欧盟（EU）2017/1569 临床试验药GMP原则和指南

欧盟（EU）2017/1569 临床试验药GMP原则和指南

COMMISSION DELEGATED REGULATION (EU) 2017/1569

of 23 May 2017

supplementing Regulation (EU) No 536/2014 of the EuropeanParliament and of the Council by specifying principles of and guidelines forgood manufacturing practice for investigational medicinal products for humanuse and arrangements for inspecti**

(Text with EEA relevance)

欧盟托管法案（EU）2017/1569    2017年5月23日

补充欧洲议会和欧盟委员会法规（EU）No.536/2014说明人用临床试验用药GMP原则和指南以及检查安排

THEEUROPEAN COMMISSION,

欧盟委员会

Havingregard to the Treaty on the Functioning of the European Union,

关于欧盟职能条约

Havingregard to Regulation (EU) No 536/2014 of the European Parliament and of theCouncil of 16 April 2014 on clinical trials on medicinal products for humanuse, and repealing Directive 2001/20/EC[1],and in particular Article 63(1) thereof,

关于欧盟议会和委员会2014年4月16日关于人用临床试验用药的法规（EU）536/2014，以及即将废止的指令2001/20/EC，尤其是其中第63（1）条

Whereas: 鉴于

(1)  The good manufacturing practice forinvestigational medicinal products for human use ensures that there isc**istency between batches of the same investigational medicinal product usedin the same or different clinical trials, and that changes during thedevelopment of an investigational medicinal product are adequately documentedand justified. The manufacturing of investigational medicinal products presentsadditional challenges comparing to the manufacturing of authorised medicinal productsbecause there are no fixed routines, there is a variety of clinical trialdesigns and c**equently packaging designs. Those challenges are due to theneed, often, of randomisation and to disguise the identity of theinvestigational medicinal products for the purpose of clinical trial(blinding). The toxicity, potency and sensitising potential of investigationalmedicinalproducts for human use may not be fully understood at the time of thetrial, and the need to minimise all  risks of cross-con**ination is thereforeof even greater importance than for authorised medicinal products. Because ofthis complexity, the manufacturing operati** should be subject to a highlyeffective pharmaceutical quality system.

人用临床试验用药GMP确保了用于相同或不同临床试验中的同种临床试验用药批次间的一致性，确保在临床试验用药研发期间的变更具有充分的记录和论证。相比于已批准的药品生产，临床试验用药的生产呈现出更多的挑战性，因为其并无固定的常规操作，临床试验设计会有变化，而包装设计也相应有变化。这些挑战通常是由于随机选择的需要，以及在临床试验中区分临床试验用药（加盲）的需要而产生的。人用临床试验药品的毒性、效价和潜在过敏性可能在试验时期并不能完全了解，因而降低交叉污染的所有风险的需求相比于已批准的药品会更为重要。鉴于此种复杂性，生产操作应在高效药物质量体系的管理之下。

(2)  Good manufacturing practice as regards bothmedicinal products authorised to be placed on the market and investigationalmedicinal products are based on the same principles. The same manufacturingsites will often manufacture both investigational and medicinal productsauthorised to be placed on the market. For that reason the principles andguidelines of good manufacturing practice for investigational medicinalproducts for human use should be aligned as much as possible with thoseapplicable to medicinal products for human use.

已批准将要上市的药品和临床试验用药品的优良生产规范是基于相同原则的。相同的生产场所通常既生产临床试验药品，也生产已批准销售的药品。因此，人用临床试验药品的优良生产规范原则和指南应尽可能与适用于人用药品的原则和指南保持一致。

(3)  In accordance with Article 61(5) ofRegulation (EU) No 536/2014 certain processes do not require the authorisationreferred to in Article 61(1) of that Regulation. In line with Article 63(2) ofRegulation (EU) No 536/2014 good manufacturing practice for investigationalmedicinal products does not apply to those processes.

依据法规（EU）536/2014第61（5）条，有些流程不需要依该法规第61（1）条进行批准。依法规（EU）536/2014第63（2）条规定，临床试验药品的优良生产规范不适用于这些流程。

(4)  For the manufacturer to be able to complywith good manufacturing practice for investigational medicinal products,cooperation between the manufacturer and the sp**or is necessary. Likewise,for the sp**or to comply with the requirements of Regulation (EU) No 536/2014cooperation with the manufacturer is necessary. Where the manufacturer and thesp**or are different legal entities, the obligati** of the manufacturer andsp**or vis-à-vis each other should be specified in a technical agreementbetween them. Such an agreement should provide for the sharing of inspectionreports and exchange of information on quality issues.

对于可以符合临床试验药品的生产商，有必要与申办方合作。类似的，对于符合法规（EU）536/2014规定的申办人，有必要与生产商进行合作。如果生产商和申办人为不同法律主体，则生产商和申办人的义务应在其双方签订的一份技术协议中做出相应规定。此协议应包括检查报告共享和质量问题信息互换。

(5)  Investigational medicinal products importedinto the Union should be manufactured by applying quality standards at leastequivalent to those in the Union. For this reason, only products manufacturedby a third country manufacturer that is entitled or authorised to do so inaccordance with the laws of the country where the manufacturer is located,should be allowed to be imported into the Union.

进口至欧盟的临床试验药品应依至少等同于欧盟的质量标准进行生产。鉴于此，只有第三国生产商生产的药品依其所在国法律获得批准或授权进行此类药品生产时才允许进口至欧盟。

(6)  All manufacturers should operate an effectivequality assurance system of their manufacturing or import operati**. Such asystem in order to be effective requires the implementation of a pharmaceuticalquality system. Good documentation c**titutes an essential part of a qualityassurance system. The documentation system of manufacturers shall enable thehistory of the manufacture of each batch and any changes introduced during thedevelopment of an investigational medicinal product to be traced.

所有生产商均应为其生产或进口操作运行一套有效的质量保证体系。此体系如需有效则应执行药物质量体系。优良文件是质量保证体系的一个基本构成部分。生产商的文件体系应使得其所生产的每个批次和在临床试验药品开发期间引入的任何变更可追溯。

(7)  Principles and guidelines of goodmanufacturing practice for investigational medicinal products should be set outin relation to quality management, personnel, premises, equipment,documentation, production, quality control, outsourced operati**, complaintsand recall, and self-inspecti**.

临床试验药品的优良生产规范原则和指南应设定质量管理、人员、设施、设备、文件、生产、质量控制、委外操作、投诉和召回和自检要求。

(8)  It is appropriate to require a productspecification file which brings together and contain all of the essentialreference documents to ensure that investigational medicinal products aremanufactured according to good manufacturing practice for investigationalmedicinal products and the clinical trial authorisation.

可制订一套产品标准文件，将所有确保临床试验药品依临床试验药品GMP和临床试验批件生产的必要参考文件放在一起包括在其中。

(9)  Due to the special characteristics ofadvanced therapy investigational medicinal products, the provisi** on goodmanufacturing practice should be adapted to those products in accordance with arisk-based approach. As regards the advanced therapy medicinal productsmarketed in the Union, Article 5 of Regulation (EC) No 1394/2007 of theEuropean Parliament and of the Council[2]provides for such adaptation. The Commission guidelines referred to in Article5 of Regulation (EC) No 1394/2007 should also set out the requirements on goodmanufacturing practice applicable to advanced therapy investigational medicinalproducts.

鉴于先进治疗临床试验药品的特殊特性，优良生产规范的条款应依基于风险的方法应用于此类产品。关于在欧盟上市的先进治疗药品，欧盟议会和委员会法规（EC）1394/2007第5条提供了此类应用。依法规（EC）1394/2007第5条所制订的EC指南亦设置了适用于先进治疗临床试验药品适用的GMP要求。

(10)In order to ensure conformity with theprinciples and guidelines of good manufacturing practice for investigationalmedicinal products, provisi** on inspecti** by the competent authorities ofthe Member States should be established. Member States should not be obliged toinspect third country manufacturers of investigational medicinal productsroutinely. The need for such inspecti** should be established according to arisk-based approach but third country manufacturers should be inspected atleast if there is a suspicion that the investigational medicinal products arenot manufactured by applying quality standards at least equivalent to thoseapplicable in the Union.

为了确保符合临床试验用药GMP原则和指南，成员国药监机构应制订检查条款。不应强制要求成员国常规性检查第三国临床试验药品生产商。应依据基于风险的方法辨别此类检查的需求，但至少应在怀疑第三国生产商未按至少等同于欧盟适用质量标准生产临床试验药品时对其执行检查。

(11)Inspectors should c**ider the Commissionguidelines on good manufacturing practice for investigational medicinalproducts for human use. To achieve and maintain mutual recognition ofinspection findings in the Union and facilitate the cooperation of the MemberStates, commonly recognised standards on the conduct of inspecti** on goodmanufacturing practice for investigational medicinal products in the form ofprocedures should be developed. The Commission guidelines and these proceduresshould be maintained and regularly updated, according to technical andscientific developments.

检查员应考虑欧盟委员会的人用临床试验用药GMP指南。为在欧盟内部达成和维护对检查所发现缺陷的互认，以及促进成员国合作，应采用程序方式制订共同认可的临床试验用药GMP检查实施标准。应依据科技发展维护并定期更新欧盟委员会指南和这些程序。

(12)During inspecti** of a site the inspectorsshould check whether a site respects good manufacturing practice as regardsboth investigational medicinal products and medicinal products authorised to beplaced on the market. For that reason, and in order to ensure the effectivesupervision, procedures and powers to carry out inspecti** to verify that goodmanufacturing practice for investigational medicinal products for human use isfollowed should be aligned as much as possible to those for medicinal productsfor human use.

在现场检查期间，检查员应检查该场所是否遵守临床试验用药GMP和已批准上市药品的GMP。因此，为了确保有效监管，实施检查以核查是否遵守人用临床试验用药GM的程序和权力，应尽可能向人用药品靠拢。

(13)To ensure that inspecti** are effective,inspectors should be appropriately empowered.

为了确保检查有效，检查员应被赋予适当权力。

(14)Member States should be able to take actionin case of non-compliance with good manufacturing practice for investigationalmedicinal products for human use.

成员国应具备能力在人用临床试验用药不符合GMP要求时采取措施。

(15)The competent authorities should be requiredto set up quality systems to ensure that the inspection procedures are observedand c**istently monitored. A well-functioning quality system should comprisean organisational structure, clear processes and procedures, including standardoperating procedures to be followed by inspectors when performing their tasks,clearly defined details of the inspectors' duties and resp**ibilities andongoing training requirements, as well as adequate resources and mechanismswhich aim to eliminate non-compliance.

应要求药监机构建立质量体系，以确保对检查程序受到观察和一致的监察。运行良好的质量体系应包括一个组织机构、清晰的流程和程序，包括检查员在完成其任务时要遵守的标准操作规程、清晰界定检查员义务和职责的详细内容和持续培训要求，以及消除不符合性所需的足够的资源和机制。

(16)This Regulation should apply from the samedate as Commission Directive (EU) 2017/1572[3],

本法规应与欧盟指令（EU）2017/1572同日适用。

HAS ADOPTEDTHIS REGULATION:

采纳本指令

CHAPTER I GENERAL PROVISI**

第一章通则

Article 1 Subject matter

第一条主旨

ThisRegulation specifies the principles and guidelines of good manufacturingpractice for investigational medicinal products for human use the manufactureor import of which requires an authorisation as referred to in Article 61(1) ofRegulation (EU) No 536/2014 and lays down arrangements for inspecti** ofmanufacturers in relation to compliance with good manufacturing practice inaccordance with Article 63(4) of that Regulation.

本法规规定了其生产或进口需要按法规EU 536/2014第61（1）条所指获得批准的人用临床试验用药优良生产规范原则和指南，规定了依据上述法规第63（4）条对生产商进行GMP符合性检查的安排。

Article 2 Definiti**

第二条定义

For thepurposes of this Regulation, the following definiti** shall apply:

本法规中涉及定义如下：

(1)  ‘manufacturer’ means any person engaged inactivities for which an authorisation is required in accordance with Article61(1) of Regulation (EU) No 536/2014;

“生产商”指从事需要按法规EU 536/2014第61（1）条所指获得批准的活动的任何人；

(2)  ‘third country manufacturer’ means any personestablished in a third country and engaged in manufacturing operati** in thatthird country;

“第三国生产商”指位于第三国并在该处从事生产操作的任何人；

(3)  ‘product specification file’ means areference file containing, or referring to files containing, all theinformation necessary to draft detailed written instructi** on processing,packaging, quality control, testing and batch release of an investigationalmedicinal product and to perform batch certification;

“产品标准文件”指含有或引用至含有一个临床试验用药生产、包装、质量控制、检测和批放行详细书面指导起草时以及执行批放行时所必须的所有信息的文件；

(4)  ‘validation’ means action of proving, inaccordance with the principles of good manufacturing practice, that anyprocedure, process, equipment, material, activity or system actually leads tothe expected results.

“验证”指依据优良生产规范原则，证明任一程序、工艺、设备、物料、活动或系统实际能得出预期结果的活动。

CHAPTER II GOOD MANUFACTURING PRACTICE

第二章优良生产规范

Article 3 Conformity with goodmanufacturing practice

第三条优良生产规范符合性

1.    The manufacturer shall ensure thatmanufacturing operati** are carried out in accordance with good manufacturingpractice for investigational medicinal products specified in this Regulationand subject to an authorisation as referred to in Article 61(1) of Regulation(EU) No 536/2014.

生产商应确保依照本法规中所指临床试验药品优良生产规范执行生产操作，并获得法规（EU）536/2014第61（1）所指批准。

2.    When importing an investigational medicinalproducts, the holder of the authorisation referred to in Article 61(1) ofRegulation (EU) No 536/2014 shall ensure that the products have beenmanufactured by applying quality standards at least equivalent to those laiddown by this Regulation and in Regulation (EU) No 536/2014, and that the thirdcountry manufacturer is authorised or entitled to in accordance with the lawsof that country to manufacture that investigational medicinal products in thatthird country.

在进口一种临床试验用药时，依法规（EU）536/2014第61（1）获得的批文持有者应确保产品生产过程应用了至少等同于本法规和法规（EU）536/2014规定的质量标准，并且第三国生产商已依据所在国的临床试验药品生产法获得批准或资质。

Article 4 Compliance withclinical trial authorisation

第四条临床试验批件符合性

1.    The manufacturer shall ensure that allmanufacturing operati** for investigational medicinal products are carried outin accordance with the documentation and information provided by the sp**orpursuant to Article 25 of Regulation (EU) No 536/2014 and as authorised inaccordance with the procedure laid down in Chapter II, or if documentation andinformation was subsequently amended, in Chapter III of above mentionedRegulation (EU) No 536/2014.

生产商应确保依据申办人按法规（EU）536/2014第25条所提供的文件和资料执行临床试验药品所有生产操作，并依第II章中规定的程序获得批准，或者如果文件和资料在后期进行了修订，则依上述法规（EU）536/2014第III章执行。

2.    The manufacturer shall regularly review hismanufacturing methods in the light of scientific and technical progress andexperience gained by the sp**or during the development of the investigationalmedicinalproduct.

生产商应依科技发展情况和在临床试验药品开发期间申办人获得的经验定期审核其生产方法。

Themanufacturer shall inform the sp**or of his reviews of the manufacturingmethods.

生产商应通知申办人其对生产方法的审核情况。

Where,following a review, an amendment to the clinical trial authorisation isnecessary, the application for the amendment shall be submitted in accordancewith Article 16 of Regulation (EU) No 536/2014 where the change to the clinicaltrial is a substantial modification or the amendment shall be carried out inaccordance with Article 81(9) of that Regulation where the change to theclinical trial is not a substantial modification.

如果在审核之后，需要对临床试验批文进行修订，如果临床试验变更为重大修订，则应依据法规（EU）536/2014第16条提交修订申请；如果临床试验变更没有重大修改，则应依该法规第81（9）条执行修订。

Article 5 Pharmaceuticalquality system

第五条药物质量体系

1.    The manufacturer shall establish, implementand maintain effective organised arrangements to ensure that theinvestigational medicinal products are of the quality required for theirintended use. Those arrangements shall include the establishment of a goodmanufacturing practice and a quality control.

生产商应建立、实施和维护有效的有组织的安排，以确保临床试验药品具备其既定用途所需的质量。这些安排应包括建立优良生产规范和质量控制。

2.    Senior management and personnel fromdifferent departments shall participate in the establishment of thepharmaceutical quality system.

高级管理人员和来自不同部门的人员应参与药物质量体系的建立。

Article 6 Personnel

第六条人员

1.    At each manufacturing site, the manufacturershall have a sufficient number of competent and appropriately qualifiedpersonnel at his disposal to ensure that the investigational medicinal productsare of the quality required for their intended use.

在每个生产场所，生产商均应有足够的具备资质并进行适当资质认定的人员受其调遣，以确保临床试验药品具备其既定用途所需的质量。

2.    The duties of managerial and supervisorystaff, including the qualified pers**, resp**ible for implementing andoperating good manufacturing practice shall be set out in their jobdescripti**. Their hierarchical relati**hips shall be set out in an organisationchart. The organisation chart and the job descripti** shall be approved inaccordance with the manufacturer's internal procedures.

负责实施和运行优良生产规范的管理人员和主管人员，包括授权人的义务应在其岗位说明书中设定。其层级关系应在组织机构图中设定。该组织机构图和岗位说明书应依据生产商内部程序获得批准。

3.    The staff referred to in paragraph 2 shall begiven sufficient authority to discharge their resp**ibility correctly.

段2中所指人员应被赋予足够的权力以正确履行其职责。

4.    The personnel shall receive initial andongoing training covering in particular the following areas:

人员应接受初次和持续的培训，培训内容应尤其覆盖以下领域：

(a)     the theory and application of the concept ofpharmaceutical quality; 药物质量概念的理论和应用；

(b)     good manufacturing practice. 优良生产规范。

Themanufacturer shall verify the effectiveness of the training.

生产商应确认培训的有效性。

5.    The manufacturer shall establish hygieneprogrammes, including procedures relating to health, hygiene practice andclothing of personnel. The programmes shall be adapted to the manufacturingoperati** to be carried out. The manufacturer shall ensure that the programmesare observed.

生产商应建立卫生程序，包括与健康、卫生规范和人员着装有关的程序。在生产操作中应执行这些程序。生产商应确保对这些程序进行观察。

Article 7 Premises andequipment

第七条设施和设备

1.    The manufacturer shall ensure that premisesand manufacturing equipment are located, designed, c**tructed, adapted andmaintained to suit the intended operati**.

生产商应确保设施和生产设备的定位、设计、构造、采用和维护适合其既定操作。

2.    The manufacturer shall ensure that thepremises and manufacturing equipment are laid out, designed and operated insuch a way as to minimise risk of error and permit effective cleaning andmaintenance in order to avoid con**ination, cross con**ination and any otheradverse effect on the quality of the investigational medicinal product.

生产商应确保设施和生产设备布局、设计和操作方式尽可能减少错误风险、使得可以进行有效清洁和维护以避免污染、交叉污染和任何其它对临床试验药品质量的不良影响。

3.    The manufacturer shall ensure that thosepremises and equipment to be used for manufacturing operati** which arecritical to the quality of the investigational medicinal products are subjectedto appropriate qualification and validation.

生产商应确保这些设施和设备经过恰当的确认和验证。

Article 8 Documentation

第八条文件记录

1.    The manufacturer shall establish and maintaina documentation system recording the following, where appropriate having regardto the activities undertaken:

生产商应制订并维护文件记录体系，记录以下内容，适当时考虑所实施的活动：

(a)  specificati**; 质量标准

(b)  manufacturing formulae; 生产配方

(c)  processing and packaging instructi**; 加工和包装指令

(d)  procedures and protocols, includingprocedures for general manufacturing operati** and conditi**; 程序和方案，包括通用生产操作和条件的程序

(e)  records, in particular covering the variousmanufacturing operati** performed and batch records; 记录，尤其要覆盖所实施的不同生产操作和批记录

(f)   technical agreements; 技术协议

(g)  certificates of analysis;  检验报告书

Thedocuments specific to any investigational medicinal product shall be c**istentwith the product specification file as relevant.

所有临床试验用药的专用文件应与药品的相关标准文件（如有）保持一致。

2.    The documentation system shall ensure thedata quality and integrity. Documents shall be clear, free from error and keptup to date.

文件系统应确保数据质量和完整性。文件应清晰、无错误并保持更新。

3.    The manufacturer shall retain the productspecification file and batch documentation for at least five years after thecompletion or discontinuation of the last clinical trial in which the batch wasused.

生产商应保存产品标准文件和批文件至少至该批次所用于的最后一次临床试验完整或中止后5年。

4.    When documentation is stored usingelectronic, photographic or other data processing systems, the manufacturershall first validate the systems to ensure that the data will be appropriatelystored during the period of storage laid down in paragraph 3. Data stored bythose systems shall be made readily available in readable form.

如果文件采用电子、图片或其它数据处理系统存贮，则生产商应首先验证该系统以确保这些数据在段3中所规定的保存期内得到恰当保存。存贮在这些系统内的数据应以可读方式易于获取。

5.    The electronically stored data shall beprotected against unlawful access, loss or damage of data by techniques such asduplication, back-up and transfer onto another storage system. Audit trails,meaning records of all relevant changes and deleti** in those data, shall bemaintained.

电子存贮的数据应受到技术性保护如复制、备份和转移至另一个存贮系统，使其不会被非法进入、丢失或损坏。应保存审计追踪和对这些数据所做的相关修改和删除记录。

6.    The documentation shall be provided tocompetent authority upon request.

当药监机构索取文件时应提供。

Article 9 Production

第九条生产

1.    The manufacturer shall carry out productionoperati** in accordance with pre-established instructi** and procedures.

生产商应依据既定指令和程序执行生产操作。

Themanufacturer shall ensure that adequate and sufficient resources are madeavailable for the in-process controls and that all process deviati** andproduct defects are documented and thoroughly investigated.

生产商应确保具备足够的资源进行中控，且所有工艺偏差和产品缺陷均进行记录和彻底调查。

2.    The manufacturer shall take appropriatetechnical or organisational measures to avoid cross con**ination andunintentional mixing of substances. Particular attention shall be paid to thehandling of investigational medicinal products during and after any blindingoperation.

生产商应采取恰当的技术和组织措施以避免物质交叉污染和无意混淆。尤其要注意在所有加盲操作中对临床试验用药的处理。

3.    The manufacturing process shall be validatedin its entirety, as far as is appropriate, taking into account the stage ofproduct development.

应验证生产工艺的完整性，适当时应考虑产品开发的阶段。

Themanufacturer shall identify the process steps that ensure the safety of thesubject, such as sterilisation, and the reliability and robustness of theclinical trial data generated in the clinical trial. Those critical processsteps shall be validated and regularly re-validated.

生产商应识别确保受试对象安全性的工艺步骤，如灭菌，和临床试验中所生成的临床试验数据的可靠性和确定性。这些关键工艺步骤应经过验证并定期重新验证。

All stepsin the design and development of the manufacturing process shall be fullydocumented.

应全面记录生产工艺的所有设计和开发步骤。

Article 10 Quality control

第十条质量控制

1.    The manufacturer shall establish and maintaina quality control system under the authority of a person who has the requisitequalificati** and is independent of production.

生产商应在一名具备所需资质并独立于生产的人授权下建立和维护一套质量控制体系。

Thatperson shall have access to one or more quality control laboratoriesappropriately staffed and equipped to carry out the examination and testing ofstarting materials and packaging materials and the testing of intermediate andfinished investigational medicinal products.

该人员应可以支配一个或多个具有恰当人员配置和仪器配置的质量控制化验室，以执行起始物料、包材、临床试验药品中间体和成品的检测和检查。

2.    The manufacturer shall ensure that thequality control laboratories comply with information provided in theapplication dossier, referred to in Article 25(1) of Regulation (EU) No536/2014, as authorised by Member States.

生产商应确保质量控制化验室符合依法规（EU）536/2014第25（1）条及成员国批准的申报文档中所提交的信息。

3.    When investigational medicinal products areimported from third countries, analytical control in the Union shall not bemandatory.

如果临床试验药品是从第三国进口，在欧盟境内进行分析控制并非强制。

4.    During the final control of the finishedinvestigational medicinal product, and before its release by the manufacturer,the manufacturer shall take into account:

在最终临床试验药品检测过程中以及生产商放行之前，生产商应考虑：

(a)  analytical results; 分析结果

(b)  production conditi**; 生产条件

(c)  the results of in-process controls; 中控结果

(d)  the examination of the manufacturingdocuments; 生产文件检查情况

(e)  the conformity of the product with itsspecificati**; 药品符合其质量标准的情况

(f)   conformity of the product with the clinicaltrial authorisation; 药品符合临床批文的情况

(g)  examination of the final finished packaging. 最终成品包装的检查情况

Article 11 Retention of samplesused for quality control

第十一条用于质量控制的留样

1.    The manufacturer shall retain sufficientsamples of each batch of bulk formulated product, of key packaging componentsused for each finished investigational medicinal product batch and of eachbatch of finished investigational medicinal product for at least two yearsafter the completion or discontinuation of the last clinical trial in which thebatch was used.

生产商应保存每批配制后产品、用于最终临床试验药品批次的关键包装材料、以及每批临床试验药品成品的足够数量样品至该批次所用于的最后一个临床试验完成或中止后至少2年。

Samples ofstarting materials, other than solvents, gases or water, used in themanufacturing process shall be retained by the manufacturer for at least twoyears after the release of the investigational medicinal product. However, thisperiod may be shortened where the period of stability of the starting material,as indicated in the relevant specification, is shorter.

用于生产工艺的起始物料样品，溶剂、气体和水除外，均应由生产商保存至临床试验药品旅行后至少2年。但是，如果起始物料的稳定性时长依相关标准所示比上述时间更短，则该时长可以缩短。

In allcases samples shall be maintained by the manufacturer at the disposal of thecompetent authority.

在所有情形下，生产商均应保存样品供药监机构处置。

2.    Upon application of the manufacturer, thecompetent authority may grant a derogation from paragraph 1 in relation to thesampling and retention of starting material and for certain productsmanufactured individually or in small quantities, or when their storage couldraise special problems.

经生产商申请，药监机构可以批准对于单独生产的特定产品，或小批量产品，或者当其存贮可能导致特殊问题时，减免段1中关于起始物料和产品的取样和留样要求。

Article 12 Resp**ibilities ofthe qualified person

第十二条授权人职责

1.    The qualified person referred to in Article61(2)(b) of Regulation (EU) No 536/2014 shall be resp**ible for the following:

依法规（EU）536/2014第61（2）（b）条要求指定的授权人应负责以下：

(a)  where investigational medicinal products aremanufactured in the Member State concerned, verifying that each productionbatch has been manufactured and checked in compliance with the requirements ofgood manufacturing practice for investigational medicinal products laid down inthis Regulation and the information provided pursuant to Article 25 ofRegulation (EU) No 536/2014, taking into account the guidelines referred to inArticle 63(1) of that Regulation;

如果临床试验用药在相关成员国生产，则核查每个生产批次均按本法规规定的临床试验药品的GMP要求和法规（EU）536/2014第25条所提供信息进行生产和检测，并考虑了依该法规的第63（1）条制订的指南。

(b)  where investigational medicinal products aremanufactured in a third country, verifying that each production batch has beenmanufactured and checked in accordance with quality standards at leastequivalent to those laid down in this Regulation and the information providedpursuant to Article 25 of Regulation (EU) No 536/2014 taking into account theguidelines referred to in Article 63(1) of that Regulation.

如果临床试验用药在第三国生产，则核查每个生产批次均按至少等同于本法规规定的质量标准和和法规（EU）536/2014第25条所提供信息进行生产和检测，并考虑了依该法规的第63（1）条制订的指南。

Thequalified person shall certify in a register or equivalent document providedfor that purpose that each production batch complies with the requirements laiddown in paragraph 1.

授权人应在一份登记或为此目的而提供的等同文件中认证每个生产批次均符合段1所规定的要求。

2.    The register or equivalent document shall bekept up to date as operati** are carried out and shall remain at the disposalof the competent authority for at least five years after the completion of orthe formal discontinuation of the last clinical trial in which the productbatch was used.

登记或等同文件在执行操作时应保持更新，并保存供药监机构处置直至该批次药品所用于的最后一次临床试验完成或正式中止后至少5年。

Article 13 Outsourced operati**

第十三条委外操作

1.    Where a manufacturing operation or operationlinked thereto is outsourced, the outsourcing shall be the subject of a writtencontract.

如果生产操作或与之相关的操作被委外，则委外活动应有书面合同。

2.    The contract shall clearly lay down theresp**ibilities of each **. It shall lay down an obligation for the **to whom the operati** are outsourced to follow good manufacturing practice andset out the manner in which the qualified person resp**ible for certifyingeach batch is to discharge his resp**ibilities.

该合同应清楚规定各方职责。其中应规定受委托方须遵守优良生产规范，并设定负责认证每个批次的授权人履行其职责的方式。

3.    The ** to whom the operati** areoutsourced shall not subcontract any of the operati** entrusted to him underthe contract without written c**ent from the contract giver.

未得委托方书面同意，受委托方不得将任何受托操作分包。

4.    The ** to whom the operati** areoutsourced shall comply with the principles and guidelines of goodmanufacturing practice applicable to the operati** concerned and shall submitto inspecti** carried out by the competent authority pursuant to Article 63(4)of Regulation (EU) No 536/2014.

受托方应遵守相关操作适用的优良生产规范原则和指南，并应依法规（EU）536/2014第63（4）条提交药监当局现场检查。

Article 14 Complaints, productrecall and emergency unblinding

第十四条投诉、产品召回和应急揭盲

1.    The manufacturer shall, in cooperation withthe sp**or, implement a system for recording and reviewing complaints togetherwith an effective system for recalling investigational medicinal products whichhave already entered the distribution network promptly and at any time. Themanufacturer shall record and investigate any complaint concerning a defect andshall inform the sp**or and the competent authority of the Member Statesconcerned of any defect that could result in a recall or abnormal restrictionon supply.

生产商应与申办人协作，在已即时录入销售网络信息的临床试验药品召回的有效系统基础上执行一套投诉记录和审核系统。生产商应记录和调查所有与缺陷有关的投诉，并应将任何可能导致召回和异常供应限制的缺陷通知给申办人和相关成员国药监当局。

All trialsites shall be identified and, in so far as possible, the countries ofdestination shall be indicated.

应识别所有试验中心，可能时，还应指明目的国。

In thecase of an authorised investigational medicinal product, the manufacturershall, in cooperation with the sp**or, inform the marketing authorisationholder of any defect that could be related to that product.

如果是已批准的临床试验用药，生产商应与申办人协作将任何可能与该药品有关的缺陷通知给上市许可持有人。

2.    Where blinding of investigational medicinalproducts is required by the protocol of a clinical trial, the manufacturer inconjunction with the sp**or shall implement a procedure for the rapidunblinding of blinded products, where this is necessary for a prompt recall asreferred to in paragraph 1. The manufacturer shall ensure that the procedurediscloses the identity of the blinded product only in so far as it isnecessary.

如果临床试验用药的加盲在临床试验方案中有要求，在有必要依段1所述执行快速召回时，生产商应联合申办人执行快速揭盲程序。生产商应确保只有在必要时才会公开识别加盲药品的程序。

Article 15 Self-inspection bythe manufacturer

第十五条生产商自检

Themanufacturer shall conduct regular inspecti** as part of the pharmaceuticalquality system in order to monitor the implementation and respect of goodmanufacturing practice. He shall take any necessary corrective action and toput in place any necessary preventive measures.

生产商应执行常规检查，将其作为药物质量体系的一部分，以监测优良生产规范的实施和自身问题。生产商亦应采取所有必需的纠正措施，并制订必须的预防措施。

Themanufacturer shall maintain records of all such inspecti** and any correctiveaction or preventive measures subsequently taken.

生产商应保存所有此类检查的记录，以及之后所采取的所有纠正措施和预防措施。

Article 16 Advanced therapyinvestigational medicinal products

第十六条先进治疗临床试验药品

The goodmanufacturing principles shall be adapted to the specific characteristics ofthe advanced therapy medicinal products when used as investigational medicinalproducts. Investigational medicinal products, which are at the same timeadvanced therapy medicinal products, shall be manufactured in accordance withthe guidelines referred to in Article 5 of Regulation (EC) No 1394/2007.

如果先进治疗药品用作临床试验用药，则应采用先进治疗药品专用GMP。临床试验用药，同时也是先进治疗药品，应依参照法规（EC）1394/2007第5条所制订的指南生产。

CHAPTER III INSPECTI**

第三章检查

Article 17 Supervision byinspection

第十七条检查监管

1.    By means of regular inspecti** as referredto in Article 63(4) of Regulation (EU) No 536/2014 the Member State shallensure that holders of an authorisation as referred to in Article 61(1) of thatRegulation comply with the principles of good manufacturing practice laid downin this Regulation and takes into account the guidelines referred in secondsubparagraph of Article 63(1) of Regulation (EU) No 536/2014.

通过依法规（EU）536/2014第63（4）条所指常规检查，成员国应确保依该法规第61（1）条所指批件持有人符合本法规规定的优良生产规范，并考虑依法规（EU）536/2014第63（1）条第2子段所制订的指南。

2.    Without prejudice to any arrangements whichmay have been concluded between the Union and third countries, a competentauthority may require a third country manufacturer to submit to an inspectionas referred to in Article 63(4) of Regulation (EU) No 536/2014 and thisRegulation. This Regulation applies mutatis mutandis to such inspecti**in third countries.

在不影响欧盟与第三国可能已达成的任何安排前提下，药监机构可以要求第三国生产商依法规（EU）536/2014第63（4）条和本法规提交检查。本法规经适当修改适用于第三国此类检查。

3.    Member States shall carry out inspecti** ofthird country manufacturers to ensure that investigational medicinal productsimported into the Union are manufactured by applying quality standards at leastequivalent to those laid down in the Union.

成员国应对第三国生产商执行检查以确保进口至欧盟的该临床试验用药依至少等同于欧盟所规定的质量标准生产。

The MemberStates are not obliged to routinely inspect third country manufacturers ofinvestigational medicinal products. The necessity of such inspecti** shall bebased on an assessment of risk, but shall take place at least if the MemberStates have grounds for suspecting that the quality standards applied to themanufacture of the investigational medicinal products imported into the Unionare lower than those laid down in this Regulation and in the guidelinesreferred to in the second subparagraph of Article 63(1) of Regulation (EU) No536/2014.

成员国无义务对第三国临床试验药品生产商执行常规检查。此类检查的必要性应基于风险评估，但如果成员国有理由质疑进口至欧盟的临床试验药品的生产所用质量标准低于本法规中规定的标准和依法规（EI）536/2014第63（1）条第2子段制订的指南要求时，应执行检查。

4.    Inspecti** may, if necessary, beunannounced.

必要时，可以执行飞行检查。

5.    Following an inspection, an inspection reportshall be drawn up by the inspector. Before the report is adopted by competentauthority, the manufacturer shall be afforded an opportunity to submit commentsin relation to the findings of the report.

在检查之后，检查员应起草检查报告。在药监机构采纳该报告之前，应给予生产商一次机会提交对报告中缺陷的意见。

6.    Where the findings of the final report showthat the manufacturer complies with the good manufacturing practice forinvestigational medicinal products, the competent authority shall within aperiod of 90 days of the inspection issue a certificate of good manufacturingpractice to the manufacturer.

如果最终报告中的缺陷显示该生产商符合临床试验药品的优良生产规范要求，则药监机构应在检查后90天内向该生产商签发GMP**。

7.    The competent authority shall enter thecertificate of good manufacturing practice which they issue into the Uniondatabase referred to in Article 111(6) of Directive 2001/83/EC of the EuropeanParliament and of the Council[4](1).

药监机构应将其签发的GMP**依欧盟议会和EC指令2001/83/EC第111（6）条规定录入欧盟数据库。

8.    Where the outcome of the inspection is thatthe manufacturer does not comply with good manufacturing practice forinvestigational medicinal products, the competent authority shall enter thisinformation into the Union database referred to in Article 111(6) of Directive2001/83/EC.

如果检查结果是该生产商不符合临床试验药品GMP要求，则药监机构亦应将此信息依欧盟议会和EC指令2001/83/EC第111（6）条规定录入欧盟数据库。

9.    The competent authority shall, upon receiptof reasoned request, send the inspection reports referred to in paragraph 5electronically to the competent authorities of other Member States or to theEuropean Medicines Agency (‘the Agency’).

药监机构在收到合理申请时，应将第5段中所指检查报告以电子方式发送给其它成员国药监机构，或发给EMA。

10. The competent authority shall enter theinformation relating to the authorisation referred to in Article 61(1) ofRegulation (EU) No 536/2014 in the Union database referred to in Article 111(6)of Directive 2001/83/EC.

药监机构应将依法规EU536/2014第61（1）条规定的批件相关信息依欧盟议会和EC指令2001/83/EC第111（6）条规定录入欧盟数据库。

Article 18 Cooperation andcoordination of inspecti**

第十八条检查合作和协作

Thecompetent authorities shall cooperate with each other and with the Agency inrelation to inspecti**. They shall share information with the Agency on bothinspecti** planned and conducted.

药监机构应与其它药监和EMA在检查方面进行合作。应与EMA分享已规划和已实施的检查信息。

Article 19 Recognition ofinspection conclusi**

第十九条检查结论的认可

1.    The conclusi** reached in the inspectionreport referred to in Article 17(5) shall be valid throughout the Union.

依据第17（5）条在检查报告中得出的结论在整个欧盟有效。

However,in exceptional cases, where a competent authority is unable, for reas**relating to public health, to recognise the conclusi** reached following aninspection under Article 63(4) of Regulation (EU) No 536/2014, that competentauthority shall forthwith inform the Commission and the Agency. The Agencyshall inform the other competent authorities concerned.

但在例外情形下，如果药监机构由于公众健康的原因不能认同依据法规（EU）536/2014第63（4）条所执行的检查得出的结论，则该药监机构应即刻通知欧盟委员会和EMA，EMA应通知其它相关药监机构。

2.    When the Commission is informed in accordancewith the second subparagraph of paragraph 1, it may, after c**ulting thecompetent authority which was unable to accept the report, request theinspector who performed the inspection to perform a new inspection. Theinspector may be accompanied by two inspectors from other competent authoritieswhich are not parties to the disagreement.

如果欧盟委员会依据第1段第2子段收到通知，委员会在听取该药监机构不能接受该报告的意见之后，可以要求执行该检查的检查员实施一次新的检查。可以由来自其它药监机构（不是不同意结论的那些药监机构）的2位检查员陪同该检查员实施检查。

Article 20 Empowerments of theinspectors

第二十条检查员赋权

1.    The competent authority shall provideinspectors with suitable means of their identification.

药监机构应为检查员提供适当的身份识别方式。

2.    Inspectors shall be empowered to:

检查员应被赋予以下权力：

(a)  enter and inspect the premises of themanufacturer and quality control laboratories having carried out checkspursuant to Article 10 for the manufacturer;

进入和检查生产商设施，进入和检查依据第10条执行为生产商实施检查的质量控制化验室的设施；

(b)  take samples, including for independent teststo be carried out by an Official Medicines Control Laboratory or a laboratorydesignated for that purpose by the Member State, and

采集样品，包括为成员国指定化验室或OMCL化验室要实施的独立测试取样，以及

(c)  examine any documents relating to the objectof inspection, make copies of records or printed documents, print electronicrecords and take photographs of the premises and equipment of the manufacturer.

检查任何与受检对象有关的文件、复印记录和打印文件、打印电子记录以及对生产商的设施和设备拍照。

Article 21 Competence andobligati** of the inspectors

第二十一条检查员的资质和义务

1.    The competent authority shall ensure that theinspectors possess adequate qualificati**, experience and knowledge. Inparticular, the inspectors shall have the following:

药监机构应确保检查员拥有足够的资质、经验和知识，尤其是具备以下：

(a)  experience and knowledge of the inspectionprocess;

检查流程知识和经验；

(b)  the ability to make professional judgementsas to the compliance with the requirements of good manufacturing practice;

进行GMP要求符合性专业判断的能力；

(c)  ability to apply the principles of qualityrisk management;

应用质量风险管理原则的能力；

(d)  knowledge of current technologies relevantfor inspecti**;

与检查相关的当前技术知识；

(e)  knowledge of the current technologies for themanufacture of the investigational medicinal products.

临床药品生产的当前技术知识。

2.    Information acquired as a result ofinspecti** shall remain confidential.

应对作为检查结果所获得的信息保密。

3.    The competent authorities shall ensure thatinspectors receive the training necessary to maintain or improve their skills.Their training needs shall be assessed regularly by the pers** appointed forthat task.

药监机构应确保检查员接受所需培训，以维持或提高其技巧。检查员培训需要由指定完成该任务的人进行定期评估。

4.    The competent authority shall document thequalificati**, training and experience of each inspector. Those records shallbe kept up to date.

药监机构应记录每位检查员的资质、培训和经验。这些记录应保持更新。

Article 22 Quality system

第二十二条质量体系

1.    The competent authorities shall establish,implement and comply with a properly designed quality system for theirinspectors. The quality system shall be updated as appropriate.

药监机构应为其检查人员建立、实施和遵守经过恰当设计的质量体系。适当时应更新质量体系。

2.    Each inspector shall be informed of the standardoperating procedures and of his duties, resp**ibilities and ongoing trainingrequirements. Those procedures shall be kept up to date.

应告知每位检查员标准操作规程以及其义务、职责和持续培训要求。这些程序应保持更新。

Article 23 Impartiality ofinspectors

第二十三条检查员公正性

Thecompetent authority shall ensure that inspectors are free of any undueinfluence that could affect their impartiality and judgment.

药监机构应确保检查人员不受到任何可能影响其公正和判断的不当影响。

Inspectorsshall be independent, in particular, of:

检查员应独立于，尤其是

(a)  the sp**or;

申办人

(b)  the management and personnel of the clinicaltrial site;

临床试验场所的管理层和人员

(c)  the investigators involved in the clinicaltrials where the investigational medicinal products manufactured by theinspected manufacturer are used;

使用受检生产商所生产的临床试验用药品时，参与临床试验的试验人员

(d)  the pers** financing the clinical trial inwhich the investigational medicinal product is used;

为使用临床试验用药品的临床试验提供资金的人

(e)  the manufacturer.

生产商

Inspectorsshall make an annual declaration of their financial interests in the partiesinspected or other links to them. The competent authority shall take thedeclaration into c**ideration when assigning inspectors to specificinspecti**.

检查员每年应声明其与受检方的经济受益情况和其它关联情况。药监机构在为特定的检查指派检查员时应考虑该声明。

Article 24 Access to premises

第二十四条进入设施

Themanufacturer shall allow inspectors access to his premises and documentation atall times.

生产商应允许检查员在任何时候进入其设施，并获得文件记录。

Article 25 Suspension orrevocation of manufacturing authorisation

第二十五条生产许可的搁置与吊销

If aninspection reveals that the holder of an authorisation as referred to inArticle 61(1) of Regulation (EU) No 536/2014 fails to comply with goodmanufacturing practice as set out in Union law, the competent authority may,with regard to this manufacturer, suspend manufacture or imports from thirdcountries of investigational medicinal products for human use, or suspend orrevoke the authorisation for a category of preparati** or all preparation.

如果检查发现依法规（EU）536/2014第61（1）条所指许可持有人未能符合欧盟法律所规定的优良生产规范要求，则药监机构可以暂停此生产商生产或自第三国进口人用临床试验药品的许可，或搁置或吊销某类剂型或所有剂型许可。

CHAPTER IV FINAL PROVISI**

第四章最后条款

Article 26 Transitionalprovision

第二十六条转换

The MemberStates may continue to apply national transposition measures adopted underCommission Directive 2003/94/EC[5]to the manufacture of investigational medicinal products used in clinicaltrials governed by Directive 2001/20/EC of the European Parliament and of theCouncil[6]in accordance with the transitional provisi** laid down in Article 98 ofRegulation (EU) No 536/2014.

依法规（EU）536/2014第98条中规定的转换条款，成员国可以继续适用依EC指令2003/94/EC制订的其国家转换措施生产欧盟议会和委员会指令2001/20/EC管辖的临床试验用药品。

Article 27 Entry into force

第二十七条生效

ThisRegulation shall enter into force on the twentieth day following that of itspublication in the Official Journal of the European Union. It shallapply from six months after the date of publication in the Official Journalof the European Union of the notice referred to in Article 82(3) ofRegulation (EU) No 536/2014 or 1 April 2018, whichever is the later. ThisRegulation shall be binding in its entirety and directly applicable in allMember States.

本法规应在欧盟官方杂志发布之后第20天生效，在欧盟官方杂志依法规（EU）536/2014第82（3）条发布通知后6个月执行，或自2018年4月1日起执行，取其迟者。本法规全本直接在所有成员国执行。

Done atBrussels, 23 May 2017.

2017年5月23日，布鲁塞尔

For the Commission

The President

Jean-Claude JUNCKER

欧盟委员会主席让-克洛德•容克

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