and dominated the market. This is due to its rapid expansion as a center for regenerative medicine research. Thanks in great part to government assistance, the nation has become a center for cellular therapy research.
Japan - Regenerative Medicine Market 2023-2027
Japan - regenerative medicine market size is estimated to grow by USD 2,328.47 million at a CAGR of 15.89% between 2022 and 2027.
One quickly evolving technique that has potential applications in regenerative medicine is stem cell treatment. The rate of adoption of stem cell technology has increased as a result of its application in the treatment of illnesses. Additionally, technological advancements in stem cell-based therapies are a major factor in these medical advancements and are altering the way researchers think about regenerative medicine. Additionally, nanotechnology is growing in significance as a vital instrument in regenerative medicine and stem cell technologies. Therefore, throughout the projection period, the market would rise due to the increasing implementation of stem cell technologies.
3. Regulatory Framework For Cellular And Tissue based Products
The Pharmaceuticals and Medical Devices Agency (PMDA) is in charge of regulating tissue-based and cellular products in Japan. The PMDA is in charge of the pre-market review and post-market monitoring phases of these goods' clearance procedure. The Office of Cellular and Tissue-based Products at PMDA is responsible for overseeing these products' regulations. (26)
3.1 Conceptual Illustration of Procedures Under The Regenerative Medicine Safety Assurance Act
The Regenerative Medicine Promotion Act in Japan, enacted in November 2013, marked a significant step in the country's approach to advanced medical therapies. The Act was introduced to promote research, development, and application of regenerative medicine, including cell therapies and tissue engineering. Here are the key points about the Act:
Objectives: The main goals of the Regenerative Medicine Promotion Act are to support innovation, increase Japan's competitiveness in the global regenerative medicine market, and ease the development and commercialization of regenerative medicine products to fulfill unmet medical needs. (27). Regulatory Framework: A framework for the authorization and control of products utilizing regenerative medicine was established under the Act. In order to supervise the approval procedure and guarantee that regenerative medicine products fulfill safety, effectiveness, and quality criteria, it created the Japan Agency for Medical Research and Development (AMED).
Conditional Approval System:
The Act established a conditional approval system to hasten patients' access to regenerative medicine treatments. As long as the medicine shows safety and some efficacy in early-stage clinical trials, this system permits promising therapies to be licensed for practical implementation even as further evidence is gathered.
Oversight and Monitoring:
To ensure the safety and effectiveness of authorized regenerative medicine products, the Act created stringent post-marketing surveillance and monitoring procedures. In addition to allowing for regulatory changes based on actual facts, this continuous assessment helps guarantee patient safety.
Cooperation and Support:
The Act promotes cooperation between government organizations, business, and academia, creating a favorable atmosphere for regenerative medicine research and development. To encourage innovation and hasten the conversion of scientific findings into useful treatments, financial assistance and other incentives are offered.
Global Recognition:
Japan's forward-thinking approach to regenerative medicine regulation has drawn notice and appreciation from all around the world. International cooperation and developments in the sector have resulted from researchers and businesses from all over the world interacting with Japan's regulatory structure.
3.2 Regulatory Framework
The Act on the Safety of Regenerative Medicine is part of Japan's unique regulatory framework for regenerative medicine. This framework was put in place to encourage regenerative medicine research, development, and use throughout the nation. These are the main components of Japan's regenerative medicine regulatory system:
1.Act on the Safety of Regenerative Medicine:
Purpose: The primary objective of this Act is to ensure the safety and efficacy of regenerative medicine products while promoting innovation and timely access to advanced medical therapies.
Regulatory Authority: The Act established the Japan Agency for Medical Research and Development (AMED) as the regulatory authority overseeing regenerative medicine products. Conditional Approval System: The Act introduced a conditional and time-limited approval system for regenerative medicine products. This allows promising therapies to be approved for practical application based on early-stage clinical trial data, with the requirement that additional data be collected post-approval.
Post-Marketing Surveillance: Rigorous post-marketing surveillance and monitoring are conducted to assess the long-term safety and efficacy of approved regenerative medicine products.
2.Guidelines and Standards:
Clinical Trials: Guidelines have been established for conducting clinical trials involving regenerative medicine products. These guidelines outline the necessary procedures and ethical considerations for researchers and clinicians.
Manufacturing Standards: Specific standards and guidelines govern the manufacturing processes of regenerative medicine products to ensure quality and safety. (28)
3.Collaboration and Support:
Industry-Academia Collaboration: The framework encourages collaboration between academic institutions, industry partners, and regulatory agencies to facilitate research and development efforts.
Funding and Support: Financial support and incentives are provided to researchers and companies engaged in regenerative medicine research, promoting innovation in the field.
4.International Collaboration:
Harmonization with International Standards: Japan collaborates with international regulatory bodies to align its standards and regulations with global best practices, fostering international research collaborations and ensuring the quality and safety of regenerative medicine products.
3.3 Pre-Market Requirements for Cellular and Tissuebased Products in Japan
The Act on the Safety of Regenerative Medicine governs Japan's pre-market regulations for regenerative medicine products. The pre-market prerequisites for regenerative medicine in Japan are as follows:(29–31) Although cellular and tissue-based products have potential advantages, there are also major drawbacks. These include the potential for negative reactions or side effects, the high expense of development and production, and the ethical considerations surrounding the use of human cells and tissues. A manufacturer in Japan must submit a pre-market application to the PMDA in order to receive clearance for a cellular or tissue-based product. The application needs to contain information about the manufacturing process, safety, efficacy, and quality. (Form 1) (Form 2)
1. Clinical Trials:
Clinical Trial Approval: Generally, a regenerative medicine product must pass clinical studies before it may be sold in Japan. The Pharmaceuticals and Medical Devices Agency (PMDA), a Japanese regulatory body, must approve these experiments. Observance of the Guidelines: Regarding the planning, execution, and reporting of clinical trials, regenerative medicine businesses are subject to particular rules and regulations established by the PMDA.(27,32,33) In Japan, clinical trials play a significant role in the regulatory procedure for goods derived from cells and tissues. Before products are authorized for sale, the PMDA mandates that producers carry out clinical trials to confirm their efficacy and safety. [ ISO 10993-1 Ed.5] (34)
2.Manufacturing and Quality Standards:
Good Manufacturing Practice (GMP): Regenerative medicine products must be manufactured in compliance with GMP standards. GMP ensures that products are consistently produced and controlled according to quality standards.
Quality Control: Stringent quality control measures are in place to ensure the safety, efficacy, and consistency of regenerative medicine products. (35–38)
3.Documentation and Data:
Regulatory Submissions: Businesses creating goods for regenerative medicine must provide the PMDA with thorough information about the product's quality, safety, and effectiveness. Data Requirements: Comprehensive data from clinical trials and preclinical research, including details on quality control and manufacturing procedures, are provided for regulatory review.
4.Conditional Approval and Post-Market Surveillance:
Conditional Approval: Based on the results of early-stage clinical trials, regenerative medicine products may occasionally be granted conditional approval. This enables patients to have access to potential treatments while further information is gathered.
Post-Market Surveillance: To evaluate the long-term safety and effectiveness of authorized regenerative medicine products, stringent post-market surveillance and monitoring are carried out.
5.Compliance with Ethical Standards:
Ethical Review: All research involving human subjects must pass ethical review by Institutional Review Boards (IRBs) or Ethics Committees. Ethical considerations are a fundamental aspect of the approval process.(39) 6. Collaboration with Regulatory Authorities:
Engagement with Regulatory Authorities: Companies developing regenerative medicine products often collaborate closely with the PMDA, seeking guidance and feedback throughout the development and approval process.
3.4 Marketing and Manufacturing of Cellular and Tissue-Based Products In Japan
Strict regulatory requirements must be followed when producing regenerative medicine products in Japan in order to guarantee their efficacy, safety, and quality. The Pharmaceuticals and Medical Devices Agency (PMDA) oversees the manufacturing process, which complies with the Act on the Safety of Regenerative Medicine's regulations. Here's an overview of the manufacturing process for regenerative medicine products in Japan:
1.Good Manufacturing Practice (GMP):
Compliance: GMP standards must be followed during the manufacturing of regenerative medicine products. GMP guarantees that goods are continuously manufactured and managed in compliance with quality standards.
Facility Requirements: In order to maintain aseptic conditions during production, manufacturing facilities must adhere to strict requirements for cleanliness, appropriate equipment, and employee training.
2.Cell and Tissue Processing:
Cell Collection and Processing: To preserve their viability and usefulness, cells or tissues used in regenerative medicine products are gathered and processed under carefully monitored circumstances.
Quality Control: To guarantee the safety and effectiveness of the finished product, strict quality control procedures are used during cell processing.
3.Quality Control and Testing:
Quality Control Testing: To verify the product's identification, potency, purity, and safety, every batch is put through a rigorous testing process.
Release Testing: Before products are made available for distribution or clinical usage, they must pass release testing procedures to ensure they fulfill predefined requirements.
4.Documentation and Record-Keeping:
Batch Records: For every batch, comprehensive records of the manufacturing process are kept, including raw ingredients, processing stages, and quality control tests.
Traceability: Extensive methods for tracking the origin of cells or tissues, production procedures, and end product distribution are in place.
5.Safety Measures:
Sterility Assurance: Products must be manufactured under sterile conditions to prevent contamination.
Endotoxin and Mycoplasma Testing: Testing for endotoxins and mycoplasma contamination is required to verify product safety.
6.Reporting and Compliance:
Regulatory Reporting: Manufacturers are required to report any adverse events or product deviations to the regulatory authorities promptly.
Compliance Audits: Regulatory authorities conduct periodic inspections and audits to ensure manufacturers adhere to regulations and guidelines.
7.Research and Development:
Innovation: To improve production methods, raise the caliber of products, and investigate novel therapeutic uses, ongoing research and development is encouraged. In order to guarantee adherence to rules and regulations, Japanese producers of regenerative medicine products work closely with regulatory bodies like the PMDA during the manufacturing process.
3.5 Labelling Requirements for Cellular and Tissuebased Products in Japan
Specific information, such as the product's name, maker, intended use, and storage conditions, must be labelled on cellular and tissue-based goods in Japan. Warnings and safety measures pertaining to the product's use must also be included on the label. When labelling cellular and tissue-based products, MHLW MO 169 Chapters 4 and 5-2 should be consulted. [Ministerial Order, or MO]
In order to guarantee patient safety and give consumers and healthcare professionals accurate information, regenerative medicine goods in Japan must adhere to strict labelling regulations. The Pharmaceuticals and Medical Devices Agency (PMDA) is in charge of these requirements in accordance with the Act on the Safety of Regenerative Medicine and its implementing rules. The following are the main elements of Japan's labelling regulations for items involving regenerative medicine:(22)
1.Product Identity:
Product Name: To facilitate easy identification, the product name must be prominently displayed on the label. Manufacturer Information: You must include the name and contact information of the distributor, manufacturer, or owner of a marketing authorization.
2.Description and Intended Use:
Description: The label should provide a clear and concise description of the product, including its intended use and indications. Usage Instructions: Instructions for use, including dosage, administration route, and frequency, must be clearly stated.
3.Safety Information:
Warnings and Precautions: The product's use should be clearly marked with any possible hazards, warnings, or precautions.
Adverse Reactions: It is necessary to give information on typical adverse reactions and side effects.
4.Batch Information:
Lot or Batch Number: A unique lot or batch number must be assigned to each product batch.
Expiration Date: The date when the product is deemed safe and effective should be prominently displayed on the label.
5.Instructions for Storage and Handling:
Storage Conditions: Particular criteria for temperature and humidity should be specified.
Instructions for Handling: Details regarding appropriate handling, including any unique needs, must to be provided.
6.Regulatory Information:
Marketing Authorization Number: The marketing authorization number that the regulatory body has given, if any, ought to be shown.
Compliance Statements: Declarations attesting to adherence to pertinent laws and guidelines.
7.Legibility and Language:
Language: Labels should be bilingual (in Japanese and another language) or in Japanese, which is Japan's official language.
Legibility: Labels ought to be easy to read, clear, and readable.
8.Inserts for packages:
Specific Details: Regenerative medicine products frequently have package inserts in addition to the label that include comprehensive information about the product, such as pharmacological characteristics, clinical studies, contraindications, and instructions for patients and healthcare providers.
3.6 Post-Market Requirements for Cellular and Tissuebased Products in Japan
The marketing authorization process for items involving regenerative medicine is governed by the PMD Act. This Act grants conditional, time-limited marketing authority for products specifically related to regenerative medicine. A benefit-risk profile is evaluated for a second final marketing clearance process after seven years. Following approval for sale in Japan, a cellular or tissue-based product's maker is required to adhere to post-market regulations. These include keeping track of the product's distribution and usage, reporting adverse events, and keeping an eye on the product's efficacy and safety.
Post-market requirements for regenerative medicine products in Japan are in place to ensure ongoing safety and efficacy once a product has been approved and introduced to the market. These requirements are designed to monitor and assess the product's performance in real-world conditions. Here are the key aspects of post-market requirements for regenerative medicine in Japan:
1.Post-Market Surveillance:
Monitoring Adverse Events: Any unanticipated side effects or adverse events related to the use of regenerative medicine products must be reported by manufacturers and medical providers. These reports are gathered and examined in order to continuously evaluate the safety profile of the product.
2.Safety Updates and Reporting:
Safety Updates: Manufacturers must notify regulatory bodies on a regular basis about any new safety issues, unfavourable incidents, or modifications to the risk-benefit profile of their products.
Timely Reporting: It's critical to disclose safety concerns as soon as possible. Healthcare providers and the Pharmaceuticals and Medical Devices Agency (PMDA) must be notified right away if a safety issue occurs.
3. Post-Market Clinical Studies:
Post-Market Studies: To obtain more information on the long-term safety and effectiveness of regenerative medicine products, regulatory bodies may mandate that manufacturers carry out post-market clinical studies. For conditional approvals, when additional data collecting is required before continuing marketing authorization, these studies are very crucial.
4.Labelling Updates:
Labelling Revisions: Manufacturers are required to update product labelling to reflect the updated safety profile in the event that new safety information becomes available. This guarantees that patients and medical professionals are informed of any new dangers or safety measures related to the product.
5.Manufacturing and Quality Control:
Continuous Compliance: In order to preserve the product's quality and consistency, manufacturers must keep up their adherence to Good Manufacturing Practice (GMP) guidelines.
Inspections: To guarantee continued adherence to quality standards, regulatory bodies may periodically inspect production sites. (19, 40–46).
6.Communication with Healthcare Professionals:
Education and Training: Through educational campaigns and training programs, healthcare professionals are kept informed about any modifications to the safety profile of the product. This guarantees that when they prescribe or administer the product, they are up to date on the most recent information.
7.Patient Monitoring and Informed Consent:
Patients undergoing treatments with regenerative medicine give their informed consent after being made aware of the possible dangers and advantages. Processes for informed consent need to be clear and strong. Long-Term Monitoring: In order to evaluate the results of the treatment and spot any delayed side events, patients may be observed over an extended period of time.
3.7 Storage Conditions for Cellular and Tissue-Based Products in Japan
The storage conditions for cellular and tissue-based products in Japan, as well as in many other countries, are critical to maintaining their viability, safety, and efficacy. Specific guidelines and regulations must be followed to ensure the integrity of these products during storage.
1.Temperature Control:
Refrigeration: Many cellular and tissue-based products require storage at temperatures between 2°C and 8°C (36°F to 46°F). This range is typical for products like certain types of stem cells and tissues to maintain their viability.
Cryopreservation: Some products, especially those involving stem cells, might require storage at much lower temperatures, often in liquid nitrogen at around -196°C (-321°F) to maintain their long-term viability. This process is known as cryopreservation.
2.Environmental Factors:
Light Sensitivity: Some products are sensitive to light and must be stored in opaque containers or in conditions where they are not exposed to light for extended periods. Moisture Control: Keeping products dry and preventing moisture exposure is crucial. Proper packaging is necessary to avoid contamination or degradation due to moisture.
3.Sterility and Contamination Control:
Aseptic Conditions: Cellular and tissue-based products should be stored in aseptic conditions to prevent contamination. Cleanrooms and controlled environments are often used for this purpose.
Contamination Prevention: Proper sealing and storage in sterile containers help prevent contamination from microorganisms.
4. Documentation and Traceability:
Labelling: Each storage container should be properly labelled with product information, including expiration dates, lot numbers, and storage conditions.
Record-Keeping: Detailed records of storage conditions, including temperature logs and any deviations from the specified conditions, should be maintained.
5.Monitoring and Alarms:
Temperature Monitoring: Continuous temperature monitoring systems should be in place.
Alarms should alert staff if storage conditions deviate from the specified range. Backup Systems: Backup power systems (such as generators) can ensure that storage conditions are maintained even during power outages.
6.Security and Access Control:
Access Control: Access to storage areas should be restricted to authorized personnel to prevent unauthorized handling or tampering of the products.
Security Measures: Security systems, including surveillance cameras and access logs, can enhance the security of storage facilities.
4. Recent Developments in Cellular and Tissuebased Products in Japan
Japan has been at the forefront of regenerative medicine research and has seen significant developments in cellular and tissue-based products. Since the field of regenerative medicine is dynamic, it's important to note that there might have been further advancements since my last update. However, based on the trends up to 2021, here are some areas of recent development in cellular and tissue-based products in Japan:
1. Induced Pluripotent Stem Cells (iPSCs): Pioneering iPSC Research: Japan has been a pioneer in induced pluripotent stem cell (iPSC) research. The discovery of iPSCs by Shinya Yamanaka in 2006 opened new avenues for regenerative medicine.
Clinical Trials: Ongoing clinical trials have been exploring iPSC-based therapies for various conditions, including heart disease, Parkinson's disease, and age-related macular degeneration.
2. Organ Transplants and Tissue Engineering:
Organ Transplants: Advancements have been made in the transplantation of lab-grown tissues and organs. Researchers are working on creating functional organs using tissue engineering techniques, potentially addressing the shortage of donor organs.
Cornea Regeneration: Japan has been a leader in corneal tissue engineering. Clinical trials and research aim to develop artificial corneas for transplantation.
3.Cancer Immunotherapy:
CAR-T Cell Therapy: Chimeric Antigen Receptor T-cell (CAR-T) therapy, a type of immunotherapy that uses genetically modified T cells to target cancer cells, has been a focus of research and clinical trials in Japan.(47–49)
4.Regulatory Developments:
Regenerative Medicine Products Approval: Several regenerative medicine products have received conditional approval in Japan, allowing patients to access these therapies under certain conditions. The regulatory environment has been supportive of innovative approaches.
5.Clinical Applications:
Spinal Cord Injuries: Research and clinical trials related to spinal cord injuries have been a focus, with efforts to develop therapies to promote nerve regeneration and functional recovery. Diabetes: Cellular therapies for diabetes, including pancreatic islet cell transplantation and stem cell-based approaches, have been under investigation.
6.Research Collaborations:
International Collaborations: Japanese research institutions collaborate with international partners, leading to diverse research initiatives and the exchange of knowledge and expertise.
7.IPS Cell Banks:
Establishment of iPS Cell Banks: Japan has established induced pluripotent stem cell banks, facilitating the sharing of high-quality iPSC lines for research and clinical purposes.
8.Genome Editing:
CRISPR Technology: The development and application of CRISPR-Cas9 gene editing technology have been explored for various genetic disorders and disease. (50)
In recent years, the PMDA has made changes to the regulatory framework for cellular and tissue-based products in Japan. These changes include new guidelines for product development and approval, as well as updates to the post- market surveillance system. For instance, In January 2021, Daiichi Sankyo Company, Limited received MHLW approval for Yescarta in Japan. With this, Japan became the only East-Asian nation with commercialized Kymriah and Yescarta for clinical use. Similarly, in October 2020, Novartis received MHLW approval for Foundation for Biomedical Research and Innovation at Kobe (FBRI) to supply and produce Kymriah in Japan.
Table 1. List of Approved Products
|
Brand Name |
Non-proprietary Name |
Approved In |
|
Abecma |
idecabtagene vicleucel |
January 2022 |
|
Alofisel |
darvadstrocel |
September 2021 |
|
Breyanzi |
lisocabtagene maraleucel |
March 2021 |
|
Carvykti |
ciltacabtagene autoleucel |
September 2022 |
|
Collategene |
beperminogene perplasmid |
March 2019 |
|
Delytact |
teserpaturev |
June 2021 |
|
Heart Sheet |
human (autologous) skeletal myoblast-derived cell sheet |
September 2015 |
|
JACC |
human autologous tissue for transplantation |
July 2012 |
|
Jace |
human (autologous) epidermal cell sheet |
October 2007 |
|
Jace |
human (autologous) epidermal cell sheet |
September 2016 |
|
Jace |
human (autologous) epidermal cell sheet |
December 2018 |
|
Jacemin |
melanocyte-containing human (autologous) epidermis-derived cell sheet |
March 2023 |
|
Kymriah |
tisagenlecleucel |
March 2019 |
|
Kymriah Partial Change Approval |
tisagenlecleucel |
August 2022 |
|
Nepic |
human (autologous) corneal limbus-derived corneal epithelial cell sheet |
March 2020 |
|
Ocural |
human (autologous) oral mucosa-derived epithelial cell sheet |
June 2021 |
|
Sakracy |
human (autologous) oral mucosa-derived epithelial cell sheet using human amniotic membrane substrate |
January 2022 |
|
Stemirac |
human (autologous) bone marrow-derived mesenchymal stem cells |
December 2018 |
|
Temcell |
human (allogeneic) bone marrow-derived mesenchymal stem cells |
September 2015 |
|
Vyznova |
neltependocel |
March 2023 |
|
YESCARTA |
axicabtagene ciloleucel |
January 2021 |
|
YESCARTA Partial Change Approval |
axicabtagene ciloleucel |
December 2022 |
|
ZOLGENSMA |
onasemnogene abeparvovec |
March 2020 |
5. CONCLUSION
In conclusion, Japan's regenerative medicine policies, with a specific focus on cellular and tissue-based products, represent a pioneering approach that has garnered significant attention and admiration worldwide. The country's proactive stance in regulating and promoting innovative therapies has paved the way for groundbreaking advancements in the field of regenerative medicine. Japan's regulatory framework, including the Pharmaceutical and Medical Devices Act and the Act on the Safety of Regenerative Medicine, has created a conducive environment for research, development, and commercialization of cellular and tissue-based products. By streamlining the approval process and fostering collaboration between academia, industry, and regulatory agencies, Japan has accelerated the translation of scientific discoveries into tangible medical treatments. Furthermore, the Japanese government's investment in research and development, coupled with its commitment to fostering a robust ecosystem for regenerative medicine, has facilitated the emergence of cutting-edge therapies. These advancements hold the promise of revolutionizing healthcare by offering novel treatments for various debilitating diseases and injuries. However, it is crucial for Japan to continue monitoring the ethical and safety aspects of regenerative medicine, ensuring that the therapies introduced into the market meet rigorous standards. Additionally, the country can serve as a role model for other nations aspiring to develop similar regulatory frameworks that support innovation while safeguarding patient welfare. In essence, Japan's progressive approach to regenerative medicine, particularly in the realm of cellular and tissue-based products, exemplifies the potential of collaborative efforts between the government, research institutions, and industry players. As these therapies continue to evolve, they offer hope to patients globally, ushering in a new era of medical treatments that have the potential to transform lives and improve healthcare outcomes.
REFERENCES
Khushi Patel*, Hitesh Raval, An Overview on Japan's Regenerative Medicine Policies: Cellular and Tissue-Based Products Examined, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 2, 1290-1311. https://doi.org/10.5281/zenodo.14878652
10.5281/zenodo.14878652
