EU GMP 最新动态

The GMP world was turning abit slower in 2016 - now, it's picking up speed again. Currently, severalcrucial changes are being made with c**equences even for national legislation. There may not be a great amount of guidelines being changed or revised at the moment, but some of the changes that are being made do have significant impact (e.g. for manufacturers of IMPs, parenterals or ATMPs).

GMP世界在2016年转的有点慢，而现在，它又重拾了其速度。当前，正在进行几个重大修改，甚至将对国家法规产生影响。目前可能还没有大量的指南进行修改或修订，但已进行的一些变更会有巨大的影响（例如，IMP、注射剂和ATMP生产商）。


The changes will also entail are structuring within the EU GMP guidelines - but let us start at bebeginning.
变化还牵涉到EU GMP指南内的重新架构—但让我们从头讲起吧。


IMPs  
临床试验用药


The reorganisation of the guidelines on clinical trials in the EU was decided upon in May 2014, already.The reason for this was the so far different implementation of Directive 2001/20/EG in the individual member states. The objective of Regulation (EU) No536/2014 "… on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC" of 16 April, 2014 is therefore to establish standardised regulati** for the execution of clinical trials in the EU.
EU的临床试验指南重构在2014年5月已经确定了，原因是截止目前各成员国对指令2001/20/EG执行各有不同。2014年4月16日“废止指令2001/20/EC，实施……人用临床试验用药”法规(EU) No 536/2014的目的是在EU建立临床试验实施的标准化法规。


To prevent future deviati**,the restructuring won't be in the form of a directive, but a regulation (the ClinicalTrial Regulation = CTR), which is directly applicable without needing to be transformed into national law.
为了防止未来的偏离，重构不会在以指令的形式，而是采用法规（临床试验法规=CTR），它直接适用，不需要转化为国家法。


Therefore, the GMP requirements for IMPs must be revised, as well. For that purpose, Directive 2003/94 "… laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal productsfor human use" will be withdrawn and replaced by two individual directives; one specifically for commercial products and one for investigational medicinal products. At the same time, specific GMP guidelines for IMPs will be issued. This entails the following new documents:
因此，IMP的GMP要求也必须进行修订。为此，“……设定了人用药品和人用临床试验药品的GMP原则和指南”的指令2003/94将要撤销，由2个单独的指令替代，一个专用于商业化药品，另一个用于临床试验用药。同时将签发IMP的专用GMP指南。这就需要制订以下新文件：

• Commission Directive (EU) 2017/1572 of 15 September 2017 "supplementing Directive 2001/83/EC of the European Parliament and of the Council as regards the principles and guidelines of good manufacturing practice for medicinal products for human use"   
• 2017年9月15日的欧盟指令(EU) 2017/1572“补充欧洲议会和委员会关于人用药GMP原则和指南的指令2001/83/EC”
• Commission Delegated Regulation (EU) 2017/1569 of 23 May 2017 "specifying principles and guidelines for good manufacturing practice for investigational medicinal products for     human use and arrangements for inspecti**"
• 2017年5月23日的欧盟托管法案(EU) 2017/1569“阐明人用临床试验用药GMP原则和指南以及检查安排”
• Detailed Guidelines "on Good Manufacturing Practice for Investigational Medicinal Products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU) No 536/2014" (replaces Annex 13 of the GMP Guidelines)
• “依法规（EU）No 536/2014第63（1）条第二段制订的人用临床试验用药GMP”详细指南（取代GMP指南附录13）
  

All this will come into forceas soon as the EU's new submission portal for clinical trials has been implemented. A transitional period of three years will follow. However, thereare some delays at the moment (probably until 2019).
一旦EU的临床试验新申报端口实施，所有这些将开始生效，之后是3年的过渡期。但是，目前还有一些延迟（可能要直到2019年）。


New GMP rules for ATMPs  
先进治疗药品的新GMP规定


Similar to the new IMP guidelines structure, advanced therapy medicinal products (ATMPs) are to bedefined in separate guidelines in the future, as well. To that end, the European Commission has issued the "New Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products"on 22 November 2017. ATMP manufacturers should implement the guideline's requirements by 22 May 2018.
与新IMP指南结构相似，先进治疗药品（ATMP）未来也将要制订独立的指南。至此，欧盟已于2017年11月22日发布了“先进治疗药品GMP新指南”。2018年5月22日前，ATMP生产商需要执行此指南要求。


New Structure of EUspecificati**  
EU标准新结构


The afore mentioned changes ultimately lead to a new structure of EU specificati**. While it is difficult to describe in writing, the following diagrams show it quite clearly.
前述变化最终会导致EU标准形成新的结构。难以用文字描述，采用了以下图示显示的更清楚。


Structure of EU specificati** so far:  
截止目前EU标准的结构：

                               
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Future structure of EU GMPspecificati** (without GDP - they remain the same):
未来EU GMP标准的结构（没有GDP---保持相同）

                               
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Revision of Annex 1 of the EU GMP Guidelines (sterile medicinal products)  
EU GMP指南（无菌药品）附录1修订


The long awaited draft of Annex 1 (Manufacture of Sterile Medicinal Products; Targeted stakeholders c**ultation) was published on 20 December 2017. What's special about it is that the revised Annex 1 won't be an independent EU document. Instead, it will also apply for the PIC/S guidelines. Even though it is still just a draft (comments can be submitted until 20 March 2018), the pharmaceutical industry will have to prepare for several changes, like:
期待已久的附录1（无菌药品生产，征求目标干系人意见稿）已于2017年12月20日发布。这次修订的附录特别的地方在于它不再是一份独立的EU文件。相反，它还适用于PIC/S指南。即使它只是一份草案（征求意见截止日期2018年3月20日），制药行业将不得不为以下几个变化做好准备，诸如：

• The revised and significantly larger Annex includes a new paragraph on Barrier Technologies (RABS and isolators). Before, only the isolator technology was mentioned. It differs between routine particle measurements and limits for initial clean room classification.
• 修订后的篇幅大增的附录包括了关于隔离技术的新段落（RABS和隔离器）。之前，只有提到隔离器技术。它区分了日常颗粒测量和初始洁净间分级限度。
• The section on viable and non-viable Environment and Process monitoring was restructured and c**iderably expanded.
• 必须和非必须环境和工艺监测部分重构并大大扩展。
• In manufacturing, almost all the previous points have been expanded, e.g. the requirement for validated downtimes and process times.
• 在生产方面，几乎所有之前的部分都进行了扩展，例如，验证的停工时长和工艺时长要求。
• The new requirements for 100% visual inspection reflect the current state of the art. Trending is expected here, too.
• 100%目视检查要求，反映了当前的理想状态。这里还要求有趋势分析。
• The secti** on sterilisation have been expanded as far as text is concerned; there are no identifiable new requirements, though.
• 灭菌部分在文字方面进行了扩展，但没有发现新要求。
• The part on Aseptic Process Simulation (APS, also: Media Fill) has been restructured and c**iderably extended. Deviation assessments and the subsequent correctional measures will be redesigned here, especially. The goal is "zero growth".
• 无菌工艺模拟部分（APS也称为培养基灌装）进行了重新构架，同时大大扩充。尤其是偏差评估和之后的纠正措施在这里要重新设计。目标是“零生长”。
  

What will become of the MRA?  
MRA会变成什么样？


The new Mutual Recognition Agreement (MRA) with the USA came into force on 01 November, 2017. Since then, the competent authorities of the EU have not conducted any inspecti** in the USA. In return, the FDA approved eight European authorities, so far: Croatia,France, Italy, Malta, Spain, Austria, Sweden and the United Kingdom. Other EUmember states will be added as soon as their evaluation by the USA is complete;by 15 July, 2019, all authorities resp. countries are supposed to be evaluated and approved.
与USA之间的新MRA已于2017年11月1日生效。自该时起，EU的官方药监机构未在USA执行任何检查。截止目前，FDA批准了8个欧洲官方药监：克罗地亚、法国、马尔他、奥地利、瑞士和英国。其它EU成员国将在USA对其评估完成之后即加入清单，到2019年7月15日，所有机构均会受到评估和批准。


Challenges: the MRA is not as simple asit sounds. For example, the FDA does not perform routine inspecti** of IMP manufacturers. After the implementation of Delegated Regulation 2017/1569 however, IMP manufacturing in third countries is to always be inspected by national EU authorities. If and how EU authorities will inspect IMP manufacturers in the US in spite of the MRA is still not clear (the regulationhas not come into force, yet, after all).
挑战：MRA并不像听起来那么简单。例如，FDA并未对IMP生产商执行常规检查。在托管法案2017/1569实施之后，第三国IMP生产都要接受EU国家药监的检查。EU药监是否要对US的IMP生产商进行检查，要如何检查仍不清楚（当然，这法规还没生效呢）。


Another problem is the non-issuing of GMP certificates. Currently, authorisation applicati** submitted to anEU authority listing drug manufacturers in the USA must prove the ownership ofa licence issued by the FDA as well as an EU GMP certificate issued to the siteby an EU authority. However, after the implementation of the MRA, these EU GMP certificates are not issued anymore. And the FDA usually does not issue GMP certificates. Therefore, an alternative approach is necessary.
另一个问题是不签发GMP**的问题。目前，列有USA药品生产商的许可申报在提交给EU药监时必须证明其持有FDA签发的许可和EU药监签发给该场所的EU GMP**。但是，在实施了MRA之后，将不再签发这些EU GMP**，而FDA通用并不签发GMP**。因此说，必须要有一个替代的方法。


ICH Q12 Lifecycle Management  
ICH Q12生命周期管理


The new ICH Q12 Guideline"Technical and Regulatory C**iderati** for Pharmaceutical Product Lifecycle" has been published for a c**ultation phase(Step 2) in December 2017.
新的ICH Q12指南“药品生命周期技术和注册考量”已于2017年12月公开征求意见（第二阶段）。


ICH Q3D Elemental Impurities:It's getting serious  
ICH Q3D元素杂质：来真格了


The requirements and revisi** resulting from the ICH Q3 guideline have been implemented in various chapters and monographs of the European Pharmacopoeia (Ph. Eur.). These changes were published in Supplement 9.3 and apply since 01 January, 2018:
ICH Q3指南引发的要求和修订已在EP不同章节实施。这些变化在增补9.3里发布，自2018年1月1日起实施。

• General chapter 5.20 "Elemental impurities" (ICH Q3D)
• 通则5.20“元素杂质”（ICH Q3D）
• General monograph "Pharmaceutical preparati**" (2619), refers to chapter 5.20
• 通论“制剂”（2619），参见第5.20章
• General monograph "Substances for pharmaceutical use" (2034) includes procedures to monitor elemental impurities
• 通论“药用物质”（2034）包括元素杂质监测程序
• General method 2.4.20 "Determination of elemental impurities" describes, amongst other things, method development and validation
• 通用方法2.4.20“元素杂质检测”描述了，除其内容外，方法开发和验证
• The now obsolete heavy metal test (2.4.8) will be removed from over 500 monographs (excepti** are substances of  natural origin or pure veterinary products, for example)
• 目前过时的重金属测试（2.4.8）将从500余份各论中删除（自然来源物质和仅兽用药除外，例如）
• Soon-to-be necessary change control procedures must be c**idered here, as well.
• 这里也必须要考虑很快就要成为必须的变更控制程序