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20120621 EMEA/CVMP/134/02 Rev 3 活性物质主文件（ASMF）申报程序指南（中英文1/6） 2014-02-08 13:00:18| 分类： EDQM |
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! T! {# N; x# j* O/ ? 21 June 2012 Committee of Human Medicinal Products CHMP/QWP/227/02 Rev 3 欧洲人药委员会 Committee of Veterinary Medicinal Products EMEA/CVMP/134/02 Rev 3 欧洲兽药委员会 Guideline on Active Substance Master File Procedure 活性物质主文件（ASMF）申报程序指南 Final 最终版 | November 2005 – January 2006 | | | | | | | Draft agreed by Quality Working Party | | | | Adoption by CHMP for release for consultation | | | | Adoption by CVMP for release for consultation | | | | End of consultation (deadline for comments) | | | | Agreed by Quality Working Party | | | | Adoption by CHMP for release for consultation | | | | Adoption by CVMP for release for consultation | | | | End of consultation (deadline for comments) | | | | Rev. 03 Agreed by Quality Working Party | | | | | | | | | | | | Rev. 03 Date for coming into effect | | | |
This guideline replaces guideline CPMP/QWP/227/02 Rev 2 (EMEA/CVMP/134/02 Rev.2). 本指南替代CPMP/QWP/227/02 Rev 2（EMEA/CVMP/134/02 Rev.2） | Active substance master file, ASMF, letter of access, submission letter 活性物质主文件、ASMF、授权信、申报函 |
Note注: The corrections introduced to this guideline aim to support the Working Group on Active Substance Master File Procedures in their initiatives to improve the ASMF procedure across the European Regulatory Network. To this end, the annexes to the guideline have been revised, and one new annex introduced. Some minor textual changes in the main part of the guideline have been introduced as a consequence of the revised annexes. 本指南中所做的修正是为了支持活性物质主文件件程序工作组启动其在欧洲法规网络促进ASMF程序。为此目的，对指南的附件进行了修订，增加了一个新附件，并根据修订后的附件对指南正文进行了一些小的文字方面的修订。 Table of contents 目录 Executive summary 实施摘要 1. Introduction (background) . 介绍 2. Scope. 范围 3. Legal basis 法规依据 4. Content of the Active Substance Master File 活性物质主文件的内容 5. Use of the Active Substance Master File Procedure 活性物质主文件申报程序的采用 6. Content of the MA-dossier when the Active Substance Master File Procedure is used 采用活性物质主文件申报程序时制剂上市许可MA文件内容 7. Changes and updates to the Active Substance Master File 对活性物质主文件的变更和更新 ANNEX 1 附件1 ANNEX 2. 附件2 ANNEX 3 附件3 ANNEX 4 附件4 ANNEX 5 附件5 ANNEX 6 附件6 ANNEX 7 附件7 Executive summary 实施摘要 1. Introduction (background) 介绍（背景） The main objective of the Active Substance Master File (ASMF) procedure, formerly known as the European Drug Master File (EDMF) procedure, is to allow valuable confidential intellectual property or 'know-how' of the manufacturer of the active substance (ASM) to be protected, while at the same time allowing the Applicant or Marketing Authorisation (MA) holder to take full responsibility for the medicinal product and the quality and quality control of the active substance. National Competent Authorities/EMA thus have access to the complete information that is necessary for an evaluation of the suitability of the use of the active substance in the medicinal product. 活性物质主文件（ASMF）申报程序，通常被称为欧洲药物主文件（EDMF）申报程序，的主要目的在于使制剂上市许可申请人或制剂上市许可（MA）持有人能对制剂产品和原料药的质量及质量控制负全责的同时，又可以使原料药制造厂家（ASM）的核心技术或有价值的机密知识产权得到保护。因而，获得授权的药政管理部门/欧洲药品评审局（EMA）可以获得完整的资料，这些资料是对制剂中原料药的使用的生进行评估时所必须的。 2. Scope 范围 This Guideline is intended to assist Applicants/MA holders in the compilation of the active substance section of their dossiers for a Marketing Authorisation Application (MAA) or a Marketing Authorisation Variation (MAV) of a medicinal product. It is also intended to help ASMF holders in the compilation of their ASMFs. 本指南旨在帮助制剂上市许可申请人/制剂上市许可持有人准备制剂上市许可申请文件（MAA），或制剂上市许可变更申请文件（MAV）中原料药部分的内容，以及帮助ASMF持有人编写其ASMF文件。 ASMF Procedure and herbal substances/preparations ASMF申报程序和草药物质/制剂 In accordance with Directive 2001/83/EC as amended, the quality of traditional herbal medicinal products for human use has to be documented in accordance with existing European legislative requirements. These criteria are laid down in the following guidelines (which are applicable for all Human and Veterinary Herbal Medicinal products): ‘Guideline on quality of herbal medicinal products/traditional herbal medicinal products’ (CPMP/QWP/2819/00, EMEA/CVMP/814/00, in their latest revisions) and the ‘Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/ traditional herbal medicinal products’ (CPMP/QWP/2820/00, EMEA/CVMP/815/00, in their latest revisions). 根据修订后法案2001/83/EC，人用传统草药制品的质量必须符合已有的欧洲法规要求。这些标准包括在以下指南中（适用于所有人用和兽用草药制品）：“草药制品/传统草药制品质量指南”（CPMP/QWP/2819/00, EMEA/CVMP/814/00, 最新版本），以及“质量标准指南：草药物质、草药制剂和草药制品/传统草药制品的检验方法和可接受标准”（CPMP/QWP/2820/00, EMEA/CVMP/815/00, 最新版本）。 It should be noted that the principles which are outlined in table 3 of Annex 1 in relation to traditional herbal medicinal products are equally applicable to other herbal medicinal products, both for Human and Veterinary use, which do not follow the simplified registration procedure. 要注意的是在附件1表3中列出的与传统草药制品有关的原则同样适用于其它人用和兽用草药制品，但人用和兽用草药制品不适用简化注册程序。 References: 参考文献 1. ‘Guideline on quality of herbal medicinal products/traditional herbal medicinal products’ (CPMP/QWP/2819/00, EMEA/CVMP/814/00, in their latest revisions); “草药制品/传统草药制品的质量指南”（CPMP/QWP/2819/00, EMEA/CVMP/814/00, 最新版本） 2. ‘Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/ traditional herbal medicinal products’ (CPMP/QWP/2820/00, EMEA/CVMP/815/00, in their latest revisions); “质量标准指南：草药物质、草药制剂和草药制品/传统草药制品的检验方法和可接受标准”（CPMP/QWP/2820/00, EMEA/CVMP/815/00, 最新版本） 3. ‘Guideline on summary of requirements for active substances in the quality part of the dossier’ (CHMP/QWP/297/97, EMEA/CVMP/1069/02, in their latest revisions). “活性物质文件质量部分要求的总结指南”（CHMP/QWP/297/97, EMEA/CVMP/1069/02, 最新版本） 3. Legal basis 法规依据 Annex I to Directive 2001/83/EC as amended Part I, 3.2 Basic principles and requirements, (8) Active Substance Master File (for Human medicinal products) and Annex I to Directive 2001/82/EC as amended, Part 2.C.1 General Requirements, 1.1. Active Substances (for Veterinary medicinal products). 修订后法规2001/83/EC附件I，第一部分3.2 基本原则和要求，（8）活性物质主文件（人用药品）和修订后法规2001/82/EC附件I，第2部分，C.1一般要求 1.1 活性物质（兽用药品）。 4. Content of the Active Substance Master File ASMF的内容 The overall content of the ASMF should contain detailed scientific information as indicated under the various headings of the relevant Notice to Applicants for Marketing Authorisations for Medicinal Products in the Member States of the European Union (NtA). ASMF文件的内容应包括详细的科学资料，这在相关的“欧盟成员国的制剂上市许可申请者需知”（NtA）中的相关章节中有叙述。 ASMFs linked to human medicinal products should be presented in the format of the Common Technical Document (CTD), see Annex 1 table 1. 与人用制剂相关的ASMF应采用CTD格式编写，参见附件1表1. ASMFs linked to veterinary medicinal products should normally be presented in accordance with the format given in Annex 1 table 2, however in accordance with Parts 1.C and 2 of Directive 2001/82/EC as amended, all parts of such ASMFs (AP, RP, and their summaries) may be presented in the CTD format in the following circumstances [1]: 与兽用制剂相关的ASMF一般按附件1表2中的格式编写，但根据修订后法规2001/82/EC的第1.C部分和第2部分，该类ASMF的所有部分（公开部分、保密部分和其它总结）也在下述情况下也可以采用CTD格式编写。 l Where the active substance has been included in a medicinal product for human use authorised in accordance with the requirements of Annex I to Directive 2001/83/EC as amended; l 该活性物质已根据修正后法令2001/83/EC附件I的要求，被录入许可人用药品内 l In the case of any application for an animal species or for indications representing smaller market sectors; l 如果有动物品种或显示的申请代表很小的市场份额 l Where the competent authority has publicly announced this possibility. l 如果药监机构公开申明可以接受 The scientific information in the ASMF should be physically divided into two separate parts, namely the Applicant’s Part (AP) and the Restricted Part (RP). The AP contains the information that the ASMF holder regards as non-confidential to the Applicant/MA holder, whereas the RP contains the information that the ASMF holder regards as confidential, see Annex 1. It is emphasized that the AP is still a confidential document that cannot be submitted by anyone to third parties without the written consent of the ASMF holder. In all cases the AP should contain sufficient information to enable the Applicant/MA holder to take full responsibility for an evaluation of the suitability of the specification for the active substance to control the quality of this active substance for use in the manufacture of a specified medicinal product. ASMF可的科学信息被分为两部分，分别称为公开部分（AP）和保密部分（RP）。公开部分包括ASMF持有人认为可以向制剂上市许可申请人/制剂上市许可持有人公开的资料，而保密部分则包括ASMF持有人认为是机密性的资料，参见附件1。要强调的是，公开部分仍然是一份机密文件，在没有获得ASMF持有人书面同意前，任何人不得提交给第三方。无论如何，公开部分所包括的信息应足以使MA申请人/MA持有人能对活性物质的质量标准适用性进行评估并承担全部责任，以控制用于某一特定药品的该活性物质的质量。 The RP may contain the remaining information, such as detailed information on the individual steps of the manufacturing method (reaction conditions, temperature, validation and evaluation data of critical steps) and the quality control during the manufacture of the active substance. The National Competent Authorities/EMA may not accept that particular information has not been disclosed to the Applicant/MA holder. In such cases, the National Competent Authorities/EMA may ask for an amendment to the AP. 保密部分则包括剩下的信息，例如生产方法的单个步骤的详细信息（反应条件、温度、验证和关键步骤的验证和评估数据），和活性物质生产过程中的质量控制。如果有些重要的信息未在公开部分中，国家药监局/EMA可能会要求对公开部分进行补充。 In addition to the AP and RP, the ASMF should contain a table of contents, and separate summaries for both the AP and the RP. In cases where the ASMF is provided in the CTD format, both summaries should be presented as a Quality Overall Summary (QOS). In cases where the veterinary NtA format is used, they should be detailed and critical summaries. Each version of the AP and RP should have unique and independent version control numbers. 除公开部分和保密部分外，ASMF还应包括一份目录，公开部分和保密部分各自的综述。如果ASMF以CTD格式编写，则两份综述均应放在质量综述（QOS）中。如果采用的是兽药的NtA格式，则应该提供详细和关键的综述。每份公开部分和保密部分均应有惟一且独立的版本控制编号。 5. Use of the Active Substance Master File Procedure ASMF申报程序的应用 An ASMF can only be submitted in support of an MAA or MAV. The relationship between the quality of the active substance and its use in the medicinal product needs to be justified in this MAA or MAV. ASMF只有在被用于支持某个制剂上市许可（MAA）或上市许可变更（MAV）时才能提交。在该MAA或MAV中，要论述活性物质的质量与其在制剂中应用的关系。 Although the ASMF procedure is developed to keep intellectual property of the ASM confidential, it is also permissible to use the procedure when there is no confidentiality issue between the Applicant/MA holder and the ASM (e.g. when the Applicant/MA holder synthesises the active substance himself). It is expected that the ASM is also the holder of the ASMF. 尽管ASMF申报程序是为了保护原料药生产厂家的机密知识产权，但如果制剂上市许可的申请人/上市许可的持有人和ASM之间不存在保密问题的话（例如，MA申请人/持有人自己合成活性物质），也可以采用本程序。这时，一般希望ASM同时也是ASMF的持有人。 The ASMF procedure can be used for the following active substances, including herbal active substances/preparations. i.e.: ASMF程序适用于以下活性物质，包括草药类活性物质/制品，即 A. New active substances; 新的活性物质 B. Existing active substances not included in the European Pharmacopoeia (Ph. Eur.) or the pharmacopoeia of an EU Member State; 已有活性物质，未包括在欧洲药典中或欧盟成员国药典中 C. Pharmacopeial active substances included in the Ph. Eur. or in the pharmacopoeia of an EU Member State. 包括在欧洲药典中，或包括在欧盟成员国药典中的药典活性物质 The ASMF procedure cannot be used for biological active substances, see Annex 5. ASMF程序不适用于生物活性物质，参见附件5. The ASMF holder may have an ASMF as well as a Certificate of Suitability (CEP) issued by EDQM for a single active substance. Generally, it is however not acceptable that the Applicant/MA holder refers to an ASMF as well as to a CEP for a single active substance of a particular MAA/MAV. In cases where the CEP contains too little information (e.g. stability) the National Competent Authorities/EMA may decide that additional information should be provided in the dossier. In such case it may be acceptable to refer both to an ASMF and a CEP. 对某一原料药，ASMF持有人可能同时也持有CEP。一般来说，对于特定的MAA/MAV中所用的同一个活性物质，不可以既引用ASMF，又引用CEP。如果CEP包括的信息太少（例如稳定性），国家药监局/EMA可能会认为需要在申报文件中提供补充信息，这种情况下，可以同时ASMF和CEP。 The ASMF holder should give permission to the National Competent Authorities/EMA to assess the data in the ASMF in relation to a specific MAA/MAV, in the form of a ‘Letter of Access’, see Annex 2. ASMF的持有人应授权国家药监局/EMA可以审阅ASMF中与指定的MAA/MAV有关的数据，授权形式为提交一份“授权信”。格式见附件2。 The ASMF holder should submit to the Applicant/MA holder: ASMF持有人应向MA申请人/MA持有人提交 l a copy of the latest version of the AP (and, if applicable, responses to deficiency letters on the AP from a NCA/EMA if not already incorporated into the AP); l 一份最新的公开部分（和，适用时，对NCA/EMA给公开部分缺陷信的回复，如果未放置在公开部分中） l a copy of the QOS or detailed and critical summary, as appropriate, on the latest version of the AP; l 一份QOS，或最新公开部分的详细的关键性总结，适当时 l a copy of the Letter of Access where this letter has not been submitted earlier for the product concerned. l 一封授权信，如果此信在早期尚未提供 In addition, it is an essential requirement that the ASMF holder should submit to all National Competent Authorities/EMA involved in the MAA/MAV procedure: 此外，ASMF持有人还要给所有与MAA/MAV程序相关的国家药监局/EMA提交 l the ASMF (and, if applicable, responses to deficiency letters from a NCA/EMA if not already incorporated into the ASMF), accompanied by a Submission Letter and Administrative Details, see Annex 3. This also applies to the ASMF holder's responses to deficiency letters from a NCA/EMA; l ASMF文件（和，适用时，未整合在ASMF中的对NCA/EMA缺陷信的回复），同时提交一份申报函和行政信息，参见附件3。本要求同样适用于ASMF持有人对NCA/EMA缺陷信的回复。 l the Letter of Access where this letter has not been submitted earlier for the product concerned. l 针对相关产品的授权信，如果早期未曾提交 The ASMF holder should submit the ASMF to the National Competent Authority/EMA either for each MAA and each MAV or only once according to national requirements. The submission of the relevant documentation by the ASMF holder to the National Competent Authority/EMA must be synchronised to arrive at approximately the same time as the MAA or the MAV i.e. not more than one month before and not after the intended MAA/MAV submission date. 根据各国家药监局/EMA的要求，ASMF持有人可能需要为每个MAA和每个MAV提交一次ASMF，也可能只需要提交一次ASMF。ASMF持有人提交的相关文件应与MAA或MAV同时到达国家药监局/EMA，即与MAA/MAV提交时间前后相关不得超过一个月。 Where the ASMF procedure is used, the Applicant/MA holder should submit the MAA or MAV to the National Competent Authorities/EMA together with the Letter of Access where this Letter has not been submitted earlier by the MA holder/Applicant himself or by the ASMF holder for the product concerned. 如果采用了ASMF申报程序，则MA的申请人或持有人应向国家药监局/EMA提交MAA或MAV。如果早期MA持有人/申请人和ASMF持有人均未给该产品提交授权信，则MA申请人或持有人同时还要提交一份授权信。 Where the same active substance is used in a number of applications for different products in one or more Member States, the ASMF holder should submit identical documentation to every National Competent Authority/EMA. Consequently, the National Competent Authorities/EMA may require that any ASMF updates made in relation to one MA should apply to all. It is the ASMF holder’s responsibility to notify the MA holders and National Competent Authorities/EMA concerned about any changes to the AP and/or RP, so that the MA holders can update all affected MAs accordingly. 如果同一种活性物质同时应用于一个或多个成员国的不同产品，则ASMF持有人应向各相关成员国药监局/EMA提交相同的文件。这种情况下，国家药监局/EMA可能会要求对ASMF所作的与其中一个MA相关的所有更新应同时应用于所有MA。因此一旦对ASMF的公开部分和/或保密部分有任何变更，ASMF持有人有责任通知相关的MA持有人和国家药监局/EMA，以使得MA持有人可以相应地对所有受影响的MA进行更新。 6. Content of the MA-dossier when the Active Substance Master File Procedure is used 采用ASMF申报程序时MA文件内容 The Applicant/MA holder is responsible for ensuring that he has access to all relevant information concerning the current manufacture of the active substance. 制剂上市许可申请人/持有人负责保证自己可以获得与活性物质现行生产相关的所有信息。 The specification used by the Applicant/MA holder to control the correct quality of the active substance should be laid down unambiguously in the MA dossier (CTD format section 3.2.S.4.1 and 3.2.S.4.2 or old human/veterinary NtA format part 2.C.1). The Applicant/MA holder should include a copy of the AP in the MA dossier (CTD format section 3.2.S or veterinary NtA format part 2.C.1). The version of the AP in the MA dossier should be the most recent and it should be identical to the AP as supplied by the ASMF holder to the National Competent Authority/EMA as part of the ASMF. The Applicant/MA holder should include all relevant details from the AP in the QOS/detailed and critical summary of the MA dossier. Issues of the ASMF that are specifically relevant to the product under consideration should be highlighted in the QOS/detailed and critical summary of the MA dossier. 在制剂上市许可文件中，应清楚地写明MA申请人或持有人用于控制活性物质的质量所采用的质量标准（CTD格式的3.2.S.4.1和3.2.S.4.2部分，或老的人用格式，或兽用NtA格式2.C.1部分）。MA申请人或持有人应在MA文件中放置一份公开部分（CTD格式的3.2.S或兽用NtA格式2.C.1部分）。MA文件中的公开部分的版本应是最新的，应与ASMF持有人提交给国家药监局/EMA中相关部分是相同的。MA申请人或持有人应在MA的QOS或详细的关键总结中放入公开部分的相关详细信息。与产品特别相关的ASMF的问题，应在MA文件的QOS或总结中特别说明。 In the case of a single supplier and where the ASMF procedure or CEP procedure is used, the specification for the active substance provided by the Applicant/MA holder in the MA dossier should in principle be identical to that of the ASMF holder or the CEP holder. However, the Applicant/MA holder does not need to accept redundant tests in the specification, unnecessarily tight specification limits or outdated analytical methods. 如果只有一个供应商，且采用了ASMF申报程序或CEP程序，则MA申请人或持有人在MA文件中提交的活性物质的质量标准应与ASMF持有人或CEP持有人所采用的基本一致。当然，MA申请人或持有人不一定非得接受质量标准中重复的检测、不必要的加严限度或过时的分析方法。 In cases where the Applicant/MA holder uses a different analytical method than that described in the ASMF, both methods should be validated. Technical tests in the specification that are relevant for the medicinal product, but which are normally not part of the specification in the ASMF (e.g. particle size), should be part of the specification of the Applicant/MA holder. 如果MA申请人或持有人使用了与ASMF中不同的分析方法，则两个方法都必须进行验证。与制剂产品相关的质量标准的技术测试，一般不包括在ASMF质量标准中（例如粒径），但应该包括在MA申请人/持有人质量标准中。 In cases where there is more than one supplier, the Applicant/MA holder should have one single compiled specification that is identical for each supplier. It is acceptable to lay down in the specification more than one acceptance criterion and/or analytical method for a single parameter with the statement ‘if tested’ (e.g. in case of residual solvents). 如果有不止一个供应商，MA申请人或持有人应只有一个质量标准，针对每个供应商均相同。对于申明为“如测试”（例如，残留溶剂）的检测项目，在质量标准中可以设置多个可接受标准，和/或多个分析方法。 7. Changes and updates to the Active Substance Master File ASMF的变更和更新 As for medicinal products, ASMF holders should keep the content of their ASMFs updated with respect to the actual synthesis/manufacturing process. The quality control methods should be kept in line with the current regulatory and scientific requirements. 对于制剂产品，ASMF持有人应保持其ASMF内容根据实际的合成或生产工艺进行更新。质量控制方法应符合现行法规和科学要求。 ASMF holders shall not modify the contents of their ASMF (e.g. manufacturing process or specifications) without informing each Applicant/MA holder and each National Competent Authority/EMA. This obligation remains valid until the Letter of Access has been withdrawn by the ASMF holder, see Annex 4. ASMF holders should provide the updated ASMF to all interested parties with reference to the revised version number. ASMF持有人对其ASMF内容进行修订时，应通知每个MA申请人或持有人，以及每个相关的国家药监局/EMA。该责任只在有ASMF持有人申请将授权信撤销时方终止，参见附件4。ASMF持有人应保持向所有利益相关方面提供更新信息，并索引至修订后的版本编号。 Any change to the ASMF should be reported by every MA holder to the relevant National Competent Authority/EMA by means of an appropriate variation procedure. A Submission Letter should be provided (Annex 3). 对ASMF的任何变更均应由各MA持有人向相关的国家药监局/EMA通过适当的变更程序进行报告。同时应提交申报函（附件3）。 In cases where the contents of the ASMF cannot be changed for a certain period of time because of other procedural provisions (i.e. mainly because of on-going MRP procedures), the ASMF holder should still provide the aforementioned data to the MA holder and National Competent Authorities/EMA making reference to this reason and requesting a later date of implementation. 如果ASMF的内容由于其它程序条款的原因无法在某段时间内进行变更（即，主要因为正在进行的MRP程序），则ASMF持有人仍需要提供上述数据给MA持有人和国家药监局/EMA，供其参考该原因，并要求推迟实施日期。 At the occasion of the 5-year renewal of a medicinal product, MA holders are required to declare that the quality of the product, in respect of the methods of preparation and control, has been regularly updated by variation procedure to take account of technical and scientific progress, and that the product conforms with current CHMP/CVMP quality guidelines. They will also declare that no changes have been made to the product particulars other than those approved by the Competent Authority/EMA. 在制剂进行5年定期更新时，MA持有人需要对其产品质量进行申明，说明其生产和控制方法已通过变更程序进行了定期更新，以保持其技术和科学的进步性，且产品符合现行CHMP/CVMP质量指南。MA持有人还要申明除已由国家药监局/EMA批准的变更外，产品未进行其它特殊变更。 MA holders should therefore verify with their ASMF holders whether the above declaration can be met in respect to the active substance particulars. In case changes have not been notified to the MA holder and National Competent Authority/EMA, the necessary variation procedure should be initiated without delay. 因此，MA持有人需要与其ASMF持有人确认与活性物质相关方面是否符合上述申明的内容。如果MA持有人和国家药监局/EMA未收到ASMF的相关变更通知，则需要立即启动必要变更程序。
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