技术帖] 欧洲药典首次允许以非蒸馏法来制备WFI

一片红云

The European Pharmacopoeia's revised monograph 169 on water for injection (WFI) will become effective by the 1st of April 2017. For the first time in Europe, a monograph will allow the production of WFI with other methods than distillation. According to the text applying as of April, all methods equivalent to distillation will be officially allowed. Reverse osmosis is only mentioned as an exemplary technique. In a previous draft, it was yet another. The European monograph also differs from the Japanese Pharmacopoeia for example in which reverse osmosis is still mentioned explicitly.
欧洲药典修订了各论169“注射用水（WFI）”并且将自2017年4月1日开始生效。这是欧洲首次允许使用蒸馏以外的其它方法来制备WFI。根据药典4月即将生效的药典内容，所有等同于蒸馏的其它方法都是允许的。反渗透法只是被提到了作为一种技术举例。在之前的草案中，还有另一种方法。欧洲药典各论也与日本药典不同，例如在日本药典中，反渗透法仍被明确提出的。
But there are still unanswered questions, e.g. how to deal with HPW systems (highly purified water) which have already been producing water with WFI quality. Many other points - mainly GMP aspects - remain unclear. Yet, it is not the duty of a pharmacopoeia to set GMP requirements. Now although there have been expectations about it, Annex 1 (currently undergoing revision) will only provide little information on WFI obtained by non-distillation methods. The only hope for more details about GMP specifications remains the Question & Answer document of the European Medicines Agency (EMA). Even though the document isn't at the top of the GMP documents hierarchy, it is likely to become one of the leading GMP guidances for the cold production of WFI. The competent expert group of inspectors (IWG) met in the 7th calendar week (2017) to discuss the revision of the first draft version of this document. Generally, content output can be expected after 4 weeks - let's say at the beginning or mid of March.
但是还是有一些问题存疑，例如，HPW系统（高纯水）要如何处理，它是采用WFI质量水源来制备的。许多其它点----主要是GMP方面的---仍然不太清楚。当然，药典并没有义务设备GMP要求。现在，尽管对这个问题有一些期望，附录1（现在正在修订中）将只是提供很少的关于采用非蒸馏法制备WFI的信息。唯一获得更多关于GMP标准的希望就是EMA的问答了。即使文件并不在GMP文件级别的首位，但也可能成为WFI冷制备法的领先GMP指南之一。相关检查员专家组（IWG）在2017年第7周开会讨论了此文件的第一个草案版本的修订。总体而言，4周后有望看到成果---姑且说是3月初或3月中吧。
So far, it is clear that the competent GMP regulatory authority has to be informed when the use of WFI by membrane is planned. When a third country is involved (like India, China or the USA), the competent body is the GMP authority of the respective importer. It is also clear that sanitisation in systems with cold-generated WFI will be playing a much greater role. The present draft of the Q&A paper addresses a routine steam sanitisation of the storage and distribution system, whereby hot-storage systems can actually be considered to be self-sanitising. What about cold storage in permanently ozonised systems? According to the draft, ozone isn't sufficient. It will be interesting to see how the final version of the paper will deal with that.
截止目前，很清楚的一点是计划使用膜制备WFI的时间要通知给药监当局。如果是第三国（如印度、中国或美国），药监当局是相应进口商的GMP药监局。还有一点也很清楚，就是冷制备WFI系统灭菌会很重要。现在的问答草案只讲到了存贮和分配系统常规的蒸汽灭菌，而高温存贮系统实际上可以认为是自带灭菌功能。那么如果是存贮在永久臭氧化系统中呢？根据草案来看，臭氧还是不够的。让我们看看最终版本要如何处理这个问题，这会很有意思。
Also the controls of feed water will become much more important. Although they don't play a really important role in distillation, impurities in the feed water of membrane processes are highly relevant. The control of conductivity and TOC will be more important too. Here, the TOC can also be considered as an indicator of the system's microbiologial contamination risk. According to the present draft, the TOC limits should be statistically justified. The use of 50% of the specification as action limit is thus invalid.
还有关于原水的控制也会变得很重要。在蒸馏制备中这个并不重要，膜过滤工艺中，原水中的杂质会产生很大影响。电导率和TOC控制也会很重要。这里，TOC也可以当作系统微生物污染风险的指标。根据目前的草案，应该论证一个令人满意的TOC限度。使用标准的50%作为行动限也就无效了。
In technical terms, because of the elimination of the phase transition from liquid to steam, the membrane of the new system will become the critical installation section. Regarding this, it is also important to know that a hot sanitation is always recommended after installation. On the one hand, the system suppliers cannot guarantee the sterility of their membranes. On the other hand, the membranes first gain their complete operational capability through tempering. Another interesting point is that the membranes used e.g. in the reverse osmosis grow old. Their selectivity (cut off) changes over the years. Yet, there exist no specifications concerning this. The membranes should also be checked after a change - analogous to a measuring instrument which has to be calibrated once more before being scrapped to demonstrate its correct functioning in the last interval to the end. Moreover, an online integrity test of the membrane would be ideal - which is however in technical terms not available yet.
从技术角度来看，由于少掉了从液相转为蒸汽的相变过程。新系统的膜会成为关键的系统部件。关于此，很重要的一点是要知道在安装完后都是推荐进行热灭菌的。一方面，系统供应商无法保证其膜的无菌性；另一方面，膜通过调整第一次达到其全产能运行。另一个有意思的点是所用的膜，例如，在反渗透系统中会老化。其选择性（阻隔功能）会随时间变化。但是关于这些并没有质量标准存在。膜在更换之后还要进行检查---类似于检测装置在报废之前必须再进行一次校正以证明其在上一次校正后到结束使用前其功能正常。另外，对膜进行在线完整性测试将会是理想的方法---但是在技术角度来说目前还不能实现。
For many users who have been operating HPW systems for years, the question naturally arises of how the transition to WFI production should run. As already mentioned, the GMP regulatory authorities have to be informed. In terms of GMP, experts agree that the treatment/purification part of the system mustn't undergo a new PQ phase. Nothing changes regarding the manufacture of water. This is not the case regarding the storage and distribution system. Here, qualification activities should demonstrate that the cold produced WFI is as safe as the distilled one. For this purpose, the activities described close to maintenance, monitoring and sanitisation will be necessary. More details regarding this are expected in the coming version of the Q&A document.
对于许多已经使用了HPW系统多年的用户来说，问题自然是如何转向WFI制备。正如已提到的，要提前通知GMP法规当局。从GMP角度来说，专家同意系统处理/纯化不必经过一个新的PQ阶段。水制备方面没有任何改变。这讲的并不是存贮和分配系统。这里，确认活动应证明冷制备WFI与蒸馏制备的WFI是一样安全的。为此，有必要描述维护、监测和灭菌活动。更多关于此的细节期望在问答文件新版中发布。
Another interesting question is how long will HPW remain as a monograph in the European Pharmacopoeia? In the pharmaceutical industry, it has in fact no application except for cleaning purposes before the final rinse with WFI. But it is different in the medical devices industry. The outcome thus remains exciting.
另一个有意思的问题是HPW在欧洲药典里还会放多久？在制药行业，实际上除了最终WFI淋洗之前所用清洁水以外，并没有其它用途。但是，在医疗器械行业就不一样了。结果如何，仍然令人猜想无限。
   

云卷云舒0415

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meiya

第二段中文中，“设备”应该是“设置”；
第四段英文中，“microbiologial”应该是“microbiological”。

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