Lifecycle of the regulated medicinal products in Japan 1. Discovery 2. Preclinical 3. Clinical 4. Dossier 5. Authorities 6. Approval 7. Manufacturing 8. Export & Import 9. Pricing & Reimbursement 10. Marketing 11. Postmarketing 12. Reevaluation and reexamination Note: The Table above represents the twelve phases of the lifecycle of the medicinal products (medicines, quasi-medicines, cosmetics and medical devices) regulated in Japan. The documents from the Japan regulatory process milestone series �Eor Milestone documents - provide concise up-to-date description of each phase of the product development. Further details could be found in the Key and Basic documents available in the JKS Document Store or by enquiring directly to Jouhou Koukai Services (JKS) at regulatory@jouhoukoukai.com. Japan Master Files (MF) TABLE OF CONTENTS 1. Regulatory background > Pharmaceutical Affairs Law (PAL) > Notification No. 0731001 2. Overview and details > MF terms > Duties of PMDA on MF registration * Figure 1. Organizational Chart of MFMG > Overview of MF registration * Figure 2. Overview of the Master File system > System of MF registration * Figure 3. Flowchart for Master File registration 3. Application for MF registration �Erequirements > Notification No. 0210004 > Notification No. 0310002 > Notification No. 0325003 > Notification No. 0208001 > Notification No. 0208003 4. “Questions and Answers�Edocuments > MF Q&A dated July 28, 2005 > MF Q&A Part 2 dated December 20, 2005 5. Registration procedure and forms > Registration Rearrangement Report Form > Written Oath Form 6. MF database Related reports Disclaimer 1. Regulatory background > Pharmaceutical Affairs Law (PAL) 1 (Excerpts) (Drug Master File) Article 14-11. A person manufacturing active pharmaceutical ingredients (including the persons manufacturing in foreign countries) may register in a drug master file the matters specified by MHLW 2Ministerial Ordinance, including name, ingredients (in the case of an unknown ingredient - its essence), methods for manufacturing, properties, quality or storage of the active pharmaceutical ingredients. 2. When an application for the registration of drug master file specified in the preceding paragraph has been made, the Minister shall register in the drug master file the matters specified by MHLW Ministerial Ordinance pursuant to the provisions of the preceding paragraph, excluding cases where the Minister, pursuant to the provisions of Paragraph 1 of the next article rejects the application for the registration. 3. When the Minister, pursuant to the provisions of the preceding paragraph registers a drug master file, the Minister shall publish the registered matters specified by MHLW Ministerial Ordinance. Article 14-12. When an application, pursuant to the provisions of Paragraph 1 of the preceding article for registration of drug master file is not accompanied by the data relevant to the manufacturing methods, properties, quality or storage of the active pharmaceutical ingredients, or when the application falls under any other cases specified by MHLW Ministerial Ordinance, the Minister shall reject the application. 2. When the application has been rejected pursuant to the provisions of the preceding paragraph, the Minister shall promptly notify the applicant and indicate the reasons for rejection. Article 14-13. When a person registered under the provisions of the Article 14-11, Paragraph 1 intends to make partial changes in the matters specified by MHLW Ministerial Ordinance pursuant to the provisions of the same paragraph (excluding the cases of minor changes as specified in the MHLW Ministerial Ordinance); the changes shall be registered in the drug master file. In such cases, the provisions of Paragraphs 2 and Paragraph 3 of the same article and the preceding article shall apply mutatis mutandis. 2. As specified by MHLW Ministerial Ordinance, the person registered under Article 14-11, Paragraph 1 shall submit a notification to the Minister about the minor changes, specified by MHLW Ministerial Ordinance. Article 15. When a person registered under the Article 14 11, Paragraph 1 falls under any one of the following conditions, the Minister shall annul the registration: (1) The registration pursuant to the provisions of Article 14-11, Paragraph 1 has been made by unfair means; (2) The registration falls under the cases specified by MHLW Ministerial Ordinance pursuant to the provisions of Article 14 12, Paragraph 1. (3) The person has violated this law, other laws and ordinances related to pharmaceutical affairs or any measures taken based on the above laws and ordinances. 2. When the Minister has annulled the registration pursuant to the provisions of the preceding paragraph, the Minister shall notify the person about annulation of the registration and announce the annulation publicly. (Duties of PMDA for Registration and Related Matters) Article 16. The Minister may request the PMDA 3 to register the matters specified by MHLW Ministerial Ordinance related to active pharmaceutical ingredients pursuant to the provisions of Article 14-12, Paragraph 2 (including cases where it shall apply mutatis mutandis under the Article 14-13 Paragraph I) and delete the registration (hereinafter referred to as “registration etc.�E pursuant to the provisions of Paragraph 1 of the preceding article. 2. The provisions of Article 14-11, Paragraph 3; Article 14-12; and Paragraph 2 of the preceding article shall apply mutatis mutandis to the cases where PMDA, pursuant to the provisions of the preceding paragraph conduct registration etc. 3. When the Minister has decided to request the PMDA to execute its duties for registration pursuant to the provisions of Paragraph 1, the person intending to register the matters specified by the government ordinance pursuant to the provisions of the same paragraph related to active pharmaceutical ingredients as specified in the Article 14-11 or Article 14-13, Paragraph 1, or the person intending to submit the notification as specified in the Paragraph 2 of the same article, notwithstanding the provisions of Article 14-11, Paragraph 2 (including cases where it shall apply mutatis mutandis under the Article 14-13, Paragraph 1) and Article 14�E3, Paragraph 2, shall submit an application or notification to PMDA. 4. When PMDA performs the duties for registration in relation the applications specified in the preceding paragraph or rejects an application, or accepts the notification specified in the said paragraph, or annuls the registration, the PMDA shall notify the Minister as stipulated in the MHLW Ministerial Ordinance. (Cont.) 5. The Minister may be requested to carry out a review as provided in the Administrative Appeal Law (Law No. 160, 1962) concerning the duties of PMDA, including the registrations based on the application specified in Paragraph 3 or its exclusion, dismissal of the application or annulment of the registration. 4 > Notification No. 0731001 (Excerpts) PFSB 5 Notification No. 0731011 dated July 31, 2002 “Law Partially Revising the Pharmaceutical Affairs Law and the Blood Collection and Supply Services Control Law�E To: Prefectural Governors From: Administrative Vice Minister, Ministry of Health, Labor and Welfare The “Law Partially Revising the Pharmaceutical Affairs Law and the Blood Collection and Supply Services Control Law�Ewas submitted on April 5, 2002 to the 154th Diet session and after certain amendments by the Upper House6, was approved on July 25, 2002. Now, it is promulgated as Law No. 96 of 2002. Recently, various scientific technologies, including biotechnology and genomics, have been used for development of drugs and medical devices, and the range of those medicinal products has become increasingly diversified. Under these circumstances, it is necessary to assure the quality, efficacy and safety of each product along with the product characteristics. In addition, it is necessary attempting further improvement of the post-marketing safety measures for drugs and medical devices, and reviewing the current approval and licensing systems, in order to respond to the diversification of commercial organizations and to maintain the international collaboration. Furthermore, aside from improving the safety of blood products, it is necessary to establish a legal framework for securing the stable supply of blood products, while considering issues such as HIV infections resulting from unheated blood products. In addressing those issues, the Pharmaceutical Affairs Law (Law No. 145 on 1960) and the Blood Collection and Supply Services Control Law (Law No. 160 on 1956) are partially revised, the regulations concerning medical devices are reviewed, and measures are taken to secure safety of biological products, in relation to their characteristics. In addition, it is decided to reform the approval and licensing systems for drugs and medical devices, and to guarantee supply of safe blood products with proper planning. The revisions are having major implications in regard to ensuring the safety of drugs and medical devices, and the stable supply of safe blood products. Therefore, this notification is issued in order to request full compliance with the revised points detailed below and especially, to make ensure their smoothly enforcement by measures such as notifying all parties concerned. Part 1. Pharmaceutical Affairs Law (Omitted) III. Improvement on post-marketing safety measures and review of the approval and licensing systems (Omitted) 3. Miscellaneous provisions (Omitted) (3) Introduction of Master File system for registering active pharmaceutical ingredients and other substances. With the purpose for protecting the intellectual properties such as manufacturing data, etc. of the manufacturers of active pharmaceutical ingredients and other substances, from the manufacturers of the finished products and manufacturing and/or marketing companies, and with the purpose to simplify the attached data required application for approval, a system under the name of “Master File system�Eis introduced enabling manufacturers of active pharmaceutical ingredients and other substances to register the manufacturing data and other intellectual properties on a master file for registration of active pharmaceutical ingredients and other substances. 7 Comment of JKS: Under the s.c. new system enforced in April 2005, the manufacturing and all sales activities (e.g. distribution, marketing and promotion of products) (commonly refereed to as “manufacturing and marketing�Eor “manufacturing/marketing�E can be separated from manufacturers, what resulted in numerous consequences, including the change in the approval system for drugs and medical devices. 2. Overview and details > MF terms Since the MF system was new to the Japanese pharmaceutical affairs, it prompted the creation of new terms: * The formal term read in Japanese as Genyakunado-toroku-genpo could be translated as Registration Ledger for Bulk, API, etc. Pharmaceuticals. (The characters used for writing the formal term are shown in the facsimile image on page 4) * The English words for master file �Etranscribed in Japanese as “masta-fairu�Eand the abbreviation “MF�Eare also commonly used and understood > Duties of PMDA on MF registration The system allowing registration of master files for API was made effective on April 1, 2005 along with the enforcement of the revised PAL. The direct responsibility for all issues related to the MF is assigned to the Master File Management Group (MFMG) of PMDA. PMDA is an independent administrative organization created on April 1, 2004, as a result of the merge between three major organizations for evaluation of medicinal products - National Institutes of Health Sciences (NIHS), Pharmaceutical and Medical Device Evaluation Center (PMDEC), Organization for Pharmaceutical Safety and Research (OPSR, formerly known as Kiko). The PMDA (commonly called in Japanese Kiko Soudan 8) is involved in conducting evaluations, reviews, handling of data, and other relevant activities that generally do not require administrative decisions (in contrast to the structures and responsibilities of the MHLW). The organizational structure of PMDA is rather complex, with four major unit, one of which is the Office of Review Administration, where MFMG belongs (see Figure 1 next page for details). PMDA �ECenter for Product Evaluation �EOffice of Review Administration �EReview Operation Division �EMaster File Management Group The MFMG handles the registration of MF, including derivative procedures such as application for slight change, withdrawal or change. As pointed below in the Q&A part, the registration is provided at no charge, and the necessary forms in electronic format are available for free download; however the applicants are expected to bear all the expenses associated form the preparation �Esuch as translation, documentation assembly, postage, retaining in-country caretaker and alike. One of the most important functions of MFMG is to provide guidance to the MF registration seekers and registrants during the lifecycle of individual MF. Aside from a series of regulatory documents issued in relation with the MF registration, the authorities have already released twice compilations of questions and answers to problems encountered by applicants and registrants. In the cases, where the applicant or registrants may request assistance in more complicated issues or individual MF, an option is available to schedule a face-to-face (i.e. actual meeting, not email exchange, videoconference or mail/fax queries) consultation with MFMG officers. Currently, the fee for MF consultation is set at 21,000 Yen per consultation, as the timing for payment is required to be “by the date of application after arrangement of the date of the face to face consultation�E The MF consultations are provided in the premises of PMDA in Tokyo, however, party requesting the consultation needs to assure an interpreter 9 if unable to communicate in Japanese. Figure 1. Organizational Chart of MFMG (As of July 1, 2006) Source: PMDA, modified. > Overview of MF system The PAL revised in 2003, was enforced on April 1, 2005, as the following main changes were implemented concerning: manufacturing and sales, licensing and approval, foreign manufacturers, MF system, classification of drugs and labeling. The main objective of the MF system is to protect the intellectual property by allowing a dual submission of relevant information on quality and manufacturing method �Efrom a registrant (MF registrant) who could differ from the drug approval applicant, and from the applicant. The MF could be submitted for the following types of products: active substances and intermediates for prescription drugs, raw materials for special formulations of bulk chemicals, raw materials for medical devices, new additives, premixes, container and packaging materials. The outline of the new MF system in Japan was more publicly disclosed at the 20th New Drug Evaluation Division Regular Meeting 10 held in Tokyo on October 22, 2004: see Figure 2. Figure 2. Overview of the Master File system (as explained by the Director of the MHLW, PFSB, Evaluation and Licensing Division) > System of MF registration The new system set up to allow registration of MF in Japan was further detailed at the 21st New Drug Evaluation Division Regular Meeting 11 held in Tokyo on May 26, 2005: see Figure 3. The system for MF incorporates options for initial registration, changes, withdrawal and revocation of MF. When the content of the registered MF is to be changed, either an application for change the MF or a slight modification notification should be submitted. For change in MF, an application for partial change of MF, however for slight modification of MF, an approval form is not required, as in either case the registrant should notify both the approval applicant and approval holder. Additional detail on the MF registration could also be found below in Chapter 4. “Questions and Answers�Edocuments and Chapter 5. Registration procedure and forms. Figure 3. Flowchart for Master File registration (as explained by the Director of the MHLW, PFSB, Evaluation and Licensing Division) MF Ethical Drugs 3. Application for MF registration �Erequirements > Notification No. 0210004 MHLW, Pharmaceutical and Food Safety Bureau Evaluation and Licensing Division Notification No. 0210004 February 10, 2005 To: Each metropolitan and prefectural Head of Public Health Department (Bureau) From: Director Evaluation and Licensing Division (ELD) Pharmaceutical and Food Safety Bureau, MHLW Items to be Included in the Master Files for Active Pharmaceutical Ingredients As the “Law Partially Revising the Pharmaceutical Affairs Law and the Blood Collection and Supply Services Control Law�Ewas promulgated as Law No. 96 of 2002, the system for Registration Ledgers for Active Pharmaceutical Ingredients (hereafter “Master Files�E(MF) is to be enforced on April 1, 2005. Therefore, you are requested to direct the relevant organizations under your jurisdiction concerning the items indicated below to ensure proper execution of the MF system. Description (Table of Contents only) 1. About the MF system 2. Range of use of MF 3. About the style etc. of the MF registered information 4. Information that MF holder has to disclose in drug approval application and to the applicant 5. About the procedure of the registration of MF 6. About the handling of the MF use for the drugs applied for both human and veterinarian use 7. Handling of APIs for which approval was acquired prior March 31, 2005 8. Handling of raw material of medical devices that have already been registered based on medical device master file system Appendices A. Presence of relation and disclosing drug master file registration items and content of description B. Presence of relation and disclosing medical device master file registration items and content of description Note: The full translation of Notification No. 0210004 to be made available online separately by JKS Publishing. > Notification No. 0310002 MHLW, Pharmaceutical and Food Safety Bureau Evaluation and Licensing Division Notification No. 0310002 March 10, 2005 To: Each metropolitan and prefectural Head of Public Health Department (Bureau) From: Director Evaluation and Licensing Division (ELD) Pharmaceutical and Food Safety Bureau, MHLW About the MF Registration prior to the Enforcement of the Revised PAL The “Law Partially Revising the Pharmaceutical Affairs Law and the Blood Collection and Supply Services Control Law�E(Law No. 96 of 2002) amended the Pharmaceutical Affairs Law (Law No. 145 on 1960) (herebelow “Revised PAL�E, whereas in the revised PAL, the “Bulk Pharmaceuticals Registration Ledger�E(herebelow “MF�E institution shall be implemented. Upon the MF implementation, items which were dealt by parties who had obtained the Manufacturer or Importer and Seller License or the Import Approval before March 31, 2005 shall be considered as having obtained the Manufacture and Sales Approval after implementation of the Revised PAL as well. Moreover, until the renewal of the Manufacturer or Importer and Seller License, imperfections of description shall be corrected so as to adapt to the Listing of Approval Documents required in the Certificate of Manufacture and Sales Approval under the revised PAL. Information on API also shall be described in the Manufacture and Sales Approval. As the description on the Certificate of Approval should be revised immediately after the enforcement of the Revised PAL, advance preparation may be necessary. Therefore, operation including acceptance of application for registration of MF before the enforcement of the Revised PAL shall be as described in the appendix below, all the metropolitan and prefectural of Public Health Departments (Bureau) are requested to fully recognize and thoroughly inform the drug manufacturers and importers under their jurisdiction. Appendix (omitted) > Notification No. 0325003 MHLW, Pharmaceutical and Food Safety Bureau Evaluation and Licensing Division Notification No. 0325003 March 25, 2005 To: Each metropolitan and prefectural Head of Public Health Department (Bureau) From: Director Evaluation and Licensing Division (ELD) Pharmaceutical and Food Safety Bureau, MHLW Handling of TSE 12 Materials According to the Enforced Revision of PAL According to the PFSB Notification No. 1069 dated October 2, 2001 entitled “Reinforcement of Quality and Safety Assurance of Drugs, Medical Devices, etc., Manufactured Using Bovine-Derived Materials as an Ingredient�E Paragraph 2, Item 1, and to the PFSB/ELD Notification No. 801001/ PFSB/SD Notification No. 0801001 13 entitled “About the handling of the risk assessment in the cases of complete change of the application for medicines and medical devices where materials originating from living organisms are used�E(hereafter Notification No. 0801001), the manufacturers, importers and sellers, in-country caretakers of the approved manufacturers outside Japan (hereafter “Manufacturers�E or supplier companies of the relevant raw materials (hereafter “Raw material supplier companies�E, have become to submit documents, which demonstrate that conditions defined in PMSB Notification No. 1069 are met (hereafter �ETSE materials�E related to raw materials derived from bovine and the like used in multiple items in advance to the application of partial change of Manufacture Approval, in order to exploit TSE materials numbers and increase efficiency of approval examination. As the “Law Partially Revising the Pharmaceutical Affairs Law and the Blood Collection and Supply Services Control Law�E(Law No. 96 of 2002) amended the Pharmaceutical Affairs Law (Law No. 145 on 1960) (herebelow “Revised PAL�E, whereas in the revised PAL, the “Bulk Pharmaceuticals Registration Ledger�E(herebelow “MF�E institution shall be newly implemented, and the efficiency of examination would be increased by exploiting MF to the examination. Hereafter, it will be possible to register TSE materials to the relevant MF and the procedure therefore shall be as described below, and all the metropolitan and prefectural of Public Health Departments (Bureau) are requested to fully recognize and thoroughly inform the drug manufacturers and importers under their jurisdiction. After the April 1, 2005 no novel TES material number based on Notification No. 0801001 shall be issued. Appendix (omitted) > Notification No. 0208001 MHLW, Pharmaceutical and Food Safety Bureau Evaluation and Licensing Division Notification No. 0280001 February 8, 2006 To: Each metropolitan and prefectural Head of Public Health Department (Bureau) From: Director Evaluation and Licensing Division (ELD) Pharmaceutical and Food Safety Bureau, MHLW About the Arrangement of the List of Items which are Registered in MF For utilization of Master files (herebelow “MF�E, the handling has been stated in the ELD Notification No. 0210004 dated February 10, 2005 and entitled “Items to be Included in the Master Files for Active Pharmaceutical Ingredients�E Procedures for disposing of items which are currently registered in MF and would be no longer produced for the reason, for example, completion of their roles, shall be as follows and all the metropolitan and prefectural of Public Health Departments (Bureau) are requested to fully recognize and thoroughly inform the drug manufacturers and importers under their jurisdiction. Content 1. When disposing of registration, notification according to the attached form should be submitted to the CEO of PMDA. Since electronic filing with medium such as floppy disk is under preparation and shall be built in the near future, written submission shall be necessary in a meantime. 2. When filing notification, Certificate(s) for the relevant items should be attached. Upon disposing of registration, testimony should be submitted which states there is no items for which have been approved utilizing the registration number or of which approval had applied but not approved yet. Attachment - Registration Rearrangement Report Form > Notification No. 0208003 MHLW, Pharmaceutical and Food Safety Bureau Evaluation and Licensing Division Notification No. 0280003 February 8, 2006 To: Chief Executive, PMDA From: Director Evaluation and Licensing Division (ELD) Pharmaceutical and Food Safety Bureau, MHLW About the Arrangement of the List of Items which are Registered in MF For information, and since a copy 14 has been already sent to Each metropolitan and prefectural Head of Public Health Department (Bureau), here it is dispatched separately. (omitted the attached text of Notification No. 0280001) 4. “Questions and Answers�Edocuments > MF Q&A dated July 28, 2005 Office Communication July 28, 2005 To: Each metropolitan and prefectural Head of Public Health Department (Bureau) From: Evaluation and Licensing Division (ELD) Pharmaceutical and Food Safety Bureau, MHLW Collection of Questions and Answers related to the Master Files for Active Pharmaceutical Ingredients The Collection of Questions and Answers related to the Master Files for Active Pharmaceutical Ingredients is included here as appendix and all the metropolitan and prefectural of Public Health Departments (Bureau) are requested to fully recognize and thoroughly inform the drug manufacturers and importers under their jurisdiction. These Q&As are scheduled to be one by one renewed according to the progress of the use of the MF system in the future. Appendix Questions and Answers related to the Master Files for Active Pharmaceutical Ingredients 15 (Question 1) Where to apply for MF registration? Do you accept application by mail? Moreover, how much cost application for registration? (Answer) 1. Application for registration should be submitted to the Review Operating Division of the Office of Review Administration, PMDA 16 2. Application by mail is also possible. Details are available from the web site of PMDA �Erefer to the “PMDA business information�E�E“Approval examination business information�E�E“Handling of the business request such as acceptances of applications, written reports, etc.�E17 3. Application for MF registration is free of charge. 18 (Question 2) Is the registration of MF indispensable (essential)? Where to seek a consultation on application prior to for registration of MF? (Answer) 1. Because the registration of MF system is to certain degree arbitrary, the MF application for registrations is not indispensable (essential). 2. Consultation of issues related to MF can be requested in the MF Management Group, Review Operating Division of the Office of Review Administration, PMDA. 3. For inquiries related to the content of the MF application, so called “MF Simplified Consultation�Eis provided. (Question 3) When a foreign manufacturer is registering a MF, to what extend Japanese language should be used? (Answer) 1. On the cover of the application, the full name and address could be given in a foreign language. Moreover, it is possible to substitute the stamping 19 with a signature its own handwriting of the representative for overseas MF manufacturer. A duplicate is a copy of the original and one original (of the application documents) and one duplicate are necessary. 2. Please, input the content of FD in Japanese. 20 3. Please, also follow the instructions given in the MHLW, Pharmaceutical and Food Safety Bureau, Evaluation and Licensing Division Notification No. 0210004 dated February 10, 2005 (hereafter referred as Notification No. 0210004). (Question 4) Is it possible for a manufacturer undertaking only purification step of API manufacturing process or only subdividing process to be registered to MF? (Answer) 1. Under revised PAL, as a rule it is stipulated principally to describe from API starting materials in a manufacturing method so that describing only purification step or subdividing process is considered to be deviated from object of MF system, whose goal is to protect know-how of manufacturing processes. In these cases, it is impossible to make a MF registration. 2. However, detailed purification process varies case by case so that you may better counsel us (i.e. registration authorities) about their registration providing specific details of each case. (Question 5) Are validations of test methods for APIs, which have been already registered in official documents abroad, necessary? For APIs already described in EP or USP, can we use the whole description written in their official documents in a new registration in Japan? (Answer) 1. According to Notification No. 568 of the Director of the Evaluation and Licensing Division of PMSB of May 1, 2001 entitled “Concerning the standards for new drugs and setting test methods�E Paragraph 2.1, Item 4 “Validated test methods of JP and evaluation methods recognized through international harmonization�Ethe test methods approved and agreed by international harmonization between JP, EP and USP are conceived basically as validated, however, their validation data may be requested to submit during review process when necessary. Other test methods described in official documents other than EP and USP need to be validated. 2. For APIs already listed in EP and USP, manufacturing process, quality control methods, specification and test methods actually undertaken by applicants have to be registered in MF. (Question 6) Could the medicinal drugs already having obtained approval and are already sold as bulk substance be registered in MF? What is a definition of bulk substances? (Answer) 1. According to Notification No. 0210004, bulk substances with special dosage forms are stipulated to register in MF, however, MF registration for medicinal drugs, which have already obtained approvals are required to be put on hold for a moment. Products used mainly as bulk substance could be registered in MF. Please consult us providing detailed descriptions of each substance before your decisions. 2. One of definitions of “Bulk substances with special dosage form�Eis “materials used for manufacturing drugs and having special pharmaceutical dosage form such as sustained–release preparation". For example, if a special know-how exists in their manufacturing process and are mainly used for manufacturing process of medicinal products such as capsules it could be subject to MF registration. (Question 7) Can APIs used for Rx or OTC be registered in MF? (Answer) 1. For these APIs, if you wish to register them, you could make an application for registration. 2. However, MF registration numbers for them can be used only for approval application of medicinal drugs or approval application of OTC containing new active ingredients. For others (types of approval), you can not use these registration numbers as described in guidelines. (Question 8) Those items already registered under the provisions of Notification No. 0310002 of the Director of the Evaluation and Licensing Division of PMSB of March 10, 2005 entitled “About the MF Registration prior to the Enforcement of the Revised PAL�Eshould be applied for alteration of registration in order to comply with the revised PAL. When these applications for alteration registrations should be submitted? (Answer) 1. Those who have already obtained MF simplified registration should apply for alteration registration in order to comply with the revised PAL and by providing required documents. As a rule, all alteration registrations shall be due by March 31, 2010. However, it is highly expected that these applications will be congested nearing the due time, so we recommend for those MF holders to apply for registration along with licensing renewals of these products or approval applications caused by approval applications if any. (Question 9) “CTD Module 2 equivalent documents�Eare stipulated to be necessary for review of drug using API already registered in MF. Can we consider those documents are the documentation describing information related with quality? When do we submit them? (Answer) 1. MF holders should submit a summary of documents which describes how the quality of the product has been kept including efficacy or safety considerations if required as by the “CTD Module 2 equivalent documents". 2. For MF registrations, a submission of “CTD Module 2 equivalent documents�Eis not required, but all the contents of MF registration is to be reviewed during drug approval review so that we recommend you to submit with the same timing as approval application of medicinal products as much as possible. However we advise you to ask review officers of PMDA for the timing of submission and to follow their advice. (Question 10) When manufacturers want APIs to register in MF, if APIs have different shipment addresses, manufacturing methods and specifications, do they have to register in MF separately? (Answer) 1. As a rule, APIs with different manufacturing methods and specifications are required to register respectively. Different manufacturing methods mean that they have different manufacturing processes with different basic chemical reactions or different manufacturing theories. 2. However, registration process may differ case by case, so please consult us with detailed descriptions of each case if necessary. (Question 11) When we apply for simplified MF registrations, can we add or delete approval numbers of medicinal drug already using the API? If we can, please let us know how to do such addition or deletion. (Answer) 1. For appendix 3 based on PFSB/ELD Notification No.0310002, please specify reasons for addition or deletion in the written document and submit revised applications during application by using FD. (Question 12) For approval application according to revised PAL, can APIs approved after April in 2005 be applied for simplified MF registration? In this case, should documents of Module 3 of CTD be attached? (Answer) 1. In this case, we can not accept them by simplified MF registrations. APIs which have already obtained approvals by March 31, 2005 can be applied by simplified MF registrations. In this case, pre-registration application should be reached to the Head of Division by the date so that APIs approved after April 2005 should be applied newly for MF registrations. 2. For new application of MF registrations, descriptions have to match with revised PAL. Also evidence data related to registrations are required to be attached as appendix such as Module 3 of CTD. (Question 13) Can API manufacturers select contents which they will register for MF? (Answer) 1. All items are not always necessary for every application; however, all the necessary information for review should be always included in order to facilitate review process efficiently. In addition, manufacturing method, specification, test method and others are very important contents in order to maintain quality so that they are basically necessary to register. (Question 14) When an application of MF registration is done by FD, where we can address questions about usage of the application software? Please let me know how to input “Approval of Deemed Foreign Manufacturers�E (Answer) 1. Please ask by fax 21 the Help Desk, when you have anything you can not understand about software applications - including all necessary information, which you would like to ask them. 2. Input the following 22 tentative contents for “Approval of Deemed Foreign Manufacturers�E Also, refer for details to the “Electronic Drug Application Software Q&A�Eon the MHLW web site. 23 Example: (for drugs) [Permission number or recognition number]: AG99999999 [Date of permission or date of recognition]: 2170401 (April 01, 2005) (Question 15) If a drug manufacturing company obtained detailed API manufacturing information from a manufacturer of the API, is it possible for the drug manufacturer to apply for MF registration based on the obtained information? (Answer) 1. The objective of MF registration is to provide detailed information about API, protecting intellectual properties, so fundamentally, MF registration should be implemented by manufactures who need protection of their intellectual properties. 2. If a drug manufacturer has obtained details of know-how to produce API, and it just described in medicinal drug’s approval application form so that the manufacturer does not need to newly register MF. (Question 16) For “TSE documentation�E when a manufacturer substitute a raw material of bovine origin with non-bovine derived materials (e.g. plant derived substances), in this case what kind of procedures are needed in order to apply for MF registration and approval applications? (Answer) 1. As the MF registration is quite independent procedure, they have to submit a new application for MF registration. 2. When the countries of origins for bovines are changed, there should be an application for a slight change in approval; however, in cases of the alteration of animals from bovines to other animals or to plants, partial alteration approval applications shall be needed. (Question 17) Can foreign manufacturers based abroad, including those producing APIs, submit directly MF registration application without selecting in-country caretaker in charge of API? (Answer) 1. When foreign manufacturers submit MF registration applications, it is necessary to appoint an in-country caretaker in Japan, so that they can not submit directly MF registration applications. Please, submit MF registration after the in-country caretaker is appointed. (Question 18) When we submit application of APIs for drugs listed in JP, should we describe details of the manufacturing methods? (Answer) 1. In the application for MF registration, it is necessary to fill in a column for manufacturing methods. The products listed in the Japanese Pharmacopoeia also need description of manufacturing method according to the requirements of Notification No. 0210001 of the Director Evaluation and Licensing Division (ELD), Pharmaceutical and Food Safety Bureau, MHLW dated February 10, 2005 “Items to be Included in the Application for Drug Approval under the Provisions of the Revised PAL�E (Question 19) Please, let us know the difference between alteration application of MF registration and a partial alteration application of approved contents of medicinal drug using the said MF. (Answer) 1. When alteration of registered contents in MF can not be considered as a slight change, an application of MF alteration registration has to be submitted. To that end, a partial alteration application of approved contents of approved medicinal drug using the said MF would be necessary. In order to achieve this, communication and discussion will be necessary between the MF holder and the drug manufacturer. Also information of approved medicinal drug using the said MF has to be described in the remarks column in an alteration application for MF registration. 2. As specified in the Article 5, Paragraph 3, Item 7 24 of the Notification No. 0210004 alteration applications of MF registration and a partial application of approval application for the medicinal drug are expected to be done simultaneously. (Question 20) When the API listing in a registration file is completed, does this mean that we have some kind of official approval (authorization)? (Answer) 1. MF registration's goal is to protect the intellectual properties of MF holders; it is made public to check styles and consistency for registration, so that the validity and adequacy of quality, and others of the API are not officially approved in this registration. The contents of registration will be reviewed associated with application, forms of dosage and properties after approval application of medicinal drug using the MF. If an inadequate content would be found after the review, modification would be requested for the registration, and then MF registration may be regarded as a part of approval application of medicinal drug. Note: as a continuation of the above Q&As related to MF in Japan, a second part is included below. > MF Q&A Part 2 dated December 20, 2005 Office Communication December 20, 2005 To: Each metropolitan and prefectural Head of Public Health Department (Bureau) From: Evaluation and Licensing Division (ELD) Pharmaceutical and Food Safety Bureau, MHLW Collection of Questions and Answers related to the Master File for Active Pharmaceutical Ingredients Part 2 The Collection of Questions and Answers related to the Master File for Active Pharmaceutical Ingredients is included here as appendix and all the metropolitan and prefectural of Public Health Departments (Bureau) are requested to fully recognize and thoroughly inform the drug manufacturers and importers under their jurisdiction. (Question 1) When an advanced registration is to be done according to the Notification No.0310002 of the Director of the MHLW, Pharmaceutical and Food Safety Bureau, Evaluation and Licensing Division, dated March 10, 2005 “About the MF Registration prior to the Enforcement of the Revised PAL�E(hereafter in this Q&A referred to as “MF advanced registration�E the alteration application for registration has to be done before March 31, 2010 in order to keep compliance with the revised PAL. In this case, if the registration will not be completed by the time, what will happen then? (Answer) 1. The Applicant should be careful because due date of application for change in registration alteration will be March 31st, 2010, so that we will advise you to complete this application simultaneously when MF holders will submit license renewal or application for change in approval of these medicinal drugs using the said MF. (Question 2) When we will apply for MF advanced registration?simplified application by FD), could you let us know how to apply for modification registration and other rules we will have to comply concerning the revised PAL. (Answer) 1. Please use “MF application for change in registration documentation�E(Format #46), when you apply. This is not new application registration or application for slight change registration. 2. Describe all contents as simplified descriptions will not be accepted. Attach appendices (such as CTD module 3), which show rational for registration. 3. You will receive a new registration certification, so that the old certification has to be returned to PMDA. If you apply by postal mail for new registration, please include an application for change in registration documentation along with an old certification enclosed in the same envelop. (Question 3) What are the precautions and procedures when registered contents are changed in order to comply with the revised PAL after completion of a MF advanced registration?simplified FD registration)? (Answer) 1. If a significant change will happen after FD simplified registration, an application for change in approval is necessary. Please, specify change details in remarks columns of the application form or attach comparative table, which can show the alterations. Also, make sure the application documentation to comply with the revised PAL. Please, see and follow other procedures described above. 2. If the change is slight, submit “MF application for slight change in registration documentation�E(Form #47). 3. If you have any further questions, please inquire the PMDA, MF Group. (Question 4) Would you describe the details of procedure specified in Question 4 (related to the possibility for purification step of API manufacturing process or only subdividing process to be registered to MF) of the Office Communication dated July 28, 2005 on “Collection of Questions and Answers related to the Master Files for Active Pharmaceutical Ingredients�E (Answer) 1. Registration of preparation procedures only has not been accepted so far in order to avoid the confusion and mixing up in the reviews, because of the already existing multiple numbers for processes. Also, MF stipulate to describe API starting materials, however, from now on those will be accepted only when if meeting the following conditions: Conditions: * First register manufacture procedures in MF from API starting materials to just one step before the preparation procedures, including cultivation or synthesis methods related with the API. After this registration, please apply for MF registration, citing the above MF registration numbers you have already obtained. * The above mentioned registration is generally accepted; however, if following this procedure is difficult, as an exception, you could disclose all manufacturing methods and describe the preparation methods in application documentation for MF registration. * In this case, exchange information with other manufacturers who hold other manufacturing methods relevant to the preparation method you want to register. Also exchange information with the drug manufacturers who have obtained approval applications of the medicinal drug. Clarify who will be responsible when incidence or other possible situations should occur because of the lack of communications. However, the above conditions are temporarily set and there will be cases MHWL or PMDA could add extra conditions in a more comprehensive judging depending on the situation. 2. For subdividing process, registration will not be accepted as before, because they are not considered a subject to MF registration system. 3. If you have any further question on this point, please submit them to the PMDA Review MF Group. (Question 5) What is the MF registration withdrawal 25 or cancellation? Would you explain the necessary procedures? (Answer) 1. When the applicant is to withdraw the MF registration applications, it should submit them on your own will before the certifications to be delivered. You could find a form for withdrawal in FD application software, and use this form. If you are not being able to understand how to use the software, inquire the Help Desk (Fax: 03-3507-0114) by fax describing questions in details. 2. Cancellation of the MF registration can be executed when the application is judged as fraudulent according to the Article 15 of PAL. If such a judgment made, a notification shall be sent to the applicant and it will be disclosed to the public. The applicant should return the certification of registration to MHLW as soon as possible according to the Article 82, Paragraph 1 of the Enforcement Regulations of PAL. (Question 6) We have several APIs, which we will not use in future but they are already registered. What shall we do to clean this up? (Answer) 1. When you would like to clean up APIs for reason that you will not use them any more, the manufacturer is be able to voluntarily withdraw the registrations. Use the withdrawal registration documentation (Registration Rearrangement Report Form) in the form we will make in near future. 26 2. Please submit to PMDA withdrawal registration application documentation as well as your certificate. Please confirm thoroughly that no other products use the MF before your submission of the withdrawal application. (Question 7) Can we reuse the documents attached to approval application documentation of API according to revised PAL as appendix for a new MF registration application? (Answer) 1. You can reuse the attachment you have already used for API approval application documentation according to revised PAL. However, please note that if there are new findings to be added after the API approval or if the review officers will request submission of other documents, please follow their order. (Question 8) Are there any qualification standards for appointing the in-country caretakers for API? When foreign manufacturers have difficulties to appoint in-country caretakers at MF registration, what shall they do to submit application? (Answer) 1. There are no qualification standards for in-country caretakers; however, please select a person who is responsible and can organize all administrative work related to your MF registration applications. 2. Selecting in-country caretakers for API is stipulated as mandatory according to Article 72, Paragraph 2 of PAL. (Question 9) Could the in-country caretaker and the person who appears on application documentation of API be one and the same? When foreign manufacturers submit approval application of medicinal drug for marketing, do they have to attach a copy of contract undertaken by the foreign manufacturer and in-country caretaker for the API? (Answer) 1. That may be possible. As long as the in-country caretakers will accept and recognize their responsibility as API in-country caretakers, they could be also the person in charge on the application documentation. 2. The copy of the contract between the foreign API manufacturers and in-country caretakers is not necessary. However, if you have to submit drug approval application, please submit a copy of contract made regarding usage of MF between your manufacturer and MF holder in accordance to Paragraph 2 of Article 5 “About the procedure of the registration of MF�Eof the ELD Notification No. 0210004. (Question 10) When a manufacturer applies for approval application of medicinal drug for marketing using MF, does the manufacturer describe information disclosed from a manufacturer of MF holder on application documentation? (Answer) 1. According to the Paragraph (3) of Article 4 “Information that MF holder has to disclose in drug approval application and to the applicant�Ein Notification No.0210004 dated February 10, 2005 of the Director of PFSB/ELD, the disclosed part of information, which is disclosed to approval applicants along with undisclosed information, which is not disclosed to approval applicants because it contains manufacturing methods, have to be described in application documentation for MF registration. 2. From above point of view, information (CTD Module 3) disclosed by MF holders to the approval applicants will not have to be described in duplicate in the approval application documentation of medicinal drug, because reviewer will be able to refer to the contents on MF registration documentation. 3. However, the approval applicant of medicinal drug will have to describe how to develop and assure the medicinal drug considering the APIs properties, which affect efficacy, safety and quality of the medicinal drug, including the disclosed part of information on information?CTD Module 2?of approval application documentation of medicinal drug. (Question 11) If multiple in-country caretakers for API submit MF registration application for same API from one foreign manufacturer, what will happen? (Answer) 1. If there are multiple registration numbers for one API, there is a possibility of confusion or delay of approval review. If problems occur during the process, applicants should take all responsibilities. 2. From this point of view, avoid registering multiple numbers for one API as much as possible. Considering other companies can refer and cite MF registration number easily, make arrangements to submit application for single registration number for one API after discussing it between parties concerned. (Question 12) Can we apply for MF registration for premixed API? (Answer) 1. Manufacturers can apply for MF registration for premixed APIs, however, when manufacturers purchase each active ingredient from other manufacturers, they have to cite their MF registration numbers, which other manufacturers hold or to describe manufacturing method of the other manufacturers on application documentation for registration. (Question 13) It is stated that MF implementation should not be used for OTC drugs. However, is it possible to utilize TSE materials which have already been registered in MF (or using MF) for OTC drugs? (Answer) 1. It is possible to utilize TSE materials which have been registered in MF also to the application for approval of OTC drugs (Question 14) Is there any priority registration or time clock up issue of the certification? (Answer) 1. There is neither a priority registration nor a time clock. Registration process will proceed as soon as possible just after application is received. (Question 15) Can a manufacturer submit approval application documentation of medicinal drug using API which MF registration is pending and registration number is not assigned and the MF registration certificate is not issued? (Answer) 1. Manufacturer can submit approval application describing that the MF registration is pending on approval application documentation of medicinal drug. In such case, use the system receipt number issued when the MF registration application is accepted. 2. However, you should substitute the above system number with the new MF registration number as soon as possible. In this case, submit a request for substitution. Please note that actual approval review will take place after the receipt of this substitution request. 3. Also, you can not cite the system number in the MF application for slight change in registration documentation. You can not submit this application when the number is not issued while MF application is pending. 4. When you make an input to FD, please input “symbol, which shows application is pending�E “system receipt number�Eand “date of application�Eon “submission information" tag. 5. Registration procedure and forms In effort to further support the applicants for MF registration and the MF registration holders, the MFMG published in 2006 the following guidance concerning the Question 6 of the MF Q&A Part 2: About the MF Registration Rearrangement Report Form Concerning the Registration Rearrangement Report Form for MF, the content is shown in the ELD Office Communication December 20, 2005 “Collection of Questions and Answers related to the Master File for Active Pharmaceutical Ingredients Part 2�Eand in the Evaluation and Licensing Division Notification No. 0280001 of February 8, 2006 “About the Arrangement of the List of Items which are Registered in MF�E The style of the Registration Rearrangement Report Form and the Written Oath Form can be downloaded here and please, use it properly. (Cont). Link to the Ministry’s main notification > ELD Notification No. 0280003 Downloads (in a MS Word format) > Registration Rearrangement Report Form > Written Oath Form Downloads > Example of Written Oath Form Inquiries concerning this case (IAO) PMDA Office of Review Administration Review Operation Division Master File Management Group Tel: 03-3506-9438 (direct dialing) > Registration Rearrangement Report Form Attachment Year Month Day Registration Rearrangement Report Form To: Chief Executive of (IAA) PMDA ______________________________ Address (If a corporation, the address of the principle office) ______________________________ Name (If a corporation, its name and the name of the representative) (SEAL) Concerning the items listed below; please make the necessary rearrangements because they will not be used in the future. Serial number Registered item Registration number Date of registration Reference Remarks Cont. �Esee notes next page (Attention to paid to) 1. It is assumed that the size of the form to be Japan Industrial Standards (JIS) A4. 2. Submit this report form in original. 3. Write the characters by the square style clearly by using the Indian ink, etc. 4. Describe the latest date of registration in the registration date column. 5. Describe the in-country caretaker for MF (if a corporation, its name and the name of the representative) and the address (if a corporation, location of the principal office) in the Remarks column when the in-country caretaker for MF is appointed. 6. For the person who manufactures API in a foreign country, describe application person's address and name in parallel in the foreign language. Moreover, it is possible to substitute the seal with a signature. > Written Oath Form Year Month Day Written Oath Form Concerning ??? (name of the registered item) (???MF?????), herewith to confirm that there is neither an approval obtained for any of the numbers listed below nor an application for approval is submitted for a drug using MF . Serial number Trade name Approval number Date of approval Correspondence Remarks ______________________________ Address (If a corporation, the address of the principle office) ______________________________ Name (If a corporation, its name and the name of the representative) (SEAL) Example for filling the Written Oath Form Year Month Day Written Oath Form Concerning ??? (name of the registered item) (???MF?????), herewith to confirm that there is neither an approval obtained for any of the numbers listed below nor an application for approval is submitted for a drug using MF . Serial number Trade name Approval number Date of approval Correspondence (Latest changes described) Remarks 1 A ••••�E•Year •Month •Day Change in the Manufacture / Sales Approval Approval Date: Year Month Day 2 B ????? ?Year ?Month ?Day Report about a Slight Change Submitted: Year Month Day 3 C ????? ?Year ?Month ?Day Report about a Approval Rearrangement Submitted: Year Month Day ______________________________ Address (If a corporation, the address of the principle office) ______________________________ Name (If a corporation, its name and the name of the representative) (SEAL) JKS comments The templates for the forms provided above and the notes and examples are easily understandable for Japanese users. However, for overseas users, it is important to consider also the following specifics of the Japanese administrative procedures: * The forms shown above are mere examples, and therefore should not be downloaded, printed and filled. As with the most of the forms used in the registration procedures, users are expected to use the provided forms as templates or to design their own forms resembling the downloadable forms. * The form could be drawn by hand or prepared using computer or word-processing device. * The user prepared forms could be filled either by hand or filled on computer and printed out as long as the templates above are followed and the text is legible. 6. MF database Under the requirements of the Article 14-11, Paragraph 3 of PAL, registration of MF shall be announced publicly. As of February 28, 2006, the number of registered MF in Japan stood at 1,647. The registration of MF for a certain substance is not by any means indication that the substance has been reviewed and /or approved as a drug under the requirements of PAL. Details of the registered MF are available in the JSK’s Japan Approvals Database (JAD) �Ean English-language online resource containing information and data on various aspects of drugs �Esubmitted or already approved in Japan. The use of JAD is limited to the registered subscribers. Subscription information and subscription options to “Japan Drug Master Files�Epart of the JAD Database and to other relevant databases are available at the JKS Subscription page accessible at the following Internet address: (https://id34113.securedata.net/jouhoukoukai/members/subscription_form.htm) The “Japan Drug Master Files�Eis accessible online and contains data on the following parameters: 1. Serial number 2. Registration number 3. Registration date 4. Registrant name 5. Alternative name 6. Registrant address 7. Registration item 8. Registration update 9. Registration classification 10. JAD ID Number 11. Status 12. Remarks Legend for the parameters: * Serial number is the consecutive number of the entries �Eat present from 1 to 1,647. * Parameters No. 2 to 9 and No. 11 are the details of the registered MF, including those which are “de-listed�E�Eor having the registration withdrawn or revoked. * Parameters No. 10 and No. 12 are internal references of JAD Databases containing the JAD Identification Number �Eunique for each compound or product in JAD Databases, and some relevant remarks. Note: Snapshot of the Subscribers Access login page Demo of JAD Master Files Database is available at the following address: www.jad-database.com. For further details send inquiry by email: * MF Registration issues: regulatory@jouhoukoukai.com * Subscription: orders@jouhoukoukai.com Related reports The repost listed below and previously published by JKS contain presentations and / or references to the topics of the present report: New Drug Evaluation Division Regular Meetings * Current Issues of QA of Medicinal Products (held in 2006): Available in the JKS Document Store Cont. * Individual reports on the New Drug Evaluation Division Regular Meetings �E18th, 19th and 20th (held in 2004), 21st and 22nd (held in 2005): Available in the JKS Document Store * 13th ICH Immediate Briefing (held in 2005): Available in the JKS Document Store * Report on the “Drugs and Medical Devices Safety Update Seminar�Eheld in Tokyo on September 16, 2005 Available in the JKS Document Store __________________________________________________________ For further references on QA, GMP and other relevant issues of medicinal products in Japan, the readers can browse the online JKS Document Store or to send inquiries to regulatory@jouhoukoukai.com Disclaimer This publication is based on information obtained through in-house research and from sources available to public and it is not a complete analysis of every material fact. Statements of fact have been obtained from sources considered reliable but no representation is made as to their completeness or accuracy. Whilst the utmost care has been taken in the preparation of Jouhou Koukai Services and Jouhou Koukai Publishing (JKS) publications and documents and JKS Store database, they are provided "as is" without warranty of any kind, either expressed or implied, including, but not limited to, the implied warranties of merchantability, accuracy, fitness for a particular purpose, or non-infringement. Any reliance on the information provided herein is solely at the user's discretion and risk and neither JKS nor any third party source would be liable for the contents of the JKS publications and documents and JKS Store database. In certain circumstances, works which have been sourced from a third party and incorporated into the JKS publications and documents and JKS Store database and any interpretations and commentaries relating thereto, may not be considered to be official versions of such works. JKS are committed to use utmost efforts to include accurate, actualized and reliably translated information, but JKS make no warranties or representations as to its accuracy. The Japanese Government does not provide authorized (officially sanctioned) translations of its documents. In case of legal dispute, the original texts in Japanese will prevail. Neither JKS, nor any party involved in creating, producing or delivering JKS publications and documents shall be liable for any direct, incidental, consequential, indirect or punitive damages arising out of access to, use of or inability to use publications and documents, or any errors or omissions in the content thereof. Jouhou Koukai Services LLC and its business Jouhou Koukai Publishing provide information and intelligence on the Japanese pharmaceutical market in the fields of medicine, pharmaceuticals, patents, licensing, copyrights and data protection, business and corporate development, information technology, including e-health, and medical communication, however, this information does not constitute for nor can it be used as such for a substitute of medical, legal or investment advice. Worldwide Copyright © 2001-2006 by JKS LLC Reproduction in whole or part without permission is forbidden. www.jouhoukoukai.com 1 Pharmaceutical Affairs Law (PAL) �ELaw No. 145 of August 10, 1960 and its amendments. PAL, also known as Yakujihou in Japanese, is the key legislation governing the regulated medicinal products (drugs, quasi-drugs, cosmetics and medical devices) in Japan. 2 MHLW, Ministry of Health, Labor and Welfare of Japan. 3 PMDA, Pharmaceuticals and Medical Devices Agency. 4 As further detailed in the Disclaimer below, all translations of regulatory texts (laws, notifications, etc.) are unofficial �Ei.e. not endorsed or otherwise authorized by the Japanese Government, and therefore in legal situations only the Original text in Japanese are valid. However, the translations included in this document are technically correct and could be used for research, planning, training and information purpose. 5 PFSB, Pharmaceuticals and Food Safety Bureau of the MHLW. 6 Upper House of the Diet (Parliament of Japan) 7 The translation of the full text of Notification No. 0731011 is to be made available online separately by JKS Publishing. 8 In some English-language publications sometimes called “New Kiko�Eor occasionally even “pemda�E�Ehowever both are incorrect. 9 Routinely, it is the appointed in-country caretaker. 10 Individual reports on the New Drug Evaluation Division Regular Meetings �E18th, 19th and 20th (held in 2004), 21st and 22nd (held in 2005) are available in the JKS Document Store at http://www.jouhoukoukai.com/Merchant2/merchant.mvc?Screen=CTGY&Category_Code=JMI1 11 Individual reports on the New Drug Evaluation Division Regular Meetings �E18th, 19th and 20th (held in 2004), 21st and 22nd (held in 2005) are available in the JKS Document Store at http://www.jouhoukoukai.com/Merchant2/merchant.mvc?Screen=CTGY&Category_Code=JMI1 12 Transmissible spongiform encephalopathy 13 PFSB, Evaluation and Licensing Division Notification No. 0801001 / PFSB, Safety Division Notification No. 0801001 14 Of Notification No. 0280001. 15 In the English translation of the Q&A documents here, the language and the style of the original text is preserved as much as possible �Efor the questions asked and answers given. 16 See details in “Duties of PMDA on MF registration�EChapter above. 17 As stipulated in PMDA Notification No 0330003 dated March 30, 2005. 18 Unless otherwise specified, all information and documents are in Japanese only. 19 Use of a seal �Eonly registered personal or corporate seals are used in Japan for legally important documents. In the cases foreigners, signatures are acceptable on a case-by-case basis. 20 In a case a manufacturer is not using paper for applying, the application documentation should be submitted on electronic media, such as floppy disks (FD). 21 Faxing from within Japan: 03-35-07-0114 22 I.e. shown in the Example. 23 In Japanese only. 24 Article 5. About the procedure of the registration of MF, Paragraph 3. Change in registered items 25 Users of the JAD Database “Japan Master Files�Ecould see the withdrawn registration only as a (defunct) registration number, while the registrant’s data are deleted. 26 It is already available �Esee below in Chapter 5. ??