发布时间 : 星期六 文章FDA高纯水系统检查指南-翻译和解读-0905更新完毕开始阅读6935c3ae941ea76e59fa0427
翻译: Pinky(@) 校对并解读: Chank (chank2006@gmail.com) 个人使用，不用做商业用途！ With the development of biotechnology products, many small companies are utilizing RO and UF systems to produce high purity water. For example, Figure 9 illustrates a wall mounted system that is fed by a single pass RO unit.
随着生物制药的发展，很多小公司用反渗透和超滤系统来生产高纯水。比如，图9阐述了一个壁挂式系统只含有一级反渗透单元。
As illustrated, most of these systems employ PVC or some type of plastic tubing. Because the systems are typically cold, the many joints in the system are subject to contamination. Another potential problem with PVC tubing is extractables. Looking at the WFI from a system to assure that it meets USP requirements, without some assurance that there are no extractables would not be acceptable.
如上阐述过的，很多系统采用了PVC(聚氯乙烯)或某些塑料材质的管道。因为这类系统是典型的冷系统，系统中很多的连接点会遭受到污染。另一个潜在的问题，就是PVC管具水萃性5。要检查一下系统，确保生产出来的注射用水符合USP的要求，如果不能确保管道没有水萃性，将不会被接受的。
The systems also contain 0.2 micron point of use filters which can mask the level of microbiological contamination in the system. While it is recognized that endotoxins are the primary concern in such a system, a filter will reduce microbiological contamination, but not necessarily endotoxin
contamination. If filters are used in a water system there should be a stated purpose for the filter, i.e., particulate removal or microbial reduction, and an SOP stating the frequency with which the filter is to be changed which is based on data generated during the validation of the system.
系统还包括使用点的0.2微米的过滤器，可以降低系统中微生物污染的水平。然而在这样的系统中，内毒素问题是首要的问题，过滤膜可以降低微生物污染，但无法降低内毒素污染。如果系统中有用到这样的过滤器，其用途要说明，比如是去除颗粒物或降低微生物水平，还必须有SOP规定多久更换该过滤器，更换频率应该是在系统验证阶段积累的数据基础上制定的。 As previously discussed, because of the volume of water actually tested (.1ml for endotoxins vs. 100ml for WFI), the microbiological test offers a good index of the level of contamination in a system.
5
即在水中一定条件下会有物质被萃取出来.
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翻译: Pinky(@) 校对并解读: Chank (chank2006@gmail.com) 个人使用，不用做商业用途！ Therefore, unless the water is sampled prior to the final 0.2 micron filter, microbiological testing will have little meaning.
如前讨论，考虑到实际检测的水样量（注射用水100毫升样品中只有0.1ml被用来检测内毒素），微生物测试为系统中微生物污染的水平提供了好的参考。因此，除非是在最后的0.2微米过滤器之前取样, 微生物测试实际的意义不大。
At a reinspection of this facility, it was noted that they corrected the deficient water system with a circulating stainless steel piping system that was fed by four RO units in series. Because this manufacturer did not have a need for a large amount of water (the total system capacity was about 30 gallons), they attempted to let the system sit for approximately one day. Figure 9 shows that at zero time (at 9 AM on 3/10), there were no detectable levels of microorganisms and of endotoxins. After one day, this static non-circulating system was found to be contaminated. The four consecutive one hour samples also illustrate the variability among samples taken from a system. After the last sample at 12 PM was collected, the system was resanitized with 0.5% peroxide solution, flushed, recirculated and resampled. No levels of microbiological contamination were found on daily samples after the system was put back in operation. This is the reason the agency has recommended that non-recirculating water systems be drained daily and water not be allowed to sit in the system. 在对该厂的复查中，发现工厂水系统的缺陷已经整改，采用了一套循环系统的不锈钢管道，用四级RO组处理。由于该厂对水的需求量不大（水系统总的产能约30加仑），他们试图让系统静置一天，图9显示，在起始点（3月10号的9：00am），并没有检测到微生物和内毒素。当过了一天后，这个静置的无循环的系统，检测出被污染了。随后每隔一小时进行了四小时的连续取样，显示了所取样品的微生物含量波动。在12：00pm最后一个样品收集后，用0.5%的双氧水溶液重新对系统进行灭菌，清洗，重新循环并再次取样。在系统回归正常使用后，在日常检查中，又没检测到微生物污染。这就是为什么当局建议对非循环的系统，需要每天排空，水不应该在系统中静置的原因。 Chank 解读
单纯的RO设备于注射用水的生产,目前已经不常见了,要注意本指南毕竟已经是近16年前的东西了,很多设计目前都不用了.但是这里提到的潜在的污染途径还是值得注意的.这里的讨论很具体了,可以直接作为设计和审计的主要考察点去考察. XI. PURIFIED WATER SYSTEMS
Many of the comments regarding equipment for WFI systems are applicable to Purified Water Systems. One type system that has been used to control microbiological contamination utilizes ozone. Figure 10 illustrates a typical system. Although the system has purported to be relatively inexpensive, there are some problems associated with it. For optimum effectiveness, it is required that dissolved ozone residual remain in the system. This presents both employee safety problems and use problems when drugs are formulated. XI．纯化水系统
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翻译: Pinky(@) 校对并解读: Chank (chank2006@gmail.com) 个人使用，不用做商业用途！ 对注射用水系统的设备的很多建议，也适用于纯化水系统。用来控制微生物污染的一种系统是利用臭氧。图-10是一个典型的系统。这个系统设备相对来说是便宜的，不过还是有问题存在的。为了灭菌的合适效力，需要在系统中存有适当的臭氧残留，这就引起了员工的安全问题和药物制剂在使用中的一些问题。
Published data for Vicks Greensboro, NC facility showed that their system was recontaminated in two to three days after the ozone generator was turned off. In an inspection of another manufacturer, it was noted that a firm was experiencing a contamination problem with Pseudomonas sp. Because of potential problems with employee safety, ozone was removed from the water prior to placing it in their recirculating system. It has been reported that dissolved ozone at a level of 0.45 mg/liter will remain in a system for a maximum of five to six hours.
位于北加州Greensboro的Vicks 化工厂发布的数据表明他们的系统在臭氧发生器关闭后2-3天内就会被污染。在另一家工厂的检查中，发现工厂曾经有假单胞细菌的污染问题。由于对员工健康的潜在风险，臭氧应该在水回到循环系统之前被除去。有报导说，系统中溶解在水里的臭氧浓度达到0.45mg/L时，会保持最久达5-6小时。
Another manufacturer, as part of their daily sanitization, removes all drops off of their ozonated water system and disinfects them in filter sterilized 70% isopropyl alcohol. This manufacturer has reported excellent microbiological results. However, sampling is only performed immediately after sanitization and not at the end of operations. Thus, the results are not that meaningful.
另一家工厂，作为日常消毒的一部分，除去水系统中所有含臭氧的水，并使用70%异丙醇消毒处理过的过滤器进行消毒处理. 该工厂报告了良好的微生物结果。然而，取样是在灭菌后立即进行的，而不是在操作后的最终时刻。因此，结果不是那么有意义。 Chank 解读
臭氧系统依然是目前纯化水消毒处理的常用手段,必须根据系统的实际规模和臭氧发生器的实际功率来确保灭菌的有效性和残留臭氧的安全性.要注意的是不是所有的产品都适用于该方法消毒,所以必要的产品兼容性试验是可以提供有用的数据和信息的.还必须考虑到臭氧对人员健康的潜在危险,模拟消毒效果的试验对于使用最低浓度的臭氧来达到消毒的效果是很有必要的. Figure 11 and Figure12 illustrate another purified water system which had some problems. Unlike most of the other systems discussed, this is a one-way and not recirculating system. A heat exchanger
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翻译: Pinky(@) 校对并解读: Chank (chank2006@gmail.com) 个人使用，不用做商业用途！ is used to heat the water on a weekly basis and sanitize the system. Actually, the entire system is a \
图-11和图-12显示了有问题的另一种纯化水系统。和其它讨论的大多数的系统不同，该系统是个单向流系统，而不是循环系统。一个热交换器被用来每周一次加热和灭菌水系统。实际上，整个的系统，就是一个“死角”。
Figure 11 also shows a 0.2 micron in line filter used to sanitize the purified water on a daily basis. In addition to the filter housing providing a good environment for microbiological contamination, a typical problem is water hammer that can cause \
the filter is shut too fast, the water pressure will reverse and can cause \typical visible sign of high back pressure while passage of upstream contaminants on the filter face is a real problem. This system also contains several vertical drops at use points. During sanitization, it is important to \water and thus, get complete exposure to the sanitizing agent.
图-11还显示了一个0.2um的管道过滤器，用来每天消毒处理纯化水系统。此外，在过滤器管道中提供了微生物污染的一个良好的环境，一个典型的问题就是水锤会引起过滤器的气泡现象。如果过滤器的下游水阀门关闭太快，水压会倒转，而形成气泡。管道振动就是一个典型的高回转压力的可见指征，而因此造成的上游污染物通过了过滤器是个真正的问题。该系统还涵盖了几个使用点的垂直弯点。在清洗消毒的过程中，把终端阀彻底打开很重要，这样，所有含水的关节和管道弯曲的地方都能完全暴露到消毒剂中。
It should be pointed out that simply because this is a one-way system, it is not inadequate. With good Standard Operational Procedures, based on validation data, and routine hot flushings of this system, it could be acceptable. A very long system (over 200 yards) with over 50 outlets was found acceptable. This system employed a daily flushing of all outlets with 80oC water.
需要指出的是，并不是因为系统是单向系统就有问题, 这样的简单判断是不够的。基于良好的操作SOP，基于验证数据和日常的热水冲洗该系统，还是可以被接受的。一个很长的系统（超过200码），包含50个以上的出口，检查中也被认为是可行的，这个系统采用了80度的水每天冲洗所有的出口。
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