EMA: 关于GMP的问答(2)

来自julia博客
EMA官网刊载了部分关于GMP的问答，共包括15个方面。由于涉及方面较多，仅翻译并转载部分。
本部分为关于“EU GMP第二部分：原料药基本要求”和“EU GMP指南附录：补充要求：附录1：无菌制剂的生产”部分。由于官方并不提供相关更新通知和预告，参考本文时请随时关注官网更新。

原文网址： http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000027.jsp&mid=WC0b01ac05800296ca

EU GMP guide part II: Basic requirements for active substances used as starting materials: GMP compliance for active substances in investigational medicinal products (IMPs)
EU GMP指南第二部分：用作起始物料的活性物质的基本要求：临床前试验制剂（IMP）所用活性物质的GMP符合性
1. Are active substances used as starting materials in the production of IMPs subject to GMP? H July 2006
用作临床前试验制剂（IMP）起始物料的活性物质是否需要在GMP状态下生产？ H 2006年7月
Directives 2001/82/EC and 2001/83/EC , as amended, include obligations for manufacturing-authorisation holders only to use active substances that have been manufactured in accordance with GMP. Provision is also made for inspections of active-substance manufacturers but only under certain specified circumstances.
法令2001/82/EC和2001/82/EC及修正案，赋予了上市许可持有人义务，要求其仅使用在符合GMP下生产的活性物质。对活性物质生产商的检查也制订了条款，但仅是在某些特定情况下有用。
IMPs are unaffected because the obligations of manufacturing-authorisation holders in this case are laid down in Directive 2005/28/EC , which does not contain corresponding requirements for active substances. Furthermore, this is made clear in the introduction to part II of the GMP guideline .
IMP不受上述法规影响，因为这种情况下上市许可持有人的责任是由法令2005/28/EC所赋予的，而该法令未对活性物质设定相应的要求。另外，在GMP指南第二部分引言中也有清楚说明。
Part II of the GMP guideline does include a short section on new active substances to be used as starting materials for IMPs and these remain as recommendations with no mandatory force. Nevertheless, active substances used in the manufacture of marketed products are already required to comply with GMP irrespective as to whether they may also used in the manufacture of IMPs.
GMP指南第二部分包括一个简短的部分，其中针对用于IMP的起始物料的新活性物质，仅作为建议，并不是强制的。尽管如此，用于上市药品生产的活性物质被要求符合GMP，不管其是否也用于IMP的生产。

EU GMP guide annexes: Supplementary requirements: Annex 1: Manufacture of sterile medicinal products – UPDATED
EU GMP指南附录：补充要求：附录1：无菌制剂的生产----更新
1. How should the integrity of sterilising filters be verified? H+V June 2007
无菌过滤器的完整性应如何确认？ H+V 2007年6月
Annex 1, paragraph 85 states, 'the integrity of the sterilised filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble-point, diffusive-flow or pressure-hold test.'
附录1，第85段说明，“无菌过滤器的完整性应在使用前和使用后采用适当的方法，例如起泡点、扩散流或保压试验进行确认”。
The filter-sterilisation process may be physically stressful for the filter. For example, high temperatures during the process may cause the filter to distort, potentially leading to fluid pathways that allow the passage of particles greater than 0.2 ?m in size. The performance of a filter can improve with use, as particles begin to block individual pathways and remove larger pathways that smaller particles could successfully navigate. For these reasons, filters should be tested both before use but after sterilisation and again after use.
过滤灭菌工艺可能使过滤器产生物理疲劳。例如，工艺过程中高温可能会导致过滤器变形，从而使得大于0.2?m的颗粒通过过滤器。过滤器的性能在使用过程中可能会得到提高，因为颗粒开始堵塞单个通道，移除更大的通道，从而使得较小的颗粒可能成功通过。由于这个原因，过滤器应该在使用前和灭菌后及使用后均进行测试。
Furthermore, testing should be performed in situ in order to verify the integrity of the filter complete with its housing.
另外，测试应在原位进行，以与其外壳一起确认过滤器的完整性。
2. What are the sampling requirements for sterility testing when a finished product batch of a terminally sterilised medicinal product is made up of more than one steriliser load? H+V October 2008
如果最终灭菌产品由不止一个灭菌装载组成，无菌测试取样要求是怎样的？ H+V 2008年10月
The sampling plan for sterility testing should take account of the definition of a batch as stated in the glossary of the GMP guideline together with the recommendations of annex 1 section 93 (section 127 in the February 2008 revision). Each steriliser load is considered to be an independent sub-batch. Consequently, one sterility test should be performed per sub-batch. The number of samples per steriliser load should conform toEuropean Pharmacopoeia requirements, section 2.6.1.3.
无菌测试的取样计划应考虑GMP指南里术语中对批的定义，以及附录1中第93部分（2008年2月版本第127部分）中的建议。每个灭菌装载均应作为一个独立的子批对待。因而，要对每个子批次进行一次无菌测试。每个灭菌装载的取样数应符合欧洲药典2.6.1.3的要求。
Can there be any exceptions to this rule? 上述规则可否有例外？
For large-volume parenterals where the sterilisation cycle has been qualified with an overkill level, an alternative sampling plan in accordance with a specific internal procedure agreed with the supervisory authority can be accepted (unless already specified in the marketing authorisation).
对于大容量注射剂，如果采用过度杀灭水平对灭菌循环进行了确认，则根据特定的内部程序进行，且经过药监监管机构同意的替代取样方案是可以接受的。
This procedure should state the need to sample from each steriliser load including the coolest location identified during the steriliser qualification. The number of samples per load should be defined based on a risk-based approach and the overall number of samples per batch should conform to European Pharmacopoeiarequirements, section 2.6.1.3. An alternative option, which would require a variation to relevant existing marketing authorisations, would be to introduce a system of parametric release, thereby avoiding the need to carry out the sterility test.
该程序应声明从每个灭菌器装载中取样的必要性，包括在灭菌器验证期间所识别的最冷点。每个装载周期的样品数量应根据基于风险的方法进行定义，每批的全部样品数量应符合欧洲药典2.6.1.3的要求。一个替代的方法，要求对相关的已有上市许可进行变更，就是引入一个参数放行系统，这样避免进行无菌测试。
3. What are the key changes in the 2008 revision of annex 1 of the EU GMP? H+V January 2010
2008版对EU GMP附录1的主要变更有哪些？ H+V 2010年1月
The revision provides updated guidance on:
该版本在以下内容有更新
l classification of the environmental cleanliness of clean rooms;
l 洁净区环境洁净度的级别
l guidance on media simulations;
l 媒质模拟指南
l guidance on capping of vials;
l 小瓶加盖指南
l bioburden monitoring prior to sterilisation.
l 灭菌前生物负载监控
4. The new revision to the annex includes a number of revised requirements. What steps are being taken by EU authorities to assure the consistent interpretation of the requirements of the revised annex by EU GMP inspectors during inspections? H+V January 2010
对附录进行的新的修订，包括一系统修订的要求。EU药监部门要采取什么措施来保证EU GMP检查人员在检查中会对修订后的附录要求持有一致的解释？
GMP inspectors from the EU have worked together with inspectors from Swissmedic to prepare harmonised guidance on the interpretation of the revised annex to be used during the inspection of manufacturers by their Inspectors. This document has subsequently been proposed and adopted as draft guidance by thePharmaceutical Inspection Cooperation Scheme (PIC/S): GMP annex 1 revision 2008: Interpretation of most important changes for the manufacture of sterile medicinal products .
EU的GMP检查人员已经和瑞士的检查人员在一起工作，准备一份关于修订后附录的一致性解释指南，在其对生产商的检查中使用。该文件之后将被建议并由PIC/S采用作为指南草案“GMP附录I于2008修订：无菌药品生产中最重要的变更解释”。
5. For an aseptically produced product, where should bioburden monitoring take place? H+V May 2013
对于无菌工艺生产的产品，应该在什么地方实施生物负载监控？ H+V 2013年5月
According to the EU GMP guideline (annex 1), the bioburden should be monitored before sterilisation and testing should be performed on each batch.
根据EU GMP指南（附录1），要在灭菌前对每一个批次进行生物负载监控。
For routine commercial manufacturing, bioburden testing should be performed on the bulk solution, immediately before its sterile filtration. If a presterilising filter is additionally installed, then sampling for bioburden testing may be performed prior to the prefiltration, provided that no holding time is scheduled for the solution between the two filtration steps.
对于常规的商业生产，生物负载测试应在无菌过滤之前的散装溶液中进行。如果额外安装了预灭菌过滤，并且在两个过滤步骤间并没有设计对溶液的保留赶时间，则生物负载测试的取样可以在预过滤前进行。
6. What is the maximum acceptable bioburden level? H+V May 2013
生物负载最大可接受水平是多少？H+V 2013年5月
The specification limits for bioburden should be NMT 10 CFU/100 ml, in line with the human and veterinary notes for guidance on manufacture of the finished dosage form (CPMP/QWP/486/95 andEMEA/CVMP/126/95).
生物负载限度应为NMT10CFU/100ml，与人用和兽用制剂生产指南注释（CPMP/QWP/486/95 和EMEA/CVMP/126/95）要求一致。
When a prefilter is installed, unless otherwise justified, a bioburden limit of 10 CFUs/100 ml before first filtration is achievable in principle and is strongly recommended from a GMP point of view. Higher bioburden limits should not be justified by the high capacity of two consecutive bacteria retaining filters.
如果安装了预过滤器，除非另有论述，否则，从GMP出发，强烈推荐原则上要求在第一次过滤前要求生物负载限度能达到10CFU/100ml。太高的生物负载限度不能由两个连续的细菌截留过滤器具有较高的过滤能力来论述。
However, when appropriate justification is submitted (processes involving fermentation or other biological or herbal components, use of purified water for ophthalmic preparations, etc.), a bioburden limit of higher than 10 CFUs/100 ml before prefiltration may be acceptable. In such cases, it should be demonstrated that the first filter has the capability to achieve a bioburden prior to the last filtration of NMT 10 CFUs/100 ml, in line with the notes for guidance on manufacture of the finished dosage form (CPMP/QWP/486/95 and EMEA/CVMP/126/95).
但是，如果提交了适当的论证（涉及发酵，或其它生物或草药组件的工艺，眼药制剂使用纯化水等），则在预过滤前生物负载限度高于10CFU/100ml也是可以接受的。在这种情形下，要证明第一次过滤具备能力使得生物负载在进行最终过滤前达到NMT10CFU/100ml，符合制剂剂型的生产指南要求（CPMP/QWP/486/95 和 EMEA/CVMP/126/95）。