Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).
注意：本文件只是审查员与其他FDA官员的参考材料。本文件不能约束FDA，也不授予任何人任何权利、特权、利益或者豁免权。
This guide discusses, primarily from a microbiological aspect, the review and evaluation of high purity water systems that are used for the manufacture of drug products and drug substances. It also includes a review of the design of the various types of systems and some of the problems that have been associated with these systems. As with other guides, it is not all-inclusive, but provides background and guidance for the review and evaluation of high purity water systems. The Guide To Inspections of Microbiological Pharmaceutical Quality Control Laboratories (May, 1993) provides additional guidance.
该指南主要从微生物方面来评估用于药物制剂和药物生产的高纯水系统，包括不同类型系统的设计审核和与这些系统相关的一些问题。与其它指南一样，该指南只对 高纯化水系统的评估提供背景资料和指导作用，但并不包括一切。另外可参考“制药质量控制实验室的微生物检查指南& rdquo;（May，1993）。
I. SYSTEM DESIGNI.
1. 系统设计
One of the basic considerations in the design of a system is the type of product that is to be manufactured. For parenteral products where there is a concern for pyrogens, it is expected that Water for Injection will be used. This applies to the formulation of products, as well as to the final washing of components and equipment used in their manufacture. Distillation and Reverse Osmosis (RO) filtration are the only acceptable methods listed in the USP for producing Water for Injection. However, in the bulk Pharmaceutical and Biotechnology industries and some foreign companies, Ultra Filtration (UF) is employed to minimize endotoxins in those drug substances that are administered parenterally.
在设计一个系统时，首先要考虑的是生产的产品类型。对注射用药品来说，应重点关注热原物质，所以使用注射用水。注射用水应用于产品的配制，部件及生产设备 的最终冲洗。USP 中规定的生产注射用水方法只有蒸馏法和反渗透法。然而，在大宗制药工业、生物技术工业及一些国外公司中，采用超滤法将注射用药物的内毒素减到最少。
For some ophthalmic products, such as the ophthalmic irrigating solution, and some inhalation products, such as Sterile Water for Inhalation, where there are pyrogen specifications, it is expected that Water for Injection be used in their formulation. However, for most inhalation and ophthalmic products, purified water is used in their formulation. This also applies to topicals, cosmetics and oral products.
在一些眼用制剂（如眼用灌洗剂）和一些吸入制剂（如吸入用无菌水）中，由于有热原标准，所以在其配制中要用注射用水。但是，大部分吸入制剂及眼用制剂都使 用纯化水配制。纯化水还用于外用制剂、化妆品及口服制剂的生产。
Another design consideration is the temperature of the system. It is recognized that hot (65 – 80℃) systems are self sanitizing. While the cost of other systems may be less expensive for a company, the cost of maintenance, testing and potential problems may be greater than the cost of energy saved.
另一个设计关注点是系统温度。温度在65～80℃的热水系统被认为是自净系统。对一个公司来说，虽然其它水系统成本可能更便宜，但是系统的维护、检测和潜 在问题产生的费用可能会比节省的能量费更高。
Whether a system is circulating or one-way is also an important design consideration. Obviously, water in constant motion is less liable to have high levels of contaminant. A one-way water system is basically a "dead-leg".
系统是循环或是单向也是设计系统时所要考虑的重点。显然，让水持续流动就不易受到高水平的污染。一个单向水系统基本上是“死角 ”。
Finally, and possibly the most important consideration, is the risk assessment or level of quality that is desired. It should be recognized that different products require different quality waters. Parenterals require very pure water with no endotoxins. Topical and oral products require less pure water and do not have a requirement for endotoxins. Even with topical and oral products there are factors that dictate different qualities for water. For example, preservatives in antacids are marginally effective, so more stringent microbial limits have to be set. The quality control department should assess each product manufactured with the water from their system and determine the microbial action limits based on the most microbial sensitive product. In lieu of stringent water action limits in the system the manufacturer can add a microbial reduction step in the manufacturing process for the sensitive drug product(s).
最后，设计系统的风险评估及期望的质量水平可能是最重要的考量部分。应该认识到不同产品需要不同质量的水。注射用药需要无内毒素的高纯水，外用制剂和口服 制剂所需水没有内毒素的要求，纯度要求稍低。即使是外用制剂和口服制剂，也有影响要用不同质量的水的各种因素，例如，在抗酸剂中防腐剂几乎不起作用，所以 得制定更严格的微生物指标。质量控制部门应评估采用水系统中的水生产的每一种产品，根据对微生物最敏感的产品制定水系统的微生物纠偏限度。代替制定严格的 水系统微生物纠偏限度的另一种方法是：对于微生物敏感的药品，生产者可在生产过程中增加一步去除微生物的步骤。
II. SYSTEM VALIDATION 系统验证
A basic reference used for the validation of high purity water systems is the Parenteral Drug Association Technical Report No. 4 titled, "Design Concepts for the Validation of a Water for Injection System."
高纯化水系统的验证的基本参考物事《注射用药协会技术报告》第4号文件，名为“注射用水系统验证的设计概念”。
The introduction provides guidance and states that, "Validation often involves the use of an appropriate challenge. In this situation, it would be undesirable to introduce microorganisms into an on-line system; therefore, reliance is placed on periodic testing for microbiological quality and on the installation of monitoring equipment at specific checkpoints to ensure that the total system is operating properly and continuously fulfilling its intended function."
绪论提供了指导并指出：“验证经常包括恰当的挑战方法的使用。在这里，没有必要把微生物引入在线系统进行挑战试验，因此，主要依靠微 生物质量的定期检测以及在特定检查点安装监测设备，以确保整个系统处于正确的运行状态和持续执行其预定功能。”
In the review of a validation report, or in the validation of a high purity water system, there are several aspects that should be considered. Documentation should include a description of the system along with a print. The drawing needs to show all equipment in the system from the water feed to points of use. It should also show all sampling points and their designations. If a system has no print, it is usually considered an objectionable condition. The thinking is if there is no print, then how can the system be validated? How can a quality control manager or microbiologist know where to sample? In those facilities observed without updated prints, serious problems were identified in these systems. The print should be compared to the actual system annually to insure its accuracy, to detect unreported changes and confirm reported changes to the system.
在审核验证报告时或在高纯水系统的验证过程中，有多个方面需要得到考虑。文件记录应包括对系统的描述和打印的图纸。图纸应显示系统中从进水到使用点的所有 设备，也应标明所有的取样点及其名称。如果系统没有图纸，通常是不能令人接受的。检查官会认为如果图纸都没有，怎么进行系统验证呢？质量控制者或微生物检 验者怎么知道哪里可以取样呢？在被观察到没有更新图纸的那些设施中，从这些系统里检查出了很多严重问题。每年应该将图纸和实际系统相对比，以确保图纸的准 确性，及时发现系统中未报告的变更和证实已报告的变更。
After all the equipment and piping has been verified as installed correctly and working as specified, the initial phase of the water system validation can begin. During this phase the operational parameters and the cleaning/ sanitization procedures and frequencies will be developed. Sampling should be daily after each step in the purification process and at each point of use for two to four weeks. The sampling procedure for point of use sampling should reflect how the water is to be drawn e.g. if a hose is usually attached the sample should be taken at the end of the hose. If the SOP calls for the line to be flushed before use of the water from that point, then the sample is taken after the flush. At the end of the two to four week time period the firm should have developed its SOPs for operation of the water system.
在确定所有的设备和管道都正确安装并按预定要求工作后，水系统验证的第一阶段就可以开始了。在此期间，将制定运行参数和清洁消毒程序、频率。每天在水纯化 过程中的每一步骤之后以及每个使用点进行取样，取2-4 周。使用点的取样程序应该描述水是怎么取出来的，例如，如果使用软管取样，应该在软管末端抽取。如果标准操作程序要求使用点用水前要先冲洗，则样品应在冲 洗后取。在2-4 周的末期，公司应该已经制定出水系统运行的标准操作程序。
The second phase of the system validation is to demonstrate that the system will consistently produce the desired water quality when operated in conformance with the SOPs. The sampling is performed as in the initial phase and for the same time period. At the end of this phase the data should demonstrate that the system will consistently produce the desired quality of water.
系统验证的第二阶段是证明当按SOP操作时，系统能持续生产出所期望的水质。取样和取样周期与第一阶段相同。该阶段末期的数据应该证明系统能持续生产出所 需质量的水。
The third phase of validation is designed to demonstrate that when the water system is operated in accordance with the SOPs over a long period of time it will consistently produce water of the desired quality. Any variations in the quality of the feedwater that could affect the operation and ultimately the water quality will be picked up during this phase of the validation. Sampling is performed according to routine procedures and frequencies. For Water for Injection systems the samples should be taken daily from a minimum of one point of use, with all points of use tested weekly. The validation of the water system is completed when the firm has a full years worth of data.
第三阶段的验证被设计用于证明当按SOPs 操作时，系统在很长时期内能持续生产出所设计质量的用水。在本验证阶段中，进水质量的任何变化都会影响系统的运行并且最终的水质将将被检出。取样按照例行 规程和频率进行。注射用水系统每天至少取样一个使用点，每周对所有使用点应进行取样。当公司有一套数年的有价值的数据时，水系统的验证就完成了。
While the above validation scheme is not the only way a system can be validated, it contains the necessary elements for validation of a water system. First, there must be data to support the SOPs. Second, there must be data demonstrating that the SOPs are valid and that the system is capable of consistently producing water that meets the desired specifications. Finally, there must be data to demonstrate that seasonal variations in the feedwater do not adversely affect the operation of the system or the water quality.
虽然以上的验证规划不是验证水系统的唯一方式，但它包含了一个水系统验证必需的要素。首先，必须有数据支持SOP；其次，必须有数据证明SOP 是合理的且系统能持续生产出符合设计质量要求的用水；最后，必须有数据证明进水的季节偏差不会影响系统的运行或水质。
The last part of the validation is the compilation of the data, with any conclusions into the final report. The final validation report must be signed by the appropriate people responsible for operation and quality assurance of the water system.
验证的最后部分是数据的汇编，在最终报告中写入若干结论。最终的验证报告必须由能对水系统运行和质量保证负责的人签字。
A typical problem that occurs is the failure of operating procedures to preclude contamination of the system with non-sterile air remaining in a pipe after drainage. In a system illustrated as in Figure 1, (below) a typical problem occurs when a washer or hose connection is flushed and then drained at the end of the operation. After draining, this valve (the second off of the system) is closed. If on the next day or start-up of the operation the primary valve off of the circulating system is opened, then the non-sterile air remaining in the pipe after drainage would contaminate the system. The solution is to pro-vide for operational procedures that provide for opening the secondary valve before the primary valve to flush the pipe prior to use.
发生的典型问题是排水后非无菌的空气残留在系统管道中造成预防系统污染的操作程序失败。在一个系统中，如图1所示，一个常见问题发生在当用密封圈或软管连 接进行冲洗，然后在该操作的末期进行排水的时候。排水之后，该阀门（系统的第二个阀门）已经关闭。如果第二天或操作启动时，循环系统下面的第一个阀门开 着，那么排水后残存在管道中的非无菌空气就会污染系统。解决该问题的方法是规范操作程序，规定在打开第一个阀门冲洗管道之前必须先打开第二阀门。
建立任何纠偏限度或水平的目的都是确保水系统处于可控状态。任何纠偏限度的建立都要依据整个纯化水系统以及制剂产品的进一步加工工艺和使用用途。例如，经 冷冻工艺处理用来生产药品的纯化水应该是无有害有机体的。“有害有机体”定义为在指导下用药时会导致感染的任何 有机体或在药品生产过程中能繁殖的任何有机体。正如《药物质量控制实验室的微生物检查指南》所指出的那样，污染物的种类通常比污染物数量更重要。
Organisms exist in a water system either as free floating in the water or attached to the walls of the pipes and tanks. When they are attached to the walls they are known as biofilm, which continuously slough off organisms. Thus, contamination is not uniformly distributed in a system and the sample may not be representative of the type and level of contamination. A count of 10 CFU/mL in one sample and 100 or even 1000 CFU/mL in a subsequent sample would not be unrealistic.
水系统中存在的有机体可能悬浮在水中或者吸附在管道壁或罐壁上。吸附在壁上的就是我们所知道的生物膜，可持续脱落出有机体。因而，在一个系统中污染并不是 均匀分布的，取样也可能无法真实反映系统的污染类型和水平。在一个样品中10CFU/ml 的量，然后在继后样品中出现100甚或1000CFU/ml 的量都不是不可能的。
Thus, in establishing the level of contamination allowed in a high purity water system used in the manufacture of a non-sterile product requires an understanding of the use of the product, the formulation (preservative system) and manufacturing process. For example, antacids, which do not have an effective preservative system, require an action limit below the 100 CFU/mL maximum.
因而，建立用于生产非无菌产品的高纯水系统允许的污染水平时，需要理解产品的用途、配方（防腐系统）和生产工艺。比如，抗酸剂没有一个有效的防腐系统，要 求的纠偏限度在最大值100 CFU/mL之下。
The USP gives some guidance in their monograph on Microbiological Attributes of Non-Sterile Products. It points out that, "The significance of microorganisms in non-sterile pharmaceutical products should be evaluated in terms of the use of the product, the nature of the product, and the potential harm to the user." Thus, not just the indicator organisms listed in some of the specific monographs present problems. It is up to each manufacturer to evaluate their product, the way it is manufactured, and establish an acceptable action level of contamination, not to exceed the maximum, for the water system, based on the highest risk product manufactured with the water.
USP 在其关于“非无菌产品的微生物特征”专论中给出一些指导，它指出“在非无菌药品中，微生物 的重要性应该结合产品的用途、产品的自然属性和对患者的潜在危害进行评估”。因而，不仅仅是在一些特定专论中列举的指示性微生物提出 问题，文章还要求每个生产厂商应该评估他们的产品和制造方式，并在用该水生产的风险最大产品基础上，给水系统建立不超过最大纠偏限度的可行的污染行动水 平。
IV. WATER FOR INJECTION SYSTEMS 注射用水系统
In the review and evaluation of Water For Injection systems, there are several concerns.
在注射用水系统的审核和评估中，有几个关注点。
Pretreatment of feedwater is recommended by most manufacturers of distillation equipment and is definitely required for RO units. The incoming feedwater quality may fluctuate during the life of the system depending upon seasonal variations and other external factors beyond the control of the pharmaceutical facility. For example, in the spring (at least in the N.E.), increases in gram negative organisms have been known. Also, new construction or fires can cause a depletion of water stores in old mains which can cause an influx of heavily contaminated water of a different flora.
大多蒸馏设备的生产商推荐对进水进行预处理，并明确要求使用RO 单元。原水质量可能会随季节的变动以及其它超越设备本身控制的外部因素而波动。例如，在春季（至少在N.E.时），大家知道革兰氏阴性菌会繁殖增多，同 时，新建筑或火灾会消耗老旧主管道中的存水，这会导致污染严重的水以不同形式流入。
A water system should be designed to operate within these anticipated extremes. Obviously, the only way to know the extremes is to periodically monitor feedwater. If the feedwater is from a municipal water system, reports from the municipality testing can be used in lieu of in-house testing.
一个好的水系统应能在这些预计到的的极端情况下保持正常运转。显然，唯一能确认极端情况的办法是定期监测原水质量。如果原水来自市政水系统，那么市政当局 的测试报告可以代替公司内部测试报告。
V. STILL 蒸馏塔
Figures 3-5 represent a typical basic diagram of a WFI system. Most of the new systems now use multi-effect stills. In some of the facilities, there has been evidence of endotoxin contamination. In one system this occurred, due to malfunction of the feedwater valve and level control in the still which resulted in droplets of feedwater being carried over in the distillate.
图3-5 是WFI 系统的一个典型图纸。大多数新系统使用多效蒸馏塔。在这些设施中，已经证实有内毒素污染的案例。在一个发生内毒素污染的系统中，由于进水阀故障和蒸馏塔的 控制不当，导致蒸馏水中携带有原水的小液滴。
标示了每套设备间的小阀门或小取样口，例如蒸馏塔后和贮罐前的阀门。这些是系统中隔离主要设备的阀门。设备的确认和可能发生的任何问题的调查是必需的。
VI. HEAT EXCHANGERS 热交换器
One principal component of the still is the heat exchanger. Because of the similar ionic quality of distilled and deionized water, conductivity meters cannot be used to monitor microbiological quality. Positive pressure such as in vapor compression or double tubesheet design should be employed to prevent possible feedwater to distillate contamination in a leaky heat exchanger.
蒸馏塔的一个主要组成部件是热交换器。因为蒸馏水和去离子水的离子质量相似，所以不能用电导仪来监控微生物质量。为了阻止热交换器渗漏时原水污染蒸馏水， 应在蒸汽压侧保持正压和采取双管板设计。
An FDA Inspectors Technical Guide with the subject of "Heat Exchangers to Avoid Contamination" discusses the design and potential problems associated with heat exchangers. The guide points out that there are two methods for preventing contamination by leakage. One is to provide gauges to constantly monitor pressure differentials to ensure that the higher pressure is always on the clean fluid side. The other is to utilize the double-tubesheet type of heat exchanger.
一个主题为“避免污染的热交换器”的FDA 检察员技术指南中，讨论了热交换器的设计和潜在问题。指南指出有两种方法可以防止泄漏产生的污染。一种是使用压差表连续监测压差以确保洁净流体这边压力较 高。另一种方法是利用双管板设计的热交换器。
In some systems, heat exchangers are utilized to cool water at use points. For the most part, cooling water is not circulated through them when not in use. In a few situations, pinholes formed in the tubing after they were drained (on the cooling water side) and not in use. It was determined that a small amount of moisture remaining in the tubes when combined with air caused a corrosion of the stainless steel tubes on the cooling water side. Thus, it is recommended that when not in use, heat exchangers not be drained of the cooling water.
在一些系统中，热交换器用来在使用点冷却水。大多情况下，热交换器不使用时冷却水不流经部件。在少数情况下，管道中的水被排出并停止使用后，管道中会形成 微孔（在冷却水侧）。这就决定了当和空气结合后，管道中残留的少量水分会腐蚀冷却水侧的不锈钢管。因此，建议在不用热交换器时，不要排干冷却水。
VII. HOLDING TANK 储罐
In hot systems, temperature is usually maintained by applying heat to a jacketed holding tank or by placing a heat exchanger in the line prior to an insulated holding tank.
在热水系统中，通常靠给带夹层的贮罐加热或在管路中进贮罐前安装一个热交换器来维持温度。
The one component of the holding tank that generates the most discussion is the vent filter. It is expected that there be some program for integrity testing this filter to assure that it is intact. Typically, filters are now jacketed to prevent condensate or water from blocking the hydrophobic vent filter. If this occurs (the vent filter becomes blocked), possibly either the filter will rupture or the tank will collapse. There are methods for integrity testing of vent filters in place.
贮罐中最有争论的一个部件是呼吸过滤器。期望对呼吸过滤器进行完整性测试以确保其完整无损。典型的，现在的过滤器都加了加热护封以防止冷凝物或水阻塞疏水 性的呼吸过滤器。如果过滤器被阻塞，可能会导致过滤器破裂或贮罐崩溃。有好几种方法可以在线测试过滤器的完整性。
It is expected, therefore, that the vent filter be located in a position on the holding tank where it is readily accessible.
因此，过滤器在贮罐中的安装位置应该易于接近。
Just because a WFI system is relatively new and distillation is employed, it is not problem-free. In an inspection of a manufacturer of parenterals, a system fabricated in 1984 was observed. Refer to Figure 6. While the system may appear somewhat complex on the initial review, it was found to be relatively simple. Figure 7 is a schematic of the system. The observations at the conclusion of the inspection of this manufacturer included, "Operational procedures for the Water For Injection system failed to provide for periodic complete flushing or draining. The system was also open to the atmosphere and room environment. Compounding equipment consisted of non-sealed, open tanks with lids. The Water for Injection holding tank was also not sealed and was never sampled for endotoxins." Because of these and other comments, the firm recalled several products and discontinued operations.
正因为WFI 系统相对较新并采用蒸馏法，所以它并不是完全没有问题。在一次注射用药品生产厂商的检查中，发现1984 年建造的一个系统，如Figure 6 所示。尽管在最初审核时系统显得有点复杂，但后来发现其实相对简单，Figure 7 是该系统的原理图。对该生产厂商的检查结论包括：“注射用水系统的操作程序没有规定进行定期的彻底冲洗和排水。系统也是敞开在空气和 室内环境中。配套设备由未密封的、敞开的带盖贮罐构成。注射用水贮罐也是非密封的并从不进行内毒素的取样检测。”由于这些原因和其它 因素，该公司召回了几个产品并停产了。
