MHLW Notification No. 210 - Standards for Raw Materials Originating from Living Organisms Table of Contents How to use this document Conventions MHLW NOTIFICATION No. 210 of MAY 20, 2003 Note: The official title of MHLW Notification No. 210/2003. Facsimile reproduction of a page of the Japanese original STANDARDS FOR RAW MATERIALS ORIGINATING FROM LIVING ORGANISMS Note concerning the translation of the text How to use this document This JKS document contains two main texts: 1. Notification No. 210 of the Minister of the Health, Labor and Welfare dated May 20, 2003 (hereafter MHLW Notification No. 210/2003) - issued to enforced the "Standards for Raw Materials Originating from Living Organisms" - pp. 5-6. 2. The "Standards for Raw Materials Originating from Living Organisms" - the full text of the document in English on pp. 8- 27, with the Table of Contents on page 8 below. Both the MHLW Notification No. 210/2003 and the "Standards for Raw Materials Originating from Living Organisms" are published in the Official Gazette of Japan No. 109 of May 20, 2003, pp. 11-14. A facsimile reproduction of a page from the original Japanese text is shown on page 5 below. The structure of the text the "Standards for Raw Materials Originating from Living Organisms" follows closely the Japanese original, as the following terms are used for clarification: Article Article... Paragraph 1... Subparagraph 1)... Item a)... Conventions In the translation of texts here from Japanese to English, the following conventions were used to uniformity and consistency of the translation and to provide comprehensive information to the non-Japanese readers. > Convention for the use of the term "living organisms": The term "living organisms" is used throughout the Japanese original, however the operational meaning is limited to materials originating human and animals. While the rules and requirements of these "Standards for Raw Materials Originating from Living Organisms" cover exclusively the human and animal (mammals, birds, and insects)-derived materials, as the other "living organisms" such as plants are excluded. > Convention for the use of the term "medicinal products": The products regulated by the Pharmaceutical Affairs Law are collectively described as "medicinal products" and fall into four regulatory categories: medicines or pharmaceutical products (pharmaceuticals, biologicals), medical devices, cosmetics and quasi-drugs. > Convention for the use of the term "raw materials": The Japanese term (genryou) used in the original text could be translated in English as either raw materials or ingredients. For the text below "raw materials" is used. The translated text of the "Standards for Raw Materials Originating from Living Organisms" contains also annotations and comments added by the JK Services for clarity. Any further enquiries regarding the documents, their contents and or related documents could be addressed to the Regulatory Group of Jouhou Koukai Services at regulatory@jouhoukoukai.com. Ministry of Health, Labor and Welfare Notification No. 210 　　　Based on the provisions of the Article 42 of the Pharmaceutical Affairs Law (Law No. 145 of 1960) Paragraph 1 (including application mutatis mutandis in Article 68) and Paragraph 2 , these "Standards for Raw Materials Originating from Living Organisms" are herewith established, shall enter into force from July 30, 2003 (as the rules from the "Standards for Raw Materials Originating from Living Organisms" concerning the record and preservation of raw materials from living organisms shall be in effect from October 30, 2003) and the current "Standards for Pharmaceutical Products and Medical Devices Utilizing Cells and Tissues" (MHLW Notification No. 101 of 2001) shall be in effect until July 29, 2003 and after then abolished. However, if the actual approval is received based on the provisions of Article 14 (including application mutatis mutandis in Article 23) and of Article 19, Paragraph 2 on the same day, it could be still based on the old standards until October 29, 2003. May 20, 2003 Minister of Health, Labor and Welfare Sakaguchi {seal} Attachments: 1. Facsimile reproduction of a page from the original Japanese text 2. Full text of the "Standards for Raw Materials Originating from Living Organisms" Attachment 1. Source: Official Gazette of Japan No. 109 of May 20, 2003 Attachment 2. Standards for Raw Materials Originating from Living Organisms Table of Contents Article 1. General rules Article 2. Basic rules for blood products Article 3. Basic rules for products from human origin Article 4. Basic rules for products from animal origin Contents Article 1. General rules 1. These Standards for raw materials or ingredients (including supplements or culture media used for the manufacturing process) from human and other living organisms (excluding plants) used for medicines (pharmaceutical products), quasi-drugs, cosmetics or medical devices (hereafter "medicinal products") are established to describe the necessary measures to be taken in manufacturing in order to assure the quality, efficacy and safety of the medicinal products. 2. These Standards shall not be applied to the bacteria and viruses used for production of vaccines or to the ingredients or raw materials used to manufacture in vitro diagnostics other than those directly applied to the human body. 3. "Raw materials" shall mean the ingredients or the raw materials used as materials for manufacturing of medicinal products. 4. "Plasma derivatives" shall mean blood from which the materials are extracted by applying as needed appropriate methods to produce blood-derived medicinal preparations from individually separated blood or from a part or from the whole blood. 5. "Donors" shall mean those persons [except for the cases concerning the brain-dead bodies as specified in the Article 6, Paragraph 2 of the Law on the Transplantation of Internal Organs (Law No. 104 of 1997)] who supply cells or tissues as ingredients or raw materials for human cell- or tissue-derived products. 6. "Donor animal" shall mean other than a human animal, who supply cells or tissues as ingredients or raw materials for animal cell- or tissue-derived products. 7. "Donor screening" shall mean concerning the donor, a diagnosis according to an oral consultation, inspection, etc., and concerning the animal donor, carrying examination tests and breeding management, so to enable judging whether the said donor or donor animal have sufficient disposition to offer cells or tissues as a source for raw ingredients or materials for products from human or animal origin. 8. "Window period" shall mean the period in the early stages of an infection when bacteria, eumycetes, or viruses or their antigens, antibodies, genes, etc. cannot be detected. 9. In term of the quality and safety of the medicinal products, when a validity of the same or higher than the level required by the regulations of these Standards level is identified, the said regulations of these Standards shall not apply to medicinal products as stated in the approval certificates issued in the cases of approvals granted under the Pharmaceutical Affairs Law. Article 2. Basic rules for blood products 1. Basic Rules for Blood Derivatives for Transfusion 1) The donor providing blood (hereafter the "blood donor") for human blood derivatives for transfusion (containing supplements or culture medium used for the production in the manufacturing process of the medicinal products; the same hereafter) shall be subjected to a verbal examination to diagnose whether the said donor may have any disease propagated through the blood circulation, and by eliminating any doubt to assure that the said donor is eligible to provide blood for human blood derivatives for transfusion. 2) The following methods shall be used for collecting blood: a) Whole-blood blood collection: for the blood-collecting set, after adding a suitable blood preservation liquid, and after having promptly the blood-drawing needle assembled, seal the set and sterilize by using a high-pressure steam. b) Blood components blood collection: when collecting individual blood components such as blood platelets, to return the rest except this component, shall do the followings: i) Applying mutatis mutandis to Item a), after the whole-blood blood collection is completed, the specific component of the blood are extracted by suitable method and the blood components other than the above component are returned ii) Using an extracorporeal blood component collecting device, by making the blood to circulate outside the body, collect the specified blood component while adding appropriate blood- preservation fluid. 3) For the materials for blood derivatives for blood transfusion, except for the cases separately specified, the blood collecting methods as of Subparagraph 2) above shall be used for the followings: a) Blood extracted by whole-blood blood collecting method b) Platelet-rich plasma or platelet-concentrated plasma collected through blood components collecting method c) Blood plasma collected through blood components collecting method 4) The material used for production of blood derivatives for transfusion shall be stored between 1 and 10 degrees Celsius . However, when manufacturing blood platelet preparations or when separating a blood component, it can put at normal temperature. 5) The blood to be used as material for blood derivatives for transfusion, shall be tested serologically to detect Treponema pallidum, Hepatitis B virus (HBV), Hepatitis C virus (HCV), human immunodeficiency virus (HIV-1 and HIV-2), and Human T lymphotropic virus type I (HTLV-I), for every blood collected from each individual donor. When disqualified as a result of those tests, the blood collected shall not be used as a material for blood derivatives for transfusion except in the cases specified in the "Standards for Biological Medicinal Products" (MHLW Notification No. 217 of 1993). 6) The blood to be used as material for blood derivatives for transfusion, nucleic acid amplification tests must be carried to detect at least Hepatitis B virus DNA, the Hepatitis C virus RNA, and Human immunodeficiency virus RNA. If as a result of the testing, Hepatitis B virus DNA, the Hepatitis C virus RNA, or Human immunodeficiency virus RNA has been detected, the blood collected shall not be used as a material for blood derivatives for transfusion. 7) The blood to be used as material for blood derivatives for transfusion shall be tested by using antisera to determine the ABO blood type and Rh group for every blood collected from each individual donor. The examination of the ABO blood types of the serum or plasma to determine the blood type shall be carried by using known A type and B type red blood cells, and by using antibodies for anti-A blood typing or antibodies for dry anti-A blood typing, or antibodies for anti-B blood typing or antibodies for dry anti-B blood typing comforting to the "Standards for Antibodies for Blood Grouping" (MHLW Notification No. 204 of 1994). The examination of blood types of Rhesus groups shall be performed according to the predetermined directions using antibodies for anti-D blood grouping or mixed antibodies for anti-D blood grouping, and D (Rh0) positivity or negativity distinction shall be judged, as when the result of this examination is negative, it shall be examined further by using anti-human globulin antibodies (multi-specific antibodies) which suit the antibody standard for blood grouping. 8) The following information shall be recorded and retained to confirm the information necessary to assure the quality and safety of blood derivatives for transfusion: a) Facility where the blood is collected b) Date when the blood is collected c) Results of diagnosis by doctors' interview, medical examination, examination or so forth for donor screening, and conditions d) Results from serological tests and nucleic acid amplification tests e) Collecting process of said blood f) The identification number which specifies the blood donor of the said blood g) Information necessary to assure the quality and safety of the blood derivatives for transfusion, besides information stated in Items a) to f). 2. General Rules for Plasma Derivatives 1) It shall be confirmed that a blood donor (hereinafter called the "blood donor" in the General Rules for Plasma Derivatives) used for the plasma derivatives (including those used as additives, culture media, etc. in the production process of drugs, and hereinafter the same) does not have any disease propagated through his/her blood, and is eligible to donate blood used for the raw materials of plasma derivatives, by an interview with a doctor, but shall not be limited to those cases in which it is confirmed that pathogens propagated through blood have been inactivated or eradicated in the production process, and in which such confirmation is stated in the approval certificates issued in the cases of approvals granted under the Pharmaceutical Affairs Law to manufacture the said plasma derivatives. 2) Blood shall be collected in accordance with the blood drawing techniques provided in Subparagraph 2) of the Paragraph 1. General Rules for Blood Derivatives for Transfusion. 3) The materials for plasma derivatives shall use one of the following materials collected in accordance with the blood drawing techniques as provided in Subparagraph 2) (above), except for the cases provided for separately: a) Blood collected in accordance with whole blood collection methods b) Platelet-rich plasma or platelet-concentrate plasma collected in accordance with blood component collection methods c) Plasma collected in accordance with blood component collection 4) When preserving the materials of the plasma derivatives, the materials subject to Item a) of Subparagraph 3) shall be preserved at a temperature of 10 degrees Celsius or lower without freezing, and the materials subject to Item b) or Item c) of Subparagraph 3) shall be preserved at a temperature of 10 degrees Celsius or lower. 5) With respect to the blood used for materials of the plasma derivatives, serologic tests for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) shall be conducted. When the result of such tests is recognized as inappropriate, said blood shall not be used for materials, except for those cases provided in the individual articles of the "Standards for Biological Medicinal Products". 6) With respect to the raw plasma of the plasma derivatives, nucleic acid amplification tests for DNA of HBV, RNA of HCV, and RNA of HIV shall be conducted, but shall not be limited to those cases in which DNA of HBV, RNA of HCV, or RNA of HIV is not detected in blood, the materials of said raw plasma, as a result of the nucleic acid amplification tests. Plasma, in which DNA of HBV, RNA of HCV, or RNA of HIV is detected as a result of these tests, shall not be used as raw plasma. 7) Raw plasma shall be preserved at a temperature of 6 degrees Celsius or lower. 8) The following information shall be recorded and retained to confirm the information necessary to assure the quality and safety of blood and raw plasma used as materials of the plasma derivatives: a) Blood collection facility where materials are collected b) Date of collection of materials c) Medical examination records of the blood donor, who is used for raw plasma, including medical records d) Records of serologic tests and nucleic acid amplification tests e) Collecting process of materials, and production process of raw plasma f) Production number of materials and raw plasma g) Number specifying the blood donor, who is used for raw plasma collection h) Information necessary to assure the quality and safety of the plasma derivatives, aside from the information stated in Items a) to g). Article 3. Basic rules for products from human origin 1. Standards for the Raw Materials from Human or Animal Cells or Tissues 1) Cells and tissues used as raw materials or ingredients for human cell/tissue products [medicines or medical devices composed of raw materials or materials derived from humans (except for blood and components produced from blood), and hereinafter the same] shall be collected in a facility, which has sufficient personnel and equipment to conduct sanitary control necessary for the collection. 2) In collecting cells or tissues used as materials for the human cell/tissue products, the following measures shall be taken: a) Measures necessary to prevent contamination by pathogenic microorganisms or other causes of diseases shall be taken in the process of collecting said cells or tissues b) With respect to collected cells or tissues, appropriate tests are conducted accordingly, in light of the latest information on infectious diseases, and it is confirmed that they are not contaminated by pathogenic microorganisms or other causes of diseases. 3) The donor shall be subject to any of the following, and shall be eligible to donate cells or tissues used as materials of the human cell/tissue products. Donor screening shall not be required when the recipient of the human cell/tissue products and the donor are the same: a) Interview with a doctor, medical examination, examination or so forth have verified that that there is no infection with bacteria, eumycetes or viruses, in accordance with the purpose of using those donors b) Examination items and examination methods stated in Item a) are appropriate in light of the latest information on infectious diseases c) Recheck in response to the examination items and examination methods stated in Item a) is conducted in time, in consideration of the window period. 4) In addition to the above, with respect to the following diseases, doctor's interview, medical examination, examination or so forth shall be conducted, and the donor shall be judged appropriate, in consideration of his/her blood transfusion or transplantation record: a) Infectious diseases with bacteria such as Treponema pallidum, Chlamydia, gonococci, M. tuberculosis, etc. b) Sepsis and possible sepsis c) Malignant tumors d) Serious metabolic and endocrine disorders e) Collagen diseases and hematological disorders f) Liver diseases g) Transmissible spongiform encephalopathy and possible spongiform encephalopathy, and dementia 5) Before donor screening, a person who collects cells or tissues shall provide a full explanation in writing of the purpose of using cells and tissues, the protection of personal information, and other matters related to collection to the person who will become a donor, so that said person understands the contents of the explanation, and shall obtain in writing consent at the discretion of said person. In providing an explanation, it shall be clarified that said person has the right to refuse and withdraw such consent, and that such refusal or withdrawal will not create any disadvantage to said person. 6) When the donor has difficulty in receiving the explanation and in giving a consent, or when the donor is incapable of providing total consent by himself/herself, the collection of cells or tissues may be conducted, as long as the following requirements are satisfied, in accordance with the consent of a legal representative (a person who exercises parental authority for such donor, or who is a spouse or guardian, or is quasi to these, and is entitled to receive explanation and to provide consent on behalf of said donor, and hereinafter the same): a) The collection of cells or tissues from said donor shall have rational reasons required for securing the quality, efficiency and safety of the human cell/tissue products b) The legal representative shall be judged as the best person to represent the intention and interests of said donor, and when the legal representative consents, records concerning the relationship between the donor and legal representative shall be prepared and retained with the consent document c) The person who collects cells or tissues shall provide a thorough explanation to the donor, adequate to donor's level of comprehension, and shall endeavor to obtain consent from the donor himself/herself d) The scientific and ethical adequacy of collecting cells or tissues from said donor shall be examined and approved at the ethics committee in the facility where the collection is conducted. 7) When cells or tissues are supplied from cadavers, approval shall be obtained from the bereaved family, upon explanation in accordance with the description in Subparagraph 5) above. The collection of cells or tissues shall be conducted only when said donor agreed to the donation of cells or tissues before his/her death. In addition, respect for the donor shall be maintained. 8) Also when using cells or tissues removed by surgical operations, approval shall be obtained in accordance with the descriptions in Subparagraphs 5) and 6) above. In such cases, said operations shall not be conducted by giving priority to the purpose of collecting cells or tissues. 9) The collection of cells or tissues from the donor shall be conducted without compensation, but not limited to cases in which, with respect to the donor's costs arising from the donation of cells or tissues, appropriate compensation is made in a consideration of the actual expenses such as transportation, etc., upon obtaining the approval of the ethics committee, etc. 10) The following information shall be recorded and retained to confirm the information necessary to assure the quality and safety of human cells or tissues used as materials of the cell tissue products: a) Facility where said cells or tissues are collected b) Date of collecting said cells or tissues c) Results of diagnosis by doctors' interview, medical examination, examination or so forth for donor screening, and conditions d) Collecting process of said cells or tissues e) Results of the discussion in the ethics committee, etc. f) Informed consent document and consent form g) Identification number of the donor h) Information necessary to assure the quality and safety of the human cell/tissue products, besides information stated in Items a) to g). 2. Standards for the Raw Materials from Human Urine 1) With respect to medicinal products manufactured using human urine as materials, the criteria for raw materials derived from human urine shall apply, and the regulations in Subparagraph 9) of Paragraph 1. Standards for the raw materials from human or animal cells or tissues shall apply mutatis mutandis. 2) Appropriate examinations for infectious diseases shall be conducted at the appropriate stage of urine or pooled urine collection (urine per donor or mixture of urine collected from two or more donors, and hereinafter the same), verifying that there is no infection with pathogenic microorganisms, but shall not be limited to cases in which it is confirmed that pathogenic microorganisms or other causes of diseases have been inactivated or eradicated in the production process, and in which such matter is stated in the approval certificates issued in the cases of approvals granted under the Pharmaceutical Affairs Law to manufacture the said products. 3) With respect to urine used as materials, nucleic acid amplification examination for DNA of HBV, RNA of HCV, and RNA of HIV shall be conducted at the appropriate stage of pooled urine collection, but shall not be limited to those cases using urine as materials, in which it is recognized that DNA of HBV, RNA of HCV, or RNA of HIV have not been detected as a result of nucleic acid amplification tests. 4) Bacteria, eumycetes or viruses are confirmed to be inactivated or removed in the production process in urine used as primary material. 5) The following information shall be recorded and retained to confirm the information necessary to assure the quality and safety of urine used as material: a) Name of institution where the pooled urine is produced b) Date of production of the pooled urine c) Results of examinations of the pooled urine d) Production process of the pooled urine e) Lot number of the pooled urine f) Information necessary to assure the quality and safety of said medicinal products, aside from the information stated in Items a) to e). 3. Standards for the Raw Materials from Human Origin 1) The results of examinations of pooled urine materials (except for bacteria or those which are known by the public scientifically to contain no risk of viral infection, and hereinafter the same in the criteria for human-derived materials) derived from humans except for blood, urine and materials of human cell/tissue products. However, the provision in Subparagraph 2) below shall not apply to the materials which are human-derived materials from a cell bank and are actually formed at the time of application of these criteria, which are recognized to have an adequacy at a level similar to or greater than the provision in Subparagraph 2) below with respect to their use as materials, from the viewpoint of preservation of quality and safety, and that such recognition is stated in the approval certificates issued in the cases of approvals granted under the Pharmaceutical Affairs Law to manufacture of the products. 2) With respect to cells or tissues (including cell lines and cells after cultivation with respect to the products produced by the cultivation of cells with a cell bank as starting materials) used as materials, tests (hereinafter called the "virus test") necessary to detect viruses shall be conducted in order to confirm the existence of viruses with the potential to produce infections or pathology in humans. Moreover, the virus test shall be conducted appropriately at the stage of unprocessed and unpurified bulk, but not limited to those cases in which partial advancement of the production process makes a test to detect viruses more effectively. When an exogenous virus is detected in these tests, said cells or tissues may not be used as materials for medicinal products, in principle. 3) With respect to materials, the treatment to inactivate or eradicate bacteria, eumycetes and viruses shall be conducted in the production process. 4) The following information shall be recorded and be retained to confirm the information necessary to assure the quality and safety of the materials: a) Name of institution where materials are produced b) Date of production of materials c) Results of examinations of materials d) Production process of materials e) Lot number of materials f) Information necessary to assure the quality and safety of said products, besides information stated in Items a) to e). Article 4. Basic rules for products from animal origin 1. Standards for the Raw Materials Derived from Ruminant Animals 1) The criteria for raw materials derived from ruminants shall apply to raw materials or materials (except for fatty acids, glycerin, fatty acid esters, amino acids, synthetic oligopeptides, and others processed with high- temperature treatment and alkali treatment) derived from ruminants. 2) The following parts of ruminants shall not be used as materials for medicinal products: a) Hypophysis b) Thymus c) Dura mater d) Pineal body e) Spinal cord f) Placenta g) Intestines h) Brain i) Cerebrospinal fluid j) Spleen k) Adrenal glands l) Tonsils m) Eyeballs n) Lymph nodes 3) When using materials (except for milk) derived from ruminants for medicinal products, the countries of origin of said ruminants shall be the following countries, and shall not be limited to wool and lanoline. In addition, when using milk as a primary material, the countries of origin of said ruminants shall be the countries except for the United Kingdom and Portugal: a) United States of America b) Argentina c) India d) Uruguay e) El Salvador f) Australia g) Canada h) Kenya i) Costa Rica j) Columbia k) Singapore l) Swaziland m) Chile n) Nigeria o) Namibia p) Nicaragua r) New Zealand s) Pakistan t) Panama u) Paraguay v) Brazil w) Botswana x) Mauritius 4) The following information shall be recorded and retained to confirm the information necessary to assure the quality and safety of materials derived from ruminants: a) Country of origin b) Date of production of the primary materials c) Conditions of breeding and slaughtering of ruminants from which the materials are derived d) Treatment and process to prevent transmissible spongiform encephalopathy with respect to materials e) Lot number of materials 5) When medical effects exceed the risk caused by using said materials, or in the case of necessity, when using the primary materials not compliant to Subparagraphs 1) or (2) is inevitable, their adequacy shall be described in the approval certificates issued in the cases of approvals granted under the Pharmaceutical Affairs Law to manufacture the products. 2. Standards for the Raw Materials for Animal Cell and Tissue Products 1) When collecting cells or tissues used as materials for animal cell tissue products (medicines or medical devices composed of raw materials or materials derived from animals except for humans, and herein after the same), measures necessary to prevent contamination by pathogenic microorganisms or other causes of diseases in the process of such collection shall be taken. 2) The donating animal shall be subject to any of the following, and shall be eligible to supply cells or tissues for raw materials or materials for the animal cell and tissue products: a) The microbiological characteristics of each category of animal are considered when selecting the donating animal b) Inspection and testing are conducted at the time of acceptance and after acceptance of the donor animal, upon establishing items of said inspection and testing, and the criteria to evaluate the results of said inspection and testing. Especially, with respect to the inspection and testing concerning infectious diseases, the area of concern is that test items differ by the category of animal c) Measures to prevent the dissemination of infectious diseases shall be taken appropriately, when accepting the donating animal d) The operation manual, which states the operation method and procedures concerning breeding control of the donating animal, is prepared e) Breeding control is conducted in the facility, which has containment facility or appropriate equipment f) The donating animal is handled humanely based on the requisites for animal welfare. 3) When using living cells or tissues of animals, the risk of viral infection shall be inspected. 4) In cases except for Subparagraph 3), it shall be confirmed that aseptic conditions have been assured and that the risk of viral infection has been investigated. 5) The following information shall be recorded and retained to confirm the information necessary to assure the quality and safety of cells or tissues of animals used as raw materials or materials for the animal cell tissue products: a) Facility where said cells or tissues are collected b) Date of collection of said cells or tissues c) Conditions of acceptance of the donated animal, of inspection and testing, and of breeding control d) Collecting process of said cells or tissues e) Lot number of said cells or tissues f) Information necessary to assure the quality and safety of said animal cell tissue products, aside from the information stated in a) to e). 6) Cells and tissues used as raw materials or materials of the animal cell tissue products shall be collected in the facility having sufficient personnel and equipment to conduct sanitary control necessary for the collection. 3. Standards for the Raw Materials from Animal Origin 1) The materials of raw materials or materials (except for bacteria or those which are known by the public scientifically to contain no risk of viral infection, and hereinafter the same in the criteria for animal-derived raw materials) derived from animals except for materials for the animal cell and tissue products shall be derived from healthy animals, except for those cases separately described in the approval certificates issued in the cases of approvals granted under the Pharmaceutical Affairs Law to manufacture of the products. When it is difficult to confirm whether materials have been derived from healthy animals or not, it shall be confirmed that aseptic conditions have been assured and that the risk of viral infection has been investigated. 2) With respect to materials, the place of origin of animals, and parts to be used shall be clarified, and also the method to obtain cells or tissues shall be clarified. 3) With respect to the products produced by cultivation of cells from a cell bank derived from animals (mammals, birds and insects), the characteristics of which have been analyzed, as starting materials, a virus test for the cell lines and cells after cultivation shall be conducted at least once, in order to confirm the existence of viruses with the potential to produce infectivity and pathogenicity in humans. Moreover, the virus test shall be conducted appropriately at the stage of unprocessed and unpurified bulk, but shall not be limited to those cases in which partial advancement of the production process makes the virus test more effective. When an exogenous virus is detected in this test, said cells or tissues may not be used for the production of the products, in principle. 4) With respect to the products produced with the whole (body) of the living animal as starting materials, the provisions in Subparagraph 3) above, and of Subparagraph 2) of the Paragraph 2. Standards for the Raw Materials for Animal Cell and Tissue Products shall apply mutatis mutandis. 5) With respect to materials obtained from cells, tissues or body fluids, the treatment to inactivate or eradicate bacteria, eumycetes and viruses shall be conducted in the production process. 6) The following information shall be recorded and retained to confirm the information necessary to assure the quality and safety of materials: a) Name of institution where materials are produced b) Date of production of materials c) Results of examinations of materials d) Production process of materials e) Lot number of materials 7) The provisions from Subparagraphs 2) to 5) shall not apply to products other than those products specified as organism-derived products. 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 text in English is provided here on a basis of a tentative translation and subsequent revision 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. 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: Pharmaceutical Affairs Law (PAL): Article 42. Standards for medicinal products 1. The Minister of Health, Labor and Welfare if necessary may establish standards for the manufacturing process, properties, quality, storage method, etc. of the medicinal products such as biological or antibiotic preparations, requiring special attention due a concern for the public health and hygiene, after hearing the opinions of the Pharmaceutical Affairs and Food Sanitation Council. Note: Pharmaceutical Affairs Law (PAL): Article 42. Standards for medicinal products 2. The Minister of Health, Labor and Welfare, in order to prevent any harm to the public health and hygiene, can establish standards for the properties, quality, performance, etc. of quasi- drugs, cosmetics and medical devices, after hearing the opinions of the Pharmaceutical Affairs and Food Sanitation Council. Note: Occasionally given in older translation of Japanese regulatory documents as "drugs, etc." Note: E.g. asking questions and collecting answers. Note: 33.8 and 50 degrees Fahrenheit, respectively. Note: 50 degrees Fahrenheit. Note: MHLW Notification No. 217 of 1993. Note: 42.8 degrees Fahrenheit. MHLW Notification No. 210/May 20, 2003 Japan Regulations Series Copyright (c) 2001-2003 by JKS LLC - 2 -