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近日，WHO發(fā)布了 《制藥用水GMP指南》，該指南英文全文29頁(yè)，包含以下內(nèi)容：

 

制藥用水系統(tǒng)的一般原則

 

飲用水、純化水、高純水、注射用水和其他級(jí)別的水的質(zhì)量標(biāo)準(zhǔn)要求

 

制水系統(tǒng)、儲(chǔ)存和分配系統(tǒng)的注意事項(xiàng)

 

水系統(tǒng)良好規(guī)范

 

系統(tǒng)消毒與生物污染控制

 

儲(chǔ)罐的要求

 

分配系統(tǒng)的要求

 

生物污染控制技術(shù)

 

第一階段、第二階段、第三階段的操作考慮點(diǎn) 

 

持續(xù)監(jiān)測(cè)的要求

 

水系統(tǒng)的維護(hù)要求

 

系統(tǒng)回顧

 

水系統(tǒng)的檢查

 

部分翻譯如下：

 

1.Introduction

 

介紹

 

2.Background to waterrequirements and uses

 

水的要求和用途背景

 

 3.General principles forpharmaceutical water systems

 

制藥用水系統(tǒng)的一般原則

 

4.Water quality specifications

 

水的質(zhì)量標(biāo)準(zhǔn)

 

4.1.  Pharmacopoeial specifications

 

4.1.藥典標(biāo)準(zhǔn)

 

4.2.  Drinking-water

 

4.2.飲用水 

 

4.3.  Bulk purified water

 

4.3.純化水

 

4.4.  Bulk highly purified water

 

4.4.高純水

 

4.5.  Bulk water for injections

 

4.5.注射用水 

 

4.6.  Other grades of water

 

4.6.其他級(jí)別的水

 

5.General considerations forwater purification systems

 

水凈化系統(tǒng)的一般考慮點(diǎn)

 

 6.Water storage and distributionsystems

 

儲(chǔ)存和分配系統(tǒng)

 

 7.Good practices for watersystems

 

水系統(tǒng)良好規(guī)范

 

 8.System sanitization and bioburdencontrol

 

系統(tǒng)消毒與生物污染控制

 

 9.Storage vessels

 

儲(chǔ)罐

 

 10.Water distribution

 

分配系統(tǒng)

 

 11.Biocontamination control techniques

 

生物污染控制技術(shù)

 

 12.Operational considerations

 

操作的考慮點(diǎn) 

 

12.5       Phase1

 

第一階段

 

12.6       Phase2

 

第二階段

 

12.7       Phase3

 

第三階段

 

13.Continuous system monitoring

 

持續(xù)系統(tǒng)監(jiān)測(cè)

 

14.Maintenance of water systems

 

水系統(tǒng)的維護(hù)

 

15.System reviews

 

系統(tǒng)回顧

 

16.Inspection of water systems

 

水系統(tǒng)的檢查

 

17.References

 

參考資料

 

18.Further reading

 

延伸閱讀

 

1 Introduction and scope

 

介紹及范圍

 

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.

 

本文件包括制藥用水（WPU）的生產(chǎn)、儲(chǔ)存和分配。本文件提供不同制藥用水標(biāo)準(zhǔn)、水系統(tǒng)質(zhì)量管理的GMP指南、水處理(生產(chǎn))系統(tǒng)、制藥用水儲(chǔ)存和分配系統(tǒng)、確認(rèn)和驗(yàn)證、以及取樣、測(cè)試和水的日常監(jiān)測(cè)相關(guān)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.

 

雖然提到了飲用水，但本文件的重點(diǎn)是經(jīng)處理的制藥用水的處理、儲(chǔ)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.

 

本文件不包括處于配方狀態(tài)的供病人使用的水，或在藥房少量使用于配制個(gè)別處方藥物的水。

 

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(視乎情況而定)用于審議中的部分和申請(qǐng)。

 

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”延伸閱讀”部分還包括一些相關(guān)出版物，在計(jì)劃、安裝和使用制藥用水系統(tǒng)時(shí)可作為補(bǔ)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).

 

本文件是對(duì)世界衛(wèi)生組織(WHO)活性藥物成分GMP(2)和WHO藥物成品GMP(3)的補(bǔ)充。

 

2.  Backgroundto 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.

 

水是制藥工業(yè)中廣泛使用的物質(zhì)。它被廣泛用作活性藥物成分（API）、中間體和成品（FPP）的生產(chǎn)、加工和配方的原料或起始材料，用于溶劑和試劑的制備，以及用于清潔（如清洗和沖洗）。水由于其極性和氫鍵，具有獨(dú)特的化學(xué)性質(zhì)。它能夠溶解、吸收、吸附或懸浮不同的化合物。這可能包括本身構(gòu)成危害或可能與預(yù)期產(chǎn)品物質(zhì)發(fā)生反應(yīng)的污染物，從而對(duì)健康造成危害。因此，水應(yīng)符合必要的質(zhì)量標(biāo)準(zhǔn)，以減輕這些風(fēng)險(xiǎn)。

 

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.

 

在水的生產(chǎn)、貯存及分配過程中，應(yīng)控制水的微生物及化學(xué)質(zhì)量。水在使用之前通常不會(huì)經(jīng)過測(cè)試和批放行。它通常來自一個(gè)按需使用的系統(tǒng)。由于微生物測(cè)試可能需要一段培養(yǎng)期時(shí)間，因此一般只有在用水后才可取得測(cè)試結(jié)果。因此，保證水的質(zhì)量以滿足用水需求是至關(guān)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:

 

為了減少與水的生產(chǎn)、儲(chǔ)存和分配有關(guān)的風(fēng)險(xiǎn)，并考慮到水的特性和用途，必須:

 

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;

 

確保預(yù)處理(飲用水的生產(chǎn))、處理(制藥用水的制備，如下純化水(PW)和注射用水(WFI))及貯存和分配系統(tǒng)得到適當(dāng)?shù)脑O(shè)計(jì)、安裝、操作和維修;

 

to perform periodic sanitization;

 

定期進(jìn)行衛(wèi)生處理;

 

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

 

采取適當(dāng)措施，防止化學(xué)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.

 

水的質(zhì)量存在不同級(jí)別。應(yīng)使用適當(dāng)?shù)乃|(zhì)（符合其既定標(biāo)準(zhǔn)）用于其預(yù)期目的。

 

3. Generalprinciples for pharmaceutical water systems

 

制藥用水系統(tǒng)的一般原則

 

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.

 

制藥用水的生產(chǎn)、儲(chǔ)存和分配系統(tǒng)應(yīng)該設(shè)計(jì)、安裝、調(diào)試、確認(rèn)、驗(yàn)證、運(yùn)行和維護(hù)，以確保一致和可靠地生產(chǎn)符合預(yù)期質(zhì)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.

 

系統(tǒng)的能力應(yīng)適當(dāng)，以滿足平均流量和峰值流量的需求。系統(tǒng)應(yīng)能夠連續(xù)長(zhǎng)時(shí)間運(yùn)行，以避免因設(shè)備頻繁開啟和關(guān)閉而造成的效率低下和設(shè)備壓力。

 

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).

 

在初始確認(rèn)(例如安裝確認(rèn)、運(yùn)行確認(rèn)、性能確認(rèn)和驗(yàn)證)后，系統(tǒng)的使用應(yīng)由質(zhì)量部門批準(zhǔn)，例如質(zhì)量保證(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.

 

應(yīng)定期監(jiān)測(cè)原水及處理后水的化學(xué)、微生物及(如適用)內(nèi)毒素污染情況。水的處理、儲(chǔ)存和分配系統(tǒng)的性能也應(yīng)監(jiān)測(cè)。應(yīng)保存監(jiān)測(cè)結(jié)果，趨勢(shì)分析，以及任何所采取行動(dòng)的記錄。

 

4.  Water quality specifications

 

水的質(zhì)量標(biāo)準(zhǔn)

 

4.1  Pharmacopoeialspecifications

 

藥典標(biāo)準(zhǔn)

 

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.

 

藥典包括水的使用和制劑標(biāo)準(zhǔn)。本文件所提及標(biāo)準(zhǔn)，例如藥典，則應(yīng)使用相關(guān)的最新版本。本文件將不重復(fù)這些內(nèi)容。如不同藥典標(biāo)準(zhǔn)之間存在細(xì)微差別，制造商應(yīng)根據(jù)向相關(guān)藥監(jiān)機(jī)構(gòu)提交的上市許可來選擇的適當(dāng)?shù)臉?biāo)準(zhǔn)。國(guó)家、地區(qū)和國(guó)際藥典(4)對(duì)制藥用水的藥典要求或指南進(jìn)行了描述，并規(guī)定或推薦了各種雜質(zhì)或雜質(zhì)類別的限值。藥典對(duì)水的微生物質(zhì)量提出了要求或指導(dǎo)。

 

4.2  Drinking-water

 

飲用水

 

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.

 

飲用水的質(zhì)量由WHO飲用水質(zhì)量指南(5)和國(guó)際標(biāo)準(zhǔn)化組織衛(wèi)生組織(ISO)及其他區(qū)域和國(guó)家機(jī)構(gòu)的標(biāo)準(zhǔn)所涵蓋。飲用水應(yīng)當(dāng)符合主管機(jī)構(gòu)的有關(guān)規(guī)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.

 

飲用水可來自天然或儲(chǔ)存的水源。自然資源的例子包括泉水、井水、河流、湖泊和海洋。在選擇飲用水處理方法時(shí)，應(yīng)考慮水源水的條件。典型的處理方法包括脫鹽、軟化、特定離子的去除、顆粒降低和抗菌處理。

 

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.

 

飲用水應(yīng)由管道系統(tǒng)在持續(xù)正壓下供應(yīng)，不得有任何可能污染任何產(chǎn)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.

 

飲用水可能來自公共供水系統(tǒng)。這包括一個(gè)工廠外的來源，比如市政當(dāng)局。供應(yīng)商應(yīng)確保適當(dāng)?shù)娘嬘盟|(zhì)。應(yīng)當(dāng)進(jìn)行檢驗(yàn)，以保證所提供的飲用水的質(zhì)量。這種測(cè)試通常在原水供應(yīng)點(diǎn)進(jìn)行。必要時(shí)，應(yīng)進(jìn)行適當(dāng)?shù)膬?nèi)部處理以達(dá)到規(guī)定質(zhì)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.

 

如果飲用水是散裝購(gòu)買，并由水罐車運(yùn)送給用戶，應(yīng)進(jìn)行控制以減少與此相關(guān)的任何風(fēng)險(xiǎn)。供應(yīng)商評(píng)估和批準(zhǔn)認(rèn)證活動(dòng)，包括確認(rèn)運(yùn)載工具的可接受性，應(yīng)以類似于任何其他起始物料的方式進(jìn)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.

 

藥品制造商有責(zé)任確保供應(yīng)純化水處理系統(tǒng)的源水符合適當(dāng)?shù)娘嬘盟蟆Ｔ谶@些情況下，應(yīng)確認(rèn)達(dá)到飲用水質(zhì)量的點(diǎn)，并在其后以規(guī)定的時(shí)間間隔取樣和測(cè)試。

 

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.

 

如果在藥物制造的某些階段直接使用飲用水，例如在原料藥生產(chǎn)或在生產(chǎn)較高質(zhì)量制藥用水的給水中直接使用飲用水，工廠應(yīng)定期進(jìn)行測(cè)試，以確認(rèn)水質(zhì)符合飲用水所需的標(biāo)準(zhǔn)。

 

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.

 

如飲用水是由原水經(jīng)現(xiàn)場(chǎng)系統(tǒng)處理而產(chǎn)生，則應(yīng)說明系統(tǒng)配置及所采用的水的處理步驟。

 

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

 

制備飲用水的典型工序例子包括:

 

desalinization;

 

脫鹽;

 

filtration;

 

過濾;

 

softening;

 

軟化;

 

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

 

消毒(例如使用次氯酸鈉{氯});

 

iron (ferrous) removal;

 

除鐵;

 

precipitation; and

 

沉降;以及

 

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

 

降低特定無(wú)機(jī)和/或有機(jī)物質(zhì)的濃度。

 

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.

 

應(yīng)實(shí)施控制以防止砂濾器、碳床和水軟化裝置受微生物污染。所選擇的技術(shù)應(yīng)該是適當(dāng)?shù)?，可以包括反沖洗、化學(xué)和/或熱消毒以及頻繁的再生。

 

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.

 

應(yīng)定期監(jiān)測(cè)飲用水的水質(zhì)，考慮可能影響源水水質(zhì)的環(huán)境、季節(jié)或供應(yīng)變化。

 

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.

 

當(dāng)用戶對(duì)飲用水進(jìn)行儲(chǔ)存和分配時(shí)，儲(chǔ)存和分配系統(tǒng)不應(yīng)在使用前降低水質(zhì)。任何此類存儲(chǔ)后，應(yīng)進(jìn)行日常測(cè)試，并符合既定程序。飲用水的儲(chǔ)存和分配應(yīng)以某種方式確保所儲(chǔ)存水的翻滾或循環(huán)足以防止停滯。

 

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

 

用于生產(chǎn)和儲(chǔ)存飲用水的設(shè)備和系統(tǒng)應(yīng)能夠排水和消毒。

 

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

 

儲(chǔ)罐應(yīng)密封，配以受適當(dāng)保護(hù)的通氣口，并應(yīng)可以目視檢查。

 

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

 

分配管道應(yīng)該能夠排水、沖洗和消毒。

 

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

 

應(yīng)確定和論證系統(tǒng)確認(rèn)范圍和程度。

 

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.

 

飲用水測(cè)試結(jié)果應(yīng)作統(tǒng)計(jì)分析，以確定趨勢(shì)和變化。如果飲用水水質(zhì)發(fā)生重大變化，但仍符合標(biāo)準(zhǔn)，則應(yīng)審查直接將這種水用作制藥用水或作為下游處理階段的給水，以審查任何風(fēng)險(xiǎn)以及審查的結(jié)果和采取的行動(dòng)并記錄。

 

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

 

系統(tǒng)或其操作的變更應(yīng)按照變更控制程序進(jìn)行。

 

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

 

如原水來源、處理技術(shù)或系統(tǒng)配置有任何變更，應(yīng)考慮進(jìn)行額外測(cè)試。

 

4.3  Bulkpurified water

 

純化水

 

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

 

純化水(BPW)應(yīng)符合相關(guān)藥典的化學(xué)和微生物標(biāo)準(zhǔn)。

 

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

 

純化水應(yīng)最少由飲用水制備而成。

 

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.

 

可使用適當(dāng)?shù)摹⒔?jīng)確認(rèn)的純化技術(shù)或技術(shù)組合制備純化水。純化水可通過，例如，離子交換、反滲透、反滲透/電去離子(EDI)、超濾和蒸汽壓縮的組合來制備。

 

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

 

在配置純化水系統(tǒng)或定義用戶需求規(guī)范(URS)時(shí)，應(yīng)考慮以下因素:

 

the quality of feedwater and its variation over seasons;

 

給水質(zhì)量及其季節(jié)變化;

 

the quantity of water required by the user;

 

用戶所需的用水量;

 

the required water-quality specification;

 

所需的水質(zhì)標(biāo)準(zhǔn);

 

the sequence of purification stages required;

 

所需的純化階段順序;

 

energy consumption;

 

能耗;

 

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

 

適當(dāng)設(shè)置取樣點(diǎn)，以避免潛在污染;以及

 

unit process steps provided and documented with the appropriateinstrumentation to measure parameters suchas flow, pressure, temperature, conductivity, pH and total organic carbon.

 

各單元處理步驟提供并記錄適當(dāng)?shù)膬x器，以測(cè)量諸如流量、壓力、溫度、電導(dǎo)率、pH值和總有機(jī)碳等參數(shù)。

 

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.

 

離子交換、反滲透和超濾等環(huán)境溫度系統(tǒng)特別容易受到微生物污染，尤其是當(dāng)設(shè)備在沒有或需水量很低處于停止的時(shí)候。為了防止和減少微生物污染，應(yīng)該定期進(jìn)行消毒處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.

 

每個(gè)純化階段都需要適當(dāng)?shù)摹⒔?jīng)過驗(yàn)證的消毒方法。如使用消毒劑，應(yīng)證明消毒效果。

 

4.3.7      Thefollowing controls should be considered:

 

應(yīng)考慮以下控制措施:

 

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

 

時(shí)刻保持水的流動(dòng)，防止滯留;

 

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);

 

通過熱交換器或工廠房間冷卻來控制系統(tǒng)內(nèi)的溫度，以減少微生物生長(zhǎng)的風(fēng)險(xiǎn)(指導(dǎo)值＜25℃);

 

the provision of ultraviolet disinfection at appropriate locationsin the system;

 

在系統(tǒng)的適當(dāng)位置進(jìn)行紫外線消毒;

 

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

 

使用可以周期性地進(jìn)行熱消毒的水處理系統(tǒng)組件;

 

in addition to thermal sanitization, the application of chemicalsanitization such as ozone, hydrogen peroxide and/or peracetic acid; and

 

除熱消毒外，使用化學(xué)消毒劑如臭氧、過氧化氫和/或過氧乙酸;以及

 

thermal sanitization at > 70 °C.

 

70℃熱消毒。

 

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.

 

純化水應(yīng)根據(jù)對(duì)系統(tǒng)和數(shù)據(jù)趨勢(shì)的知識(shí)，確定微生物純度的適當(dāng)行動(dòng)和警戒限。應(yīng)該防止二次污染和微生物繁殖。

 

4.4  Bulkhighly purified water

 

高純水

 

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

 

高純水(BHPW)必須達(dá)到與WFI相同的質(zhì)量標(biāo)準(zhǔn)，包括內(nèi)毒素標(biāo)準(zhǔn)。

 

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

 

高純水應(yīng)最低使用飲用水制備。

 

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.

 

可使用適當(dāng)并經(jīng)確認(rèn)的純化技術(shù)，或者技術(shù)組合制備高純水。高純水通常采用兩級(jí)反滲透與超濾和去離子等其他適當(dāng)技術(shù)相結(jié)合的方法制備。

 

4.4.4      BHPWshould also be protected from recontamination and microbial proliferation.

 

還應(yīng)保護(hù)高純水免受再污染和微生物增殖。

 

4.4.5      BHPWand WFI have identical microbiological requirements.

 

高純水和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節(jié)提供的純化水指南同樣適用于高純水。

 

4.5  Bulkwater for injections

 

注射用水

 

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.

 

注射用水(BWFI)應(yīng)符合相關(guān)藥典的化學(xué)和微生物純度(包括內(nèi)毒素)標(biāo)準(zhǔn)。注射用水是最高質(zhì)量的制藥用水。

 

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.

 

散裝注射用水不是無(wú)菌水，也不是成品制劑。它是一種適合在配方中作為配料使用的中間體產(chǎn)品。

 

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

 

注射用水的制備應(yīng)采用穩(wěn)健的技術(shù)，在設(shè)計(jì)注射用水系統(tǒng)時(shí)應(yīng)考慮以下因素:

 

the quality of feedwater (e.g. drinking-water, usually with furthertreatment, or PW);

 

給水的質(zhì)量(例如飲用水，通常需要進(jìn)一步處理，或者PW);

 

the required water quality specification;

 

所需的水質(zhì)標(biāo)準(zhǔn);

 

the quantity of water;

 

水量;

 

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

 

基于部件和系統(tǒng)類型的選擇，適當(dāng)?shù)腢RS、確認(rèn)和驗(yàn)證;

 

the optimum generator size or generators with variable control toavoid over-frequent start/stop cycling;

 

制水機(jī)最優(yōu)規(guī)格或可調(diào)控制的制水機(jī)，以避免頻繁啟動(dòng)/停止;

 

blow-down and dump functions; and

 

吹掃和排放功能;以及

 

l cool-down venting to avoid contamination ingress.

 

冷卻水排放，防止污染進(jìn)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.

 

注射用水可以通過蒸餾作為最后的提純步驟來制備。或者，諸如去離子、電去離子、納米過濾、超濾、水軟化、除垢、預(yù)過濾和除氣、紫外線處理以及其他技術(shù)，可以與一級(jí)或兩級(jí)反滲透系統(tǒng)一起考慮。

 

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

 

注射用水應(yīng)有適當(dāng)?shù)男袆?dòng)和警戒限度，并應(yīng)防止再污染和微生物增殖。

 

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

 

注:詳細(xì)說明請(qǐng)參閱非蒸餾法制備注射用水指南。

 

4.6  Othergrades of water

 

水的其他級(jí)別

 

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.

 

當(dāng)一個(gè)特定的工藝需要特殊的非藥典級(jí)別的水時(shí)，其標(biāo)準(zhǔn)必須在公司的質(zhì)量體系中規(guī)定。至少，它必須滿足與劑型或工藝步驟類型所需的制藥用水等級(jí)相關(guān)的藥典要求。

 

5.  General considerations for water purificationsystems

 

純化水系統(tǒng)的一般考慮點(diǎn)

 

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.

 

藥物制造商在選擇和使用合適的純化水系統(tǒng)時(shí)，應(yīng)采用現(xiàn)行的質(zhì)量風(fēng)險(xiǎn)管理原則。制藥用水(WPU)的生產(chǎn)應(yīng)采用合適的方法。

 

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

 

制藥用水的生產(chǎn)、儲(chǔ)存、分配、使用和監(jiān)測(cè)的每個(gè)階段都應(yīng)確定風(fēng)險(xiǎn)和控制措施。

 

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.

 

應(yīng)分析和評(píng)估所識(shí)別的風(fēng)險(xiǎn)，以確定該系統(tǒng)的驗(yàn)證和確認(rèn)的范圍和程度，包括用于制備、控制和監(jiān)測(cè)的計(jì)算機(jī)化系統(tǒng)。

 

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.

 

風(fēng)險(xiǎn)管理應(yīng)作為制藥用水質(zhì)量管理過程的一個(gè)持續(xù)的部分。應(yīng)實(shí)施一種機(jī)制，以審查或監(jiān)測(cè)與制藥用水的生產(chǎn)、儲(chǔ)存、分配和使用有關(guān)的事件。

 

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.

 

應(yīng)遵循變更和偏差的管理程序。適當(dāng)時(shí)，變更和偏差的管理應(yīng)進(jìn)行適當(dāng)?shù)娘L(fēng)險(xiǎn)和影響評(píng)估。