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文章录入:卫生安全检测评价网   文章来源:GMP办公室   添加时间:2020-5-13



2.Background to waterrequirements and uses


 3.General principles forpharmaceutical water systems


4.Water quality specifications


4.1.  Pharmacopoeial specifications


4.2.  Drinking-water


4.3.  Bulk purified water


4.4.  Bulk highly purified water


4.5.  Bulk water for injections


4.6.  Other grades of water


5.General considerations forwater purification systems


 6.Water storage and distributionsystems


 7.Good practices for watersystems


 8.System sanitization and bioburdencontrol


 9.Storage vessels


 10.Water distribution


 11.Biocontamination control techniques


 12.Operational considerations


12.5       Phase1


12.6       Phase2


12.7       Phase3


13.Continuous system monitoring


14.Maintenance of water systems


15.System reviews


16.Inspection of water systems




18.Further reading




1 Introduction and scope



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.



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.



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.




1.4  Thedocument can be used in whole or in part, as appropriate, to the section andapplication under consideration.



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.



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).




2.  Backgroundto water requirements and uses



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.



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.



2.3  Toreduce the risks associated with the production, storage and distribution ofwater and, considering the properties and use of water, it is essential:



  • to ensure the appropriate design, installation, operation andmaintenance of the pre-treatment (production of drinking-water), treatment(production of WPU such as purified water (PW) and WFI), and storage anddistribution 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;

  • to perform periodic sanitization;

  • 定期进行卫生处理;

  • to take the appropriate measures in order to prevent chemical andmicrobial contamination; and

  • 采取适当措施,防止化学和微生物污染;以及

  • to prevent 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.



3. Generalprinciples for pharmaceutical water systems



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.



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.



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).



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.




4.  Water quality specifications



4.1  Pharmacopoeialspecifications



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.



4.2  Drinking-water



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.



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.



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.



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.



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.



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.



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.



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.



4.2.9      Examplesof typical processes employed to produce drinking-water may include:



  • desalinization;

  • 脱盐;


  • filtration;

  • 过滤;


  • softening;

  • 软化;


  • disinfection or sanitization (e.g. by sodium hypochlorite {chlorine}injection);

  • 消毒(例如使用次氯酸钠{});


  • iron (ferrous) removal;

  • 除铁;


  • precipitation; and

  • 沉降;以及


  • the reduction of concentration of specific inorganic and/or organicmaterials.

  • 降低特定无机和/或有机物质的浓度。


4.2.10 Controls should be implemented toprevent 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.



4.2.11 The quality of drinking-water shouldbe monitored routinely to account for environmental, seasonal or supply changeswhich may have an impact on the source water quality.



4.2.12 Where drinking-water is stored anddistributed by the user, the storage and distribution systems should not allowthe degradation of the water quality prior to use. After any such storage,testing should be carried out routinely and in accordance with a definedprocedure. The storage and distribution of drinking-water should be done in amanner to ensure a turnover or recirculation of the stored water sufficientenough to prevent stagnation.



4.2.13 The equipment and systems used toproduce and store drinking-water should be able to be drained and sanitized.



4.2.14 Storage tanks should be closed withappropriately protected vents and should allow for visual inspection.



4.2.15 Distribution pipework should be ableto be drained or flushed and sanitized.



4.2.16 The scope and extent ofqualification for the system should be identified and justified.



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.



4.2.18 Changes to a system or to itsoperation should be made in accordance with change control procedures.



4.2.19 Additional testing should be consideredif there is any change in the raw water source, treatment techniques or systemconfiguration.



4.3  Bulkpurified water



4.3.1      Bulkpurified water (BPW) should meet the relevant pharmacopoeial specifications forchemical and microbiological purity.



4.3.2      BPWshould be prepared from drinking-water as a minimum-quality feedwater.



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.



4.3.4      Thefollowing should be considered when configuring a water purification system ordefining user requirement specifications (URS):



  • the quality of feedwater and its variation over seasons;

  • 给水质量及其季节变化;


  • the quantity of water required by the user;

  • 用户所需的用水量;


  • the required water-quality specification;

  • 所需的水质标准;


  • the sequence of purification stages required;

  • 所需的纯化阶段顺序;


  • energy consumption;

  • 能耗;


  • appropriately located sampling points designed in such a way so asto avoid potential contamination; and

  • 适当设置取样点,以避免潜在污染;以及


  • unit process steps provided and documented with the appropriateinstrumentation 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.



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.



4.3.7      Thefollowing controls should be considered:



  • the maintenance of water flow at all times, in order to preventwater from stagnating;

  • 时刻保持水的流动,防止滞留;


  • control of temperature in the system by heat exchangers or plantroom cooling in order to 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);


  • the provision of ultraviolet disinfection at appropriate locationsin the system;

  • 在系统的适当位置进行紫外线消毒;


  • the use of water-treatment system components that can periodicallybe thermally sanitized;

  • 使用可以周期性地进行热消毒的水处理系统组件;


  • in addition to thermal sanitization, the application of chemicalsanitization such as 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


  • thermal sanitization 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.



4.4  Bulkhighly purified water



4.4.1      Bulkhighly purified water (BHPW) must meet the same quality standards as WFI,including the limit for endotoxins.



4.4.2      BHPWshould be prepared from drinking water as a minimum-quality feedwater.



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.



4.4.4      BHPWshould also be protected from recontamination and microbial proliferation.



4.4.5      BHPWand WFI have identical microbiological requirements.



Note: The   guidance  provided    in    section 4.3  for       BPW  is       equally applicable to  BHPW.



4.5  Bulkwater for injections




4.5.1      Bulkwater for injections (BWFI) should meet the relevant pharmacopoeialspecifications for chemical and microbiological purity (including endotoxins).BWFI is the highest quality of pharmacopoeial WPU.




4.5.2      BWFIis not sterile water and is not a final dosage form. It is an intermediate bulkproduct suitable to be used as an ingredient during formulation.



4.5.3      Asa robust technique should be used for the production of BWFI, the followingshould be considered when designing a water purification system:



  • 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 quality specification;

  • 所需的水质标准;


  • the quantity of water;

  • 水量;


  • based on the selection of components and type of system, theappropriate URS, qualification and validation;

  • 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 or generators 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


l cool-down venting to avoid contamination ingress.

  • 冷却水排放,防止污染进入。


4.5.4      BWFImay be prepared, for example, by distillation as the final purification step.Alternatively, techniques such as deionisation, electro deionization, nanofiltration, ultrafiltration, water softening, descaling, pre-filtration anddegasification, ultraviolet treatment, along with other techniques, may beconsidered in conjunction with a single or double pass RO system.



4.5.5      BWFIshould have the appropriate action and alert limits and should also beprotected from recontamination and microbial proliferation.



Note: For a full description, seeProduction of water for injection by means other than distillation.



4.6  Othergrades of water




When a specific process requires a specialnon-pharmacopoeial grade of water, its specification must be documented withina company’s quality system. As a minimum, it must meet the pharmacopoeialrequirements relating to the grade of WPU required for the type of dosage formor process step.



5.  General considerations for water purificationsystems



5.1  Pharmaceuticalmanufacturers should apply the current principles of quality risk management(6) in selecting and using the appropriate water purification systems. Anappropriate method for the production of WPU should be used.



5.2  Risksand controls should be identified for each stage of the production, storage,distribution, use and monitoring of WPU.



5.3  Risksidentified should be analyzed and evaluated in order to determine the scope andextent of validation and qualification of the system, including thecomputerized systems used for the production, control and monitoring of WPU.



5.4  Riskmanagement should be an ongoing part of the quality management process for WPU.A mechanism to review or monitor events associated with the production,storage, distribution and use of WPU should be implemented.



5.5  Proceduresfor managing changes and deviations should be followed. Where applicable, theappropriate risk and impact assessments should be done where changes anddeviations are managed.