Manufacture and Quality Control of drugs and medical devices originating from living organisms MHLW, Pharmaceutical and Food Safety Bureau Notification No. 0520004 May 20, 2003 To: Each Metropolitan and Prefectural Governor From: Director-General Pharmaceutical and Food Safety Bureau MHLW Partial revision of the Ministerial Ordinance on manufacture and quality control of medicines and quasi-medicines (About the handling of products originating from living organisms ) The Ministerial Ordinance (MHLW Ordinance No. 95) on "Partial revision of the Ministerial Ordinance on manufacture and quality control of medicines and quasi-medicines" was promulgated on May 20, 2003 and shall enter into force on July 30, 2003. All the prefectural governments are expected to thoroughly understand and to inform the pharmaceutical manufacturers and importers under their jurisdiction of this Notification. In addition to the above, copies of this Notification will be sent to the heads of the relevant industry organizations. Appendix: Content of the revision Note: The title of the PFSB Notification in Japanese. Appendix Partial revision of the Ministerial Ordinance on manufacture and quality control of medicines and quasi-medicines (About the handling of the products originating from living organisms) Table of Contents 1. Purpose of the revision 2. Coverage 3. Outline of the revision 4. Partial revision of GMP 5. Revision of existing Notifications Annex Content 1. Purpose of revision 　　　In order to provide the quality assurance of the medicines, quasi-medicines, cosmetics, and medical devices (hereafter referred as "medicinal products") affecting the standards for granting the Manufacture and Import Approval, the "Regulations for Manufacture and Quality Control of Medicines and Quasi-medicines" was established by the MHLW Ordinance No. 16 of 1999 (hereafter, the GMP regulations) and in July 2002 the Law partially revising the Pharmaceuticals Affairs Law and the Bleeding and Blood Donor Supply Service Control Law (Law No. 96 of 2002) was promulgated in accordance with the amended Pharmaceuticals Affairs Law (Law No. 145 of 1960) to improve the quality and safety of the products originating from living organisms by adding the necessary manufacture and quality control standards to the GMP regulations. 2. Coverage 　　　The provisions added to the GMP regulations in accordance with the amendment of this time shall apply to the cases of manufacture or of import and sales of the products originating from living organisms, designated by the subject (MHLW Notification No. 209 of 2003) which specifies the products originating from living organisms and specific products originating from living organisms designated by the Ministry of Health, Labor and Welfare. 3. Outline of the revision 　　　In manufacturing or importing and selling the products originating from living organisms, the criteria concerning the following manufacturing controls or quality controls are specified, and full observance of such criteria shall be requested, in order to assure their quality and safety. 1) Regarding the buildings and facilities concerning the manufacturing of specific products originating from living organisms, requirements equal to those concerning conventional biological products shall apply. 2) Regarding the manufacturing controls and quality controls, requirements equal to those concerning conventional biological products shall apply. 3) The retention period of records concerning manufacture or import and sales, etc. shall be extended. 4) The retention period of the reference standards of the specific products originating from living organisms shall be extended. 5) The traceability of records from the raw materials to the products shall be assured. 4. Partial revision of GMP regulations 1. Partial amendment of the Regulations for Buildings and Facilities for pharmacies, etc. (MHW Ordinance No. 2 of 1961) A) Article 8-2 Among the production facilities of medicinal products, in addition to the provisions set forth from Article 5-2 to Article 8, the provision set forth in this article shall apply to the criteria for buildings and facilities of the production facilities for specific products originating from living organisms, as well as the conventional biological products . B) Article 14-4 Among the production facilities of medical devices, in addition to the provisions set forth in Articles 14-2 and 14-3, the provision set forth in this article shall apply to the criteria for buildings and facilities of the production facilities of the specific products originating from living organisms, as well as the description in Part 4. 1. A) of this Notification . 2. Partial amendment to the Regulations for manufacturing control and quality control of medicines and quasi-medicines A) Article 4 (1) As well as for the conventional biological products, the product standard document of the products originating from living organisms shall describe the "names of human, animals, plants, or materials obtained from microorganisms, which are used as raw materials, as well as their nature, property and ingredients, their content, and other specifications," and "specification (including a method of breeding control) of animals (including donated animals, and hereinafter called the "used animals"), which are used for manufacture, or for inspection and testing". (2) "Other specifications" shall indicate matters concerning origin, growing district, methods of manufacturing control and quality control and the like, which are necessary to confirm the quality of raw materials, and necessary matters concerning raw materials specified by the criteria for the raw materials originating from living organisms (MHLW Notification No. 210 of 2003, hereafter "Standards for raw materials originating from living organisms") shall be included in the product standard document as a matter concerning this article. In addition, in the case of products originating from living organisms that are manufactured using human blood specified by the provision set forth in Article 62-6 of the Enforcement Regulations of the Pharmaceutical Affairs Law (Ministry of Health and Welfare Ordinance No. 1 of 1961), or for which active ingredients are obtained from such human blood, and of the specific products originating from living organisms other than these that are manufactured using human blood as materials [the origin of raw materials or materials (including those used in the production process, and hereinafter the same), and hereinafter the same], the name of country where the blood of materials are collected and the method of blood donation [whether donated (defined as voluntary, non-remunerated blood donation) or not donated] shall be also included in "other specifications." B) Article 6 (1) Regarding the products originating from living organisms, the provisions of Paragraph 1, Item 4 regulate that the records of the specific products originating from living organisms, and of the products originating from living organisms manufactured using human blood as materials shall be retained for a period obtained by adding 30 years to the effective term of such products, and that the records of other products originating from living organisms shall be retained for a period obtained by adding 10 years to the effective term, in order to make investigations possible in case infectious diseases are caused by the products. (Same shall apply to the Article 6-1, Paragraph 2, sub-items J, L and M, and Paragraph 3, Item 2, and Article 8, Paragraph 1, Item 3, and Paragraph 2, Item 1, Item ho, and Paragraph 3, Item 2, and Article 10, Paragraph 1, Item 3 and Paragraph 2, and Article 11, Paragraph 2, and Article 12, Paragraph 3, and Article 13, Paragraph 1, Item 3 and Paragraph 2, and Article 15, Paragraph 5, Item 3.) (2) Regarding the products originating from living organisms, the provisions set forth in Paragraph 2 shall apply. (3) The provision of the Paragraph 2, Item 1, sub-item L regulates that the records of the results shall be prepared and retained, upon confirming that the raw materials originating from living organisms that are used for the manufacture of products originating from living organisms satisfy the conditions of raw materials in light of the matters concerning manufacturing approval described in the product standard document, or of the prescribed matters for the criteria for the raw materials originating from living organisms. (4) The "agencies collecting materials of said raw materials originating from living organisms" in the Paragraph 2, Item 1, sub-item M shall indicate agencies (hereinafter called the "agencies collecting materials") which collect or produce materials, and which manufacture materials/intermediate products from materials. (Same shall apply to the Article 8, Paragraph 1, Item 1, sub-item C.) (5) "Appropriately" in the Paragraph 2, Item 1, sub-item M shall mean that, during the retention period specified in said Item, any deletion, loss or mixture of records shall be prevented, and the records shall be managed so that the agencies collecting materials can provide necessary records immediately, at the request of manufacturers. In addition, when causing the agencies collecting materials to retain relevant records, the manufacturers shall make an "agreement" concerning retention conditions of these, and shall secure the appropriateness thereof. (6) Regarding the products originating from living organisms, the provisions of Paragraph 4 regulate that all records at every stage, from collection of materials for the raw materials originating from living organisms until the shipment of products manufactured using said materials, shall be managed so as to be traced, in order to make prompt determination of applicable products or investigation of the cause possible in case any problem is found in the raw materials, resources or products, and in case infectious diseases are caused by the products. C) Article 8 (1) The reference standard stated in the Paragraph 1, Item 1, sub-item C shall be retained as follows: a) Regarding the specific products originating from living organisms or cell- and tissue-derived medicinal products which constitute lots, a quantity of the products twice or more the quantity necessary for testing of the approved standards described in the product standard document shall be conventionally retained per lot for 3 years (or a period of adding 1 year (or 1 month for radiopharmaceuticals) to their effective term) as a reference standard, however, from the viewpoint of safety measures concerning infectious diseases including the occurrence of unknown infectious diseases, said provision regulates that a reference standard for the products or raw materials shall be retained much longer. However, "quantity twice or more the quantity necessary for the prescribed testing" concerning retention of the products after the lapse of 3 years (or a period of adding 1 year (or 1 month for radiopharmaceuticals) to the effective term) shall indicate a quantity twice or more the quantity necessary for the inspection and testing concerning investigation of the cause of infectious diseases such as viruses. b) Regarding the specific products originating from living organisms which do not constitute lots, manufacturers themselves shall retain, or shall cause the agencies collecting materials to retain, as the reference standard, the raw materials for the products originating from living organisms twice or more the quantity necessary for the inspection and testing concerning investigation of the cause of infectious diseases, per production number for a case in which the raw materials originating from living organisms correspond to the products one to one, or per lot of the raw materials originating from living organisms for a case in which one lot of the raw materials originating from living organisms are used for two or more products. When causing the agencies collecting the materials to retain said reference standard, manufacturers shall cause them to retain such specimens appropriately, upon making an "agreement" concerning quantity retained, retention conditions, etc. c) Regarding the specific products originating from living organisms, the retention period of the reference standard shall be a period obtained by adding 10 years to the effective term, in order to provide them for investigation of the cause of infectious diseases including the occurrence of unknown infectious diseases as a safety measure. (2) Regarding the products originating from living organisms, the provision of Paragraph 2 shall apply. (3) The provision of Paragraph 4 shall have the same purport as the description of Part 4. 2. B) (6) of this Notification , and regulates the management of all stages from the inspection and testing at the stage of acceptance of raw materials until the inspection and testing to determine availability of the shipment of the products, so as to make the tracing available. D) Article 15 When a part of production process of the products originating from living organisms is consigned to other manufacturers, an agreement concerning provision of information that said products are relevant to the products originating from living organisms, retention period of records, retention period of the reference standard, security of traceability of records between consignor and consignee, and other matters necessary for manufacturing control or quality control of said products shall be made, under the provision set forth in Paragraph 1. 3. Partial amendment to the Regulations for Manufacturing Control and Quality Control of Medical Devices (MHW Ordinance No. 40 of 1995) Regarding the medical devices designated as products originating from living organisms, it shall be required to take the same measures as those for medicinal products designated as products originating from living organisms. 4. Ministerial Ordinance partially revising the Regulations for import and sales control, and quality control of medicines and quasi-medicines (MHW Ordinance No. 62 of 1999) A) Article 3 The product standard document of the products originating from living organisms shall describe matters necessary for import and sales control, and quality control of said products, including matters specified by the criteria for the raw materials originating from living organisms, as well as Part 4. 2. A) mentioned above . B) Article 5 (1) The confirmation that "medicinal products to be imported are manufactured under the appropriate manufacturing control and quality control" in the Paragraph 1, Item 1 shall mean that it is necessary to confirm that the manufacturing control and quality control for medicinal products are exercised at an exporter's manufactory in accordance with the quality requirements such as approved matters, that the requirements of the GMP observed by an exporting manufacturer or contents required by the criteria concerning quality assurance on behalf of the GMP are equivalent to the requirements of our country's GMP, and that said manufactory conforms to said criteria. Therefore, regarding the products originating from living organisms, this amendment shall require confirmation that the manufacturing process control, retention period of records, retention of the reference standard, traceability of records and the like are exercised appropriately at the exporter's manufactory. (2) "Other necessary matters" in Paragraph 1, Item 6 concerning the products originating from living organisms shall include an agreement for a case in which the following records are retained at an exporting manufacturer for the prescribed period, in addition to the provision specified in Article 3.2 (5) E of the "Enforcement of Cabinet Order partially revising the Enforcement Ordinance of the Pharmaceutical Affairs Law" (PMSB Notification No. 890 dated July 23, 1999). However, in this case it is necessary to make an agreement so that an exporting manufacturer provides necessary records immediately at the request of an importer: a) Records concerning manufacture, and the inspection and testing of the raw materials and products b) Records concerning collection of materials for the products originating from living organisms regulated by the criteria for the raw materials originating from living organisms, etc. (3) Regarding the products originating from living organisms, as well as the regulations for manufacturing control and quality control of medicines and quasi-medicines, the provisions in Paragraph 3, Item 3 regulate that the records of the specific products originating from living organisms, and of the products originating from living organisms derived manufactured using constituents of human blood as materials shall be retained for at least a period obtained by adding 30 years to the effective term, and that the records of other products originating from living organisms shall be retained for a period obtained by adding 10 years to the effective term, in order to make investigations possible in case infectious diseases are caused by the products. (Same shall apply to the Article 5, Paragraph 4, and Article 6, Paragraph 1, Item 9, Paragraph 2, Item 6, Paragraph 3, Item 1 and Item 2, and Paragraph 4, Item 4, and Article 7, Paragraph 2, Item 3 and Paragraph 3, Item 3, and Article 9, Item 2, and Article 10, Item 3, and Article 11, Paragraph 1, Item 3 and Paragraph 2.) C) Article 6 (1) The purport of the Paragraph 2, Item 3, Paragraph 3, Paragraph 5 shall be the same as that of the Article 8, Paragraph 1, Item 1, sub-item C, and Article 6, Paragraph 2, Item 1, sub-item L and sub-item M, and Article 6, Paragraph 4, and Article 8, Paragraph 4 of the Regulations for manufacturing control and quality control of medicines and quasi-medicines. (2) The "exporting manufacturers" in the Paragraph 2, Item 3 shall indicate exporting manufacturers, agencies collecting or producing materials for the raw materials originating from living organisms, and agencies manufacturing materials/intermediate products from raw materials (hereinafter called the "exporting manufacturers") (Same shall apply to the Paragraph 3, Item 2). 5. Ministerial Ordinance partially revising the Regulations for import and sales control, and quality control of medical devices (Ministry of Health and Welfare Ordinance No. 63 of 1999) Regarding the medical devices designated as products originating from living organisms, it shall be required to take the same measures as those for medicinal products designated as products originating from living organisms. 6. Partial revision of the Ministerial Ordinance (MHW Ordinance No. 26 of 1994) concerning the manufacturing control and quality assurance regulations for medicines, quasi-medicines, cosmetics, and medical devices manufactured pursuant to the provisions of the Article 1-2-2, Paragraph 1, Items 1, 2 and 4 of the Enforcement Ordinance of Pharmaceutical Affairs Law in two or more factories A) Article 5 Regarding the products originating from living organisms, as well as the regulations for manufacturing control and quality control of medicines and quasi-medicines, the provisions of the Paragraph 4, Item 3 regulate that the records of the specific products originating from living organisms, and of the products originating from living organisms manufactured using constituents of human blood as materials shall be retained for at least a period obtained by adding 30 years to the effective term, and that the records of other products originating from living organisms shall be retained for a period obtained by adding 10 years to the effective term, in order to make investigations possible in case infectious diseases are caused by the products. (Same shall apply to the Article 8-4, Article 10-3, Article 12-2, Article 13-3, Article 14, Paragraph 1-3, and Paragraph 2, and Article 18-2.) B) Article 10 The purport of Item 1, sub-item C shall be the same as that of Article 8, Paragraph 1, Item 1, sub-item C of the Regulations for manufacturing control and quality control of medicines and quasi-medicines. C) Article 18 The purport of Item 3 shall be the same as that of Article 8, Paragraph 1, Item 1, sub-item C of the Regulations for manufacturing control and quality control of medicines and quasi-medicines. 5. Revision of existing Notifications Accompanying the enforcement of this notice, the following notices shall be treated as follows: 1. The "Enforcement of the Law partially revising of the Pharmaceutical Affairs Law and The Law Concerning the Organization for Drug ADR Relief, Research & Development Promotion and Product Review (PAB Notification No. 333 dated March 31, 1994) shall be partially revised as follows: Regarding the descriptions in the Article 11-2, (2), A), the words "biological products" shall be changed to "products originating from living organisms," and "Article 15 of the Law" shall be changed to "Article 68-2". Regarding the description in the Article 11-3, (4), A), the words "1 year" shall be changed to "30 years". 2. The "On the Standards for manufacturing control and quality control of biological products" (PAB Notification No. 506 dated April 1, 1997) in relation to the "Standards for manufacturing control and quality control of biological products" shall be amended partly as follows: Regarding the description in Article 2, the words "or medicinal products using medicinal products manufactured by making use of technology growing cells of human or animals, as raw materials" shall be changed to ", medicinal products or products originating from living organisms using medicinal products manufactured by making use of technology for growing cells of human or animals, as raw materials". 3. The "Enforcement of Ministerial Ordinance partially revising the Regulations for Manufacturing Control and Quality Control" (PMSB Notification No. 200 dated September 29, 1997) shall be partially revised as follows: Regarding the description in 2, (3) D, the words "Item 4 of the preceding Paragraph" shall be changed to "Item 4 of the preceding Paragraph, and L and M of the preceding Item". 4. The "Enforcement of Ministerial Ordinance partially revising the Enforcement Regulations of the Pharmaceutical Affairs Law (concerning the handling of cell- and tissue-derived medicinal products and cell- and tissue-derived medical devices)" (PMSB Notification No. 266 dated March 28, 2001) shall be partially revised as follows: In Paragraph 3-2, Item 3, sub-item A (1), the words "Item 4 sub-item B" shall be changed to "Item 4" and the words "Article 8, Paragraph 1, Item 3, sub-item B" to "Article 8, Paragraph 1, Item 3". In Paragraph 3-2, Item 3, sub-item M, the words "(2)" shall be changed to "(3)". In Paragraph 3-2, Item 5, sub-item AE the words "Paragraph 3, Item 3, sub-item B" shall be changed to "Paragraph 3, Item 3", "Article 5, Paragraph 4, Item 2" to "Article 5, Paragraph 4, Item 3", "Article 6, Paragraph 1, Item 9, sub-item B" to "Article 6, Paragraph 1, Item 9", "of the same Article Paragraph 2, Item 6, sub-item B and Paragraph 3, Item 4" to "of the same Article Paragraph 2, Item 6, Paragraph 3, Item 1 and Item 2, and Paragraph 4, Item 4", "Article 7, Paragraph 2, Item 3, sub-item B and Paragraph" to "Article 7, Paragraph 2, Item 3 and Paragraph 3, Item 3" as well. In Paragraph 3-2, Item 5, sub-item A (1) the words "Paragraph 2, Item 3, sub-item B, Paragraph 3, Item 1" shall be changed to "Paragraph 2, Item 3, sub-item C, Paragraph 4, Item 1", and "Paragraph 3, Item 2" to "Paragraph 4, Item 2" as well. In Paragraph 3-2, Item 5, sub-item A (2) the words "Paragraph 3, Item 1" shall be changed to "Paragraph 4, Item 1". In Paragraph 3-2, Item 7, sub-item AE the words "Article 8, Paragraph 4, sub-item B" shall be changed to "Article 8, Paragraph 4", "Article 10, Paragraph 3 , sub-item B" to "Article 10-3", "Article 18, Paragraph 2 and Paragraph 3, sub-item B" to "Article 18, Paragraph, 2 and Paragraph 3" as well. In Paragraph 3-2, Item 7, sub-item AE the words "Item 1, sub-item B (2)" shall be changed to "Item 1, sub-item C (3)". 5. The "Enforcement of the Law partially revising the Pharmaceutical Affairs Law" (PMSB Notification No.600 dated June 26, 1995) shall be partially revised as follows: In Paragraph 4-2, Item 4, sub-item AD the words "Paragraph 2" shall be changed to "Paragraph 5", and "Item 2" to "Item 2, sub-item A. 6. The "Application of GMP for medical devices" (PMSB/IGD Notification No. 50 dated June 26, 1995) shall be partially revised as follows: Regarding the description in 1 (4) sub-item N, the words "Paragraph 2" shall be changed to "Paragraph 5". Annex (Ministerial Ordinances) * Ministerial Ordinance partially revising the Regulations for Buildings and Facilities for pharmacies, etc. (Ministry of Health, Labor and Welfare Ordinance No. 92 of 2003) * Ministerial Ordinance on Partial revision of the Ministerial Ordinance on manufacture and quality control of medicines and quasi-medicines (Ministry of Health, Labor and Welfare Ordinance No. 95 of 2003) * Ministerial Ordinance partially revising the Regulations for manufacture and quality control of medical devices (Ministry of Health, Labor and Welfare Ministerial Ordinance No. 94 of 2003) * Ministerial Ordinance partially revising the Regulations for import retail management and quality control of medicines and quasi-medicines (Ministry of Health, Labor and Welfare Ordinance No. 97 of 2003) * Ministerial Ordinance partially revising the Regulations for import retail management and quality control of medical devices (Ministry of Health, Labor and Welfare Ordinance No. 96 of 2003) * Ministerial Ordinance partially revising the Ministerial Ordinance concerning the manufacturing control and quality assurance regulations for medicines, quasi-medicines, cosmetics, and medical devices manufactured pursuant to the provisions of the Article 1-2-2, Paragraph 1, Items 1, 2 and 4 of the Enforcement Ordinance of Pharmaceutical Affairs Law in two or more factories (Ministry of Health, Labor and Welfare Ordinance No. 93 of 2003) Source: Ministry of Health, Labor and Welfare. Translation: JKS LLC Note concerning the translation of the text All original documents issued by the Japanese Government, other authorities and industry group are issued only in Japanese, including their titles, table of contents and texts. Translation of the titles in English is provided here solely by the Jouhou Koukai Services. While utmost care has been taken both linguistically and organizationally to reflect into the English translation the language, abbreviations, professional jargon, style and conventions used in the original texts, no claims either expressed or implied are made for completeness and correctness. Some of the conventions used originate from legacy documents earlier translated to English under the supervision of the MHLW. The Japanese Government does not provide authorized (officially sanctioned) translations of its documents. The translations here are tentative. In a case of legal dispute, the original texts in Japanese will prevail. The translation, formatting, indexing and hyperlinking of the text are copyrights of the Jouhou Koukai Services LLC Worldwide Copyright (c) 2001-2003 by JKS LLC Reproduction in whole or part without permission is forbidden. www.jouhoukoukai.com Note: Medicines (largely pharmaceutical and biologicals) and quasi-medicines (quasi-drugs) are the first two categories of the regulated medicinal products in Japan. The other two categories are cosmetics and medical devices. As stated elsewhere in the text, the amendments detailed in this Notification are equally relevant for medical devices as well. Note: "Living organisms" or "life-originating" is used in the Japanese original with the meaning of materials or products derived from human, animal, plants and microorganisms. Note: More comprehensive overview of the GMP in relation with the regulated medicinal products in Japan could be found in the JKS Document Store in 7_D_M001 document. Note: Ministry of Health and Welfare was the name of the institution prior the formation of the present Ministry of Health, Labor and Welfare. Note: In the text there is no definition of the "conventional biological products", however it should be understood as those products obtain through the traditional methods - e.g. herbal products, and not by the contemporary scientific and medical technologies. Note: see page 6 above. Note: See details in JKS Document Store in documents JM_N_002 and 7_D_K004. Note: see page 9 above. Note: see page 6 above. Note: Summarily for the regulatory documents issued by the Japanese regulatory authorities - see details in JKS Document Store in documents JM_N_001 and JM_N_002. Note: At present the formal name of the Organization is changed to The Organization for Pharmaceutical Safety and Research (OPSR). Note: ADR, Adverse Drug Reactions. Note: Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare, at present renamed to Pharmaceutical and Food Safety Bureau, PFSB. Note: Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare, at present renamed to Pharmaceutical and Food Safety Bureau, PFSB. Note: Pharmaceutical and Medical Safety Bureau of the Ministry of Health and Welfare, at present renamed to Pharmaceutical and Food Safety Bureau, PFSB. Note: Pharmaceutical and Medical Safety Bureau of the Ministry of Health and Welfare, at present renamed to Pharmaceutical and Food Safety Bureau, PFSB. Note: IGD, Inspection and Guidance Division of PMSB (now defunct). PMSB Notification No. 0520004/May 20, 2003 Japan Regulations Series Copyright (c) 2001-2003 by JKS LLC - 2 - Copyright (c) 2001-2003 by JKS LLC - 21 -