EU GMP，想说爱你不容易

julia朱玉姣

EU GMP，象个妖精，昨天才把它研究透，今天它又变了。

EU GMP，象个小三，昨天才满足了它的要求，今天它又有了新要求。

想说爱它可真是不容易啊。

与FDA若干年难得一变的GMP相反，EU GMP可谓是少女的心情，一年三变。究其原因，大抵是因为在美国，GMP是法（code），修改要走法案修订程序；而在欧洲，GMP是指南，走的是技术类指南的修订程序。也就好比说，一个是娶来做的原配，不好轻易离婚再娶，另一个是女朋友，想换就换了。

2015年，欧盟对公众开放了原来用于欧盟成员国汇总和交换EU GMP检查信息的数据库系统EU GDMP数据库。公众不需注册即可直接登录查看EU GMP检查信息。它使得EU GMP检查信息更为透明、快捷，作为客户不再需要从供应商处获取检查信息。大家不免担心是不是以后欧盟一说谁家检查失败，立马全球皆知。谁知道CFDA是不是天天也在看这个，然后作为飞检的重点呢。担心啊……

2015年，EDQM公布了CEP 电子提交的展望。大家不免担心以后提交是不是都要先买十几万的软件呢。愁人啊……

2015年，由于对印度一临床中心的检查发现数据造假，欧洲受影响MA多达1000余张，最终700多张MA被吊销。这是中国临床的机会呢还是风险呢，忐忑啊……

以下是ECA总结的2015年EU GMP的变化及今年的展望，翻译供大家参考。

GMP News
03/02/2016

The GMP year 2015 - what was new in the EU?

EU GMP在2015年有哪些新的东西？

The previous year 2015 was another eventful year.Again there were new developments in the GMP environment as well asannouncements of changes that preoccupied the pharmaceutical industry. 2016won't be less exciting, also because now many of the new requirements must beimplemented.

过去的2015年是另一个意义重大的年份。GMP有很多新的发展，同时制药行业也有了很多变更公布。2016年不会太好过，也因为许多新的要求必须要实施了。

Hereinafter a few highlights:

这里列出一些重要的地方：

The main changes in the new chapter 3 EUGuidelines to Good Manufacturing Practice "Premises and Equipment" concern the sections onmeasures to prevent cross-contamination. The changes are closely associatedwith the revision of chapter 5 (Production) and with the new EMA-Guideline onsetting health based exposure limits for use in risk identification in themanufacture of different medicinal products in shared facilities(EMA/CHMP/CVMP/SWP/169430/2012). The new text provides for a risk-basedassessment of the topic on the basis of toxicological data. This means thatdedicated facilities are only required if the identified risks cannot becontrolled using adequate technical or organisational measures.

EU GMP指南新的第3章“设施和设备”主要的变化在于防止交叉污染的措施部分。变更与第5章（生产）的修订关系很大，还有新的EMA指南：“共用设备中不同药物生产中风险识别里暴露限度设定” (EMA/CHMP/CVMP/SWP/169430/2012)。新的文件提供了基于毒性数据的风险评估。这意味着只有当所识别的风险在使用充分的技术或组织措施仍无法控制时才需要使用专用设备。

This is also supported by EMAs ToxicologicalGuideline, mentioned above. It is valid since 1 June 2015 and describes a riskassessment based on the toxicological evaluation of the products manufacturedin the shared facilities/production areas.

这也得到上述EMA“毒性指南”的支持。该文件自2015年6月1日开始生效，其中描述了在共用设施/生产区域中生产不同药品时基于毒性评估的风险评估。

The new chapter 5"Production" of the EU Guidelines to Good Manufacturing Practice is in operation since 1 March2015. This chapter contains much more changes:

EU GMP新的第5章“生产”自2015年3月1日开始实施。本章包括了更多变更：

• An extended description of the technical and organisational measures     to prevent cross-contamination;  
• 防止交叉污染的技术和组织措施的更多描述
• Use of quality risk management processes;
• 质量风险管理程序的使用  
• Requirements concerning the selection, qualification and trending of     starting materials, packaging materials and their suppliers;  
• 起始物料、包装材料和其供应商的选择、确认和趋势分析要求
• Control and traceability of the supply chain;  
• 供应链控制和追溯
• Requirements concerning the adoption of (data) from certificates of     analysis by the manufacturer or supplier;  
• 生产商或供应商COA数据采用的要求
• Requirements concerning the notification of authorities in the case     of restrictions in production or supply.
• 生产或供应受限时授权通知的要求
  

Annex 15 of the EUGuidelines to Good Manufacturing Practice "Qualification and Validation" also entered in force in its revised version (1October 2015). It adopts principles from the ICH Guidelines Q8, Q9, Q10 and Q11with reference to the application of quality risk management (QRM), processanalytical technology (PAT), quality by design (QbD) and real-time release testing(RTRT).

EU GDMP指南附录15“确认和验证”也开始实施修订版本（2015年10月1日）。它采用了ICH指南Q8、Q9、Q10和Q11的关于质量风险管理应用（QRM）的原则、过程分析技术（PAT）、质量源于设计（QBD）和实时放行测试（RTRT）。

It was coordinated with the EMA "Guideline onprocess validation for finished products - information and data to be providedin regulatory submissions" (in operation as of 24 August 2014).

它与EMA“制剂工艺验证指南---法规申报里提交的资料和数据”相呼应（自2014年8月24日起实施）。

The new Annex 15 lays down extended requirements onthe validation master plan and the documentation. New is a general requirementfor user requirement specifications (URS), factory acceptance test und siteacceptance test (FTA/SAT). There were only few changes concerning IQ/OQ/PQ(they may be combined in justified cases). The most important changes concernprocess validation itself (consistent with the EMA Guideline mentioned above).A so-called retrospective validation now is obsolete and there is only a prospectivevalidation. Two principal approaches are possible to process validation; the"traditional" one with three consecutive validation batches and a"continuous process verification" with reference to QbD. They canalso be mixed (hybrid approach).

新的附录15给出了验证主计划和文件记录的更多要求。新的内容是用户需求手册（URS）、供应商现场测试和接收方现场测试（FTA/SAT）的通用要求。关于IQ/OQ/PQ只有很小的变化（它们可以在验证案例中合并）。最重要的变化是关于工艺验证本身（与上述EMA指南一致）。所谓回顾性验证现在已经过时了，只能使用前瞻性验证。原则上工艺验证可以采用两个方法，“传统”方法采用三个连续验证批次，和“持续工艺确认”是与QBD有关的。他们也可以混合使用（混合方法）。

The requirements concerning the cleaning validationare described in more detail and go hand in hand with the requirements inChapter 3 and with the "Toxicological Guideline".

关于清洁验证的要求描述更为详细，与第3章和“毒性指南”并肩而来。

The chapter on transport verification in Annex 15 iscompletely new. The chapter recognises that it is difficult to validatetransports. It is recommended to also monitor other critical parameters besidestemperature such as vibration, humidity etc.

在附录15中关于运输确认的章节是全新的。章节里承认要验证运输是很困难的。其中建议也对温度以外的其它关键参数，例如震动、湿度等进行监测。

By the way, FDAs "new" Guidance on ProcessValidation is valid since January 2011. There is a (satisfyingly) high level ofagreement between the FDA Guidance on Process Validation and the revised Annex15. But there are alsodifferences that companies wishing to serve the US market as well as the Europeanmarket must be well aware of.

顺便说一下，FDA的工艺验证“新”指南是自2011年1月生效的。修订的附录15和FDA的工艺验证指南显示出高度的一致性。但还是有些差异，希望同时供应美国市场和欧洲市场的公司必须要知道的。

The long awaited Annex 16 "Certificationby a Qualified Person and Batch Release" was finally published inOctober 2015.

期待已久的附录16“QP证明和批放行”最终在2015年10月公布了。

It is pointed out in a central position that theprincipal task of a Qualified Person (QP) is to certify batches for theirrelease. In this context the QP must verify personally that theresponsibilities listed in chapter 1.6 are fulfilled. Chapter 1.7 lists quite afew other responsibilities of the QP. But the related activities may bedelegated and in doing so the QP can rely on the respective quality managementsystems. But the QP should make sure continuously that this confidence isjustified.

它在中心位置指出QP的主要任务是证明批次的旅行。在此文中，QP必须以个人身份确认其履行了在第1章1.6节列出的职责。在1.7中列出了QP的一些其它职责，但相关的活动可以被委托给其它人，此时，QP可以依赖于相应的质量管理体系。但QP应持续保证对此可信度有经过判定。

It is the first time that the GMP expectationsconcerning excipients are described in a Guideline. The "Guidelines on the formalised riskassessment for ascertaining the appropriate good manufacturing practice forexcipients of medicinal products for human use" were published in March2015. Central topic is that the manufacturing authorisation holder is requiredto ensure that the excipients are suitable for use in medicinal products. Forthis he shall ascertain the appropriate good manufacturing practice he expectson the basis of a formalised risk assessment. This means that Part II EU GMPGuideline was not extended to include excipients.

首次，关于辅料的GMP期望被放在了指南里。“确认人用药品所用辅料的适当GMP的正式风险评估指南”在2015年3月公布。中心主题是生产许可持有人必须确保辅料适用于药品生产。为此，持有人应基于正式的风险评估来确定辅料生产商所需的适当GMP水平。这意味着EU GMP指南第二部分不会包括辅料。

The ICH Q3D Guideline forElemental Impurities was published at the end of 2014. EMA published the relevantrecommendations (EMA Elemental impurities in marketed products -Recommendations for implementation) on 26 February 2015. These recommendationsare addressed to manufacturers of medicinal products and to the nationalregulatory authorities. The latter should comply with the recommendations whencarrying out their activities in order to ensure a consistent approach.

ICH Q3D元素杂质指南在2014年底公布。EMA于2015年2月26日公布了相关的建议（已上市药品的EMA元素杂质---实施建议）。这些建议主要是给予药品生产商和国家药监机构。后者在实施其活动确保方法持续时应符合这些建议。

What will happen in the future?  未来会发生什么呢？

A new Annex is planned for the EU Guidelines to GoodManufacturing Practice: Annex 21 for Importers of MedicinalProducts. The concept paper was published on 13 May 2015. The consultationprocess ended in August 2015. The paper did not provide much information andthe first draft of the new annex is expected soon for public consultation.

EU GMP指南计划一个新的附录：附录21关于药品进口商。概念文章已于2015年5月13日公布。征求意见将于2015年8月截止。文章并未提供很多信息，新附录首稿预期很快会公布征求意见。

There also was a concept paper on Annex 1 of the EUGuidelines to Good Manufacturing Practice (Manufacture of SterileMedicinal Products) (published on 2 February 2015). First publicconsultation ended in March 2015. A first draft of the revised annex isexpected soon for public consultation. The revision is not supposed to createnew expectations, but it will contain some adjustments.

还有EU GMP指南附录1的概念文章（无菌药品生产）也在2015年2月2日公布。首次公布的征求意见将于2015年3月结束。修订后附录的首稿预期很快会公布征求意见。修订并不是要创建新的要求，但会有一些调整。

Annex 17 of the EUGuidelines to Good Manufacturing Practice (Real Time Release Testing)is to be modified completely. The revised document was published on 15September 2015, public consultation ended on 11 December 2015. The change ofname alone signalises a complete reorientation. In the end, the actual annex 17"Parametric Release" was restricted to be used for the routinerelease of products sterilised in the final container without sterility testson the basis of sterilisation parameters. Now the revision shall also implementthe principles of the concepts of ICH Q8, Q9 and Q10.

EU GMP指南附录17 （实时放行测试）将要彻底修订。修订后的文件于2015年9月15日公布，公开征求意见截止2015年12月11日。标题的变化说明了该文件将重新定位。在结尾，实际的附录17“参数旅行”被限制于用于基于灭菌参数的在不进行无菌测试的最终容器中进行灭菌的的药品的常规放行。现在，修订也实施了ICH Q8、Q9和Q10概念中的原则。

There have also been new developments in the GDP area:

新实施的当然还有GDP领域的内容：

Good DistributionPractice for Active Ingredients: The Guidelines on Good Distribution Practice forActive Substances for Medicinal Products for Human Use which were published on19 March 2015 are in force since 21 September 2015; irrespective of whetherthey are produced by the distributor himself, by someone else or whether theyare imported. Distribution comprises all activities consisting of procuring,importing, holding, supplying or exporting active substances with the exceptionof brokering (nothing more than brokering). This determines the right ofauthorities to inspect distributors. Repackaging or relabeling aremanufacturing activities and are regulated by GMP.

活性成分的优良销售规范。人用药用活性成分的GDP指南于2015年3月19日公布，于2015年9月21日实施。该指南适用于销售商自身生产的、其它人生产的和进口的活性成分。销售包括采购、进口、存贮、供应或出口活性物质的所有活动，只有代理（只代理，并无其它活动）除外。它赋予了药监当局检查销售商的权利。重新包装或重新标签属于生产活动，受GMP管理。

Distributors of active substances are to implement aquality system setting out responsibilities, processes and risk managementprinciples. Analogously to the GMP Guidelines they have to be adequately resourcedwith competent personnel, for example, and they must have a person with definedauthority and responsibility at each location where distribution activities areperformed ("designated person").

活性物质的销售商要实施一个质量体系，其中设定职责、工艺和风险管理原则。与GMP指南相似，这必须要有充分的资源，有资质的人员，例如，销售商必须在每个岗位都有一个人，具有指定的权力和职责（委任人员）。

syhorchid

谢谢分享

syhorchid

阐述深刻，顶一下。

胜利者

学习了

大呆子

不错，及时了解了最新信息

两个GMP比喻的非常贴切

叶非

这几年，无论是国内的法规，还是欧盟和FDA的法规，都更新的挺快的。原来的FDA被人们称为最保守和最没有效率的部门，现在估计这方面的吐槽会少了！国内的 药企，不能在闭门造车了，就是走出去的，也并非一劳永逸了！系统的维护，远远比新认证的难度大多了。

北重楼

行业竞争将越来越激烈，走出去需要自身硬，了解市场所在国家的GMP及其法规或指南越来越重要

北重楼

行业竞争将越来越激烈，走出去需要自身硬，了解市场所在国家的GMP及其法规或指南越来越重要

晴天悠悠

楼主总是很及时的更新信息，非常感谢您的分享。之前追你的博客，现在追你的贴子。我是你的忠实粉丝哟！

是是而非

谢谢分享

宝丽金

Guidelines on the formalised riskassessment for ascertaining the appropriate good manufacturing practice forexcipients of medicinal products for human use
没搜到这个文件的正式版呢？

zutong

法规更新很快，一点都不能松懈呀

摆脱陈词滥调

谢谢楼主分享，学习啦

hongyu

谢谢