EU GMP附录15新修订版本公布---生效日期2015年10月1日

20150402 ECA新闻：EU GMP附录15新修订版本公布---生效日期2015年10月1日  

2015-04-04 18:02:59|  分类： ECA新闻

GMP News
02/04/2015

New EU GMP Annex 15 Revision published - Valid as of 1 October 2015

EU GMP附录15新修订版本公布---生效日期2015年10月1日

In February 2014 the draft for the revision of EU GMP Annex 15 was published (see the GMP-News from 11 February 2014 "Revision of the EU GMP Annex 15 for Qualification and Validation published"). Compared with the currently valid version the changes were significant in some parts (see also the GMP-News from 21 March 2014 "Detailed Analysis of Annex 15 Draft". Now the draft was published as final document and will be valid as of 1 October 2015.

在2014年2月，EU GMP附录15修订版本公布（参见2014年2月11日GMP新闻“EU GMP附录15“确认与验证”修订版草案公布”）。相比于现行版本，有些部分有了重大改变（参见2014年3月21日GMP新闻“附录15草案详细分析”）。现在草案作为最终版本公布，并将于2015年10月1日生效。

What will change? Following you will find an overview about the changes.

哪些是要改变的呢？以下你能找到关于变化的一个综述：

With 16 pages the document is much more comprehensive than the current version (11 pages). In the section "principles" it is stated that the new EU GMP Annex 15 may also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II"

该文件共16页，比现行版本内容更多（11页）。在“总则”中说到新的EU GMP附录15也可以作为是活性物质指南的可选指南，但并不是对欧洲药事法第4卷第二部分的额外要求。

Life cycles build the centre of the new Annex 15, whether with regard to the product or to the process, whether with regard to equipment and the process validation itself. A special emphasis is on risk management which is mentioned in several sections in the guideline instead of being mentioned in one section only on risk assessment.

生命周期成为了新附录15的核心，不管是关于产品还是关于工艺，不管是关于设备还是关于工艺验证本身。指南中有几个部分特别强调了风险管理，而不是只在风险评估一个部分提到。

The new Annex 15 now specifically excludes a retrospective validation.

新的附录15里特别排除了回顾性验证。

Validation Master Plan 验证主计划
The content of the validation master plan (VMP) has been extended. Deviation management is also supposed to be described in the VMP in the future, just as well as the standards for the development of acceptance criteria and the organisational structure. Compared to the draft version the mention of an "ongoing validation strategy" has been deleted. The request for naming the resources has also been omitted compared to the draft.

验证主计划（VMP）的内容被进行了扩展。在将来，偏差管理也被认为是应该在VMP里描述的内容，还有建立可接受标准的指标以及组织结构。草案中提到的“持续验证策略”已被删除了。草案中提出的写出资源名称的要求也被忽略了。

Qualification 确认
The possibility to combine qualification documents (e.g. IQ and OQ as IOQ) is explicitly mentioned. It is also foreseen to include manufacturer documents. Fortunately there is the possibility of conditional releases in the area of qualification. The final document contains a requirement to establish user requirements and/or functional specifications as a starting point of a qualification. The DQ is now the second step in a qualification. Additional new requirements are the Factory Acceptance Test (FAT) and the Site Acceptance Test (SAT). Especially for equipment with new or complex technology a FAT "may" be conducted. Compared to the draft this is a less strict requirement. In the draft document it was stated that a FAT "should" be conducted. If appropriate and assessed, tests and documentation reviews as part of the FAT can be taken over in other steps without repeating them in the IQ/OQ. This is a very helpful definition.

其中清楚地提到了将验证文件（例如，IQ和OQ合为IOQ）合并的可能性，还预见了将生产商文件也包括进去的情况。好的消息的是在确认领域有条件地放行成为可能。最终文件包括了要求建立用户需求和/或功能性需求作为验证的起始点。DQ现在在验证中是第二个步骤。新增的要求是生产商外可接受测试（FAT）和现场可接受测试（SAT）。特别是对于可以实施FAT的新的或复杂技术设备。其中的要求没有草案中那么严格了。在草案中说的是“必须”实施FAT。如果适当且经过评估，可以在其它步骤中进行测试和文件审核，而不需要在IQ/OQ里重复。这是说法还是很有用的。

With regard to the PQ it is now also explicitly mentioned that (in certain cases) it can be combined with the OQ or the process validation. In difference to the draft it is stated that IQ, OQ and PQ "should" be conducted.

现在清楚地提到了（在特定情形下）PQ可以与OQ合并，或并入工艺验证中。不同于草案中所说的“应”实施IQ OQ 和PQ。

The chapter "Requalification" is new. Unfortunately the sub-chapter on established (in-use) equipment qualification has been completely omitted.

“再确认”一章是新的。不幸的是，子章节已有设备的确认已经被全部略去了。
Process Validation 工艺验证
The options with regard to process validation have been extended. The previous "traditional" approach is still mentioned as a possibility, though - also with the determination of 3 validation batches. For a 3 batch validation further data from following batches may be necessary according to an "ongoing process verification". The possibility of a "continuous process verification" as described in ICH Q8, and a hybrid approach as a mix of the before mentioned two approaches is new. This is a clear difference to the US FDA Process Validation Guidance where only one approach is mentioned. According to the final EU GMP Annex 15 a "bracketing" approach can be used with respect to the number of runs, strength, batch size, packaging sizes and types. This is already known from the US.

工艺验证的可选方法被扩展了。之前的“传统”方法仍在其中作为可选的方法，并且仍然提到3个批次的。如果一个工艺是经过三个批次的验证，则可能还需要根据“持续同期工艺确认”来收集之后的批次数据。在ICH Q8里描述的“持续工艺确认”，以及前面提到的两种方法的混合验证法则是新的概念。这与美国FDA工艺验证指南有明显区别，在FDA的指南中，只提到一种方法。根据EU GMP附录15的最终版本，可以使用一种“分组法”来包括验证批次数量、不同产品剂量、批量、包装规格和包装类型，这是美国指南中已经提过的。

As part of the "ongoing process verification" the product quality should be monitored during the product life cycle to show that the "state of control" is fulfilled and that trends are assessed. This is also known as "Continued Process Verification" from the US. The "ongoing process verification" should be based and reported according to a protocol or equivalent documents, latter is new compared to the draft. Completely omitted has been the subject of a (regular) revalidation.

作为“持续同期工艺确认”的一部分，需要在产品的生命周期对产品质量进行监控，以证明满足“控制状态”，并应对趋势进行评估。这在美国也被称为“持续工艺确认”。“持续同期工艺确认”的实施和报告应是基于一个方案或相等同的文件，后者是草案里没有提到的。（常规）再验证则完全被省略掉了。

The chapters "Transport Verification", "Packaging Validation" and "Qualification of Utilities" as well as a separate chapter on "Validation of Analytical Methods" are new.  Compared to the draft the new final document now addresses also the qualification of equipment for secondary packaging.

“运输确认”、“包装验证”和“公用设施确认”章节以及另一个单独的章节“分析方法验证”是新的。相比于草案，最终版本里现在还说明了外包装设备的确认。

Cleaning Validation 清洁验证
The chapter Cleaning Validation comprises clear changes. The number of subitems is more than double now. Fortunately it is possible now to group equipment if this grouping is justified accordingly. The acceptance criterion "visibly clean" as single acceptance criterion is designated as not acceptable. Limits for the carryover of contaminations are supposed to be based on a toxicological evaluation. There is a reference to the EMA Guideline on Shared Facilities (see GMP News from 21 November 2014 "Shared and Dedicated Facilities: EMA publishes final Guideline on Setting health based exposure limits (PDEs)". The so far common acceptance criteria 1/1000-Dose or 10 ppm are not mentioned. As part of the cleaning validation "dirty und clean-hold times" should be defined. The request from the draft to use the last rinse water as a sample in the application of rinsing methods has been omitted. Recovery rates should be determined. Interestingly the number of validation runs is supposed to be determined risk based. When producing clinical trial samples a cleaning verification could replace a cleaning validation.

清洁验证章节包括了明确的变更。子项目的数量现在多出了一倍不止。幸运的是，现在如果对一组设备进行了分组论证，则可以对一组设备进行分组方式确认。“目视清洁”的可接受标准作为单一的可接受标准是不能接受的。污染物的残留限度应基于毒性评估。这里引用了EMA关于共用设施的指南（参见2014年11月21日GMP新闻“共用和专用设施：EMA公布基于PDE设定健康暴露限指南最终版”）。到目前为止仍很常见的可接受标准千分之一剂量或10ppm现在没提了。作为清洁验证的一部分， 要定义“脏设备放置时间和清洁设备放置时间”。删除了草案中要求使用最后淋洗水作为淋洗方法申请中的产品的要求。应确定回收率。有意思的是，验证轮次的数量要求基于风险决定。如果生产临床试验样品，则清洁确认可以取代清洁验证。

In the chapter Change Control it is defined that an efficiency control is supposed to follow a change. This is an adaption to chapter 1, part I of the EU GMP Guide.

在变更控制章节里定义了在变更后需要有效控制。这是采纳了EU GMP指南第一部分第一章的内容。

The glossary contains new terms.

在术语中包括了新的术语。

Conclusion 结论
The revision is quite comprehensive. Influences from the ICH Guides ICH Q8, Q9 and Q10 can be clearly noticed. This makes the document more modern, and it is more adapted to the current state of science and technology. The addressing of API manufacturer is somewhat irritating. Although the new Annex 15 comprises clear changes it is not supposed to cause new requirements in the area of APIs. But how is that supposed to work?

修订内容的确很多，其中可以清楚地看到ICH指南ICH Q8 Q9 Q10的影响。这使得文件看起来更现代化，更多采纳了目前的科学技术。关于原料药生产商的说明可能有点让人恼火。尽管新的附录15包括了明显的变化，但这些变化并没有对原料药领导芹出新的要求。那原料药要怎么办呢？

The statement that Process Validation is a life cycle is comparable to the FDA view.

工艺验证要求是针对产品的生命周期的，与FDA的观点一致。

The clear focus on user requirements in the area of qualification will also have an impact on equipment suppliers. Process validation will become a difficult task in the future. With 3 different approaches there are clear differences to the US. However, the ongoing process verification means additional effort and is now comparable to the US requirements.

在设备确认领域对用户需求的明确要求对设备供应商也会产生影响。工艺验证将来会成为一个困难的任务。其中的三种不同方法与美国的要求明显不同。但是，持续同期工艺确认显示是需要额外的工作，现在与美国的要求基本一致。

Transport verification, the qualification of utilities as well as the validation of analytical methods are not new in the GMP enviroment. However, the topic packaging validation was not the main focus so far. This probably means additional effort for some companies.

运输确认、公用系统确认以及分析方法验证现在被置于GMP环境之内。但是，包装验证到目前为止还不是主要关注点。这可能表示有些公司还要多做一些工作。

The new Annex will result in considerable changes in the area of cleaning validation. A lot has fortunately been adapted to the current state of technology. However, the strong focus on toxicological evaluations as acceptance criteria with regard to existing products will certainly cause uncertainties.

新的附录将会导致清洁验证方面巨大的变化。幸运的是，现在的技术情况允许只用一个批次来做验证。但是，对已有产品的进行毒性评估来作为可接受标准将成为重要的关注点，这肯定会引起诸多不确定性。

Altogether there are plenty of new requirements which, however, partly only show the state of technology. Due to the (necessary) integration of ICH Q8-Q11 and the life cycle approach the new Annex 15 is now more comprehensive, but unfortunately also more vague. A close coordination with the FDA Guideline on process validation would have been desirable.

尽管如此，还是有很多新的要求，但只有一部分是配合了现行技术。由于要求结合ICH Q8-11，以及生命周期方法，新的附录15现在包括内容更广泛了，但不幸的是也更模糊了。现在其中关于艺验证的要求与FDA指南中的要求将迫切需要进行紧密协调。

Please find the new EU GMP Annex 15 on the EU Commission Webpage

新版本EU GMP附录15可以在上述网站找到。

The new EU GMP Annex 15 will be covered at two ECA events. On 22/23 April the ECA offers the seminar "The new FDA/EU Approach to Process Validation" in Hamburg. And, at the 6th European GMP Conference on 9/10 June in Heidelberg the EU GMP Annex and the consequences will be discussed in a dedicated session.

新版本EU GMP附录15将在2次ECA会议中包括：4月22-23日ECA在汉堡的研讨会“新的工艺验证FDA/EU方法”，以及6月9-10日在海德堡的“第6届欧洲GMP会议”中，EU GMP附录和影响将在专门的会议中讨论。
来源：http://zhuyujiao1972.blog.163.com/blog/static/986947272015346259156/