EU GMP附录1的2016修订本-行业期待什么?

GMP News

25/05/2016

EU GMP Annex 1 Revision 2016 - what does the pharmaceutical industry expect?

EU GMP附录1的2016修订本—行业期待什么？

Europe's biggest Pharma Congress of its kind took place in Düsseldorf on 12 and 13 April. With more than 1000 participants, 90 exhibitors and 10 GMP conferences this Congress 2016 has been the biggest since the first one 18 years ago. 50 lectures, almost exclusively case studies from pharmacuetical companies such as Pfizer, Novartis, Boehringer Ingelheim and many more were discussed. Special attention was paid to the keynotes at the beginning of each congress day.

欧洲最大的药业集会于4月12-13日杜塞尔多夫举行。参与者超过1000人，有90个参展商，10个GMP会议。此次集会是18年来规模最大的一次。会议里讨论了50次演讲，案例研究，这些案例几乎都是都来自药业公司，例如，辉瑞、诺华、勃林格殷格翰，和其它案例。在每个集会日的开始，主题演讲就特别吸引注意。

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote speech about the revision of Annex 1 of the EU Guidelines to Good Manufacturing Practice. The first version dates already back to the year 1972. Dr Haefele stated that there had already been five revisions since this time but no fundamental review. This means the time has come to revise this fundamental document on the regulation of sterile manufacture in Europe.

Dr Friedrich Haefele，勃林格殷格翰的灌装&成品生物制品副总裁，在其主题演讲中谈到了EU GMP指南附录1修订。第一版本要回溯到1972年。Dr Haefele说自那时起，已经进行了5次修订，但没有原则性的审核。这意味着已经到了对此欧洲无菌生产法规的基本文件进行修订的时机。

Dr Haefele demonstrated the need for action on one hand by a comparison with the FDA Aseptic Guide and on the other hand by means of his own commenting. Friedrich Haefele said that priority should be given to harmonisation. He basically believes that Annex 1 should remain reserved for sterile parenteral products and that other sterile products or active pharmaceutical ingredients should be regulated in other documents or in specific annexes. He also wants a separation between aseptically manufactured and terminally sterilised products in the new Annex 1.

Dr Haefele一方面与FDA无菌指南进行对比，另一方面讲了自己的意见，说明了采取行动的必要性。Friedrich Haefele说，要优先照顾协调性。他非常相信附录1应该保留，用于无菌注射剂，而其它无菌药品或原料药应采用其它文件或者采用特定的附录来规范管理。他还想在新的附录1里将无菌生产和最终灭菌药品分开。

He considers DIN ISO 14644-1 to be a central document that is used for the classification of clean rooms in the European Guideline but also in the US Guide. Dr Haefele is not bothered by the fact that the limit for 5 um particles has been deleted from the grade ISO 5 (ISO 4.8). According to him it should also be deleted from the European requirements. Deviations in the case of 0.5 and 5 um particles occur essentially in parallel so that it should be possible to renounce to the limit for 5 ?m particles.

他考虑到DIN ISO14644-1将会是核心文件，在欧洲指南中用于洁净区分级，并且也用于美国指南中。Dr Haefele并不担心5.0um颗粒的限度被从ISO5（ISO4.8）中删除了。他认为，欧洲要求里也应该删除这个要求。如果0.5和5.0um颗粒同时超标，则有可能放弃 5.0um颗粒的限度。

Dr Haefele also proposed a simplification for the microbiological environmental monitoring. Settle plates as well as microbial air sampling are required in Europe at the moment. According to Dr Haefele only the microbial air sampling should be compulsory whereas the use of settle plates should be optional or additional. The use of average values in the microbiological monitoring in the clean room should be dismissed. With the use of isolators with validated decontamination cycles the microbiological monitoring could be reduced to the essential pursuant to ICH Q9 Quality Risk Management.

Dr Haefele还提议对微生物环境监测进行简化。在欧洲，目录要求沉降菌和浮游菌都应取样。Dr Haefele认为，只有浮游菌是必须符合要求的，而使用沉降菌应该是可选项或者是附加的。应取消在洁净室微生物监测中使用平均值。如果使用隔离器，除污染循环进行了验证，可以根据ICH Q9风险管理减少微生物监测。

In contrast to the FDA Aseptic Guide the European Annex 1 contains requirements concerning the crimping process as well as a differentiation between aseptic and clean processes. For the latter Dr Haefele wants a clear definition of 'Grade A Air Supply' that should be used for protection during the process according to Annex 1. Dr Haefele stated that the industry has its opinion concerning this but that it should also be recorded in the relevant official document. By this he meant the use of air filtered according to the requirements of grade A without considering the microbiological requirements.

与FDA无菌指南相反，欧洲附录1包括了轧盖过程中的要求，以及无菌和洁净工艺之间的差异。对于后者，Dr Haefele想要对“A级送风”有一个清楚的定义，根据附录1用于工艺中的保护。Dr Haefele 说，行业对此有得选择，但要在相关的正式文件中记录。他说这些的意思是根据A级要求使用过滤过的空气，不需要考虑微生物要求。

There are important differences between Annex 1 and the Aseptic Guide in the area of sterilisation. The US document contains no indications for a terminal product sterilisation. It is contained in the EU document. Dr Haefele proposes to limit the requirement for a sterilisation with pure steam primariliy to the terminal product sterilisation and to also allow other methods e.g. sterilisation with ethylene oxide for example for so-called ready-to-use materials.

在附录1和灭菌领域无菌指南之间有重大差异。美国文件没有包括最终产品灭菌指示剂。在欧盟文件里则包括了。Dr Haefele提议限制使用纯蒸汽灭菌的要求，优先使用最终灭菌，还允许使用其它方法，例如，所谓随时可用物料的环氧乙烷灭菌。

He sees further potential for improvement concerning the topic sterile filtration. He considers that the integrity testing after sterilisation immediately before filling can be omitted since the data of the filter validation and the integrity testing after filling give adequate security. To renounce to the obligatory integrity testing after sterilisation and before use, reduces the complexity of the aseptic set-up and when constructing facilities.

他看到无菌过滤改进的可能性。他认为可以省去灌装之前灭菌之后立即进行完整性测试，因为过滤器的验证数据和灌装之后的完整性测试提供了足够的安全保证。拒绝进行灭菌之后使用之前的强制完整性测试，可以降低无菌装置及工厂建议的复杂性。

A further difference concerns the quality oversight. In Europe there is no requirement that the quality assurance (physically) must take place on-site during aseptic processes. But the Aseptic Guide requires a QC oversight and here, especially the media fill is mentioned. Dr Haefele invoked a harmonisation of the requirements, in order to strengthen the European philosophy, however. Quality assurance is a system and not an organisation. Mr. Haefele proposed a further change concerning the media fill in isolators. Here, interventions are carried out from the outside when carrying gloves. This means that they are 'person-neutral'. The requirement that the qualification of interventions during the media fill has to be done person-specific should therefore be omitted for media fills in isolators.

更多的差异是关于质量监管。在欧洲，没有要求在无菌工艺过程中必须有现场质量保证（物理）。但是无菌指南则要求有QC监管，尤其提到了培养基灌装。Dr Haefele援引了不同要求的协调，为了加强欧洲哲理，质量保证是一个系统而不是一个组织。Mr. Haefele提议对隔离器里培养基灌装进一步变更。这里，当使用手套操作时从外面介入。这意味着他们是“中性的”。必须由人来做培养基灌装中介入的确认要求可以省去。

As concerns the topic disinfection Mr. Haefele would prefer the admission of hydrogen peroxide for the decontamination of surfaces in isolators and material locks as well as the dispensation with the mandatory rotation when using disinfectants.

关于灭菌，Mr. Haefele倾向于采用过氧化氢清除隔离器和物料锁表面的污染，以及在使用消毒剂时采用搅拌来分散。

A further topic in Annex 1 is the monitoring of the integrity of containers containing sterile medicinal products. At the moment, the Annex requires a 100% integrity testing only for containers closed by fusion (glass ampoules and BFS containers). Dr Haefele would prefer more openness up to suitable controls for all packaging systems or pharmaceutical dosage forms.

在附录1中另一个主题是装有无菌药品的容器完整性的监测。目前，附录只要求对熔融封闭的容器（玻璃安瓿和BFS容器）进行100%完整性测试。Dr Haefele倾向于对所有包装系统或药物剂型适当控制具有更大开放性。

Finally, he reaffirmed the use of modern barrier techniques for the aseptic manufacture as state-of-the-art and repeated his wish for a harmonisation of the requirements for sterile and aseptically produced medicinal products. MRA, mutual recognition agreements, could reduce the number of regulatory inspections at the companies.

最后，他重申使用现代隔离技术用于无菌生产是理想状态，重复了他对无菌要求和无菌生产药品协调的希望。MRA、互认协议可以减少对公司进行法规检查的数量。

Currently, the publication of the draft of the new EU GMP Annex 1 is planned for autumn 2016.

现在，EU GMP附录1新版草案计划于2016年秋公布。

Source: Pharma Kongress 2016 (companies who wish to book a booth in 2017 can register here)

来源：药业集会2016.要预订2017年展位的可以登记。