20140903 ECA新闻：关于“制药用水”的问答

0140903 ECA新闻：关于“制药用水”的问答  

2014-09-04 17:40:06|  分类： ECA新闻|举报|字号 [url=]订阅[/url]

GMP News
03/09/2014

Questions and Answers on the Topic "Pharmaceutical Water"

关于“制药用水”的问答

During our courses and conferences participants quite frequently raise questions on pharmaceutical water preparation and distribution. Therefore following you will find some of these questions and their respective answers.  

在我们的培训课程和会议中，有参加者非常频繁地问到一些关于制药用水制备和分配的问题。因此，我们对这些问题及对应的答案汇总如下：

Question 1:  Which concentrations of ozone are required in water systems?

问1：水系统中臭氧浓度应该是多少？

The technical literature delivers different information about the ozone concentrations in water systems: e.g. ISPE Baseline Water and Steam: 0.02 ppm - 0.2 ppm; Collentro, Pharmaceutical Water: 0.2 ppm - 0.5 ppm and W.Setz, Ciba-Geigy 1990: max 0.04 ppm, for sanitisation 0.05 ppm.
The indications provided by the ISPE Baseline refer to the concentration required to prevent microbial growth. One can thus assume that a concentration of 20 ppb ozone can prevent any growth.

技术文献对于水系统中的臭氧浓度给出了不同的信息：例如，ISPE 基线水和蒸汽：0.02ppm-0.2ppm；COLLERTRO，制药用水：0.2ppm-0.5ppm，以及W SETZ，汽巴-嘉基1990：最高0.04ppm，消毒0.05ppm。ISPE基线所提供的指标表示该浓度是防止细菌滋生所需的浓度。因此我们可以假定浓度为20ppb的臭氧可以防止任何细菌滋生。

If systemic protection is desired i.e. the constant presence of ozone in the water, lower ozone values are sufficient.

如果需要进行系统地保护，即保持水中的臭氧，则较低的臭氧浓度就足够了。

In practice, approx. 0.02 to 0.05 ppm should be sufficient for Aqua Purificata. For sanitisation, it naturally depends on the sanitation time intervals - daily or weekly. Finally, the required ozone concentration for the system should be determined within the framework of the validation for the whole system.

在实际操作中，约0.02-0.05ppm的浓度对于Aqua Purificata就足够了。用于消毒时，主要取决于消毒的时间间隔---每天还是每周。最后，系统所需的臭氧浓度应根据整个系统的验证框架来决定。

Question 2: How many ozone measurement points should be available in the water system?

问2：水系统中要设置多少臭氧的测量点？

If ozone is used for the sanitisation of the distribution system, the effect should also be proven by means of - indirectly - the determination of the KBE values on the one hand, and on the second hand through the proof that the ozone concentration is measured at the appropriate points in the water system. For this purpose, the ISPE Baseline mentions at least 3 measurement points:

如果臭氧用于分配系统的消毒，其效果还应采用（间接）KBE值来测量证明，另一方面通过在水系统适当点测得的臭氧浓度来证明。为此，ISPE基线提到至少应有3个测量点：

• In the storage tank
• 贮罐中
• After the UV system
• UV灯后面
• In the return flow
• 回水中
  

The measurement in the storage tank shows that the concentration is sufficient during the permanent ozonisation. After the UV system, a measurement is done to assure destruction of the ozone. The post-use point in the return flow of the pipeline system is measured to prove that the ozone concentration is sufficient during sanitisation.

贮罐中检测点的测量显示持续臭氧化中臭氧浓度是否足够。在紫外系统后，其测量用以保证臭氧被降解。管道中回水处已使用点的测量是要证明臭氧浓度在消毒过程中的浓度是足够的。

Question 3: Is there - from a GMP point of view - a preferred sanitisation method?

问3：从GMP观点来看，是否有比较优先的消毒方法？

Basically, the following three sanitisation procedures are used today:

基本来说，以下三种消毒方法目前都在使用中

• Hot water sanitisation
• 热水消毒
• Sanitisation with steam
• 蒸汽消毒
• Chemical sanitization
• 化学消毒
  

The FDA, as well as the ISPE in its Baseline - are in favour of thermal sanitisation with steam. The Guidance for Industry: Sterile drug products produced by aseptic processing Prepared by Task Force (Japan) contains the following note:

FDA，还有ISPE在其基线中，倾向于采用蒸汽进行高温消毒。行业指南（日本：无菌工艺生产的无菌产品）包括以下的注释：
"Since water for injection needs to be microbiologically pure, the equipment used for its production should be capable of withstanding periodic sterilization with pure steam at temperatures over 121°C for a given length of time. If steam sterilization is not possible because of low heat tolerance, an alternative sterilization or sanitization procedure (e.g., hot water or chemical agents) should be used for the equipment."

“由于注射用水需要具有微生物纯度，因此用于该生产的设备必须能承受蒸汽的周期消毒，应在给定的时长采用超过121度的温度消毒。如果因为耐热能力差而不能采用蒸汽消毒，则应采用替代的消毒方法或灭菌程序（例如，热水或化学试剂）。”
GMP doesn't specify any method. According to the state of the art, one should prefer sanitisation with steam.

GMP里并没有指明任何一种消毒方式。按理想情况来说，企业应优先考虑蒸汽消毒。

Question 4: Is cold storage allowed in WFI systems?

问4：注射用水是否可以使用低温存贮？

For WFI and purified water, different temperatures are used. WFI is usually stored under heat.
In FDA's Guide to Inspections of High purity Water Systems you can find two indications of temperatures which are actually contradictory. The first temperature interval is described under "System Design". "The fist chapter basically states under "System Design" that it is recognized that hot water systems (here to understand as 65 to 80°C systems) are self sanitizing. Another temperature interval is indicated in the chapter "Piping". This concretely means here that the Guide applies to hot 75 - 80°C circulating systems. These indications are in connection with the 6D rule:

注射用水和纯化水应使用不同温度存贮。注射用水一般存贮在加热条件下。在FDA指南（高纯水系统检查指南）中，你可以发现有两个温度指标，它们实际上是相互矛盾的。第一个温度差异是在“系统设计”里描述的，第一章系统设计里说热水系统（这里理解为65-80度的系统）自身是可以消毒的。另一个温度范围是在“管线”章节里，这里具体地说明了指南适用于75-80度热水循环系统。这两个指标与6D规则相关。
FDA - GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS

FDA—高纯水系统检查指南
"One common problem with piping is that of "dead-legs". The proposed LVP Regulations defined dead-legs as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use. It should be pointed out that this was developed for hot 75 - 80°C circulating systems."

“一个常见的管线问题是“死角”。提议的LVP规范定义死角为不使用的管线，其从管道轴心开始测量的长度大于6倍不使用管道直径。要指出的是，对于75-80度热水循环系统来说，这个观点已经有新的进展。”
It follows from the above that cold systems for WFI actually don't comply with the requirements. Under these circumstances, it is likely that at least the FDA doesn't accept cold WFI systems.

这个问题是继上述注射用低温水系统后的，它实际上并不符合要求。在这样环境下，FDA至少不会接受注射用低温水系统。

If appropriate measures (system design and sanitisation measures) can ensure that microbial growth is prevented, cold storage could basically be used. Different limits for cold storage can be found in guidelines and standards (Wallh?user: 4°C;  ISPE: 4° to 10°C). A sanitisation concept for cold storage determined within validation is imperative and should also consider the increased high-risk of bio film formation.

如果进行适当的措施（系统设计和消毒措施）可以保证能防止微生物滋长，则原则上来说，低温存贮是可以使用的。低温存贮的不同限度可以在指南和标准（Wallh?user: 4°C;  ISPE: 4° to 10°C）上找到。在验证范围内确定低温存贮的消毒概念是必须的，同时还要考虑增长的生物膜形成所增加的高风险。

Question 5: Are sterilizing filters permitted in water systems?

问5：水系统中允许安装无菌过滤器吗？

The answer to that question requires the examination of the legal provisions and the standards and guidelines on the topic "Water". The EU GMP Guide describes in a few points the requirements for facilities and equipment. Relating to the sterilizing filters, the following indications may be authorised:

对这个问题的回答需要检查法规中的条款，以及在“水”标题下的标准和指南。EU GMP指南有几点中描述了设施和设备的要求。以下几点与无菌过滤有关的可以参考

• EU GMP 3.38: "Equipment should be installed in such a way as to prevent any risk of error or contamination."
• EU GMP 3.38：设备安装应能防止错误操作或污染风险
• EU GMP 3.39: "Production equipment should not present any hazard to the products."
• EU GMP 3.39：生产设备应对产品不产生危害
• EU GMP 3.36: "Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned."
• EU GMP 3.36：生产设备设计应易于彻底清洁
• EU GMP Annex 1: "Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality."
• EU GMP附录1：水处理站和分配系统的设计、建造和维护应保证能可靠地提供适当质量的水源
  

In almost all guidelines, references are made to sterilizing filters. As an example, see the following statement from a Japanese guideline: Sterile drug products produced by aseptic processing (Japan 2006)

无菌过滤器几乎引用了所有指南。举例来说，以下一份日本指南中声明：无菌工艺生产的无菌药品（日本2006）

"As a rule, sterilizing filters should not be placed at water use points since the filters could mask microbiological contamination in the water system. Endotoxins could also be released from dead microorganisms retained in the filters. If the use of filters is unavoidable, the interval of replacement should be based on validation results."

“规范要求，无菌过滤器不应安装在水的使用点，因为过滤器会掩盖水系统中的微生物污染情况。过滤器里的细菌尸体还会释放内毒素。如果不能避免地要使用过滤器，则要根据验证的结果对过滤器进行定期更换。”

In this Japanese document, the position to filters is obvious: no sterilizing filters should normally be used. Yet, there can definitely be exceptions. The filters shouldn't serve for masking too high KBE values. Finally, one should justify the use of such a filter.

在上述日本文件中，过滤器的处境说的很明白：一般不应使用过滤器。当然，还是会有例外的。过滤器不应用于掩盖过高的KBE值。最后，生产商应自己判断是否必须使用这样的过滤器。

该资料来自于nmwang66的网易微博

感谢分享，辛苦

无菌过滤器不得安装在水的使用点？

学习了，O(∩_∩)O谢谢