近日，欧盟药监局（EMA）发布了一份关于GMP和MAH的反思文件。该文件重点阐述了适用于上市许可持有人(MAH)的GMP责任和每个GMP要求，并对其关键信息进行了说明或总结。该文件已翻译完成，现在分享给大家！由于微信字数限制，未展示全部内容，点击“阅读原文”下载完整中英文对照文件!

1. Introductionand purpose

1.介绍和目的

This ReflectionPaper is focussed on the GMP-related responsibilities that apply to MarketingAuthorisation Holder (MAH) companies. While it is recognised that many MAHcompanies are not directly engaged in the manufacture of medicinal productsthemselves, the current European Commission (EC) guide to GMP (hereafterreferred to as the ‘GMP guide’) refers, in several places, to MAHs and theirresponsibilities in relation to GMP.

本文重点阐述了上市许可持有人(MAH)公司与GMP相关的职责。虽然人们认识到许多MAH公司本身并不直接从事医药产品的生产，但现行的欧洲委员会GMP指南(以下简称“GMP指南”)在很多地方提到了MAHs及其与GMP相关的职责。

In general, theseresponsibilities relate to outsourcing and technical agreements, that requirethe MAH to perform certain specific tasks (e.g. evaluating the results ofproduct quality reviews, agreeing irradiation cycles with manufacturers, etc.).These responsibilities are spread over the various chapters and annexes of theGMP guide, and are quite numerous.

一般来说，这些职责涉及外包和技术协议，要求MAH执行某些特定任务(例如评估产品质量回顾的结果，与制造商商定辐照程序等)。这些职责分散在GMP指南的各个章节和附件中，并且相当多。

This ReflectionPaper seeks to provide clarity as to what the various responsibilities are andwhat they mean for MAHs at a practical level. In addition to the MAHresponsibilities in the GMP guide, this paper also addresses the variouslegislative provisions (i.e. in European Directives and in other guidelines)which relate to GMP and which concern MAHs. Some of the responsibilities statedin the legislation (e.g. in Directives 2001/83/EC and 2001/82/EC) and inapplicable guidelines are written in a way that they apply to marketingauthorisation applicants, and they are included in this Reflection Paperbecause those provisions also convey responsibilities upon marketingauthorisation holders in the post-authorisation phase.

本反思文件旨在明确各种责任以及它们在实际层面上对MAHs意味着什么。除了GMP指南中规定的职责外，本文还讨论了与GMP有关的各种立法规定(即欧洲指令和其他指南)。法例(例如第2001/83/ec号指令及第2001/82/ec号指引)及适用的指南所述的一些责任，是以适用于上市许可持有人的方式编写的，这些责任已包括在本反思文件内，因为这些条文亦传达了上市许可持有人在获得许可后的责任。

It should benoted that, as indicated in Annex 16 of the GMP guide, the ultimateresponsibility for the performance of a medicinal product over its lifetime,its safety, quality and efficacy, lies with the MAH. It is also important tonote that, while certain activities of an MAH may be delegated to amanufacturer or other party, the MAH retains the responsibilities whichare outlined in this paper. The GMP guide also does not provide for reducedMAH responsibilities (or for the delegation of responsibilities) insituations where the MAH and the manufacturer belong to the same overall groupof companies but where the two companies are different legal entities. There isno difference in the responsibilities that apply to the MAH in this situationrelative to when the MAH and the manufacturer are from separate and unrelatedcompanies.

需要指出的是，正如GMP指南附录16所指出的那样，药品在其生命周期的性能、安全性、质量和功效的最终责任在于MAH。还必须指出的是，虽然MAH的某些活动可以委托给制造商或其他机构，但MAH仍负有本文中概述的职责。GMP指南也没有规定，在MAH和制造商属于同一总公司集团但两家公司是不同法律实体的情况下，减少MAH的责任(或下放责任)。在这种情况下，MAH的责任与MAH和制造商来自不相关的独立公司没有区别。

While relevantactivities pertaining to the GMP-related responsibilities held by MAHs may bedelegated by the MAH to its representative (if there is one) in a member state,none of the responsibilities may be delegated to that person. (Note: Therepresentative of the MAH, commonly known as the local representative, is theperson designated by the MAH to represent him in the Member State concerned.(Ref. Part 18a of Article 1 in Directive 2001/83/EC and Part 17a of Article 1of Directive 2001/82/EC).

虽然MAH承担的与GMP有关的责任的相关活动可由MAH委派给成员国的代表(如果有的话)，但任何责任都不得委派给该人。(注:马来西亚马来西亚马来西亚马来西亚马来西亚马来西亚马来西亚马来西亚马来西亚马来西亚马来西亚马来西亚马来西亚马来西亚马来西亚马来西。(参考文献。指令2001/83/ec第1条第18a部分和指令2001/82/ec第1条第17a部分)。

It is recognisedthat, while MAHs have a significant role in facilitating GMP and MA compliance,their responsibilities in this area can, in some cases, be difficult tocomprehend when reading the GMP guide or the applicable legislation.Notwithstanding this, such responsibilities are there and may be inferred. ThisReflection Paper seeks to provide clarity on these.

人们认识到，虽然MAH在促进GMP和符合MA方面发挥着重要作用，但在某些情况下，他们在这方面的职责在阅读GMP指南或适用的法例时可能难以理解。尽管如此，这些责任是存在的，可以推断出来。本反思文件旨在明确这些问题。

All of thereferences currently in the GMP guide (as of April 2019) that relate to MAHresponsibilities are discussed in this Reflection Paper. This paper, however,should not be taken to provide an exhaustive list of those references onan ongoing basis. Rather, it sets out the general GMP-relatedresponsibilities and activities of the MAH, and it presents them under a numberof differentthemes. These themes are outlined below in Section 5. MAHcompanies should have a system in place to ensure that they remain up-to-datewith current GMP requirements and updates thereafter.

目前在GMP指南(截至2019年4月)中涉及的所有MAH相关的职责都在本反思文件中进行了讨论。然而，不应认为本文件提供了所涉及的详尽清单。相反，它规定了MAH的一般性GMP相关责任和活动，并在若干不同的主题下提出这些责任和活动。下文第5节概述了这些主题。MAH公司应该有一个适当的系统，以确保他们与当前的GMP要求保持同步，并在此后进行更新。

Where possible,the text within each theme provides an explanation of what the variousresponsibilities may mean at a practical level for MAHs; guidance is also givenon what is expected of an MAH when fulfilling that responsibility. It should benoted, however, that this Reflection Paper does not provide guidance on ‘how’the various responsibilities might be fulfilled.

在可能的情况下，每个主题中都解释了各种责任在实际层面上对MAHs意味着什么;此外，还就 MAH 在履行该责任时的期望提供指导。然而，应当指出，本《反思文件》没有就"如何"履行各种责任提供指导。

Article 111 ofDirective 2001/83/EC and Article 80 Directive 2001/82/EC give powers to memberstate authorities to inspect the premises of MAH companies; this includessituations in which there are grounds for suspecting non-compliance with thelegal requirements laid down in the Directives, including with the principlesand guidelines of GMP. When such inspections are carried out, this ReflectionPaper may serve as useful guidance for the competent authorities performing theinspections.

第2001/83/ec号指令第111条和第80条第2001/82/ec号指令授权成员国当局检查MAH公司的场所;这包括有理由怀疑不符合指令中规定的法律要求，包括不符合GMP的原则和指导方针的情况。在进行这种检查时，本反思文件可作为进行检查的主管当局的有益指导。

2. Scope

2.范围

The ReflectionPaper concerns the responsibilities and activities of MAHs with respect to theEuropean Commission’s guide to GMP (Parts I, II, and its relevant Annexes) formedicines for human and veterinary use.

本文件包括MAH根据欧盟委员会人用和兽用药物GMP指南(第一、第二部分及其相关附录)所承担的职责和开展的活动。

The scope alsoextends to certain legislative provisions that have relevance to GMP,such as those stated in the GMP Directives 2003/94/EC and 92/412/EC (asamended), as well as relevant articles in Directive 2001/83/EC and Directive2001/82/EC.

本文件同时延伸至某些与GMP有关的立法条文，例如2003/94/EC和92/412/EC(修订本)中所述的条文，以及指令2001/83/EC和2001/82/EC中的相关条文。

When referring tomanufacturers and manufacturing sites, the Reflection Paper is referring to anysite engaged in manufacturing and related activities (e.g. contract analysis)that are subject to EU GMP requirements. This includes contract testingfacilities whether listed in the MA (e.g. laboratories performing batch releasetesting) or not (e.g. laboratories performing ongoing stability testing).

当提及制造商及制造工厂时，本文件指任何从事制造及相关活动(例如合同分析)并符合欧盟GMP规定的工厂。这包括合同工检验机构，不管其列入MA(例如进行批放行检验的第三方实验室)与否(例如进行持续稳定性测试的第三方实验室)。

This ReflectionPaper is focussed on the GMP-related responsibilities that apply to all MAHcompanies, including Registration Holder (RH) and Traditional-useRegistration Holder (TRH) companies. When this paper makes reference tothe responsibilities and activities of the MAH, it is understood that theprinciples are equally applicable to the RH and TRH.

本反思文件的重点是GMP相关的责任，适用于所有的MAH公司，包括注册持有人(RH)和传统使用注册持有人(TRH)公司。当本文提及MAH的职责和活动时，可以理解为这些原则同样适用于RH和TRH。

FMD: The relevantprovisions of the Falsified Medicines Directive 2011/62/EU and the relatedDelegatedRegulations (including the Safety Features Regulation 2016/161) are also withinscope of this Reflection Paper.

FMD:药品伪造指令2011/62/EU的相关条款和相关条例(包括安全特性条例2016/161)也属于本反思文件的范围。

ATMPs: The principlesset out in this paper also generally apply to MAHs of ATMPs. However, thespecificprovisions of Part IV of the GMP guide are not specifically discussed here, andthere are certain specific requirements that apply to ATMPs, as stated in PartIV (such as a 30 year data retention requirement) that differ from what is setout in this Reflection Paper.

ATMP:本文所阐述的原则也普遍适用于ATMP的MAHs。然而，GMP指南第四部分的具体条款在这里没有具体讨论，而且正如第四部分所述(例如30年数据保留要求)，某些适用于ATMP的具体要求不同于本反思文件所列出的要求。

GDPResponsibilities: While thisReflection Paper is not intended to address the GDP-relatedresponsibilitiesthat may apply to MAHs, it is considered important to highlight here that MAHsdo need to understand the type of interfaces that may need to be in place withthe wholesalers they employ or engage. For example, current EU GDP guidelinesrequire that medicines wholesalers notify the MAH of certain information, e.g.information concerning falsified products and quality defects (Ref. EU GDPGuidelines, 2013, Sections 6.2 and 6.4). As a result, it is considered thatMAHs should have systems in place to accept and act upon such information fromthe wholesale distribution chain when received.

GDP职责:虽然本反思文件并不打算讨论可能适用于MAHs的与GDP有关的职责，但重要的是要在这里强调，MAHs确实需要了解可能需要与他们雇用或参与的批发商建立的接口类型。例如，现行的欧盟GDP指南要求药品批发商将某些信息通知MAH，例如关于伪造产品和质量缺陷的信息。（欧盟GDP指南，2013年，第6.2和6.4节）。因此，我们认为MAHs应该建立系统，在收到批发分销链的信息时接受这些信息并对其采取行动。

The Reflection Paper does not extend toother MAH responsibilities and activities that may be set-out in other officialguidance documents and legislation, such as those relating to other GxP areas,pharmacovigilance, etc.

本文件没有扩展到可能在其他官方指南和立法中规定的其他MAH责任和活动，例如那些与其他GxP领域、药物安全等有关的文件和立法。

3. How this Reflection Paper sets out thevarious MAH responsibilities

本文件如何规定MAH的各项责任

In section 5 ofthis paper, each GMP requirement that applies to the MAH is outlined, with itskey message stated or summarised.

在本文的第5节中，概述了适用于MAH的每个GMP要求，并对其关键信息进行了说明或总结。

This is then followedby the exact text that is in the GMP guide (or in applicable legislation or inother guidelines) on this point. In some cases, the exact text is presentedbetween quotation marks;

然后，这是随后的确切文本，是在GMP指南(或在适用的立法或其他指南)在这一点。在某些情况下，精确的文本在引号之间显示;

A clear reference to the relevant part of the GMP guide or theapplicable legislation is then stated;

明确提及GMP指南的相关部分或适用的法律;

Where possible,an explanation of what the requirement means at a practical level for the MAHis provided, in italics.

在可能的情况下，用斜体字解释了某要求在实际层面上对MAH意味着什么。

4. The role of the MAH in facilitatingcompliance with GMP and the Marketing Authorisation (MA)

MAH在促进符合GMP和上市许可(MA)中的作用

As noted above,MAHs have an important role in facilitating compliance with GMP and the MA;this is reflected in the multiple references to MAH responsibilities that arein the GMP guide. These responsibilities generally relate to:

如上所述，MAHs在促进符合GMP和MA方面发挥着重要作用;这在GMP指南中多次提到MAH职责。这些责任一般涉及:

The provision ofinformation by the MAH to competent authorities, manufacturing sites andQualified Persons;

MAH向主管当局、生产工厂和质量受权人提供信息;

The collation ofquality-related information from different actors in the manufacturing anddistribution chain.

整理来自制造和分销链中不同行为者的质量相关信息。

Evidence of GMPcompliance: When submittinga new application for an MA, the applicant has theresponsibility tomake sure that the proposed manufacturers hold a valid MIA, a valid GMPCertificate (or equivalent). In the same way, during the life-cycle of aproduct, the MAH must ensure that the manufacturers are authorised andcompliant with GMP.

符合GMP的证据：当提交新的MA申请时，申请人有责任确保拟议的制造商持有有效的MIA（生产与进口许可），有效的GMP证书(或同等)。同样，在产品的生命周期中，MAH必须确保制造商获得许可并符合GMP。

Abbreviatedversion of CTD module 3: In theintroductory chapter to the GMP guide, it is statedthat “Throughout theGuide, it is assumed that the requirements of the Marketing Authorisationrelating to the safety, quality and efficacy of the products, aresystematically incorporated into all the manufacturing, control and release forsale arrangements of the holder of the Manufacturing Authorisation.” Thisimplies that the MAH has a responsibility to communicate what is registered inthe MA to the manufacturing sites. In doing this, MAHs sometimes prepareabbreviated versions of CTD module 3 of the MA for use by the manufacturingsites and QPs; this is considered acceptable; as long as those abbreviatedversions are sufficiently comprehensive and are subject to formal changecontrol and oversight activities.

CTD模块3的简化版本:GMP指南的导言部分指出:”在整个指南中，已上市许可中有关产品的安全、质量和功效的要求已系统地纳入生产许可持有人的所有生产、控制和放行销售安排中，这意味着MAH有责任向生产工厂通报在MA中注册的内容。为此，MAH有时编制CTD模块3的简化版本，供制造工厂和质量受权人员使用;这被认为是可以接受的;只要这些简化版本足够全面，并受到正式的变更控制和监督活动的约束。

Labelling andproduct information: Care shouldalso be taken to ensure that, what is registered inCTD module 1 of thedossier in relation to the approved product labelling (including the packageleaflet) and changes to same are communicated to the manufacturer in atimeframe which will enable the manufacturer to ensure that all batches itproduces have the correct labelling and product information.

标签和产品信息:还应注意确保在档案的CTD模块1中登记的与经批准的产品标签(包括包装说明书)有关的内容及其变更在一定时间内告知制造商，使制造商能够确保其生产的所有批次都有正确的标签和产品信息。

Chapter 7 andMAHs: While Chapter 7 is primarily intendedto deal with “the responsibilities ofmanufacturers towards theCompetent Authorities of the Member States with respect to the granting ofmarketing and manufacturing authorisations” (Ref. Chapter 7, Principle), it isalso directly relevant to MAHs, as indicated by paragraph 7.3. This states:“Where the marketing authorisation holder and the manufacturer are not the same, appropriatearrangements should be in place, taking into account the principles describedin this chapter.” (Ref. Chapter 7, Paragraph 7.3).

第7章和MAHs：虽然第7章主要是处理"制造商对成员国主管当局在销售放行和生产许可方面的责任"（参见，第7章，原则），如第7.3段所述，它也与MAHs直接相关。该规定："如果上市许可持有人和制造商不同，应作出适当安排，同时考虑到本章所述的原则。（参考第7章，第7.3段）。

MA variations: The need toprovide the relevant manufacturing sites with the necessary informationaboutMA variation approval and target implementation dates is considered anotherimportant responsibility for the MAH. It is a key activity which enables thosesites to ensure that future batches of the product, which may be QP-certifiedafter a certain date, comply with the varied MA. This responsibility may beinferred from Chapter 7 of the GMP guide, in relation to Outsourced Activities,which states:

Ma变更: MAH的另一项重要责任是向相关生产工厂提供关于MA变更批准和目标实施日期的必要信息。这是一个关键的活动，使得这些工厂可以确保后续批次的产品，在经QP放行后，符合多变的MA。这项责任可以从GMP指南第7章中推断出来，关于外包活动，该章规定:

“The ContractGiver should provide the Contract Acceptor with all the information andknowledge necessary to carry out the contracted operations correctly inaccordance with regulations in force, and the Marketing Authorisation for theproduct concerned.” (Ref. Chapter 7, Paragraph 7.6).

合同授予方应向合同接受方提供一切必要的信息和知识，以便按照现行规定和有关产品的上市许可正确进行合同操作(参考文献。第7章，第7.6段)。

Regulatorycommitments: The managementof regulatory commitments (which are often madebetween an MAH and acompetent authority) is another area that can have a significant impact upon MAcompliance generally, if it is not under an appropriate level of control by theMAH. This is especially the case in relation to the communication of suchcommitments to the manufacturing sites by the MAH; thus, the importance ofrobust communication processes is highlighted in this Reflection Paper. Indeed,the management of regulatory commitments may assume increased importance in thecoming years, given that the regulatory environment may move towards greaterflexibility in the area of post-approval change management, via ICH Q12,related to medicinal products for human use. Such flexibility is likely to relyon the effectiveness of the pharmaceutical quality system that is in place, asthis will help assure regulatory compliance in the implementation of suchpost-approval changes. MAHs may have an important role in this area.

监管承诺:监管承诺的管理(通常是由MAH和主管当局之间作出的)是另一个领域，如果不在MAH的适当控制范围内，往往可能对MAH符合情况产生重大影响。尤其是MAH向制造工厂传递此承诺方面;因此，本反思文件强调了强有力的沟通过程的重要性。事实上，鉴于监管环境可能朝着更灵活的方向发展，通过ICHQ12，对供人类使用的医药产品进行批准后的变更管理，监管承诺的管理在未来几年可能会变得更加重要。这种灵活性很可能依赖于现有的药品质量体系的有效性，因为这将有助于在实施这种批准后变更的过程中确保法规符合性。MAHs可能在这一领域扮演着重要角色。

Two-waycommunication systems: MAHs canfacilitate compliance by establishing robust two-waycommunicationsystems with national competent authorities, manufacturing sites, QualifiedPersons (QPs), and any organisations relevant to the monitoring ofpost-marketing quality (e.g. complaints processing and on-going stabilitymonitoring). Doing so can help ensure that:

双向沟通系统:MAH可与国家主管当局、生产工厂、质量受权人和任何与上市后质量监测有关的组织(例如投诉处理和持续稳定性监测)建立强有力的双向沟通系统，以促进合规性。这样做有助于确保:

The MAHs haveadequate knowledge of the details of the manufacturing processes and theirrelated controls at the finished product and active substance manufacturingsites, including situations where there are Active Substance Master Files (ASMFs)and Certificates of the European Pharmacopoeia (CEPs) in place.

MAH对成品和活性物质生产工厂的生产工艺和相关控制的细节有足够的知识，包括活性物质主文件(ASMFs)和CEP证书的情况。

The manufacturingsites and QPs have visibility of what is registered in the marketingauthorisation and what, if any, regulatory commitments have been agreed withthe competent authorities;

生产工厂和QP验证方案可以看到上市许可中登记的内容，以及与主管当局商定的监管承诺(如果有的话);

The MAHs areadequately informed of change management activities at the manufacturing sites,particularly in relation to changes which may impact upon modules 1, 2 and 3 ofthe MA as well as on the contents of ASMFs and CEPs. This can help ensure thatthe MAHs are involved in regulatory impact assessments for relevant changeproposals and that any necessary notifications or variation applications aremade to the competent authorities.

制造工厂的变更管理活动，特别是可能影响MA模块1、2和3以及活性物质主文件(ASMFs)和CEP内容的变更，均已向MAH充分通报。这可有助于确保MAH参与相关变更提案的法规影响评估，并确保向主管当局提交任何必要的通知或变更申请。

Data integrity: This is anotherarea of relevance to MAHs; it can result in GMP non-compliances ifthereare not robust control systems to assure the integrity of data pertaining tothe MA, which may be used or required by the manufacturers. Thus, it isconsidered that MAHs should have systems in place to ensure the integrity andreliability of the data that are used to discharge their responsibilities.There should be assurance that product lifecycle data relating to GMPactivities, including relevant MA variations, are reliable, complete andaccurate. The MAH should also ensure the long term security and archiving ofthe data upon which the MA relies.

数据完整性：这是与MAH有关的另一个领域；如果没有可靠的控制系统来确保制造商可能使用或要求的与MA有关的数据的完整性，则可能导致不符合GMP。因此，MAHs应建立系统以确保用于履行其职责的数据的完整性和可靠性。应确保与GMP活动有关的产品生命周期数据，包括相关的MA变更，是可靠、完整和准确的。MAH还应确保MA所依赖的数据的长期安全性和存档。

Compliancemanagement process: MAHs should beaware of the ‘Compliance Management’ processthat has been put in placewithin the EEA; this is used in situations where a manufacturing site has beenfound to be on the border between achieving a minimum level of GMP complianceand serious GMP non-compliance. MAHs should be aware of their ability tofacilitate compliance, and may find that their involvement in theremediation of such issues is necessary.

合规管理程序:MAH应了解欧洲经济区内实施的”合规管理”程序;这一程序用于发现生产工厂处于符合GMP最低要求和严重不符合GMP之间的边界。MAH应当认识到它们促进合规的能力，并可能发现他们有必要参与这些问题的整改。

Non-compliancewith MAH obligations: Based onArticle 116 of Directive 2001/83/EC, a MA forwhich the MAH does notfulfil its various obligations may be suspended, revoked or varied by thecompetent authority. It states that an authorisation shall be “suspended,revoked, withdrawn or varied where the particulars supporting the applicationas provided for in Article 8 or Articles 10, 10a, 10b, 10c and 11 are incorrector have not been amended in accordance with Article 23, or where the controlsreferred to in Article 112 have not been carried out.”

不遵守MAH义务:根据第2001/83/EC号指令第116条，主管当局可暂停、撤销或更改MAH不履行其各项义务的MA。该条规定，”如果第8条或第10条、第10a条、第10b条、第10c条和第11条所规定的用以支持申请的详细信息不正确或没有根据第23条进行修改，或者没有实施第112条所指的控制，则应暂停、撤销、撤回或更改许可”

5. Areas of the EC guide to GMP that relate to MAHs

5.欧盟GMP指南中与MAH有关的部分

As noted in theIntroduction, there are various references within the GMP guide to MAH-relatedresponsibilities. These span a number of different chapters and annexes, and inthis Reflection Paper, they are grouped together under a number of different themes.These are set out below. While there is some duplication across the differentthemes, it is considered helpful to consider the responsibilities andactivities in this way.

正如导言中所指出的，GMP指南中提到了与MA有关的职责。这些文件跨越若干不同的章节和附录，在这份反思文件中，它们被归入若干不同的主题之下。以下是一些建议。虽然不同主题之间存在一些重复，但以这种方式考虑责任和活动被认为是有益的。

A number of the legislativeprovisions that exist within EU medicines legislation which concern theGMP-related responsibilities of MAHs are also included within the variousthemes, where relevant. The themes are:

欧盟药品立法中的一些立法条款涉及到MAHs与GMP有关的责任，这些条款也在相关的各个主题中列入。主题如下:

Outsourcing and technical agreements;

外包和技术协议;

Audits and qualification activities;

审计及确认活动;

Communicationwith manufacturing sites (e.g. MA dossier information, variations, regulatorycommitments, etc.);

与生产工厂沟通(例如MA档案信息、变更、法规承诺等);

Product Quality Reviews;

产品质量回顾;

Quality defects, complaints and product recalls;

质量缺陷、投诉和产品召回;

Maintenance of supply of medicinal products;

维持药品供应;

Continual improvement activities.

持续改进活动。

(Note that FMD-related responsibilities are discussed in Chapter 6).

(请注意，与FMD有关的职责将在第6章中讨论)。

5.1. Outsourcingand technical agreements

5.1.外包和技术协议

This sectiondiscusses the various MAH responsibilities which apply to outsourced activitiesand technical agreements. Section 5.2 below, relating to Audits andQualification, is also relevant here and its contents should be noted.

本节讨论了适用于外包活动和技术协议的各种MAH责任。下面第5.2节有关审计和确认的内容在这里也是相关的，应注意其内容。

See also section5.3 below in relation to the importance of a technical agreement being in placebetween the MAH and manufacturer when they are different legal entities. Thatsection also addresses the merits of having a technical agreement in placebetween the MAH and the active substance manufacturer to address certaincommunication requirements in relation to situations in which there is anActive Substance Master File (ASMF) or a CEP registered for a MA.

另见下文第5.3节，其中说明了MAH和制造商作为不同法律实体达成技术协议的重要性。该节还论述了在MAH和活性物质制造商之间订立技术协议的好处，以解决MA中注册的与活性物质主文件(ASMF)或CEP相关的某些沟通要求。

5.1.1. Delegation of activities

5.1.1.活动授权

As noted earlierin this Reflection Paper, there is no provision within the GMP guide or inapplicable legislation for the delegation of responsibilities by an MAH toother parties. However, there may be delegation of the tasks and activitieswhich relate to those responsibilities, and this is relevant to the topic ofoutsourcing. It is considered that any such delegation should be described inwriting and agreed by the relevant parties.

正如本反思文件前面所指出的，在GMP指南或适用的立法中没有规定由MAH将责任下放给其他各方。但是，与这些责任有关的任务和活动可能会下放，这与外包的专题有关。委员会认为，任何此类委托都应以书面形式说明，并经有关各方同意。

In general terms,it is the responsibility of the MAH to ensure that the person or entity, towhom any task or activity has been delegated, possesses the requiredcompetence, information and knowledge to successfully carry out the outsourcedactivities (Ref: GMP guide Chapter 7, Paragraphs 7.5 and 7.6). Specialattention should be given to situations where tasks have been delegated in afragmented way - to more than one party – as applying oversight of multipleparties can be a challenge in the life-cycle management of the medicinalproduct.

一般而言，MAH有责任确保接受任何任务或活动委托的个人或实体拥有成功开展外包活动所需的能力、信息和知识(参见:GMP第7章，第7.5和7.6段)。应特别注意任务分散下放给一个以上当事方的情况，因为对多个当事方进行监督可能是医药产品生命周期管理的一个挑战。

5.1.2.Documenting outsourced activities

5.1.2.记录外包活动

There areobligations to ensure that outsourced activities are described in writing.Chapter 7 of the GMP guide requires that “any activity that is outsourcedshould be appropriately defined, agreed and controlled in order to avoidmisunderstandings which could result in a product or operation ofunsatisfactory quality.” (Ref: GMP guide Chapter 7, Principle).

有责任确保外包活动以书面形式说明。GMP第7章规定，”任何外包的活动都应得到适当的规定、同意和控制，以避免可能导致产品或操作质量不符合要求的误解”(参见:GMP指南第七章原则)。

Chapter 7 of theGMP guide also states that “Where the marketing authorisation holder and themanufacturer are not the same, appropriate arrangements should be in place,taking into account the principles described in this chapter.” (Ref. Chapter 7,Paragraph 7.3). In practice there are various scenarios that may apply. Forexample, the two parties may be different legal entities within the samecompany group, or they may be unrelated companies. Regardless of suchscenarios, it is considered that the arrangements between the parties should bedocumented in technical agreements.

GMP第7章还规定:“如果上市许可持有人和制造商不相同，则应根据本章所述的原则作出适当安排。”(参见，第7章，第7.3段)。实际上，可能会出现各种各样的情况。例如，双方当事人可能是同一公司集团内的不同法人实体，也可能是不相关的公司。不管情况如何，我们认为当事人之间的安排应该记录在技术协议中。

Where an MAH isengaged in an outsourcing activity, the above means that the MAH should agreein writing what exactly the activity is, and how it will be controlled.

当MAH从事外包活动时，上述意味着MAH应该同一编写活动内容以及如何控制。

5.1.3. Compliancewith the Marketing Authorisation

5.1.3.符合上市许可

If an outsourcedactivity is one that may affect compliance with the MA, there should be controlsin place which provide assurance that the requirements of the MA are compliedwith. This also has relevance in relation to activities concerningpost-approval changes and their implementation.

如某项外包活动可能会影响MA符合性，则应设有控制措施，以确保外包活动符合MA的要求。批准后变更及其实施的相关活动亦是如此。

The GMP guidestates that “All arrangements for the outsourced activities including anyproposed changes in technical or other arrangements should be in accordancewith regulations in force, and the Marketing Authorisation for the productconcerned, where applicable.” (Ref. Chapter 7, Paragraph 7.2)

GMP指南声明:「所有有关外包活动的安排，包括任何技术或其他方面上的拟议变更，均须符合现行法例及相关产品的上市许可(如适用)。」(参见。第7章，第7.2段)

Chapter 1 of theGMP guide states that “Where manufacture is outsourced, the technical agreementbetween MAH and manufacturer should address the respective responsibilities in producingand evaluating the product quality review.” (Ref. Chapter 1, Paragraph 1.11). Thismeans that the manufacturer may be responsible for compiling andevaluating certain elements of the PQR, while the MAH may be responsible forcompiling and evaluating other parts of the PQR. (See below and also section5.4 for further information in relation to PQRs). It is noted that PQRs containinformation in relation to the MA, in terms of variations, post-approvalcommitments, etc.

GMP指南第一章规定:“当生产外包时，MAH和制造商之间的技术协议应包含生产和评估产品质量回顾的各自责任。”(参见，第1章，第1.11段)。这意味着制造商可能负责编写和评估PQR的某些元素，而MAH可能负责编写和评估PQR的其他部分。(有关PQR进一步资料，请参阅下文及第5.4节)。需要注意的是，PQR包含与MA有关的信息，如变更、批准后委托等。

5.1.4. Document retention

5.1.4.文件保存

There are certain document retention requirementsstated in the GMP guide which are important from the perspective of the MAH, asthey support the MA and documentation retention activities may be the subjectof outsourcing.

在GMP指南中规定了某些文件保存的要求，从MAH的角度来看，这些要求很重要，因为它们支持MA，文件保存活动可能是外包的主题。

It is consideredthat, while document retention activities may be delegated (i.e. outsourced) tothe manufacturer, the MAH remains responsible for these. Chapter 4 of the GMPguide provides useful guidance relating to the storage and retentionrequirements of documentation. It states that “…the retention period willdepend on the business activity which the documentation supports. Criticaldocumentation, including raw data (for example relating to validation orstability), which supports information in the Marketing Authorisation should beretained whilst the authorisation remains in force.” (Ref. Chapter 4, Paragraph4.12).

我们认为，虽然文件保存活动可以委托制造商进行(即外包)，但是MAH仍需对此负责。GMP指南的第4章提供了有关文件的存储和保存要求的有用指导。它说“...保存期限将取决于文件所支持的业务活动。用以支持上市许可中的信息关键文件，包括原始数据(例如与验证或稳定性有关的数据)，应在许可有效期内保存。”(参考文献。第4章，第4.12段)。

由于字数限制，未展示全部翻译内容。

德斯特DST 服务项目认证咨询

（FDA/WHO/中国GMP）
计算机化系统验证丨工艺核对咨询

实验室管理丨工厂厂房设计

模拟GMP认证检查丨数据可靠性审计

GMP合规性审计丨企业管理咨询