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GMP News
7 u' g5 D; {8 z+ w' H$ H7 {26/11/2014
Shared and Dedicated Facilities: EMA publishes final Guideline on Setting health based exposure limits (PDEs)
共线和专线生产设施：EMA公布其根据暴露限（PDE）设定安全限度的指南最终版
The EMA has now published the long awaited final version of the Guideline which sets the exposure limits of products manufactured in so-called shared facilities (multipurpose). In other words, the question is how much from a product can be carried over in another one (cross contamination) without posing any risk to patient health. The previous EMA Draft Guideline was released in January 2013. EMA刚刚公布期待已久的在所谓共用生产设备（多功能线）中生产产品的暴露限设定指南的最终版，换句话说，就是关于一个产品可以残留多少到另一个产品中（交叉污染），而不会对患者健康产生任何风险。之前EMA指南草案是在2013年1月公布的。
The possibility to deviate from the main procedure on setting limits if adequately justified is a major change highlighted several times in the document. Also the use in the API production is now defined as optional which means that the main principles can be used when it's necessary.
在文件中有好几次都强调了，如果进行了充分的论证，则偏离主程序设定限度是一个主要变更。还有，在原料药生产中的使用现在定义为可选的，这表示必要时可以使用主要原则。
As expected, there has been no change to the basic calculation of the limits (PDE = Permitted Daily Exposure). However, the No-Effect Level coming in the formula is now the NOAEL = no-observed-adverse-effect-level (previously NOEL). This could lead to discussions about what ?adverse' is and what isn't.
与预期一样，对于限度的基本计算方法并没有改变(PDE=允许日暴露值)。但是，现在用于公式的无影响水平是NOAEL=无可观察的副反应水平（之前的NOEL）了。这可能会导致关于什么是副反应，什么不是副反应的讨论。
The limit for genotoxic residues of intermediate products is now the same as for genotoxic impurities from the manufacturing process itself: 1.5 ?g (instead of 0.15 ?g/day in the draft).
中间体的基因毒性物质残留限度现在与生产工艺本身产生的基因杂质水平是一样的了，即1.5?g（取代了草案中的0.15?g/天）。
According to the guideline, the PDE approach may not apply to macromolecules since these molecules can be chemically or thermally inactivated. The observation of the completeness of an inactivation or possible degradation products isn't addressed in the present document.
根据指南，PDE方法可能不适用于大分子物质，因为其分子可能被化学或热力灭活。现在的文件中没有对灭活的完整性或可能的降解产物信息。
Development products from Phase I and II have been newly added, for which limited toxicological or pharmacological data are available and make thus the estimation of the PDE very difficult. Here, scientific publications are mentioned which describe alternative procedures.
新增加了I期和II期研发药品，在该研发期间，毒性或药理数据较为有限，因为很难进行PDE估计。这里提到了一些描述了可替代程序的科学出版物。
The new section 6 now contains more details about how the authority excepts the derivation of the PDE values incl. the necessary correction factors and the lead effects. A summary of this derivation is also explicitly required for GMP inspectors who - in practice - have to deal with the plausibility of these scientific reports and with e.g. derived limits for cleaning validation.
新的第6部分现在包括更多细节，关于药监当局对PDE值计算方法的期望的详细内容，包括必要的校正因子和领先效果。GMP检查员也很明确地要求该对计算进行总结，在实践中，检查员必须对这些貌似合理的科学报告，以及例如，清洁验证的限度。
The transitional period - which is described in several stages - is also new. The transitional period for new products or products introduced for the first time into shared manufacturing facilities is 6 months from publication of the guideline. In the guideline the 1st of June 2015 is written as the date for coming into effect. For products already manufactured in shared facilities the transition period is 1 year. For shared facilities were only products for veterinary use are manufactured, the transition period is 2 years.
过渡时期----在几个阶段进行了描述----也是新的内容。新产品或将产品第一次引入共用生产线的过渡时期为自指南公布开始6个月。在指南中，2015年6月1日是书面的生效时间。对于已经在共线上生产的产品，过渡时间为1年。对于只生产兽用药的共用生产设施，过渡时间为2年。
Now the interesting question is how welcome and ranked this guideline in practice will be and how deviating approaches from the procedure described will be assessed. In the drafts of Chapter 5 of the EU GMP Guide (Production), EMA's Guideline and the procedure for the calculation of PDEs have been explicitly named. This reference is missing in the finale version. Yet, the EMA guideline refers to the chapters 3 and 5 of the EU Guide and the required scientific and risk-based approach on the handling of products in multipurpose facilities. In the chapter on cleaning validation of the current draft version of the Annex 15 of the EU GMP Guide (Validation & Qualification) the reference to the EMA Paper is still available. One should expect further changes to the finale version of Annex 15 - finally, one will have to wait for the finale version of the document. See also: Quo Vadis Cleaning Validation. 现在，一个有意思的问题该指南是否受到行业的欢迎，以及如何付诸实践，如果采取的方法与所述的程序有差异，又该如何评估。在EU GMP指南第5章（生产）草案中，清楚列出了EMA的指南和PDE计算方法。在最终版中，该引用没有了。EMA指南引用了EU指南的第3章和第5章，要求在处理多功能生产设施中的产品时要根据科学和基于风险的方法。在目前EU GMP指南附录15（验证和确认）草案版本的清洁验证章节中，还是引用了EMA概念文章。我们还是要期望对附录15最终版本有进一步的变化---不管怎样，我们还是必须等待该文件的最终版本。
指南的最终版可以在EMA的官网上找到。
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