[ECA新闻]EU GMP附录1：欧盟委员会发布修订文件

罗伊鲱

20.02.2020 Annex 1:European Commission Publishes Revised Document

On 20 February, the Directoratefor Health and Food Safety of the European Commission published a further draftfor the revision of Annex 1 of the EU GMP Guide to Good Manufacturing Practice.This document enters a 3-month phase of commenting by concerned organisationsand stakeholders.
2月20日，欧盟委员会健康与食品安全局发布了欧盟GMP附录一《无菌产品生产》进一步草案。新修订文件向相关组织和利益相关者征求意见，为期3个月。

Background  背景
Annex 1 "Manufacturing of sterile medicinal products" was first published in1971. In the following years it was updated several times, e.g. to adapt theclassification table of cleanrooms to include guidelines on media simulationand biological stress monitoring in 2005 and 2007 as well as the guidelines onvial sealing in 2010.
附录1《无菌药品生产》于1971年首次发布。在随后的几年中，它进行了数次更新，例如，调整了洁净室的分级，以包括2005年和2007年的培养基模拟和生物压力监测，以及2010年的玻璃瓶密封。
At the end of 2017, the first draft of a fundamentalrevision was published, which was intended to focus on a more structuredguidance, including state-of-the-art principles such as quality risk managementand consideration of new technologies and innovative processes. At that time,the draft contained new sections, e.g. for utilities, and extended sections ontopics such as production and specific technologies or on the requirements ofAseptic Process Simulation (APS).
2017年底，发布了基本修订的初稿，其重点是更加结构化的指南，包括最新的原则，例如质量风险管理和考虑新技术和创新过程。当时，该草案包含新的部分（例如，公用系统和诸如生产和特定技术等主题的扩展，以及无菌工艺模拟（APS）的要求）。
During the following public consultation over 6000 commentswere submitted to EMA, which then had to be processed in parallel with thechallenge of moving to Amsterdam.
在随后的征求意见中，EMA收到了6000多条意见，然后与搬到阿姆斯特丹的挑战同时进行了处理。
The current document  新的文件
The currentdocument contains a large number of changes compared to the 2017 draft and nowcomprises just over 50 pages divided into 11 sections:
与2017年草案相比，本文档包含大量更改，现在包含50余页，分为11个部分：
1. Scope - Includes additionalareas (other than sterile products) where the general principles of the annexcan be applied.
范围——包括可以应用新文件一般原则的其他领域（不限于无菌产品）。
2. Principle - Generalprinciples as applied to the manufacture of sterile products.
原则——适用于无菌产品生产的一般原则。
3. Pharmaceutical QualitySystem (PQS) - Highlights the specific requirements of the PQS when applied tosterile products.
药品质量体系（PQS）——强调将PQS应用于无菌产品时的特定要求。
4. Premises - General guidanceregarding the specific needs for premises design and also guidance on thequalification of premises including the use of Barrier Technology.
厂房——有关厂房设计特定需求的通用指南，以及关于厂房确认（包括使用隔离技术）的指南。
5. Equipment - Generalguidance on the design and operation of equipment.
设备——设备设计和操作的一般指南。
6. Utilities - Guidance withregards to the special requirements of utilities such as water, gas and vacuum.
公用系统——有关公用系统（如水，气体和真空）特殊要求的指南。
7. Personnel - Guidance onthe requirements for specific training, knowledge and skills. Also givesguidance to the qualification of personnel.
人员——有关具体培训，知识和技能的要求的指南。还提供了人员确认的指南。
8. Production and specific technologies- Discusses the approaches to be taken with regard to aseptic and terminalsterilization processes. Discusses approaches to sterilization of products,equipment and packaging components. It also discusses different technologiessuch as lyophilization and Form-Fill-Seal where specific requirements apply.
生产和特定技术——讨论在无菌和最终灭菌工艺中应采取的方法。讨论对产品，设备和包装组件进行灭菌的方法。还讨论了适用特定要求的不同技术，例如冻干和成形—灌装一密封。
9. Viable and non-viableenvironmental and process monitoring - This section differs from guidancegiven in section 4 in that the guidance here applies to ongoing routinemonitoring with regard to the design of systems and setting of action limitsalert levels and reviewing trend data. The section also gives guidance on therequirements of Aseptic Process Simulation (APS).
活性和非活性粒子的环境和工艺监测——本节与第4节中给出的指南的不同之处在于，本节适用于日常监测，包括监测系统设计，行动限报警水平的设置和趋势数据回顾。本节还提供有关无菌工艺模拟（APS）要求的指南。
10. Quality control (QC) - Givesguidance on some of the specific Quality Control requirements relating tosterile products.
质量控制（QC）——就与无菌产品有关的某些特定质量控制要求提供指导。
11. Glossary - Explanation ofspecific terminology.
词汇表——具体术语的解释。
In detail, we will present the changesin a series of articles on this website arranged by topic or section to bepublished soon. At this point, we would like to present only a few selected,partly comprehensive changes to give you a first impression.
详细地，我们将在本网站上按主题或章节排列的一系列文章中介绍更改，这些更改将很快发布。 在这一点上，我们只想介绍一些选定的，部分全面的更改，以给您第一印象。
Scope and principles  范围和原则
A first significantdifference to the currently valid Annex 1 and also to the draft of 2017 canalready be seen in the title or the table of contents. Annex 1: Manufacture ofSterile Medicinal Products has become Annex 1: Manufacture of Sterile Products,i.e. the range of products covered by Annex 1 is significantlyextended. This is also made clear in the scope by the sentence "Includes additional areas(other than sterile products) where the general principles of the annex can beapplied". It further continues: "The manufacture of sterileproducts covers a wide range of sterile product types (active substance,sterile excipient, primary packaging material and finished dosage form), packedsizes (single unit to multiple units), processes (from highly automated systemsto manual processes) and technologies (e.g. biotechnology, classical smallmolecule manufacturing and closed systems)."
在标题或目录中已经可以看到与现行版的附录1以及与2017年草案的第一个重大差异。标题“无菌药品生产”已改为“无菌产品生产”，即该文件涵盖的产品范围已大大扩展。新文件字句“在其中包括可以应用本文件一般原则的其他区域（无菌产品除外）”在范围内也清楚表明了这一点。文件接着说：“无菌产品的生产涵盖了多种无菌产品类型（活性物质，无菌辅料，内包装材料和制剂），包装规格（从单个单元到多个单元），工艺（从高度自动化系统到手动工艺）和技术（例如生物技术，小分子生产和隔离系统）。”
The importance of Quality RiskManagement (QRM) is also emphasized in greater detail than in the 2017 version,which of course includes a general evaluation of the existing processesaccording to criticality as shown in the scope: "ThisAnnex provides general guidance that should be used for the manufacture of allsterile products using the principles of Quality Risk Management (QRM), toensure that microbial, particulate and pyrogen contamination is prevented inthe final product." On the other hand, QRM is also seen as the basis for justifying anynecessary deviation from the specified requirements. This is stated in thecurrent draft: "Where alternative approaches are used,these should be supported by appropriate rational and risk assessment andshould meet the intent of this Annex. QRM priorities should include good designof the facility, equipment and process in the first instance, thenimplementation of well-designed procedures, with monitoring systems as thefinal element that demonstrate that the design and procedures have beencorrectly implemented and continue to perform in line with expectations.Exclusively monitoring or testing does not give assurance of sterility."
与2017版相比，质量风险管理（QRM）的重要性也得到了更详细的强调，其中包括根据关键程度对现有的工艺进行的总体评估。另一方面，QRM也被视为证明有必要偏离指定要求的依据。当前草案中对此进行了说明：“使用替代方法时，这些方法应得到适当的理由和风险评估的支持，并应符合本附录的要求。QRM应首先考虑设施，设备和工艺的良好设计，然后实施设计合理的程序，最后才是监测系统，以表明设计和程序已正确实施并持续符合预期。只采取监测或测试不能保证无菌。”
With regard to contamination control,an area which is generally mainly attached to quality assurance, the term"Contamination Control Strategy (CCS)", which appeared in the draftof 2017, is emphasized even more strongly.  The principle of a coherentconcept across the entire manufacturing process and all related areas ("...acrossthe facility in order to define all critical control points and assess theeffectiveness of all the controls (design, procedural, technical andorganisational) andmonitoring measures employed to manage risks associated withcontamination") is clearly required. It is also emphasised that this mustbe a dynamic system that requires continuous updating.
关于污染控制，一个通常主要依附于质量保证的领域，2017年草案中出现的"污染控制策略"一词受到更强烈的强调。明确要求在整个制造过程和所有相关领域，（"...在整个工厂内，定义所有关键控制点，并评估所有控制（设计、程序、技术和组织）的有效性，以及用于管理污染相关风险的监控措施"。还强调，这必须是一个需要不断更新的动态系统。
Premises and Qualification  厂房和确认
In the context ofCCS consideration, it is also possible to build a bridge to the topic ofinsulators and RABS. These are already supplemented with a sub-item in Premiseswhich emphasises that they are "useful in ensuring the necessaryconditions and minimisation of microbial contamination associated with directhuman intervention" and shouldbe considered in a CCS.
在考虑CCS时，还可以为隔离器和RABS搭建桥梁。在“厂房”一章中增加了一个子标题，强调其“有助于确保必要的条件并最大程度地减少与人为直接干预相关的微生物污染”，应在CCS中予以考虑。
It is also new that the topic oftransfer of materials, equipment and other components is already taken intoaccount in Premises with sub-sections 4.10 and 4.11, i.e. immediately beforethe section on airlocks. The latter is related to this in terms of content andhas undergone a number of supplements compared with the previous Annex,particularly with regard to one-way concepts and anchoring in CCS.  In thechapter on the qualification of cleanrooms, reference is made to ISO 14644, asbefore. However, as before, reference is made to the measurement of particlesizes 0.5 and 5 μm: "For cleanroom classification, the airborne particulates equalto or greater than 0.5 and 5 μm should be measured. For Grade A zone and GradeB at rest, classification should include measurement of particles equal to orgreater than 0.5 μm; however, measurement using a second, larger particle size,e.g. 1 μm in accordance with ISO 14644 may be considered. This measurementshould be performed both at rest and in operation."
同样新鲜的是，在“厂房”的第4.10和4.11小节中已经考虑了物料，设备和其他组件的传递，即在“气闸”之前。后者在内容上与此相关，并且与先前的附录相比进行了许多补充，特别是在单向概念和CCS方面。在有关洁净室确认的章节中，与以前一样参考ISO 14644。但是，与以前一样，需要监测粒径0.5和5μm粒子：“对于洁净室分级，应测量等于或大于0.5和5 μm的悬浮粒子。对于A级区域和静态B级，分级时应包括对等于或大于0.5 μm的粒子进行测量；但是，可以考虑较大的粒子（中间粒径），例如ISO 14644的1 μm粒子。该监测应在静态和动态下进行。”
The current difference to ISO 14644,which only refers to one of the two sizes, is therefore still maintained.
因此，本草案仍保持与ISO 14644的当前差异，该差异仅涉及两种大小中的一种。
In today's News, we have only addresseda few topics of interest. More detailed analyses will follow in the nextNewsletters, especially as the revision will raise further questions, e.g. whatwill happen with the Guidance for Industry "Sterile Drug Products Producedby Aseptic Processing" dated 2004. Particularly, the question ariseswhether it still represents the current state-of-the-art in science and technology,and how to assess this when manufacturing for both the US market andthe European market.
在今天的新闻中，我们只讨论了一些有趣的话题。 在下一个新闻通讯中将进行更详细的分析，尤其是在修订版将引发更多问题时，例如 2004年的《无菌加工生产的无菌药品》工业指南将发生什么情况。特别是，问题在于它是否仍代表了当前的最新科学和技术水平，以及在同时为美国市场和欧洲市场制造时如何对其进行评估。
On the website of the EuropeanCommission you will find the completedraft of Annex 1: Manufacture of Sterile Products.
在欧洲委员会的网站上，您可以找到附件1：无菌产品的制造的完整草案。

https://www.gmp-compliance.org/g ... es-revised-document

小兵123

1000多欧，太贵了

yuansoul

小兵123 发表于 2020-2-28 12:28
1000多欧，太贵了

信则灵

小兵123

yuansoul 发表于 2020-3-2 09:26
信则灵

还是看看D版的算了

罗伊鲱

PIC/S 2ND TARGETED CONSULTATION DOCUMENT ON REVISION OF ANNEX 1 (MANUFACTURE OF STERILE MEDICINAL PRODUCTS), 2020-02-20

小金库

谢谢分享。