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欧盟GMP第一章质量管理一、原则Principle生产许可证持有厂家只能生产医药产品，以确保药品符合其预期的使用目的，符合销售许可证的要求，并不因药品安全性、质量或药效方面的问题而给患者带来风险。
达到这一质量目标是高层管理者的责任，同时也需要公司各部门、各层次的职员以及公司的供应商和销售商的参与并承担义务。
为了确保达到该质量目标，必须全面设计并正确贯彻实施包括GMP 与质量控制(QC)在内的质量保证(QA) 体系。
该体系应用文件明文规定并对其有效性加以监控。
质量保证体系的所有部门都必须充分配备胜任的人员，适宜足够的厂房、设备及设施。
与此同时，生产许可证持有者及受权人员具有另外的法律责任。
The holder of a Manufacturing Authorisation must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorisation and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the comp any’s suppliers and by the distributors. To achieve the quality objective in a reliable manner there must be a comprehensively designed and correctly implemented system of Quality Assurance incorporating Good Manufacturing Practice and thus Quality Control. It should be fully documented and its effectiveness monitored. All parts of the Quality Assurance system should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the Manufacturing Authorisation and for the Qualified Person(s).1.1 质量保证、GMP 和质量控制的基本概念是内在相互联系的。
201306 PA/PH/CEP(09)108 2R CEP电子提交和纸质提交指南（中英文）官网原文下载：.edqm.eu/en/Guidance-for-electronic-and-paper-submissions-1585.html?mbID=107新版本生效日期：2013年8月1日Certification of Substances DivisionFK/CBPUBLIC DOCUMENT公开文件(LEVEL 1)第一层次English only/Anglais seulement仅英文版PA/PH/CEP(09)108, 2RStrasbourg, June 2013 Certification of suitability to Monographs of the European PharmacopoeiaGuidance for electronic and paper submissionsFor Certificates of Suitability (CEP) applicationsCEP电子和纸质申报指南Date of implementation: 1 August 2013Address: 7, sllee Kastner, CS 30026F-67081 Strasbourg (France)Telephone: 33(0)3 88 41 30 30 – Fax: 33 (0) 3 88 41 27 71 – :cepedqm.euInternet:.edqm.euTable of content目录1Introduction介绍2Scope and general requirements围和一般要求3Electronic submission formats电子申报格式3.1eCTD submission format eCTD申报格式3.2NeeS submission format NeeS申报格式3.3PDF format PDF格式4Submission of paper dossiers纸质文件提交5Content and structure of an application申报的容和结构6Lifecycle management of applications申报的生命周期管理6.1Granularity and updated sections章节分类和更新部分6.2When to submit a baseline Module 3?什么时候提交基准模块37Validation by the EDQM EDQM验证8Routes (or pathways) of submission递交方式（途径）9Security安全性1Introduction介绍This document is guidance for electronic and paper submissions for Certificates of Suitability (CEPs) applications. Information and requirements described in this document are intended to facilitate the handling and assessment of submissions for certificates of suitability (CEPs) and to maintain their lifecycle even if the submission is not an eCTD.本文件意在指导CEP的电子和纸质申报。
欧洲药典适用性证书(COS, Certificate of Suitability), 是由欧洲药典委员会颁发的用以证明原料药品的质量是按照欧洲药典有关各论描述的方法严格控制的, 其产品质量符合欧洲药典标准的一种证书。
COS证书在欧洲药典委员会的二十八个成员国内得到承认，它与欧洲药物管理档案,即（EDMF，European Drug Master File）在程序和作用上相类似但又有不同：1．两者都是一种支持性材料，用于支持使用该原料药的制剂产品在成员国的上市申请（MAA）；2．两者都是用于证明制剂产品中所使用的原料药质量的文件，是其它国家原料药品进入28个欧洲药典委员会成员国的市场必需提交的文件；3． COS和EDMF都可作为原料药进入欧洲市场的申请程序，可任选其一，没有必要重复申请；4． COS与EDMF的主要不同是COS可由原料药生产商独立申请，而EDMF则必需与使用该原料药的制剂的上市申请（MAA）同时进行。
也就是说，COS 的申请不需要事先找到欧洲代理商，而EDMF的申请就必需事先找到使用该原料药的欧洲代理商；5． COS 是一个证书，而EDMF只给一个参考号（Reference No.）。
申请COS的基本程序：1．按照有关当局的要求编写合格的文档（即Dossier）；2．填写申请表格；3．通过银行向有关机构汇去有关费用，并递交上申请表格和所需的文档；时、波斯尼亚黑塞哥伟那、克罗地亚、塞普路斯、捷克、丹麦、芬兰、法国、德国、希腊、匈牙利、冰岛、爱尔兰、意大利、卢森堡、荷兰、挪威、葡萄牙、斯洛伐克、斯洛文利亚、西班牙、瑞典、瑞士、马其顿、土耳其、英国和欧共体。
欧洲药物质量理事会认证秘书处给予适应性证明书（COS），用以证明原料药生产商生产的产品的质量是以欧洲药典专论适当控制的。
要取得此证书，生产商需要提交一详细的档案，其中可能含有机密资料，此证书用户表明通过应用欧洲药典有关专论，能够检查药物原料和辅料是否适用于人用药品的生产，也就是说，从这一特殊方法（包括原材料）生产的药品的所有可能1．活性成分生产厂家的名称和地址、电话、传真、邮件、公司的简介1.1. 质量标准和常规检测1.1.1 质量标准（药典标准，最好能与厂内标准相比较、杂质的标准、粒度、密度、包装）1.1.2 常规检验（应按照1.1.1节所列的项目给出所有测定方法）1.2 科学资料1.2.1 名称- 化学名- 普通名称- 其它名称1.2.2 描述-性状-溶解性-结构式-分子式-分子量-CAS-登记号（药典上结构式右下方）1.2.3 生产方法-简述（反应式、流程图和简单的文字描述）1.2.5 发展化学-分析用标准品的制备-分析用标准品的检验抱告-化学结构证明：红外光谱紫外光谱核磁共振氢谱核磁共振碳谱质谱多晶型性物理化学特性元素分析-分析方法的有效性：高效液相色谱法的含量测定杂质的检测（高效液相色普法）其它相关物质（薄层色普法）残留溶剂的检测（气象色普法）1.2.6 杂质-潜在杂质来源-来源于起始原料和中间体的杂质-在合成中形成的杂质-由于降解产生的杂质-残留溶剂-简要的结果1.2.7 批分析（包括杂质）（连续5批）part II F: 稳定性1．活性物质的稳定性试验（3批）-运用的试验方法-结果表格-推荐的货物寿命，结论文件目录-生产厂商保密部分part II C: 原料药品的控制1. 活性成分1.2.3 生产方法-合成路线/流程图（反应式，流程图）-过程的详细描述（包括对生产人员的书面指导/生产记录）-溶剂、试剂、催化剂-纯化步骤1.2.4 合成中的质量控制-起始原料（鉴别、质量标准、外观、含量、杂质控制项目）-中间体的控制-纯化过程中所用原料的质量标准-工艺过程的合理性及其资料的评价阅附录II"活性成分的化学"中的细节。
欧洲药典各论的适用性证书关于CEP申请暂停或撤销及关闭的政策本文描述了EDQM根据欧洲会议决议AP-CSP (07) 1实施的CEP申请的暂停或撤销及关闭的政策。
1. 定义• CEP：EDQM颁发的符合欧洲药典各论的适用性证书。
• 暂停：应CEP持有人或经EDQM决定，一个颁发的CEP的临时取消。
在某些情况下，CEP 可能会被恢复。
• 撤销：根据CEP持有人的要求或EDQM的决定，最终取消授予的CEP。
• 关闭：应CEP持有人或EDQM的要求，取消正在进行的CEP申请。
• 听证：关于CEP或CEP申请的有效性，无论是在EDQM检查方案中还是在CEP评估内容中，听证为申请人或CEP持有人提交书面请求，重新审议EDQM特设委员会作出的决定提供了机会。
2. 范围本政策适用但不限于以下情形：2.1 CEP的暂停2.1.1 在下列情况下，特设委员会可决定暂停CEP：- 在EDQM认证计划的框架内，对一家公司进行的检查显示出严重和（或）重大缺陷并且得出结论，即该公司的运作不符合欧盟GMP，因此对公众健康造成潜在风险，和/或检查明，生产过程不符合提交的CEP档案。
- 由欧洲经济区（EEA）成员国或与欧盟就API-GMP检查达成相互承认协议的国家进行的公司检查表明，该公司的运作不符合GMP，如果该公司提交了CEP申请，其有效性很可能受到检查结论的影响。
- CEP档案不符合认证程序的要求且持有者没有提交适当的信息来维护。
2.1.2 CEP的持有者也可要求暂停CEP，例如，如果CEP持有人无法履行对所提交的CEP档案的承诺。
典型的例子是暂时停止生产，升级或部分生产现场的破坏，或暂时无法满足修订后的欧洲药典各论。
暂停期限为2年。
如果没有正当的、被EDQM接受的延长暂停期的理由，不符合解除暂停条件的CEP会被撤销。
2.2. CEP的撤销:2.2.1以下情况，CEP可能被EDQM的特设委员会撤销，例如：- 经EDQM检查后，在需要采取紧急行动（公共卫生问题）且认为不可能采取纠正行动的情况下；- 当EDQM检查显示CEP档案由伪造的数据组成，或有证据表明现场有大量和系统的伪造文件时；- 在CEP暂停后，当公司无法满足认证程序中有关更新CEP档案和遵守GMP的要求时（例如，重复的GMP不符合要求，即使检查不是连续的）。
Guidance for IndustryChanges to an ApprovedNDA or ANDA已批准申请的新药变更指南U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)April 2004CMCRevision 1I. INTRODUCTION AND BACKGROUNDThis guidance provides recommendations to holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) who intend to make post approval changes in accordance with section 506A of the Federal Food, Drug, and Cosmetic Act (the Act) and § 314.70 (21 CFR 314.70). The guidance covers recommended reporting categories for postapproval changes for drugs other than specified biotechnology and specified synthetic biological products. It supersedes the guidance of the same title published November 1999. Recommendations are provided for postapproval changes in (1) components and composition, (2) manufacturing sites, (3) manufacturing process, (4) specifications, (5) container closure system, and (6) labeling, as well as (7) miscellaneous changes and (8) multiple related changes.本指南给打算将已批准变更的新药上市申请和新药报审简表申请的持有者提供建议，使其按照联邦食品、药品、化妆品法案的506A部分和§ 314.70 (21 CFR 314.70)。
Certification of Substances DivisionFS/CBPUBLIC DOCUMENT(Level 1)English only/Anglais seulementPA/PH/CEP (11) 76Strasbourg, July 2012斯特拉斯堡，2012年7月Certification of Suitability toMonographs of the European PharmacopoeiaGuidance on frequent changes to applicationsfor Certificates of Suitability (CEPs)欧洲药典适用性证书常见CEP变更申请指南Address: 7 allée Kastner CS 30026 - F 67081 StrasbourgTelephone: 33 (0) 3 88 41 30 30 - E-mail:cep@edqm.eu - Fax: 33 (0) 3 88 41 27 71Internet : http://www.edqm.euThis document should be considered as an explicative note and should be read jointly with the EDQM Guideline on Revision/Renewal of Certificates of Suitability to the Monographs of the European Pharmacopoeia (PA/PH/CEP (04) 2).This document is intended as a guide to applicants when compiling their documentation fornotification/revision/renewal of their applications for certificates of suitability (CEPs). It has arisen from frequent issues occurring in submissions of notifications and revisions of dossiers for chemical purity, and it describes the key points to be considered.By improving the quality of the data submitted, the time for the evaluation of the dossiers will be reduced and requests for additional information will be limited. 本文件应被当作是解释性的文字，应与EDQM关于CEP修订/更新指南(PA/PH/CEP (04) 2)一起解读。
COUNCIL OF EUROPEPUBLIC HEALTH COMMITTEE(Partial Agreement)RESOLUTION AP-CSP (07) 1(adopted by the Public Health Committee (Partial Agreement) (CD-P-SP)on 21/02/2007Certification of suitability to the monographs of the European Pharmacopoeia(revised version)欧洲议会公共卫生委员会（局部协定）决议AP-CSP (07) 1号2007年2月21日欧洲议会公共卫生委员会（局部协定）（CD-P-SP）通过欧洲药典适用性证书（修订版）The public Health Committee (Partial Agreement) (CD-P-SP) consisting, for the purposes of the Convention on the Elaboration of a European Pharmacopoeia, of delegations appointed by the Parities to the said Convention, namely the delegations of Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, the Czech Republic, Denmark, Estonia, Finland, "the Former Yugoslav Republic of Macedonia", France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxemburg, Malta, Montenegro, the Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, Turkey, United Kingdom and the European Union.Considering the implementation of the Procedure for the certification of suitability of monograph of the European Pharmacopoeia adopted on 1 July 1993 by the Public Health Committee (Partial Agreement) (CD-P-SP) in its resolution AP-(CSP (93) 5 and revised on:- 4 October 1996 Resolution AP-CSP (96) 5- 8 May 1998 Resolution AP-CSP (98) 2- 22 December 1999 Resolution AP-CSP (99) 4Having regard to the decision by the European Pharmacopoeia Commission at its session of November 2006 to update and complete the resolution AP-CSP (99) 4.Has therefore decided to amend the resolution AP-CSP (99) 4 and to replace it by the text attached.根据建立欧洲药典协定公约，公共卫生委员会（局部协定）(CD-P-SP)由以下公约成员国指定代表组成，即以下国家代表：奥地利、比利时、波斯尼亚和黑塞哥维那、保加利亚、克罗地亚、塞浦路斯、捷克共和国、丹麦、艾沙尼亚、芬兰、“前南斯拉夫的马其顿共和国”、法国、德国、希腊、匈牙利、冰岛、爱尔兰、意大利、拉脱维亚、利陶宛、卢森堡、马耳他、门的内哥罗、荷兰、挪威、波兰、葡萄牙、罗马尼亚、塞尔维亚、斯洛伐克共和国、斯洛文尼亚、西班牙、瑞典、瑞士、土耳其、英国和欧盟。
药品注册用英语现在做注册资料经常会涉及英语表达，为了使我们写注册资料时的英语更纯正，希望各位达人能积极勇跃提供经常涉及的英语表达，使我们的注册水平更上一层楼。
我先抛砖引玉CEP：欧洲药典适应性证书certificate of suitability to monograph of European Pharmacopoeia。
是欧洲药典所收载的原料药的一种认证程序，用以确定原料药的质量可以用欧洲药典的方法加以控制。
这一程序适用于生产的和提取的有机或无机物质以及发酵生产的非直接基因产品。
DMF：Drug master File美国药物主文件档案。
是指提交给FDA的用于提供关于人用药品的生产设备、工艺或生产、工艺处理、包装和储存中使用的物料的详细的和保密的信息。
分为五种类型：I：生产地点、设备、操作程序和人员II：原料药、原料药中间体、生产原料药和中间体使用的物料和药品III：包装材料IV：赋形剂、色素、调味剂、香料或生产这些物质所用的物料V：FDA接受的参考信息EDMF：European Drug Master File欧洲药物主文件档案。
是指欧洲制剂申请中有关原料药信息的文件，又称原料药主文件档案（ASMF）。
EDMF 只有在制剂申请的支持下才能提交。
EDMF分为两部分：1．申请人部分（AP）：供制剂申请人使用的非保密信息；2. 限制部分（RP）：EDMF持有人认为是保密的信息。
EDMF的使用范围：1. 新原料药2. 已知的但欧洲药典或其成员国药典没有收载的原料药3. 欧洲药典或成员国药典已收载的原料药ANDA：Abbreviated New Drug Application 美国简略新药申请。
是FDA规定的仿制药申请程序。
Generic：仿制的，非特殊的API：Active Pharmaceutical Ingredient 原料药Dossier：文档，档案。
TSE：Transmitting animal Spongiform Encephalopathy agent 传播性动物海绵状脑病体Q7A：ICH（国际协调会议）原料药GMP 指南。
欧洲药典CEP证书修订更新规定指南中英对照版Date of implementation: 1 March 2010Introduction:The holder of a Certificate of suitability shall inform the EDQM of any change to the information in the certification dossier by sending an application form and all necessary documents demonstrating that the conditions laid down in the present guideline are met.Classification of changesThe changes have been classified in three categories (notification/minor/major) depending on the potential impact of the change on the quality of the final substance. These three categories are based on those (IA-IAIN/IB/II) of the Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisation for medicinal products for human use and veterinary medicinal products.Any change not classified as a notification or a major change should be classified as a minor change except in the following cases where a new application should be submitted:- addition of a new route of synthesis and/or a new manufacturing site where the specifications of the final substance are different from the one already approved- transfer to a new holder that is not the same legal entity as the approved one, where the transfer does not occur because of a merger or because the company is sold, and where the manufacturer does not take out the Certificate of suitability in their own name.The changes related to Ph. Eur. monograph revisions or any other regulatory requirements are treated separately andgenerally initiated by the EDQM.执行日期：2010年3月1日介绍：欧洲药典适用性证书持有人必须向EDQM报告所有与申报文件有关的变更，申报时应填写申请表格和所有必要的资料，证明变更符合现行指南的规定。
Procedures for management of revisions/renewals of certificates of suitability to the European Pharmacopoeia monographs Certification of suitability to Monographs of the European Pharmacopoeia欧洲药典适用性证书PROCEDURES FOR MANAGEMENT OF REVISIONS/RENEWALS OF CERTIFICATES OF SUITABILITY TO THE EUROPEAN PHARMACOPOEIAMONOGRAPHS欧洲药典适用性证书的变更/更新的管理程序Introduction:介绍This document should be read in conjunction with the EDQM “Guideline on Requirements on Revision/Renewal of Certificates of Suitability to the European Pharmacopoeia monographs”(PA/PH/CEP (04) 2, as amended), which describes the conditions to be fulfilled as well as the documentation to be submitted for each request for revision.此文件应该与EDQM的“欧洲药典适用性证书修订与更新规定指南” (PA/PH/CEP (04) 2)联合起来阅读，后者描述了每个变更所要求满足的条件，以及要提供的文件资料。
The procedures for the management of revisions of certificates of suitability (CEPs) are described below and have been revised according to the revised European Regulation for Variations to Marketing Authorisation Applications.对于CEP证书变更管理的程序，在下面进行了描述，并且按照新修订的欧洲市场授权申请的有关法规进行了修订。
The revised system includes:修订的制度包括：- Introduction of a “Do and Tell” procedure where some notifications may be submitted within 12 months of implementation引进了一种“Do and Tell”的程序，规定一些通知性变更可以在实施后12个月以内进行提交。
- Introduction of “Minor revision by default”, for the changes which are not described in the EDQM guideline for revisions引进了一种“微小变更不完全列出”的管理方式，目的是将那些在EDQM指南中未描述到的变更包括进来。
- Introduction of “grouped procedures” for changes affecting more than one CEP application引进了一种“组合程序”来处理那些可能不止影响一个CEP申请的变更。
- The possibility to submit several changes in the same request for revision was already in place and is maintained. Consequential changes are considered as part of the original variation.以相同的变更要求相同时可以同时提交几个变更。
由于变更而引起的间接变更可以作为最初变更的一部分。
- Some changes to procedural aspects and deadlines for the treatment of revisions of CEP applications for alignment with the EU Regulation.为了与欧盟法规一致，对CEP变更的处理期限和程序方面做了一些变更。
Following the initial assessment of the request for revision, a single deficiency letter may be sent. Should the response not sufficiently address the request for information, the application for revision will be rejected.在对变更的要求进行最初的评价之后，如有可能仅会发出一封缺陷信。
如果回复信息不能完全的将所要求信息提交上去，变更申请可能会被拒绝。
1. Implementation1. 实施All requests for revision/renewal received from 1st March 2010 will be treated according to this updated policy.从2010年3月1日起收到的变更申请都应该按照这一新政策来处理。
2. How to apply for a request for revision/renewal ?2. 如何申请变更或更新？Application form:申请表A specific EDQM application form for revisions/renewals is to be submitted with each request for revision. It can be downloaded from the EDQM website.每次变更时都要提交专门的变更/更新申请表。
可以从EDQM网站上下载。
Documentation to be submitted:提供的文件Each application for a revision/renewal should include:每次变更/更新申请都应该提交以下内容：- A cover letter- A description of the kind of changes with reference to the EDQM Guideline for revision/renewal, as well as data showing, where applicable, that the conditions have been met. Consequential changes should be identified and the relation between the changes should be described.- Supportive information, including comparative data with the previous version of the dossier (in tabular format) showing the approved and the proposed section and highlighting the changes- Updated version of each relevant section of the dossier.- 封面信- 参照EDQM变更/更新指南，对变更的种类进行描述，如有需要还要有证明条件被满足的数据。
由此引起的间接变更应该被鉴定，并且变更之间的关系也应该被描述。
- 支持性信息，包括与前一版本的DMF文件的对比列表，列出变更前后的内容，将变更地方进行突出显示。
- 版本更新后的DMF文件各相关部分The documentation to be submitted for each request for revision/renewal is described in the EDQM “Guideline on Requirements on Revision/Renewal of Certificates of Suitability”.每个变更/更新申请所要求提供的文件在EDQM的“欧洲药典适用性证书修订与更新规定指南”进行了描述。
Fees and timelines:费用和时间期限The fees and timelines depend on the kind of revision. Timelines are described in Section 4.Fees are described in the EDQM application form. They have to be paid after validation of the request by EDQM and receipt of an invoice.费用和时间期限依据变更的类型。
时间期限在第4部分进行了描述。
费用在EDQM申请表中进行了描述。
在EDQM对变更要求完成确认和收到发票后要将费用付清。
3. Procedures3. 程序3.1 Notifications3.1 通知性变更Annual reporting: With the exception of Immediate Notifications which have to be submitted immediately, reporting of notifications may be done by way of an annual report compiling all the notifications that have been implemented within the last 12 months.年报：除了立即的通知变更需要马上提交外，其他的通知性变更需要以年报形式来提交，在年报中将过去12月之内实施的变更编辑在一起。
The evaluation of validity of a notification or a group of notifications is completed by EDQM within 30 days after receipt of a valid request. Then either an acknowledgement of a valid notification is sent to the holder or a revised certificate is granted if necessary.If the notification is incomplete at receipt, clarification may be requested by EDQM prior to sending any confirmation of a valid or rejected notification.However, if the conditions for a notification are not met, or if the application is largely deficient a letter of rejection is sent to the holder. This means that the applicant will have to resubmit the appropriate package of data and again pay the relevant fee.在收到一个有效的变更申请要求时，要在30天内完成对这个通知或这一组通知性变更的有效性的评价。
