GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS 高纯水系统检查指南 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). 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. 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。 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”（May，1993）。 I.系统设计 I. SYSTEM DESIGN One of the basic considerations in the design of a system is the type of product that is to 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be manufactured. For parenteral products where there is a concern for pyrogens, it is 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expected that Water for Injection will be used. This applies to the formulation of products, 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as well as to the final washing of components and equipment used in their manufacture. 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Distillation and Reverse Osmosis (RO) filtration are the only acceptable methods listed in 外公司中，采用超滤法将注射用药物的内毒素减到最少。 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）For some ophthalmic products, such as the ophthalmic irrigating solution, and some inhalation products, such as Sterile Water for Inhalation, where there are pyrogen 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specifications, it is expected that Water for Injection be used in their formulation. 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However, for most inhalation and ophthalmic products, purified water is used in their 及口服制剂的生产。 formulation. This also applies to topicals, cosmetics and oral products. Another design consideration is the temperature of the system. It is recognized that hot 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(65 – 80℃) systems are self sanitizing. While the cost of other systems may be less 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expensive for a company, the cost of maintenance, testing and potential problems may be greater than the cost of energy saved. 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. 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Obviously, water in constant motion is less liable to have high levels of contaminant. A 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”。 one-way water system is basically a \"dead-leg\". Finally, and possibly the most important consideration, is the risk assessment or level of 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 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products require less pure water and do not have a requirement for endotoxins. Even 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with topical and oral products there are factors that dictate different qualities for water. 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。For example, preservatives in antacids are marginally effective, so more stringent 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microbial limits have to be set. The quality control department should assess each 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product manufactured with the water from their system and determine the microbial 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action limits based on the most microbial sensitive product. In lieu of stringent water 生产过程中增加一步去除微生物的步骤。 action limits in the system the manufacturer can add a microbial reduction step in the manufacturing process for the sensitive drug product(s). II. SYSTEM VALIDATION II.系统验证 A basic reference used for the validation of high purity water systems is the Parenteral 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Drug Association Technical Report No. 4 titled, \"Design Concepts for the Validation of a 件，名为“注射用水系统验证的设计概念”。 Water for Injection System.\" The introduction provides guidance and states that, \"Validation often involves the use of 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 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for microbiological quality and on the installation of monitoring equipment at specific 处于正确的运行状态和持续执行其预定功能。” checkpoints to ensure that the total system is operating properly and continuously fulfilling its intended function.\" 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In the review of a validation report, or in the validation of a high purity water 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system, there are several aspects that should be considered. Documentation 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 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，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. 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 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specified, the initial phase of the water system validation can begin. During this phase 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、the operational parameters and the cleaning/ sanitization procedures and frequencies 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，will be developed. Sampling should be daily after each step in the purification process 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and at each point of use for two to four weeks. The sampling procedure for point of use 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sampling should reflect how the water is to be drawn e.g. if a hose is usually attached 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the sample should be taken at the end of the hose. If the SOP calls for the line to be 制定出水系统运行的标准操作程序。 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. The second phase of the system validation is to demonstrate that the system will 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consistently produce the desired water quality when operated in conformance with the 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SOPs. The sampling is performed as in the initial phase and for the same time period. At 统能持续生产出所需质量的水。 the end of this phase the data should demonstrate that the system will consistently produce the desired quality of water. 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 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produce water of the desired quality. Any variations in the quality of the feedwater that 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could affect the operation and ultimately the water quality will be picked up during this 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phase of the validation. Sampling is performed according to routine procedures and 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frequencies. For Water for Injection systems the samples should be taken daily from a 成了。 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. While the above validation scheme is not the only way a system can be validated, it 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. 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 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final report. The final validation report must be signed by the appropriate people 证报告必须由能对水系统运行和质量保证负责的人签字。 responsible for operation and quality assurance of the water system. A typical problem that occurs is the failure of operating procedures to preclude 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contamination of the system with non-sterile air remaining in a pipe after drainage. In a 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system illustrated as in Figure 1, (below) a typical problem occurs when a washer or 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。hose connection is flushed and then drained at the end of the operation. After draining, 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this valve (the second off of the system) is closed. If on the next day or start-up of the 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 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pro-vide for operational procedures that provide for opening the secondary valve before 打开第一个阀门冲洗管道之前必须先打开第二阀门。 the primary valve to flush the pipe prior to use. Another major consideration in the validation of high purity water systems is the acceptance criteria. Consistent results throughout the system over a period of time constitute the primary element. III. MICROBIAL LIMITS 微生物限度 Water For Injection Systems 注射用水系统 Regarding microbiological results, for Water For Injection, it is expected that they be essentially sterile. Since sampling frequently is performed in non-sterile areas and is not truly aseptic, occasional low level counts due to sampling errors may occur. Agency policy is that less than 10 CFU/100ml is an acceptable action limit. None of the limits for water are pass/fail limits. All limits are action limits. When action limits are exceeded the firm must investigate the cause of the problem, take action to correct the problem and 高纯水系统验证所需考虑的另外一个主要问题是验收标准。一段时期内，整个系统从始至终的持续一致的结果构成了验收标准的主要要素。 III.微生物限度 注射用水系统 对注射用水来说，微生物指标要求本质上无菌。由于经常在非无菌区进行取样操作，偶尔产生的取样错误会导致低水平微生物污染。行政政策可接受的纠偏限度为小于10CFU/100ml。水的限度没有所谓的合格/失败限度，所有的限度都是指纠偏限度。当超过纠偏限度时，公司必须调查assess the impact of the microbial contamination on products manufactured with the water and document the results of their investigation. With regard to sample size, 100 - 300 mL is preferred when sampling Water for Injection systems. Sample volumes less than 100 mL are unacceptable. The real concern in WFI is endotoxins. Because WFI can pass the LAL endotoxin test and still fail the above microbial action limit, it is important to monitor WFI systems for both endotoxins and microorganisms. Purified Water Systems 纯化水系统 问题的原因并采取行动纠正问题，评估微生物污染对使用这些水生产的产品造成的影响，并记录调查处理的结果。 关于取样体积，100～300ml 是注射用水取样的首选，样品体积不可少于100ml。注射用水中真正关注的是内毒素。因为注射用水可以既通过鲎试剂内毒素测试又通不过上述的微生物纠偏限度，所以对注射用水系统来说监控内毒素和微生物同样重要。 纯化水系统 For purified water systems, microbiological specifications are not as clear. USP XXII specifications, that it complies with federal Environmental Protection Agency regulations for drinking water, are recognized as being minimal specifications. There have been attempts by some to establish meaningful microbiological specifications for purified water. The CFTA proposed a specification of not more than 500 organisms per ml. The USP XXII has an action guideline of not greater than 100 organisms per ml. Although microbiological specifications have been discussed, none (other than EPA standards) have been established. Agency policy is that any action limit over 100 CFU/mL for a purified water system is unacceptable. 对纯化水系统来说，微生物规定不是很明确。USP XXII 的标准遵从《联邦环境保护署法规》关于饮用水的标准，该标准被认为是最低限度标准。一些人尝试为纯化水建立有意义的微生物标准。CFTA 建议不超过500CFU/ml，USP XXII 有一个不超过100CFU/ml 的指导方针。尽管微生物标准已经被讨论过，但除了EPA（环境保护署）标准外并未建立任何标准。从政策上来说，纠偏限度超过100CFU/ml 即为不合格。 The purpose of establishing any action limit or level is to assure that the water system is under control. Any action limit established will depend upon the overall purified water 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system and further processing of the finished product and its use. For example, purified 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water used to manufacture drug products by cold processing should be free of objectionable organisms. We have defined \"objectionable organisms\" as any organisms 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that can cause infections when the drug product is used as directed or any organism 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capable of growth in the drug product. As pointed out in the Guide to Inspections of 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Microbiological Pharmaceutical Quality Control Laboratories, the specific contaminant, rather than the number is generally more significant. 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 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 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contamination. A count of 10 CFU/mL in one sample and 100 or even 1000 CFU/mL in a 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subsequent sample would not be unrealistic. 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 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the product, the formulation (preservative system) and manufacturing process. For 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example, antacids, which do not have an effective preservative system, require an action 个有效的防腐系统，要求的纠偏限度在最大值100 CFU/mL之下。 limit below the 100 CFU/mL maximum. The USP gives some guidance in their monograph on Microbiological Attributes of 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Non-Sterile Products. It points out that, \"The significance of microorganisms in 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 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indicator organisms listed in some of the specific monographs present problems. It is up 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to each manufacturer to evaluate their product, the way it is manufactured, and establish 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an acceptable action level of contamination, not to exceed the maximum, for the water 系统建立不超过最大纠偏限度的可行的污染行动水平。 system, based on the highest risk product manufactured with the water. IV. WATER FOR INJECTION SYSTEMS 注射用水系统 IV.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 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。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 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external factors beyond the control of the pharmaceutical facility. For example, in the 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spring (at least in the N.E.), increases in gram negative organisms have been known. 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Also, new construction or fires can cause a depletion of water stores in old mains which 严重的水以不同形式流入。 can cause an influx of heavily contaminated water of a different flora. 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 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，feedwater is from a municipal water system, reports from the municipality testing can be 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used in lieu of in-house testing. 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 V. 蒸馏塔 Figures 3-5 represent a typical basic diagram of a WFI system. Most of the new systems 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now use multi-effect stills. In some of the facilities, there has been evidence of endotoxin 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contamination. In one system this occurred, due to malfunction of the feedwater valve 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and level control in the still which resulted in droplets of feedwater being carried over in 水的小液滴。 the distillate. In another system with endotoxin problems, it was noted that there was approximately 50 liters of WFI in the condenser at the start-up. Since this water could lie in the condenser for up to several days (i.e., over the weekend), it was believed that this was the reason for unacceptable levels of endotoxins. More common, however, is the failure to adequately treat feedwater to reduce levels of endotoxins. Many of the still fabricators will only guarantee a 2.5 log to 3 log reduction in the endotoxin content. Therefore, it is not surprising that in systems where the feedwater occasionally spikes to 250 EU/ml, unacceptable levels of endotoxins may occasionally appear in the distillate (WFI). For example, recently three new stills, including two multi-effect, were found to be periodically yielding WFI with levels greater than .25 EU/ml. Pretreatment systems for the stills included only deionization systems with no UF, RO or distillation. Unless a firm has a satisfactory pretreatment system, it would be extremely difficult for them to demonstrate that the system is validated. The above examples of problems with distillation units used to produce WFI, point to problems with maintenance of the equipment or improper operation of the system indicating that the system has not been properly validated or that the initial validation is no longer valid. If you see these types of problems you should look very closely at the system design, any changes that have been made to the system, the validation report and the routine test data to determine if the system is operating in a state of control. Typically, conductivity meters are used on water systems to monitor chemical quality and have no meaning regarding microbiological quality. Figures 3-5 also show petcocks or small sampling ports between each piece of equipment, such as after the still and before the holding tank. These are in the system to isolate major pieces of equipment. This is necessary for the qualification of the equipment and for the investigation of any problems 在存在内毒素问题的另一系统中，（我们）注意到启动时冷凝器中有将近50 升WFI。由于水在冷凝器中可能存贮好几天（例如，整个周末），这被认为是使内毒素水平超标的原因。 然而，更普遍的是不能充分处理原水以降低内毒素水平。许多蒸馏塔制造者将只保证降低2.5 至3 个log 的内毒素水平。因此，在系统中原水偶尔会高达250EU/ml 的内毒素，蒸馏水中偶而出现内毒素超标就并不令人惊讶。例如，最近的3 种新蒸馏塔，包括两种多效蒸馏塔，都被发现会周期性地产出内毒素大于0.25 EU/ml的WFI。蒸馏塔的预处理系统只包括去离子系统而没有UF、RO 或蒸馏。除非一个公司有一个令人满意的预处理系统，否则很难证明系统是有效的。 以上用蒸馏塔来生产WFI 所存在问题的例子，指出了设备维护的问题或系统不正确操作的问题，这些问题表明系统没有经过合理验证或者早前的验证不再有效。如果你发现此类问题，应该非常仔细地查看系统设计，看系统是否有任何变更，看验证报告和日常测试数据，以确定系统是否在控制状态下运行。 典型地，电导仪用来监控水系统的化学质量，但对于微生物质量控制却没有任何意义。 图 3-5 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。 which might occur. VI. HEAT EXCHANGERS 热交换器 VI.热交换器 One principal component of the still is the heat exchanger. Because of the 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similar ionic quality of distilled and deionized water, conductivity meters 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cannot be used to monitor microbiological quality. Positive pressure such as 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。 in vapor compression or double tubesheet design should be employed to prevent possible feedwater to distillate contamination in a leaky 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An FDA Inspectors Technical Guide with the subject of \"Heat Exchangers to Avoid Contamination\" discusses the design and potential problems associated 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。with heat exchangers. The guide points out that there are two methods for preventing contamination by leakage. One is to provide gauges to constantly 另一种方法是利用双管板设计的热交换器。 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. 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 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use. In a few situations, pinholes formed in the tubing after they were 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drained (on the cooling water side) and not in use. It was determined that a 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small amount of moisture remaining in the tubes when combined with air 不用热交换器时，不要排干冷却水。 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. VII. HOLDING TANK VII.储罐 In hot systems, temperature is usually maintained by applying heat to a 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jacketed holding tank or by placing a heat exchanger in the line prior to an 个热交换器来维持温度。 insulated holding tank. 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. It is expected, therefore, that the vent filter be located in a position on the holding tank where it is readily accessible. 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. VIII. PUMPS 泵 Pumps burn out and parts wear. Also, if pumps are static and not continuously in operation, their reservoir can be a static area where water will lie. For example, in an inspection, it was noted that a firm had to install a drain from the low point in a pump housing. Pseudomonas sp. contamination was periodically found in their water system which was attributed in part to a 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。 因此，过滤器在贮罐中的安装位置应该易于接近。 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。 VIII.泵 泵烧坏和部件磨损。如果泵是静止的并且不连续运转，则它们的泵腔可能变成储水的静态区域。例如，在一次检查中，（我们）注意到一个公司不得不从泵外罩的最低处安装排放管，在他们的系统中周期性地发现有假单胞菌污染，主要原因是由于泵不连续运行。 pump which only periodically is operational. IX．管路 IX. PIPING 管路 Piping in WFI systems usually consist of a high polished stainless steel. In a WFI 系统中的管道系统通常由内壁高度抛光的不锈钢组成。在一些案例few cases, manufacturers have begun to utilize PVDF (polyvinylidene 中，厂商已经开始使用PVDF 管道。据说该管道可以承受无生命存在的fluoride) piping. It is purported that this piping can tolerate heat with no 消毒温度。PVDF 管道的一个主要问题是它需要考虑支撑。当对其加热extractables being leached. A major problem with PVDF tubing is that it 时，容易下垂并可能张紧焊接处从而导致泄漏。此外，至少最初时，氟requires considerable support. When this tubing is heated, it tends to sag and 化物水平较高。这种管道对低水平金属污染就可能加速药品降解的产品may stress the weld (fusion) connection and result in leakage. Additionally, 传输系统有益，如生物技术工业。 initially at least, fluoride levels are high. This piping is of benefit in product delivery systems where low level metal contamination may accelerate the degradation of drug product, such as in the Biotech industry. One common problem with piping is that of \"dead-legs\". The proposed LVP 管道的一个普遍问题是有“死角”。LVP 规则给“死角”下的定义是不Regulations defined dead-legs as not having an unused portion greater in 使用部分的长度不得大于不使用部分管道直径（从使用管道的轴心开始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 - 80o 测量）的6倍。需要指出的是这是对75-80℃热水循环系统而言。对于较冷系统（65-75℃），任何下垂部分或任何长度管道的不使用部分都可能形circulating systems. With colder systems (65 - 75oC), any drops or unused portion of any length of piping has the potential for the formation of a biofilm 成生物膜，应尽可能消除死角或采取特殊的消毒程序。在制药用水系统中不应该有螺纹配件。所有的管道、阀门连接必须采用卫生型配件或对and should be eliminated if possible or have special sanitizing procedures. There should be no threaded fittings in a pharmaceutical water system. All 焊。卫生型配件普遍用在管件连接阀门的地方，还有因为维护或更换必pipe joints must utilize sanitary fittings or be butt welded. Sanitary fittings 须移除的贮罐和其它设备。因此，在检查时应该审核和评估该公司的消will usually be used where the piping meets valves, tanks and other 毒程序和实际的管道系统。 equipment that must be removed for maintenance or replacement. Therefore, the firm's procedures for sanitization, as well as the actual piping, should be reviewed and evaluated during the inspection. X. REVERSE OSMOSIS 反渗透 X. 反渗透 Another acceptable method for manufacturing Water for Injection is Reverse 另外一个可接受的生产注射用水方法是反渗透（RO）。然而，由于这些Osmosis (RO). However, because these systems are cold, and because RO 系统是冷系统，且因为RO 不是绝对过滤，所以微生物污染并不是不平filters are not absolute, microbiological contamination is not unusual. Figure 常。Figure 8 展示的是几年前使用的一个系统。在该系统中有并联的五个8 shows a system that was in use several years ago. There are five RO units in this system which are in parallel. Since RO filters are not absolute, the filter manufacturers recommend that at least two be in series. The drawing also illustrates an Ultraviolet (UV) light in the system downstream from the RO units. The light was needed to control microbiological contamination. 反渗透单元。由于RO 不是绝对过滤，过滤器厂商建议系统中至少两级串联。该图纸也标示系统中处于RO 单元下游的紫外（UV）灯，该灯是控制微生物污染所必需的。 Also in this system were ball valves. These valves are not considered sanitary 系统中也有球阀。这些阀不被认为是卫生阀，因为当阀关闭时它中间会valves since the center of the valve can have water in it when the valve is 有水，形成一个积水池，是微生物能生长的地方且会为生物膜的形成提closed. This is a stagnant pool of water that can harbor microorganisms and 供起点。 provide a starting point for a biofilm. As an additional comment on RO systems, with the recognition of 意识到微生物问题，作为RO 系统的另一项附加意见，一些厂商在RO 过microbiological problems, some manufacturers have installed heat exchangers immediately after the RO filters to heat the water to 75 – 80℃ to 滤器后安装热交换器，把水加热到75～80℃，将微生物污染降到最低。 minimize microbiological contamination. With the development of biotechnology products, many small companies are 随着生物制品的发展，许多小公司用RO 和UF 系统制造高纯水。例如，utilizing RO and UF systems to produce high purity water. For example, Figure 9 列举的是一个由单级RO 单元供水的墙式安装系统。 Figure 9 illustrates a wall mounted system that is fed by a single pass RO unit. As illustrated, most of these systems employ PVC or some type of plastic 如图所示，这些系统大多数使用PVC 或某种类型的塑料管。因为这些系tubing. Because the systems are typically cold, the many joints in the system 统都是冷水系统，所以系统中的许多连接点易受污染。PVC 管存在的另are subject to contamination. Another potential problem with PVC tubing is 一个潜在问题是它具有溶出性。从一个系统中研究WFI 以确保其符合extractables. Looking at the WFI from a system to assure that it meets USP USP 要求而不能保证PVC 不具有溶出性，是不可接受的。 requirements without some assurance that there are no extractables would not be acceptable. 这些系统在使用点也使用了0.2 微米过滤器，它能降低系统中的微生物污The systems also contain 0.2 micron point of use filters which can mask the 染水平。虽然知道在这样一个系统中内毒素是重要的，使用过滤器可以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 减少微生物污染，但是未必能减少内毒素污染。如果在系统中使用过滤器，就应该陈述使用过滤器的目的，例如，去除微粒或减少微生物污染， microbiological contamination, but not necessarily endotoxin contamination. If filters are used in a water system there should be a stated purpose for the 并且SOP 应描述过滤器更换的频率，基于系统验证期间得到的数据。 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. 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. Therefore, unless the water is sampled prior to the final 0.2 micron filter, microbiological testing will have little meaning. 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. XI. PURIFIED WATER SYSTEMS 纯化水系统 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 如前所述，由于实际测试的水体积（0.1ml 用于内毒素测试vs 100ml 用于微生物测试），微生物测试给系统的污染水平提供了参考指标。因此，除非在最后的0.2 微米过滤器之前取样，否则微生物测试没什么意义。 在对该设施的复检中，（我们）注意到他们用一个循环的不锈钢管路系统结合串联的四个RO 单元进行供水以纠正原来的缺陷水系统。由于该厂商不需要大量水（系统总容量大约是30 加仑），他们尝试让系统停运约一天。Figure 9 显示，在零时刻(at 9 AM on 3/10)没有检测到微生物和内毒素污染，一天后，发现静止的非循环系统已经被污染了，四次连续的每小时取样也显示了样品间有变化。在12PM 时取完最后一个样品后，他们用0.5%的过氧化物溶液重新消毒、冲洗、循环、取样，系统重新运行后每天的样品中没发现有微生物污染。这就是行政部门推荐非循环水系统每天要排空而不让水留在系统中的原因。 XI.纯化水系统 WFI 系统设备的许多评论可应用于纯化水系统。有一类系使用臭氧控制微生物污染，Figure10 是该类系统的图示。虽然据说该系统相对较便宜，但却有些问题。要达到最佳效果，需要溶解在系统中的臭氧达到一定浓度，这表示制药时要同时关注员工的安全问题和使用问题。 required that dissolved ozone residual remain in the system. This presents both employee safety problems and use problems when drugs are formulated. 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. 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. 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 is used to heat the water on a weekly basis and sanitize the system. Actually, the entire system is a \"dead-leg.\" 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 \"ballooning\" of the filter. If a valve downstream from the filter is shut too fast, the water pressure will reverse and can cause \"ballooning\". Pipe vibration is a 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 Vicks Greensboro，NC 设施的公开数据表明，在臭氧产生器关闭后2 到3 天内他们的系统就又重新被污染了。在另一生产厂商的检查中，我们注意到该公司正遇到假单胞菌污染的问题。由于对员工安全的潜在问题，臭氧在水进入循环系统之前已经被除去。据报道，溶解在水中的臭氧量为0.45 mg/l，在系统中最多保持5-6 小时。 另一个生产厂家，作为每天消毒处理的一部分，排尽臭氧水系统里面所有的水，并用经无菌过滤的70%异丙醇消毒。该厂家的微生物结果报告很好，但是，他们只是在消毒后立刻取样，而不是在全部操作结束时取样，因此，结果不具代表意义。 Figure 11 和Figure12 列举的是另一类有问题的纯化水系统。不像所讨论的大多数其它系统，该系统是单向非循环系统。系统有一个热交换器，用来每周加热消毒系统一次。实际上，这整个系统就是一个“死水系统”。 Figure 11 也标示了一个0.2 微米的在线过滤器，用来每天过滤纯化水。除过滤器腔室为微生物污染提供良好环境外，一个典型问题是水锤效应引起过滤器表面上飘现象，如果过滤器下游的阀门关得太快，则水压会逆转并导致上飘现象。管道振动是高回压的显著标志，然而过滤器表面的上游污染物的通过才是问题的关键所在。该系统也包括了几个使用点处的垂直排水口，在消毒时，打开终端阀很重要，可以使管道中所有的弯头和弯管处都充满水，使其完全暴露在消毒剂中。 sanitization, it is important to \"crack\" the terminal valves so that all of the elbows and bends in the piping are full of water and thus, get complete exposure to the sanitizing agent. It should be pointed out that simply because this is a one-way system, it is 需要指出的是仅仅因为该系统是一个单向系统，就说它不符合要求适不not inadequate. With good Standard Operational Procedures, based on 合适的。在验证数据基础上，有完善的标准操作程序和热冲洗程序，该validation data, and routine hot flushings of this system, it could be 系统是可以被接受的。一个非常长的（大于200 码）带有50 多个出水口acceptable. A very long system (over 200 yards) with over 50 outlets was 的系统也是可以接受的。该系统每天用80℃的水冲洗所有出水口。 found acceptable. This system employed a daily flushing of all outlets with 80oC water. The last system to be discussed is a system that was found to be objectionable. Pseudomonas sp. found as a contaminant in the system (after 最后要讨论的系统是一个被发现不合格的系统。系统中发现的假单胞菌污染（FDA 测试）同时也出现在一个类固醇产品中（FDA 测试）。该FDA testing) was also found in a topical steroid product (after FDA testing). Product recall and issuance of a Warning Letter resulted. This system (Figure 公司产品被召回并被FDA 发布了一封警告信。该系统（如Figure 13 所示）13) is also one-way that employs a UV light to control microbiological 也是一个单向系统，它使用UV 灯控制微生物污染，UV灯只在需水时打contamination. The light is turned on only when water is needed. Thus, there 开，因而，有段时期水是保留在系统中，该系统也包括一条非常难消毒are times when water is allowed to remain in the system. This system also 的软管。UV 灯必须恰当地维护以保持正常工作，紫外灯的玻璃套管必contains a flexible hose which is very difficult to sanitize. UV lights must be 须保持清洁，否则射线的效力将会减弱。在多紫外灯单元中必须有能监properly maintained to work. The glass sleeves around the bulb(s) must be 测每个紫外灯正常工作的装置。需知道的是UV 灯最多只能杀死进入系kept clean or their effectiveness will decrease. In multibulb units there must 统中90%的生物。 be a system to determine that each bulb is functioning. It must be remembered that at best UV light will only kill 90% of the organisms entering the unit. XIII.工艺用水 XIII. PROCESS WATER 工艺用水 Currently, the USP, pg. 4, in the General Notices Section, allows drug 现在，USP 第4 页的总则章节，允许用饮用水生产药用原料。它反对任substances to be manufactured from Potable Water. It comments that any 何剂型都必须用纯化水、注射用水或一种无菌水生产。既然片剂的制粒dosage form must be manufactured from Purified Water, Water For Injection, 必须使用纯化水，而饮用水又可用做药用原料的最终纯化，这两种陈述or one of the forms of Sterile Water. There is some inconsistency in these 中存在一些矛盾。 two statements, since Purified Water has to be used for the granulation of tablets, yet Potable Water can be used for the final purification of the drug substance. The FDA Guide to Inspection of Bulk Pharmaceutical Chemicals comments on FDA 的《原料药检查指南》中，对药用原料生产用的水质作了评论，特the concern for the quality of the water used for the manufacture of drug 别是那些用于注射剂生产的药用原料。由于纯化时使用的水存在污染，substances, particularly those drug substances used in parenteral 因此在药用原料中发现有微生物或内毒素污染超标的现象。用于注射剂manufacture. Excessive levels of microbiological and/or endotoxin 生产的药用原料在最终的合成/纯化步骤中不必使用注射用水，但是，用contamination have been found in drug substances, with the source of 于注射剂生产的原料药的最后一步处理的水系统应经过验证以确保内毒contamination being the water used in purification. At this time, Water For 素和微生物污染限度达到最低。 Injection does not have to be used in the finishing steps of synthesis/purification of drug substances for parenteral use. However, such water systems used in the final stages of processing of drug substances for parenteral use should be validated to assure minimal endotoxin/ microbiological contamination. In the bulk drug substance industry, particularly for parenteral grade 在原料药制造工业中，尤其是注射用级别的药用原料，普遍在水系统中substances, it is common to see Ultrafiltration (UF) and Reverse Osmosis 使用超滤（UF）和反渗透（RO）。虽然超滤在减少热原方面可能不是很(RO) systems in use in water systems. While ultrafiltration may not be as 显著，但可减少高分子量的内毒素（水系统中的一种污染物）。与反渗efficient at reducing pyrogens, they will reduce the high molecular weight 透一样，UF 也不是绝对有效，但可以减少污染物数量。此外，如前所述endotoxins that are a contaminant in water systems. As with RO, UF is not 的冷水系统，该类系统也需要大量的维护工作。 absolute, but it will reduce numbers. Additionally, as previously discussed with other cold systems, there is considerable maintenance required to maintain the system. For the manufacture of drug substances that are not for parenteral use, there 对于非注射用制剂的药用原料的生产，虽然没有注射剂级别的药用原料is still a microbiological concern, although not to the degree as for parenteral 要求高，但同样关注微生物问题。世界上有些地区，饮用水可能不存在grade drug substances. In some areas of the world, Potable (chlorinated) 微生物问题（漂白过的）。但是，可能会有其它问题，例如，漂白过的water may not present a microbiological problem. However, there may be 水一般会使氯化物含量增加。在有些地区，工艺用水可能直接从淡水资other issues. For example, chlorinated water will generally increase chloride 源获得。 levels. In some areas, process water may be obtained directly from neutral sources. 在一次检查中， 一厂家从一条位于农业区的河水中获得工艺用水。需要In one inspection, a manufacturer was obtaining process water from a river located in a farming region. At one point, they had a problem with high levels 指出的一点是，该水中有大量从该地区农田里流入的杀虫剂污染。生产of pesticides which was a run-off from farms in the areas. The manufacturing process and analytical methodology was not designed to remove and identify trace pesticide contaminants. Therefore, it would seem that this process water when used in the purification of drug substances would be unacceptable. 工艺和分析方法并没有被设计用于去除和鉴别痕量的杀虫剂污染。因此，该工艺用水用于药用原料的纯化是不可接受的。 XIV. INSPECTION STRATEGY 检查策略 XIV. INSPECTION STRATEGY 检查策略 通常厂家将会把纯化水系统的监测结果定期打印输出或制表。这些打印Manufacturers typically will have periodic printouts or tabulations of results for their purified water systems. These printouts or data summaries should 输出或数据总结应予以审核。此外，当超过限度时的调查报告也应进行be reviewed. Additionally, investigation reports, when values exceed limits, 审核。 should be reviewed. Since microbiological test results from a water system are not usually 既然水系统的微生物测试结果一般会在药品生产后才能得到，当微生物obtained until after the drug product is manufactured, results exceeding 限度的测试结果超标时，就应审查使用该水配制的药品。关于这种药品limits should be reviewed with regard to the drug product formulated from 的进一步处理或放行，应由特定的污染物、产品的工艺和最终的使用共such water. Consideration with regard to the further processing or release of 同决定。这样的情形通常要具体情况具体分析。这种情况是一次很好的such a product will be dependent upon the specific contaminant, the process 实践，评估应包括调查报告以及报告中关于产品放行/拒绝理由的论述。and the end use of the product. Such situations are usually evaluated on a 产品最终的微生物测试，虽然提供了一些信息，但不能作为放行药品的case-by-case basis. It is a good practice for such situations to include an investigation report with the logic for release/rejection discussed in the firm's 唯一理由。应该认识到微生物取样和测试的局限。 report. End product microbiological testing, while providing some information should not be relied upon as the sole justification for the release of the drug product. The limitations of microbiological sampling and testing should be recognized. Manufacturers should also have maintenance records or logs for equipment, 厂家也应该有设备的维护记录或日志，如蒸馏塔。应该审查这些记录，such as the still. These logs should also be reviewed so that problems with 从而可以评估系统和设备发生的问题。 the system and equipment can be evaluated. In addition to reviewing test results, summary data, investigation reports and 此外，应审查测试结果，汇总数据、调查报告和其它资料，当进行实物other data, the print of the system should be reviewed when conducting the 检查时，应审查系统的打印图纸。如前所述，为了证明系统是经过验证actual physical inspection. As pointed out, an accurate description and print of the system is needed in order to demonstrate that the system is validated. 的，系统的精确描述和打印图纸是必须的。