WHO《制药用水GMP指南》-2020版（中英文对照）！

验证师

原创 翻译组  制药经理人  昨天
Workingdocument QAS/20.842
工作文件QAS/20.842
May2020
二零二零年五月


                                                                                                                           




DRAFTWORKING DOCUMENT FOR COMMENTS:
征求意见草案:

Goodmanufacturing practices:
优良制造规范（GMP）:

waterfor pharmaceutical use
制药用水





Background
背景

The control of water quality,including microbiological and chemical quality, throughout production, storageand distribution processes is a major concern. Unlike other product and processingredients, water is usually drawn from an on-demand system and is not subjectto testing and batch or lot release prior to use. The assurance of waterquality to meet the on-demand expectation is, therefore, essential.
水的制备、存贮和分配过程中对水质的控制，包括微生物和化学质量，是一个重要关注点。与其它产品和工艺成分不同，水通常是来自一个按需运行的系统，在使用之前不会进行检测，也不会进行批放行，因此确保水质符合所需要求就至关重要了。

In recent years, following extensiveconsultation with stakeholders, several pharmacopoeias have adopted revisedmonographs on water for injection (WFI) that allow for production bynon-distillation technologies, such as reverse osmosis (RO). In 2017, the WorldHealth Organization (WHO) Expert Committee on Specifications for PharmaceuticalPreparations (ECSPP) recommended that the WHO Secretariat collect feedback onwhether or not they should revise the WHO specifications and good manufacturingpractices (GMP) on WFI, and how to do so. Following discussions during severalconsultations, the ECSPP agreed that the monograph in The International Pharmacopoeia(Water for injections) and the guideline WHO Good manufacturing practices:water for pharmaceutical use (1) should both be revised to allow fortechnologies other than distillation for the production of WFI. In early 2019,the WHO Secretariat commissioned the preparation of a draft guidance text forthe production of WFI by means other than distillation. Following severalpublic consultations, the text was presented to the Fifty-fourth ECSPP. TheExpert Committee adopted the Production of water for injection by means otherthan distillation guideline and recommended that it should also be integratedinto WHO’s existing guideline on Good manufacturing practices: water forpharmaceutical use.
近年来，由于干系人提出非常多的建议，几部药典均对注射用水（WFI）进行了修订，允许采用非蒸馏技术如反渗透（RO）制备 WFI。 2017 年， WHO 制剂标准专家委员会（ECSPP）建议 WHO 秘书处收集各方对于是否认为应修订 WHO 标准和 WFI GMP 以及如何修订的反馈。在几次征求意见期间经过讨论之后， ECSPP 同意对国际药典各论（注射用水）和 WHO 指南“GMP：制药用水” 进行修订，允许使用非蒸馏技术制备 WFI。 2019 年早期， WHO 秘书处协调起草了非蒸馏方法制备 WFI 的指南草案。经过几次公开征求意见之后，该文件被提交给第 54 次 ECSPP。专家委员会采纳了“非蒸馏方法制备注射水” 的指南，并将建议整合至 WHO 现有指南“GMP：制药用水”中。

This current document is a revision ofWHO Good manufacturing practices: water for pharmaceutical use, previouslypublished in the WHO Technical Report Series, No. 970, Annex 2, 2011.
本文件是之前发布为 WHO TRS 970 附录 2， 2011 的“WHO GMP：制药用水”修订本。

1.   Introduction
介绍
2.   Backgroundto water requirements and uses
水的要求和用途背景
3.    General principles forpharmaceutical water systems
制药用水系统的一般原则
4.   Waterquality specifications
水的质量标准
4.1.  Pharmacopoeial specifications
药典标准
4.2.  Drinking-water
饮用水
4.3.  Bulk purified water
纯化水
4.4.  Bulk highly purified water
高纯水
4.5.  Bulk water for injections
注射用水
4.6.  Other grades of water
其他级别的水
5.   Generalconsiderations for water purification systems
水净化系统的一般考虑点
6.   Waterstorage and distribution systems
储存和分配系统
7.   Goodpractices for water systems
水系统良好规范
8.   Systemsanitization and bioburden control
系统消毒与生物污染控制
9.   Storagevessels
储罐
10. Waterdistribution
分配系统
11. Biocontaminationcontrol techniques
生物污染控制技术
12. Operationalconsiderations
运行的考虑点
12.5       Phase1
第一阶段
12.6       Phase2
第二阶段
12.7       Phase3
第三阶段
13. Continuoussystem monitoring
持续系统监测
14. Maintenanceof water systems
水系统的维护
15. Systemreviews
系统回顾
16. Inspectionof water systems
水系统的检查
17. References
参考资料
18. Furtherreading
延伸阅读

1 Introduction andscope
介绍及范围

1.1  Thisdocument concerns water for pharmaceutical use (WPU) produced, stored anddistributed in bulk form. It intends to provide informationabout different specifications for WPU; guidance on GMP regarding the qualitymanagement of water systems; water treatment (production) systems; waterstorage and distribution systems; qualification and validation; and sampling,testing and the routine monitoring of water.
本文件包括制药用水（WPU）的生产、储存和分配。本文件提供不同制药用水标准、水系统质量管理的GMP指南、水处理(生产)系统、制药用水储存和分配系统、确认和验证、以及取样、测试和水的日常监测相关的信息。

1.2  Althoughdrinking-water is addressed, the focus of this document is on the treatment,storage and distribution of treated water used in pharmaceutical applications.
虽然提到了饮用水，但本文件的重点是经处理的制药用水的处理、储存和分配。

1.3  Thisdocument does not cover water for administration to patients in the formulatedstate or the use of small quantities of water in pharmacies to compoundindividually prescribed medicines.
本文件不包括处于配方状态的供病人使用的水，或在药房少量使用于配制个别处方药物的水。

1.4  Thedocument can be used in whole or in part, as appropriate, to the section andapplication under consideration.
本文件可全部或部分(视乎情况而定)用于审议中的部分和申请。

1.5  Inaddition to this document, the “Further reading” section at the end of thisdocument includes some relevant publications that can serve as additionalbackground material when planning, installing and using systems intended toprovide WPU.
除本文件外，本文件末尾的”延伸阅读”部分还包括一些相关出版物，在计划、安装和使用制药用水系统时可作为补充背景材料。

1.6  Thisdocument is supplementary to the World Health Organization (WHO) Goodmanufacturing practices for active pharmaceutical ingredients (2), and WHO Goodmanufacturing practices for pharmaceutical products: main principles (3).
本文件是对世界卫生组织(WHO)活性药物成分GMP(2)和WHO药物成品GMP(3)的补充。


2.  Background to water requirements and uses
水的要求和使用背景

2.1  Wateris a widely used substance in the pharmaceutical industry. It is extensivelyused as a raw material or starting material in the production, processing andformulation of active pharmaceutical ingredients (APIs), intermediates andfinished pharmaceutical products (FPP), in the preparation of solvents andreagents, and for cleaning (e.g. washing and rinsing). Water has uniquechemical properties due to its polarity and hydrogen bonds. It is able todissolve, absorb, adsorb or suspend different compounds. These would includecontaminants that may represent hazards in themselves or that may be able toreact with intended product substances, resulting in hazards to health. Watershould therefore meet the required quality standards to mitigate these risks.
水是制药工业中广泛使用的物质。它被广泛用作活性药物成分（API）、中间体和成品（FPP）的生产、加工和配方的原料或起始材料，用于溶剂和试剂的制备，以及用于清洁（如清洗和冲洗）。水由于其极性和氢键，具有独特的化学性质。它能够溶解、吸收、吸附或悬浮不同的化合物。这可能包括本身构成危害或可能与预期产品物质发生反应的污染物，从而对健康造成危害。因此，水应符合必要的质量标准，以减轻这些风险。

2.2  Themicrobiological and chemical quality of water should be controlled throughoutthe production, storage and distribution of water. Water is not usuallysubjected to testing and batch or lot release before use. It is usually drawnfrom a system on-demand for use. Results from testing arenormally available only after water has already been used as microbiologicaltests may require periods of incubation. The assurance of quality to meet theon-demand expectation of water is therefore essential.
在水的生产、贮存及分配过程中，应控制水的微生物及化学质量。水在使用之前通常不会经过测试和批放行。它通常来自一个按需使用的系统。由于微生物测试可能需要一段培养期时间，因此一般只有在用水后才可取得测试结果。因此，保证水的质量以满足用水需求是至关重要的。

2.3  Toreduce the risks associated with the production, storage and distribution ofwater and, considering the properties and use of water, it is essential:
为了减少与水的生产、储存和分配有关的风险，并考虑到水的特性和用途，必须:

       toensure the appropriate design, installation, operation and maintenance of thepre-treatment (production of drinking-water), treatment (production of WPU suchas purified water (PW) and WFI), and storage and distribution systems;
       确保预处理(饮用水的生产)、处理(制药用水的制备，如下纯化水(PW)和注射用水(WFI))及贮存和分配系统得到适当的设计、安装、操作和维修;
       toperform periodic sanitization;
       定期进行卫生处理;
       totake the appropriate measures in order to prevent chemical and microbialcontamination; and
       采取适当措施，防止化学和微生物污染;以及
       toprevent microbial proliferation.
       防止微生物繁殖。

2.4  Differentgrades of water quality exist. The appropriate water quality, meeting itsdefined specification, should be used for the intended application.
水的质量存在不同级别。应使用适当的水质（符合其既定标准）用于其预期目的。


3. Generalprinciples for pharmaceutical water systems
制药用水系统的一般原则

3.1  Pharmaceuticalwater production, storage and distribution systems should be designed,installed, commissioned, qualified, validated, operated and maintained toensure the consistent and reliable production of water of intended quality.
制药用水的生产、储存和分配系统应该设计、安装、调试、确认、验证、运行和维护，以确保一致和可靠地生产符合预期质量的水。

3.2  Thecapacity of these systems should be appropriate to meet the average and peakflow demand. The systems should be able to operate continuously for significantperiods of time in order to avoid the inefficiencies and equipment stressesthat occur when equipment cycles turn on and off too frequently.
系统的能力应适当，以满足平均流量和峰值流量的需求。系统应能够连续长时间运行，以避免因设备频繁开启和关闭而造成的效率低下和设备压力。

3.3  Theuse of the systems following an initial qualification such as installationqualification (IQ), operational qualification (OQ), performance qualification(PQ) and validation should be approved by the quality unit, e.g. qualityassurance (QA).
在初始确认(例如安装确认、运行确认、性能确认和验证)后，系统的使用应由质量部门批准，例如质量保证(QA)。

3.4  Watersources and treated water should be monitored regularly for chemical,microbiological and, as appropriate, endotoxin contamination. The performanceof water treatment, storage and distribution systems should also be monitored.Records of the results monitored, trend analysis and any actions taken shouldbe maintained.
应定期监测原水及处理后水的化学、微生物及(如适用)内毒素污染情况。水的处理、储存和分配系统的性能也应监测。应保存监测结果，趋势分析，以及任何所采取行动的记录。


4.  Water quality specifications
水的质量标准


4.1  Pharmacopoeial specifications
药典标准

4.1.1      Pharmacopoeiasinclude specifications for both bulk and dosage form types of water. Where thisdocument refers to specifications, such as the pharmacopoeias, the relevant,current publications should be used. This document does not attempt to duplicatesuch material. Where subtle points of difference exist between pharmacopoeialspecifications, the manufacturer should choose the appropriate specification inaccordance with the related marketing authorization submitted to the relevantmedicine’s regulatory authority. Pharmacopoeial requirements or guidance forWPU are described in national, regional and international pharmacopoeias (4)and limits for various impurities or classes of impurities are either specifiedor recommended. Requirements or guidance are given in pharmacopoeias on themicrobiological quality of water.
药典包括水的使用和制剂标准。本文件所提及标准，例如药典，则应使用相关的最新版本。本文件将不重复这些内容。如不同药典标准之间存在细微差别，制造商应根据向相关药监机构提交的上市许可来选择的适当的标准。国家、地区和国际药典(4)对制药用水的药典要求或指南进行了描述，并规定或推荐了各种杂质或杂质类别的限值。药典对水的微生物质量提出了要求或指导。


4.2  Drinking-water
饮用水

4.2.1      Thequality of drinking-water is covered by the WHO drinking-water qualityguidelines (5) and standards from the International Organization forStandardization (ISO) and other regional and national agencies. Drinking-watershould comply with the relevant regulations laid down by the competentauthority.
饮用水的质量由WHO饮用水质量指南(5)和国际标准化组织卫生组织(ISO)及其他区域和国家机构的标准所涵盖。饮用水应当符合主管机构的有关规定。

4.2.2      Drinking-watermay be derived from a natural or stored source. Examples of natural sourcesinclude springs, wells, rivers, lakes and the sea. The condition of the sourcewater should be considered when choosing a treatment to produce drinking-water. A typical treatment would include desalinization, softening, removal ofspecific ions, particle reduction and antimicrobialtreatment.
饮用水可来自天然或储存的水源。自然资源的例子包括泉水、井水、河流、湖泊和海洋。在选择饮用水处理方法时，应考虑水源水的条件。典型的处理方法包括脱盐、软化、特定离子的去除、颗粒降低和抗菌处理。

4.2.3      Drinking-watershould be supplied under continuous positive pressure by a plumbing system freeof any defects that could lead to contamination of any product.
饮用水应由管道系统在持续正压下供应，不得有任何可能污染任何产品的缺陷。

4.2.4      Drinking-watermay be derived from a public water supply system. This includes an off-sitesource, such as a municipality. The appropriate drinking-water quality shouldbe ensured by the supplier. Tests should be conducted to guarantee that thedrinking-water delivered is of drinking quality. This testing is typicallyperformed on water from the water source. Where required, the quality may beachieved through appropriate processing on-site.
饮用水可能来自公共供水系统。这包括一个工厂外的来源，比如市政当局。供应商应确保适当的饮用水水质。应当进行检验，以保证所提供的饮用水的质量。这种测试通常在原水供应点进行。必要时，应进行适当的内部处理以达到规定质量。

4.2.5      Wheredrinking-water is purchased in bulk and transported to the user by watertanker, controls should be put in place to mitigate any risks associatedtherewith. Vendor assessment and authorized certification activities, includingconfirmation of the acceptability of the delivery vehicle, should be undertakenin a way similar to that used for any other starting material.
如果饮用水是散装购买，并由水罐车运送给用户，应进行控制以减少与此相关的任何风险。供应商评估和批准认证活动，包括确认运载工具的可接受性，应以类似于任何其他起始物料的方式进行。

4.2.6      Itis the responsibility of the pharmaceutical manufacturer to assure that thesource water supplying the PW treatment system meets the appropriatedrinking-water requirements. In these situations, the point at whichdrinking-water quality is achieved should be identified and a water sampletaken and tested at defined intervals thereafter.
药品制造商有责任确保供应纯化水处理系统的源水符合适当的饮用水要求。在这些情况下，应确认达到饮用水质量的点，并在其后以规定的时间间隔取样和测试。

4.2.7      Ifdrinking-water is used directly in certain stages of pharmaceuticalmanufacture, such as in the production of APIs or in the feedwater for theproduction of higher qualities of WPU, then testing should be carried outperiodically by the water user’s site to confirm that the quality meets thestandards required for drinking-water.
如果在药物制造的某些阶段直接使用饮用水，例如在原料药生产或在生产较高质量制药用水的给水中直接使用饮用水，工厂应定期进行测试，以确认水质符合饮用水所需的标准。

4.2.8      Wheredrinking-water is produced through the treatment of raw water by a systemon-site, the system configuration and water-treatment steps used should bedescribed.
如饮用水是由原水经现场系统处理而产生，则应说明系统配置及所采用的水的处理步骤。

4.2.9      Examplesof typical processes employed to produce drinking-water may include:
制备饮用水的典型工序例子包括:

       desalinization;
       脱盐;
       filtration;
       过滤;
       softening;
       软化;
       disinfectionor sanitization (e.g. by sodium hypochlorite {chlorine} injection);
       消毒(例如使用次氯酸钠{氯});
       iron(ferrous) removal;
       除铁;
       precipitation;and
       沉降;以及
       thereduction of concentration of specific inorganic and/or organic materials.
       降低特定无机和/或有机物质的浓度。

4.2.10 Controls should be implementedto prevent the microbiological contamination of sand filters, carbon beds andwater softeners. The techniques selected should be appropriate and may includebackflushing, chemical and/or thermal sanitization and frequent regeneration.
应实施控制以防止砂滤器、碳床和水软化装置受微生物污染。所选择的技术应该是适当的，可以包括反冲洗、化学和/或热消毒以及频繁的再生。

4.2.11 The quality of drinking-watershould be monitored routinely to account for environmental, seasonal or supplychanges which may have an impact on the source water quality.
应定期监测饮用水的水质，考虑可能影响源水水质的环境、季节或供应变化。

4.2.12 Where drinking-water is storedand distributed by the user, the storage and distribution systems should notallow the degradation of the water quality prior to use. After any suchstorage, testing should be carried out routinely and in accordance with adefined procedure. The storage and distribution of drinking-water should bedone in a manner to ensure a turnover or recirculation of the stored watersufficient enough to prevent stagnation.
当用户对饮用水进行储存和分配时，储存和分配系统不应在使用前降低水质。任何此类存储后，应进行日常测试，并符合既定程序。饮用水的储存和分配应以某种方式确保所储存水的翻滚或循环足以防止停滞。

4.2.13 The equipment and systems usedto produce and store drinking-water should be able to be drained and sanitized.
用于生产和储存饮用水的设备和系统应能够排水和消毒。

4.2.14 Storage tanks should be closedwith appropriately protected vents and should allow for visual inspection.
储罐应密封，配以受适当保护的通气口，并应可以目视检查。

4.2.15 Distribution pipework should beable to be drained or flushed and sanitized.
分配管道应该能够排水、冲洗和消毒。

4.2.16 The scope and extent ofqualification for the system should be identified and justified.
应确定和论证系统确认范围和程度。

4.2.17 The results from testingdrinking-water should be subjected to statistical analysis in order to identifytrends and changes. If the drinking-water quality changes significantly, but isstill within specification, the direct use of this water as a WPU, or as thefeedwater to downstream treatment stages, should be reviewed for any risks andthe results of the review and action to be taken and documented.
饮用水测试结果应作统计分析，以确定趋势和变化。如果饮用水水质发生重大变化，但仍符合标准，则应审查直接将这种水用作制药用水或作为下游处理阶段的给水，以审查任何风险以及审查的结果和采取的行动并记录。

4.2.18 Changes to a system or to itsoperation should be made in accordance with change control procedures.
系统或其操作的变更应按照变更控制程序进行。

4.2.19 Additional testing should beconsidered if there is any change in the raw water source, treatment techniquesor system configuration.
如原水来源、处理技术或系统配置有任何变更，应考虑进行额外测试。


4.3  Bulk purified water
纯化水

4.3.1      Bulkpurified water (BPW) should meet the relevant pharmacopoeial specifications forchemical and microbiological purity.
纯化水(BPW)应符合相关药典的化学和微生物标准。

4.3.2      BPWshould be prepared from drinking-water as a minimum-quality feedwater.
纯化水应最少由饮用水制备而成。

4.3.3      Anyappropriate, qualified purification technique, or sequence of techniques, maybe used to prepare BPW. BPW may be prepared by, for example, a combination ofion exchange, RO, RO/electro-deionization (EDI), ultrafiltration and vapourcompression.
可使用适当的、经确认的纯化技术或技术组合制备纯化水。纯化水可通过，例如，离子交换、反渗透、反渗透/电去离子(EDI)、超滤和蒸汽压缩的组合来制备。

4.3.4      Thefollowing should be considered when configuring a water purification system ordefining user requirement specifications (URS):
在配置纯化水系统或定义用户需求规范(URS)时，应考虑以下因素:

       thequality of feedwater and its variation over seasons;
       给水质量及其季节变化;
       thequantity of water required by the user;
       用户所需的用水量;
       therequired water-quality specification;
       所需的水质标准;
       thesequence of purification stages required;
       所需的纯化阶段顺序;
       energyconsumption;
       能耗;
       appropriatelylocated sampling points designed in such a way so as to avoid potentialcontamination; and
       适当设置取样点，以避免潜在污染;以及
       unitprocess steps provided and documented with the appropriate instrumentation to measure parameters suchas flow, pressure, temperature, conductivity, pH and total organic carbon.
       各单元处理步骤提供并记录适当的仪器，以测量诸如流量、压力、温度、电导率、pH值和总有机碳等参数。

4.3.5      Ambient-temperaturesystems such as ion exchange, RO and ultrafiltration are especially susceptibleto microbiological contamination, particularly when equipment is static duringperiods of no or low demand for water. Sanitization, at defined intervals, aswell as other controls, should be defined to prevent and minimizemicrobiological contamination.
离子交换、反渗透和超滤等环境温度系统特别容易受到微生物污染，尤其是当设备在没有或需水量很低处于停止的时候。为了防止和减少微生物污染，应该定期进行消毒处理以及其他控制措施。

4.3.6      Appropriate,validated methods for sanitizing each stage of purification needs to be inplace. Where agents are used for sanitization, their removal must be proven.
每个纯化阶段都需要适当的、经过验证的消毒方法。如使用消毒剂，应证明消毒效果。

4.3.7      Thefollowing controls should be considered:
应考虑以下控制措施:

       themaintenance of water flow at all times, in order to prevent water fromstagnating;
       时刻保持水的流动，防止滞留;
       controlof temperature in the system by heat exchangers or plant room cooling in orderto reduce the risk of microbial growth (guidance value < 25 °C);
       通过热交换器或工厂房间冷却来控制系统内的温度，以减少微生物生长的风险(指导值＜25℃);
       theprovision of ultraviolet disinfection at appropriate locations in the system;
       在系统的适当位置进行紫外线消毒;
       theuse of water-treatment system components that can periodically be thermallysanitized;
       使用可以周期性地进行热消毒的水处理系统组件;
       inaddition to thermal sanitization, the application of chemical sanitization suchas ozone, hydrogen peroxide and/or peracetic acid; and
       除热消毒外，使用化学消毒剂如臭氧、过氧化氢和/或过氧乙酸;以及
       thermalsanitization at > 70 °C.
       70℃热消毒。

4.3.8      BPWshould have the appropriate action and alert limits for microbiological puritydetermined from a knowledge of the system and data trending. BPW should beprotected from recontamination and microbial proliferation.
纯化水应根据对系统和数据趋势的知识，确定微生物纯度的适当行动和警戒限。应该防止二次污染和微生物繁殖。


4.4  Bulk highly purified water
高纯水

4.4.1      Bulkhighly purified water (BHPW) must meet the same quality standards as WFI,including the limit for endotoxins.
高纯水(BHPW)必须达到与WFI相同的质量标准，包括内毒素标准。

4.4.2      BHPWshould be prepared from drinking water as a minimum-quality feedwater.
高纯水应最低使用饮用水制备。

4.4.3      Anyappropriate and qualified purification technique, or sequence of techniques,may be used to prepare BHPW. BHPW is often produced by double pass RO coupledwith other suitable techniques such as ultrafiltration and deionization.
可使用适当并经确认的纯化技术，或者技术组合制备高纯水。高纯水通常采用两级反渗透与超滤和去离子等其他适当技术相结合的方法制备。

4.4.4      BHPWshould also be protected from recontamination and microbial proliferation.
还应保护高纯水免受再污染和微生物增殖。

4.4.5      BHPWand WFI have identical microbiological requirements.
高纯水和WFI具有相同的微生物要求。

Note: The   guidance  provided   in    section 4.3  for       BPW  is       equally applicable to  BHPW.
注:第4.3节提供的纯化水指南同样适用于高纯水。


4.5 Bulkwater for injections
注射用水

4.5.1     Bulkwater for injections (BWFI) should meet the relevantpharmacopoeialspecifications for chemical and microbiological purity (includingendotoxins).BWFI is the highest quality of pharmacopoeial WPU.
注射用水(BWFI)应符合相关药典的化学和微生物纯度(包括内毒素)标准。注射用水是最高质量的制药用水。

4.5.2     BWFIis not sterile water and is not a final dosage form. It is an intermediatebulkproduct suitable to be used as an ingredient during formulation.
散装注射用水不是无菌水，也不是成品制剂。它是一种适合在配方中作为配料使用的中间体产品。

4.5.3     Asa robust technique should be used for the production of BWFI, thefollowingshould be considered when designing a water purification system:
注射用水的制备应采用稳健的技术，在设计注射用水系统时应考虑以下因素:

·        the quality of feedwater(e.g. drinking-water, usually with furthertreatment, or PW);
·        给水的质量(例如饮用水，通常需要进一步处理，或者PW);
·        the required water qualityspecification;
·        所需的水质标准;
·        the quantity of water;
·        水量;
·        based on the selection ofcomponents and type of system, theappropriate URS, qualification andvalidation;
·        基于部件和系统类型的选择，适当的URS、确认和验证;
·        the optimum generator size orgenerators with variable control toavoid over-frequent start/stop cycling;
·        制水机最优规格或可调控制的制水机，以避免频繁启动/停止;
·        blow-down and dump functions;and
·        吹扫和排放功能;以及
·        cool-down venting toavoid contamination ingress.
·        冷却水排放，防止污染进入。

4.5.4 BWFImaybe prepared, for example, by distillation as the final purificationstep.Alternatively, techniques such as deionisation, electro deionization,nanofiltration, ultrafiltration, water softening, descaling, pre-filtrationanddegasification, ultraviolet treatment, along with other techniques, may beconsideredin conjunction with a single or double pass RO system.
注射用水可以通过蒸馏作为最后的提纯步骤来制备。或者，诸如去离子、电去离子、纳米过滤、超滤、水软化、除垢、预过滤和除气、紫外线处理以及其他技术，可以与一级或两级反渗透系统一起考虑。

4.5.5 BWFIshouldhave the appropriate action and alert limits and should also beprotected fromrecontamination and microbial proliferation.
注射用水应有适当的行动和警戒限度，并应防止再污染和微生物增殖。

Note:For a full description, seeProduction of water for injection by means otherthan distillation.
注:详细说明请参阅非蒸馏法制备注射用水指南。


4.6 Othergrades of water
其他级别的水

Whena specific process requires a specialnon-pharmacopoeial grade of water, itsspecification must be documented withina company’s quality system. As aminimum, it must meet the pharmacopoeialrequirements relating to the grade ofWPU required for the type of dosage formor process step.
当一个特定的工艺需要特殊的非药典级别的水时，其标准必须在公司的质量体系中规定。至少，它必须满足与剂型或工艺步骤类型所需的制药用水等级相关的药典要求。


5. General considerations for water purification systems
水纯化系统的一般考虑

5.1 Pharmaceutical manufacturers should apply the current principles of qualityrisk management(6) in selecting and using the appropriate water purification systems.Anappropriate method for the production of WPU should be used.
药物制造商在选择和使用合适的水纯化系统时，应采用现行的质量风险管理原则。制药用水(WPU)的生产应采用合适的方法。

5.2 Risksand controls should be identified for each stage of the production,storage,distribution, use and monitoring of WPU.
制药用水的生产、储存、分配、使用和监测的每个阶段都应确定风险和控制措施。

5.3 Risksidentified should be analyzed and evaluated in order to determine thescope andextent of validation and qualification of the system, includingthecomputerized systems used for the production, control and monitoring of WPU.
应分析和评估所识别的风险，以确定该系统的验证和确认的范围和程度，包括用于制备、控制和监测的计算机化系统。

5.4 Riskmanagement should be an ongoing part of the quality management process forWPU.A mechanism to review or monitor events associated with theproduction,storage, distribution and use of WPU should be implemented.
风险管理应作为制药用水质量管理过程的一个持续的部分。应实施一种机制，以审查或监测与制药用水的生产、储存、分配和使用有关的事件。

5.5 Proceduresfor managing changes and deviations should be followed. Whereapplicable, theappropriate risk and impact assessments should be done where changesanddeviations are managed.
应遵循变更和偏差的管理程序。适当时，变更和偏差的管理应进行适当的风险和影响评估。

5.6 The chosen water purification system,method or sequence of purification steps must be appropriate inorder to ensure the production of water of an intended grade. Based on the outcomeof the risk assessment, the following should at least be consideredwhen selecting the water treatment system and method:
所选择的制水系统、方法或纯化步骤序列必须恰当，以确保制备出既定级别的水。根据风险评估的结果，在选择水处理系统和方法时应至少考虑以下方面：

       the quality of the available feedwaterand the variation over time (seasonal changes);
       原水质量和其随时间的变化（季节性变化）
       the availability of suitable supportfacilities for the system (e.g. electricity, heating, steam,
       chilled water and compressed air);
       适当的支持设施的可及性（例如，供电、供热、蒸汽、冷却水和压缩空气）
       the extent of pre-treatment required;
       所需预处理的程度
       the sequence of purification stepsrequired;
       所需纯化步骤的顺序
       the design and location of samplingpoints;
       取样点的设计和位置
       the sanitization strategy;
       消毒策略
       the availability of water-treatment equipment on the market;
       市场上水处理设备的可及性
       the reliability and robustness of the water-treatment equipment inoperation;
       在用水处理设备的可靠性和耐用性
       the yield or efficiency of the purification system;
       纯化系统的产水率或效率
       the ability to adequately support and maintain the waterpurification equipment;
       充分支持和维护水纯化设备的能力
       the continuity of operational usage considering hours/days/yearsand planned downtime;
       运行使用的连续性，考虑小时/天/年度和计划停机时间
       the total life-cycle of the system (including capital, operationand maintenance);
       系统的全生命周期（包括资金、运行和维护）
       the final water quality specification; and
       最终水的质量标准
       the quantity of water required by the user.
       用户需水量

5.7 The specifications for waterpurification equipment, storage and distribution systems should take into accountthe following:
制水设备、储存和分配系统的URS应考虑以下方面：

       the location of the plant room;
       制水间的位置
       the extremes in temperature that thesystem will encounter;
       系统将遇到的极端温度
       the risk of contamination, forexample, from materials of construction (contact materials) and theenvironment;
       污染风险，例如来自构造材料（接触材料）和环境
       the adverse impact of adsorptivecontact materials;
       吸附性接触材料的不良影响
       hygienic or sanitary design, whererequired;
       卫生设计（如要求）
       corrosion resistance;
       耐腐蚀性
       freedom from leakage;
       防泄漏
       system configuration to avoidproliferation of microbiological organisms;
       系统配置，以避免微生物增殖
       tolerance to cleaning and sanitizingagents (thermal and/or chemical);
       清洁和消毒剂的接受性（热消毒和/或化学）
       the sanitization strategy;
       消毒策略
       system capacity and output requirements; and
       系统产能和输出需求
       the provision of all necessary instruments, test and samplingpoints in order to allow for all the relevant critical quality parameters ofthe complete system to be monitored.
       所有必需仪表、检测和取样点应保证可监测整个系统的所有相关关键质量缺陷


5.8  The design, configuration and layout of thewater purification equipment, storage and distributionsystems should also take into account the following physical considerations:
水纯化设备、储存和分配系统的设计、配置和平面布局亦应考虑以下实际因素：

       the ability to collect samples;
       取样的能力
       the space available for theinstallation and environment around the system;
       系统可用安装空间和周围环境
       structural loadings on buildings;
       建筑物的结构性负载
       the provision of adequate access formaintenance and monitoring; and
       提供足够的空间进行维护和监测
       the ability to safely handleregeneration and sanitization chemicals.
       安全处理再生和消毒化学品的能力


6. Water storage and distribution systems
储存和分配系统

6.1 Wheredrinking water is stored and distributed, the appropriate controls should be determined andimplemented in order to mitigate risks. This applies to all stages in thesupply, storage and distribution of drinking-water.
如果储存和分配的是饮用水，应制定和执行恰当的控制以降低风险。该要求适用于饮用水的供应、储存和分配的各阶段。

6.2 Thewater storage and distribution systems for PW, BHPW and BWFI should beappropriately designed, installed, qualified, operated andmaintained in order to ensure the storage and distribution of water is ofconsistentquality to the user points.
纯化水、高纯水和注射用水储存和分配系统应经过恰当设计、安装、确认、运行和维护，以确保为使用点储存和分配具备一致质量的水。


7. Good practices for water systems
水系统优良规范

7.1 Thecomponents of water systems, including but not limited to pipework, valves andfittings, seals, diaphragmsand instruments, should be appropriate and should satisfy the followingobjectives for the full range of the working temperature and potentialchemicals that will come into contact with the system at rest, in operationand during sanitization. The construction materials should be of anappropriate quality.
水系统的部件，包括但不仅限于管道、阀门和配件、密封件、隔膜和仪表，均应恰当，并满足系统在静态/动态及消毒期间可能接触的全部工作温度范围和潜在化学品的以下目标。结构材料应具备恰当的质量。

7.2 As a minimum, thefollowing should be considered:
最低要求应考虑以下方面：
       Compatibility and suitability.
       兼容性和适用性
       No leaching, adsorbing and absorbing.
       无浸出、吸收和吸附
       Corrosion resistance.
       耐腐蚀
       Materials of construction: the materials used should beappropriate, for example, sanitary specification plastics such aspolypropylene, polyvinylidene-difluoride and perfluoro alkoxy. Other materials,such as unplasticized polyvinyl-chloride (uPVC), may be used for treatment equipmentdesigned for less pure water such as ion exchangers and softeners. Plasticsused should be manufactured from materials that should at least meet theminimum food grade standards, be non-toxic and be compatible with all chemicalsused. Their chemical and biological characteristics should meet any relevantpharmacopoeial specifications or recommendations. Stainless-steel grade 316L orhigher is generally recommended. The choice of material should take intoaccount the intended sanitization method.
       结构材料：所用材料应恰当，例如，卫生级塑料如聚丙烯、聚偏二氟乙烯和可熔性聚四氟乙烯。其它材料如未增塑聚氯乙烯（uPVC）亦可用于较低纯水处理设备的设计，如离子交换和软化器。所用塑料应采用至少符合食品级标准的材料生产，无毒，与所用化学品相容。其化学和生物特性应符合相关的药典标准或建议。一般建议使用不锈钢级别 316L 或更高级别。
       Passivation: passivation should be considered after initialinstallation and after significant modification in accordance with a documentedprocedure defining the solution to be used, its concentration, the temperatureand contact time.
       钝化：初次安装之后和重大改造之后应考虑按书面程序规定进行钝化，程序应规定有所用溶液、浓度、温度和接触时长。
       Smooth internal finish: internal finish should be smooth in orderto prevent the formation of biofilms and corrosion (e.g. an arithmeticalaverage surface roughness of not greater than 0.8 micrometre (Ra); mechanicaland electro-polishing of stainless steel).
       内表面光滑处理：内表面处理应光滑以防止形成微生物膜和腐蚀（例如，算术平均表面粗糙度不大于 0.8μm（Ra），不锈钢机械和电子抛光）
       Jointing: the manner in which pieces are jointed should beappropriate and controlled. Where welding is used, the process should include,as a minimum, the qualification of the operator, documentation of the welderset-up, work session test pieces (coupons or weld samples), logs of all weldsand records (e.g. photographs or videos) of visual inspection of a definedproportion of welds (e.g. 100% hand welds or 10% automatic welds). Threadedconnections should be avoided.
       连接：连接所用零件应恰当并受控。如果采用焊接，则焊接工艺应至少需要焊接工持有资质、对焊工组成有文件记录、焊样、所有焊接日志和目视检查（例如手焊 100%或自动焊 10%）焊接指定部分的记录（例如，图片或视频）。
       Flanges, unions and valves: where flanges, unions or valves areused, they should be of a hygienic or sanitary design. The appropriate checksshould be carried out in order to ensure that the correct seals and diaphragmsare used and that they are fitted and tightened correctly.
       法兰、管接头和阀门：如果使用了法兰、管接头和阀门，则应为卫生设计。应进行恰当检查，以确保所用密封和隔膜正确，安装和坚固正确。
       Documentation:all system components should be fully documented and be supported byoriginal orcertified copies of material quality certificates. Where these are not available or traceable,on-site tests should be performed and test reports should be available. Alldocumentation related to the qualification andvalidation of the system should be available. Documentsshould include, as a minimum, system drawing, isometric drawings, specifications for components, qualification and validationprotocols and reports, calibration certificates.
       所有系统的组件均应有完整文件记录，并有原始或经过认证副本的材料质量证书支持。如果没有或不可追溯，则应进行现场测试，测试报告应可提供。所有与系统确认和验证有关的文件均应可提供。文件应至少包括系统图纸、等距图、组件标准、确认和验证方案和报告、校正证书。

8. System sanitization andbioburden control
系统消毒和生物负载控制

8.1 Water-treatment,storage and distribution systems should be subjected to controls that willreduce the risk of contamination and the proliferation of microbiologicalorganisms.
水处理、储存和分配系统应进行控制，降低污染风险和微生物激增风险。

8.2 Validated, detailedprocedures for sanitizing all relevant parts of the system should be followed. Thetechniques employed should be considered during the design stage of the systemas the procedure and technique may impact on the components and materials ofconstruction.
应遵守经过验证的所有相关系统部件的详细消毒程序。在系统设计阶段应考虑准备使用何种技术，因为程序和技术可能会对部件和结构材料产生影响。

8.3 Systems that operateand are maintained at elevated temperatures (e.g. > 65) are generally less susceptibleto microbiological contamination than systems that are maintained at lowertemperatures. When lower temperatures are required due to the water treatmentprocesses employed, or the temperature requirements for the water in use,special precautions should be taken to prevent the ingress of contaminantsincluding microorganisms (see section 9.2 for guidance).
以较高温度（例如>65 度）运行和维护的系统更不容易受到微生物污染。如果因为所采用的水处理工艺的原因而需要使用较低温度，或者水在使用时的温度要求较低，则应采取预防措施防止污染物包括微生物侵入（参见第 9.2 节中的指导）。

8.4 Where the chemicalsanitization of the water systems is part of the biocontamination control programme,a validated procedure should be followed in order to ensure that the sanitizingprocess selected is effective and that the sanitizing agent has been effectivelyremoved.
如果水系统化学消毒是生物污染控制计划的一部分，则应遵守经过验证的程序，以确保所选择的消毒过程有效，消毒剂可有效清除。

8.5 Records ofsanitization should be maintained.
应保存消毒记录。


9. Storage vessels
储罐

9.1 Storage vesselsinstalled and used later should be appropriate for their intended use.
安装和使用的储罐应适合其既定用途。

9.2 As a minimum, thefollowing should be considered:
最少应考虑以下方面

       the design and shape;
       设计和形状
       the provision for drainage of water from the vessel, whenrequired;
       储罐排水需求（必要时）
       construction materials;
       结构材料
       capacity, including buffer capacity, between the steady state,water generation rate and the potentially variable simultaneous demand fromuser points, short –term reserve capacity in the event of failure of thewater-treatment system or the inability to produce water (e.g. due to a regenerationcycle);
       产能，包括稳定状态、水制备速度和使用点潜在波动同时需求、水处理系统失败或不能产水（例如因再生循环））时短期存水能力之间的缓冲能力，
       prevention of stagnant water in the vessel (e.g. the headspacewhere water droplets can accumulate);
       防止储罐中水停滞（例如，水滴可能累积的顶部空间）
       theneed for the use of a spray-ball or distributor devices to wet the innersurfaces of the vessel;
       使得储罐内表面润湿的喷淋球和分配装置的使用需求
       limitation and design of nozzles within the storage vessels;
       储罐内喷嘴的限制和设计
       the fitting of heated, bacteria-retentive, hydrophobic ventfilters which are tested for their integrity at appropriate intervals;
       应以恰当的时间间隔检测加热、抑菌、疏水排气阀等配件的完整性·
       the fitting of pressure-relief valves and bursting discs which areof a sanitary design (bursting discs should be provided with external ruptureindicators to ensure that loss of system integrity is detected);
       泄压阀和爆破片的卫生设计（爆破片应在外部有破裂指示器，以确保可发现系统完整性失败情况）
       the design and sanitization, as required, of level indicators;
       水位指示器的设计与消毒（需要时）
       the design and location of valves, sampling points and monitoringdevices and sensors; and
       阀门、取样点和监测装置和探头的设计与位置选定
       theneed for heat exchangers or jacketed vessels. Where these are used, controlsshould be put in place in order to ensure that thereis no risk of contamination of water.
       是否需要热交换器或带夹套罐。如果使用了，则应制订控制措施以确保不会有水污染风险


10. Water distribution
分配系统

10.1 The water distributionsystem should be designed as a loop, with continuous circulation of BPW, BHPWand BWFI. Where this is not the case, a good justification for using anon-recirculating one-way system should be provided.
水分配系统应设计为环路，可连续循环 BPW、 BHPW 和 BWFI。如果不是这样，则应为非循环式单路系统进行完善的论证。

10.2 As a minimum, thefollowing should be considered:
至少应考虑以下方面：
       controls to prevent proliferation of contaminants;
       为防止污染物激增而采取的控制措施
       the length of the distribution system;
       分配系统的长度
       material of construction, joints and impact as a result of sanitization;and
       结构材料、接头和消毒的影响
       design and location of devices, sensors and instruments such asflow meters, total organic carbon (TOC) analysers and temperature sensors;
       装置、探头和仪表如流量计、总有机碳（TOC）分析仪和温度探头的设计和位置选定

10.3 Filtration should not usually beused in distribution loops or at take-off user points as these are likelyto conceal system contamination.
分配循环和取用水点一般不进行过滤，因为可能会掩盖系统污染情况。

10.4 Where heat exchangers areemployed to heat or cool WPU within a system, precautions should be taken inorder to prevent the heating or cooling utility from contaminating the water.
如果使用了热交换器加热或冷却系统中的 WPU，则应采取预防措施防止加热或冷却系统对水产生污染。

10.5 Secure types of heat exchangers,such as double tube plate, double plate and frame, or tube and shellconfiguration, should be considered. Where these types are not used, analternative approach whereby the utility is maintained and monitored at a lowerpressure than the WPU may be considered. The latter approach is not usuallyappropriate in BWFI systems.
应考虑使用安全型的热交换器，如双管板、双板和双框，或管壳设计的热交换器。如果不是使用此类热交换器，则应考虑维持公用系统的压力低于 WPU 并进行监测。后一种方法通常不合适用于 BWFI 系统。

10.6 Where heat exchangers are used,they should be arranged in continually circulating loops or subloops in orderto avoid unacceptable static water in the system.
如果使用了热交换器，则应采用连续循环回路或子回路，以避免系统中有不可接受的死水。

10.7 When the temperature is reducedfor processing purposes, the reduction should occur for the minimum necessarytime. The cooling cycles and their duration should be proven satisfactoryduring the qualification of the system.
如果因工艺原因降低水温，则降低时间应缩短至最短需要时间。应在系统确认过程中证明冷却循环及其时长满足要求。

10.8 Circulation pumps should be of asanitary design with the appropriate seals to prevent contamination of thesystem.
循环泵应为卫生设计，具有适当密封，可防止系统污染。

10.9 Where stand-by pumps areprovided, they should be configured or managed to avoid dead zones trappedwithin the system.
如果有备用泵，则其参数设置或管理方式应可避免系统内有不在循环内的死区。

10.10 Consideration should be given topreventing contamination in systems where parallel pumps are used, especiallyif there is stagnant water when one of the pumps is not being used.
如果使用了双泵，则应考虑预防系统污染，尤其是当其中一台泵不用时是否会有死水。   


11. Biocontaminationcontrol techniques
生物污染控制技术

11.1 Water purificationsystems should be sanitized using chemical and or thermal sanitization proceduresas appropriate (e.g. production, storage and distribution). The procedure andconditions used, such as times and temperatures, should be suitable.
适当时应使用化学或加热消毒方法对水纯化系统进行消毒（例如，制备、储存和分配）。所用程序和条件如时长和温度应适当。

11.2 Other controltechniques to be considered include:
其它可考虑的控制技术包括：
       The maintenance of a continuous circulation of water: a turbulentflow of 1.2m/s, for example.
       保持水连续循环，例如流速 1.2m/s
       Ensuring the shortest possible length of pipework.
       确保管道尽可能短
       Isolating pipework for ambient temperature systems from adjacenthot pipes.
       将室温系统管道与邻近热管道隔绝
       Minimizing dead legs, including in the pipework, through theappropriate design. Dead legs are measured and calculated and, as a guide,should not exceed three times the branch diameter (3D).
       通过适当的设计尽可能减少死管，包括管道中的死管。死管应进行测量和计算，作为指导值，不得超过支管直径的 3 倍（3D）。
       Separate pressure gauges from the system by membranes.
       用隔膜将压力表与系统分开
       Using hygienic pattern diaphragm valves.
       使用卫生隔膜阀
       Installing pipework to allow for full drainage. A guidance figurefor the slope is 1:100.
       安装管道应可以完全排空。坡度指导值为 1:100
       Considering ultraviolet radiation sources in pipework andmaintaining the system at an elevated temperature (e.g. >65 ℃).
       考虑管道中的紫外辐射源，维持系统在较高温度（例如>65 ℃）
       Periodicsanitization by suitable means, e.g. hot water (guidance temperature >70°C),super-heated hot water or clean steam, and/or routine chemicalsanitization using ozone or other suitable chemicalagents.
       采用适当方法定期消毒，例如热水（指导温度> 70°C），过热水或清洁蒸汽，和/或使用臭氧或其它适当的化学试剂进行日常化学消毒

11.3 When chemicalsanitization is used, it is essential to prove that the agent has been removedprior to using the water.
如果使用了化学消毒，有必要证明在用水之前试剂得到清除。


12. Operationalconsiderations
运行的考虑点

12.1 Water systems shouldbe appropriately qualified and validated (7). The scope and extent of
qualification should bedetermined based upon risk assessment.
水系统应进行恰当的确认和验证。应基于风险评估确定确认的范围和程度。

12.2 There should bedocumented evidence of consideration and execution of stages of qualificationincluding, as appropriate, URS, factory acceptance testing (FAT), siteacceptance testing (SAT), design qualification (DQ), IQ, OQ and PQ.
应有书面证据证明考虑和执行了不同阶段的确认，包括（适当时） URS、工厂接收测试（FAT）、现场接收测试（SAT）、设计确认（DQ）、 IQ、 OQ 和 PQ。

12.3 Commissioning workdone should be documented. Commissioning is not a replacement for qualification.
所做的调试工作应有记录。调试不可代替确认。

12.4 In order to validatethe reliability and robustness of a system and its performance, a three-phase approachshould be used over an extended period of time. Tests on the sourcewater(drinking-water) should be included within the validation programme andcontinued as part of the routine monitoring, and these results should meetspecifications.
为了验证系统及其性能的可靠性和稳健性，应分三阶段进行较长时间的确认。在验证计划中应包括有原水检测（饮用水），并作为日常监测的一部分继续对其进行检测。这些结果均应符合标准。

12.5 Phase 1
第一阶段

Phase I should cover aperiod of at least two weeks. The system should be monitored intensively forits performance. The system should operate continuously without failure orperformance deviation. Normally, water should not be used for FPP manufacturingduring this phase.
第一阶段应持续至少 2 周。应加严监测系统性能。系统应连续运行，不得有失败或性能偏差。一般来说，本阶段不应将水用于 FPP 生产。

The procedures and protocolsfor Phase I should cover at least the following activities and testingapproaches:
第一阶段的程序和方案应覆盖至少以下活动和检测方式：
       chemical and microbiological testing in accordance with a definedplan;
       按既定计划进行的化学和微生物检测
       sample, test and monitoring of the incoming feedwater daily toverify its quality;
       日常对进厂源水的取样、检测和监测，以核查其质量
       sample, test and monitoring after each step in the purificationprocess;
       纯化过程中各步骤的取样、检测和监测
       sample, test and monitoring at each point of use and at otherdefined sample points;
       每个使用点和其它规定取样点的取样、检测和监测
       develop the appropriate operating ranges;
       建立适当的运行范围
       develop and finalize the operating, cleaning, sanitizing andmaintenance procedures;
       起草和定稿操作、清洁、消毒和维护程序
       demonstrate the production and delivery of product water of therequired quality and quantity;
       证明可制备和送出所需质量和数量的产水
       use and refine the standard operating procedures (SOPs) foroperation, maintenance, sanitization
       and troubleshooting;
       使用和改进操作、维护、消毒和问题解决的标准操作规程（SOP）
       verify provisional alert levels; and
       核查临时报警水平
       develop and refine test-failure procedure.
       起草和改进检测不合格程序

12.6 Phase 2
第二阶段

Phase 2 should cover atleast a further test period of two weeks. The system should be monitored while deployingall the refined SOPs after the satisfactory completion of Phase 1. The samplingprogram should be generally the same as in Phase 1. The use of the water forFPP manufacturing purposes during this phase may be acceptable, provided thatboth commissioning and Phase 1 data demonstrate the appropriate water qualityand the practice is approved by QA.
第二阶段应持续至少 2 周的进一步检测期。应在圆满完成第一阶段后，采用所有改进后的 SOP 对系统进行监测。取样程序一般应与第一阶段相同。在此阶段可将产水用于 FPP 生产，前提是调试和第一阶段数据证明水质满足要求，且该做法获得 QA 批准。

The approach should also:
该方法应亦：

       demonstrate consistent operation within established ranges; and
       证明在既定范围内可持续运行
       demonstrate consistent production and delivery of water of therequired quantity and quality when the system is operated in accordance withthe SOPs.
       证明当系统按 SOP 运行时可持续生产并送出所需质量和所需数量的水

12.7 Phase 3
第三阶段   

Phase 3 should cover atleast a further 12 months after the satisfactory completion of Phase 2. Thesample locations, sampling frequencies and tests may be reduced to the normalroutine pattern based on the established procedures proven during Phase 1 andPhase 2. After completion of the qualification and validation programme ofPhase 3, a system review should be undertaken. This may include the trending ofresults and the evaluation of system performance capability. The appropriateaction should be taken where identified.
第三阶段应在圆满完成第二阶段之后再持续至少 12 个月。取样位置、取样频率和检测可降至第一阶段和第二阶段所证明的既定程序中规定的日常模式。在完成第三阶段确认和验证后，应进行系统回顾审核。其中可包括结果趋势分析和系统性能的评估。如果发现趋势，则应采取适当措施。

Water can be used duringthis phase (e.g. for manufacturing and cleaning) which has the following objectives:
在此阶段可正常用水（例如，生产和清洁）。第三阶段的目的为：

       to demonstrate a reliable performance over an extended period oftime; and
       证明在较长时间内系统具有可靠表现
       to ensure that seasonal variations are evaluated.
       确保对季节性变化进行评估


13. Continuous systemmonitoring
系统持续监测

13.1 The system should besubject to continuous monitoring.
应对系统进行连续监测。

13.2 A monitoring planshould be followed where samples are collected in accordance with a written procedure.
应根据监测计划，按书面程序采集样品。

13.3 A combination ofonline and offline instruments, linked to appropriately qualified alarmsystems, should be used. Parameters such as flow, pressure, temperature,conductivity and TOC should be monitored with online devices with periodicoffline testing to confirm the results. Other parameters may be monitoredthrough offline testing.
应联合使用连接至经过适当确认的报警系统的在线和离线仪表。应采用在线仪器监测参数如
流量、压力、温度、电导率和 TOC，并定期进行离线检测以对结果进行确认。其它参数可
通过离线检测进行监测。

13.4 Offline testing(including physical, chemical and microbiological attributes) should be done inaccordance with a predetermined programme.
应根据既定程序进行离线检测（包括物理、化学和微生物属性）。

13.5 Offline samplesshould be taken from points of use or dedicated sample points where points ofuse cannot be sampled. All water samples should be taken using the samemethodology as detailed in production procedures, e.g. with a suitable flushingand drainage procedure in place.
应从使用点或专用取样点（如果使用点无法取样）采集离线样品。所有水样均应使用生产程序中详细规定的相同方法采集，例如有适当淋洗和排水程序。

13.6 Tests should becarried out to ensure that the approved pharmacopoeial specification (andcompany specification, where applicable) has been met. This may include themicrobiological quality of water, as appropriate.
应进行检测以确保满足已批准的药典标准（和公司标准，适用时）。其中可包括水的微生物
质量（适当时）。

13.7 Monitoring datashould be subjected to trend analysis, e.g. monthly, quarterly and annually.The results should be within defined control limits, such as 2 or 3 sigma.
应对监测数据进行趋势分析，例如，月度、季度和年度。结果应在规定的控制限度内，例如
2 或 3σ。

13.8 Alert and actionlevels should be established based on historically reported data.
应根据历史报告数据制订警戒限和行动限。

13.9 Trends andout-of-limit results should be investigated for the root cause, followed by theappropriate corrective actions.
应调查趋势和超限结果的根本原因，并制订恰当的纠正措施。


14. Maintenance of watersystems
水系统维护

14.1 WPU systems should bemaintained and recorded in accordance with an approved and documented maintenanceprogramme.
WPU 系统应根据已批准的书面维护计划进行维护并记录。

14.2 The programme shouldtake into account at least the following:
计划中应至少考虑以下内容：

       defined frequency for system elements;
       规定的系统要素频次
       the calibration programme;
       校正程序
       SOPs for specific tasks;
       特殊任务的 SOP
       control of approved spares;
       已批准备件的控制
       preventive maintenance and maintenance plan and instructions;
       预防性维护和维护计划与指导
       a review and approval of systems for use upon completion of work;and
       在工作完成时进行审核并批准使用
       a record and review of problems and faults during maintenance
       在维护中记录和审核问题和错误


15. System reviews
系统回顾

15.1 WPU systems should bereviewed at described intervals.
WPU 系统应按指定时间间隔回顾。

15.2 The review teamshould be comprised of representatives from engineering, utilities, validation,QA, quality control, microbiology, production and maintenance, and so on.
审核组应包括来自工程、公用系统、验证、 QA、质量控制、微生物、生产和维护等部门的代表。

15.3 The review teamshould consider matters such as:
审核组应考虑如以下方面：

       changes made since the last review;
       自上次回顾以来所做的变更
       system performance and capability;
       系统性能和系统能力
       reliability;
       可靠性
       quality trends;
       质量趋势
       failure events and alarms;
       失败事件和报警
       investigations;
       调查
       out-of-specification and out-of-limit results;
       OOS 和 OOL 结果
       compliance with current GMP requirements for WPU systems;
       符合现行 WPU 的 GMP 要求
       documentation being a current reflection of the WPU system;
       文件记录反映目前的 WPU 系统情况
       records including log books and electronic data;
       记录包括日志和电子数据
       the current SOPs relating to WPU; and
       与 WPU 有关的现行 SOP，以及
       the computerized system linked to the water system, e.g. SCADA(Supervisory Control and Data Acquisition).
       与水系统关联的计算机化系统，例如， SCADA（数据采集与监视控制系统）

15.4 The application of specifictypes of water to processes and dosage forms should be considered.     
工艺和制剂应考虑使用特定类型的水。     

15.5 Pharmaceuticalmanufacturers should use the appropriate grade of WPU during, for example, the manufacture of APIs and different dosage forms; fordifferent stages in washing and cleaning; in thepreparation of reagents and solutions; and in the synthesis of materials andproducts.
在例如 API 和不同制剂剂型生产中，制药企业在清洗和清洁、试剂和溶液制备以及物料和产
品合成的不同阶段使用适当级别的 WPU。

15.6 The grade of waterused should take into account the nature and intended use of the intermediate orfinished product and the stage in the manufacturing process at which the wateris used.
选择用水级别时应考虑水所用于的中间体或成品及生产工艺步骤的属性和既定用途。

15.7 BHPW can be used inthe preparation of products when water of high quality (i.e. very low in microorganismsand endotoxins) is needed, but the process stage or product requirement doesnot include the constraint on the production method defined in some of thepharmacopoeia monographs for BWFI.
如果需要高质量水（例如微生物和内毒素非常低），但加工步骤或产品需求不包括有些药典
各论中对 BWFI 规定的制备方法的限制，可将 BHPW 用于成品制备。

15.8 BWFI should be used,for example, in the manufacture of injectable products, such as dissolving ordiluting substances or preparations during the manufacturing of parenteral products,and for the manufacture of sterile water for preparation of injections. BWFIshould also be used for the final rinse after the cleaning of equipment andcomponents that come into contact with injectable products, as well as for thefinal rinse in a washing process in which no subsequent thermal or chemicaldepyrogenization process is applied.
注射产品生产应使用 BWFI，例如注射剂产品生产过程中溶解或稀释物质或制剂，以及注射剂无菌水的生产。与注射剂产品接触的设备和部件清洁后，如果后续没有高温或化学除热原工艺，则最终淋洗时亦应使用 BWFI。

15.9 When steam comes intocontact with an injectable product in its final container or with equipment forpreparing injectable products, it should conform to the specification for BWFIwhen condensed.
如果蒸汽要与已装入最终容器的注射剂产品，或与注射剂产品制备用设备接触，则应确认冷
凝时符合 BWFI 质量标准。


16. Inspection of watersystems
水系统的检查

16.1 WPU (BPW, BHPW andBWFI) systems are likely to be the subject of regulatory inspection from timeto time. Users should consider conducting routine audits and self-inspection ofestablished
water systems.
WPU（BPW、 BHPW 和 BWFI）系统可能会不时接受监管检查。用户应考虑对已建好的水系统进行定期审计和自检。

16.2 This document can beused as the basis of an audit and inspection. A tour of the water system, treatmentsystem, storage and distribution system, as well as visible pipework and userpoints, should be performed to ensure that the system is appropriatelydesigned, installed, qualified, validated, maintained and monitored.
本文件可用作审计和检查的基础。现场查看水系统、处理系统、储存和分配系统，以及可见管道和使用点，以确保系统经过恰当设计、安装、确认、验证、维护和监测。

16.3 The following itemscould be included in an audit or inspection:
审计或检查中可包括以下项目：

       a review of current drawings of the water system showing allcomponents in the system from the inlet to the points of use, along withsampling points and their designations;
       审核显示系统中所有部件的现行水系统图纸，从使用点进口到取样点及其标示
       a physical check to ensure that the system matches the piping andinstrumentation diagram or drawing (P&ID);
       实物检查，以确保系统与管道和仪表图（PID）相符
       approved piping drawings (e.g. orthographic and/or isometric);
       已批准的管道图（例如，正交和/或等距图）
       qualification and validation protocols, reports and results;
       确认和验证方案、报告和结果
       a sampling and monitoring plan with a drawing of all sample pointswith evidence of sample
       management, sample preparation, testing and results;
       取样和监测计划，有所有取样点的图和样品管理、样品制备、检测和结果证据
       a training programme for sample collection and testing;
       取样和检测的培训计划
       the setting and monitoring of alert and action levels;
       警戒和行动水平的设置与监测
       monitoring of results and evaluation of trends;
       结果监测和趋势评估
       absence of leaks;
       无泄漏
       a review of any changes made to the system since the last audit orinspection;
       审核自上次审计或检查以来的所有系统变更
       a review of deviations recorded and their investigation;
       审核所记录的偏差及其调查
       a general inspection of the system for status and condition;
       对系统状态和情况的一般性检查
       a review of maintenance, failure and repair logs;
       审核维护、失败和修理日志
       a check of calibration and standardization of critical instrumentsand devices;
       检查关键仪表和装置的校正和标准化
       a review of the performance capability of the system; and
       审核系统性能能力
       procedures and records for sanitization.
       消毒程序和记录

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