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今年5 月，世衛(wèi)組織（WHO） 修訂了自 2012 年起生效的制藥用水指南，發(fā)布征求意見(jiàn)草案。根據(jù)反饋意見(jiàn)，7 月 30 日，WHO發(fā)布了該指南草案的修訂稿，用于二次征求意見(jiàn)。 基于第二次征求意見(jiàn)收到的反饋，將形成最終版本，并計(jì)劃于今年10 月舉行的第55屆藥物制劑專家委員會(huì)（ECSPP）會(huì)議上對(duì)此進(jìn)行討論，以通過(guò)本指南的定稿。 該版本在初稿的基礎(chǔ)上做了較大的修訂，主要變化的中英對(duì)照總結(jié)如下：主要變化：強(qiáng)調(diào)了水的等級(jí)應(yīng)與產(chǎn)品性質(zhì)、用途、階段相匹配。修訂內(nèi)容：描述水的質(zhì)量標(biāo)準(zhǔn)時(shí)，引用了藥典2.4 Different grades of water quality exist. The appropriate water quality, meeting its defined specification (such as described in a pharmacopoeia), should be used for the intended application.存在有不同級(jí)別的水質(zhì)。應(yīng)根據(jù)目標(biāo)用途使用符合指定質(zhì)量標(biāo)準(zhǔn)的水，如參考藥典的要求。2.5 The application of specific types of water to processes and dosage forms should be considered.2.5應(yīng)考慮將特定類型的水應(yīng)用于工藝和劑型。2.6 Pharmaceutical manufacturers should use the appropriate grade of WPU during, for example, the manufacture of APIs and different dosage forms, for different stages in washing and cleaning, and in the synthesis of materials and products.2.6制藥商應(yīng)在 生產(chǎn)API和不同劑型，清洗和清潔的不同階段、以及材料和產(chǎn)品的合成過(guò)程中，使用適當(dāng)級(jí)別的WPU（制藥用水）。2.7 The grade of water used should take into account the nature and intended use of the intermediate or FPP and the stage in the manufacturing process at which the water is used.2.7用水等級(jí)應(yīng)考慮中間體或FPP的性質(zhì)和預(yù)期用途、以及 生產(chǎn)過(guò)程中使用該水的階段。2.8 Bulk water for injections (BWFI) should be used, for example, in the manufacture of injectable products, such as dissolving or diluting substances or preparations during the manufacturing of parenteral products, and for the manufacture of water for preparation of injections. BWFI should also be used for the final rinse after the cleaning of equipment and components that come into contact with injectable products, as well as for the final rinse in a washing process in which no subsequent thermal or chemical depyrogenization process is applied.2.8散裝注射用水（BWFI）應(yīng)用于生產(chǎn)注射產(chǎn)品，例如注射產(chǎn)品生產(chǎn)過(guò)程中溶解或稀釋物質(zhì)或制劑，以及用于生產(chǎn)注射用水。BWFI還應(yīng)用于清潔與可注射產(chǎn)品接觸的設(shè)備和組件之后的最終沖洗，以及用于清洗過(guò)程中的最終沖洗（不進(jìn)行后續(xù)熱或化學(xué)去熱原工藝）。第4章：水的質(zhì)量標(biāo)準(zhǔn)新增內(nèi)容：第 4.2 節(jié)“飲用水“增加備注Note: The requirements for the design, construction and commissioning of drinking water systems are usually controlled through local regulations. Drinking water systems are not usually qualified or validated.注意：飲用水系統(tǒng)的設(shè)計(jì)、建造和調(diào)試要求通常由當(dāng)?shù)胤ㄒ?guī)控制。飲用水系統(tǒng)通常未經(jīng)確認(rèn)或驗(yàn)證。刪除原第 4.4 節(jié)“散裝高純水“的內(nèi)容4.4 Bulk highly purified water
第 7 章：水系統(tǒng)的良好實(shí)踐修訂7.2小節(jié)-設(shè)計(jì)和施工方法（design and construction practices）：該部分進(jìn)行了分類細(xì)化，分別從“飲用水貯存、供應(yīng)和分配系統(tǒng)”以及“純化水和散裝注射用水系統(tǒng)”，闡述了水系統(tǒng)的良好實(shí)踐。For drinking water storage, supply and distribution systems on-siteMaterials of construction should be selected based on the following requirements:· ability to operate at the temperatures/pressures required;· lack of impact to the final water quality;· resistant to any sanitizing chemicals that may be used;· threaded and flanged joints are permitted; and· sample valves should preferably be of sanitary design.Note that the system may have a design life at the end of which it should be replaced/adequately maintained.用于現(xiàn)場(chǎng)的飲用水存儲(chǔ)、供應(yīng)和分配系統(tǒng)結(jié)構(gòu)材料應(yīng)根據(jù)以下要求進(jìn)行選擇：- 對(duì)最終水質(zhì)沒(méi)有影響；
- 進(jìn)樣閥最好采用衛(wèi)生設(shè)計(jì)。
請(qǐng)注意，系統(tǒng)可能具有設(shè)計(jì)壽命，應(yīng)在使用壽命結(jié)束時(shí)對(duì)其進(jìn)行更換/充分維護(hù)。For purified water and bulk water for injection systemsNote: Construction standards are generally aligned with potable water standards up to the process stage.· Materials of construction should be appropriate. It should be non-leaching, non- adsorbing, non-absorbing and resistant to corrosion. Stainless-steel grade 316L or PVDC is generally recommended. The choice of material should take into account the intended sanitization method.· Stainless steel systems should be orbitally welded, with manual welds where necessary. Inter-weldability between materials should be demonstrated with the maintenance of weld quality through a defined process. Documentation for such a system should be kept and should include, as a minimum, the qualification of the welder, welder set-up, work session test pieces (coupons or weld samples), proof of quality of gas used, welding machine calibration record, weld identification and heat numbers, and logs of all welds. Records, photographs or videos of inspection of a defined proportion of welds (e.g. 100% manual welds, 10% orbital welds).· Joints should be made using sanitary connections, for example, Tri-clover joints. Threaded joints should not be permitted. Polyvinylidene fluoride or polyvinylidene difluoride (PVDF) systems should be fusion joined and visually inspected.· Passivation should be considered for stainless steel systems, for example, for non- electropolished surfaces (after initial installation and after significant modification) in accordance with a documented procedure defining the solution to be used, its concentration, the temperature and contact time.· Internal finish should be smooth.· Flanges, unions and valves should be of a hygienic or sanitary design. Valves should be diaphragm type forged or machined body, with points of use constructed so that they can drain. Sample valves should be sanitary type with the surface roughness of 1.0 micron for PW and WFI systems and are typically installed between process stages and on the distribution loop return. The appropriate checks should be carried out in order to ensure that the correct seals and diaphragms are used and that they are fitted and tightened correctly.· The system should be installed to promote drainability with a recommended minimum slope of 1/100.· Where appropriate, pressure or hydro-tests for leaks, spray-ball functionality test and flow turbulence should be considered.· Provision should be made for on-line measurement for total organic carbon (TOC), conductivity and temperature.· Documents should provide evidence of system components and qualification. These include as applicable drawings, original or certified copies of certificates of conformity for materials of construction, records of on-site tests performed, weld/joining records, calibration certificates, system pressure test records and records of passivation.注意：在整個(gè)過(guò)程階段，施工標(biāo)準(zhǔn)通常與飲用水標(biāo)準(zhǔn)保持一致。- 結(jié)構(gòu)材料應(yīng)適當(dāng)。它應(yīng)該是非浸出、非吸附、非吸收和耐腐蝕的。通常建議使用不銹鋼等級(jí)316L或PVDC。材料的選擇應(yīng)考慮到預(yù)期的消毒方法。
- 不銹鋼系統(tǒng)應(yīng)進(jìn)行軌道焊接，并在必要時(shí)進(jìn)行手工焊接。材料之間的可焊接性應(yīng)通過(guò)規(guī)定的過(guò)程證明保持焊接質(zhì)量。應(yīng)保留此類系統(tǒng)的文件，并且至少應(yīng)包括焊工的資格、焊工的設(shè)置、工作階段的試件（焊縫樣品）、所用氣體的質(zhì)量證明、焊機(jī)校準(zhǔn)記錄、焊縫識(shí)別和加熱編號(hào)，以及所有焊縫的記錄。檢查一定比例的焊縫的記錄、照片或錄像（例如100％手工焊，10％軌道焊）。
- 接頭應(yīng)使用衛(wèi)生連接制成，例如三葉接頭。不允許使用螺紋接頭。聚偏二氟乙烯或聚偏二氟乙烯（PVDF）系統(tǒng)應(yīng)進(jìn)行熔接，并進(jìn)行目視檢查。
- 對(duì)于不銹鋼系統(tǒng)，例如對(duì)于未經(jīng)電拋光的表面（在初次安裝后和進(jìn)行重大改造后），應(yīng)考慮鈍化，要按照規(guī)定使用溶液，其濃度、溫度和接觸時(shí)間按照書(shū)面程序進(jìn)行。
- 法蘭、活接頭和閥門(mén)應(yīng)設(shè)計(jì)衛(wèi)生。閥門(mén)應(yīng)為膜片式鍛造或機(jī)械加工閥體，其使用點(diǎn)應(yīng)構(gòu)造成可以排放的。樣品閥應(yīng)為衛(wèi)生型，用于PW和WFI系統(tǒng)的表面粗糙度為1.0微米，通常安裝在工藝階段之間和分配回路的回流口上。應(yīng)進(jìn)行適當(dāng)?shù)臋z查，以確保使用正確的密封件和隔膜，并正確安裝和擰緊它們。
- 應(yīng)安裝系統(tǒng)以提高排水性，建議的最小斜率為1/100。
- 在適當(dāng)?shù)那闆r下，應(yīng)考慮對(duì)泄漏的壓力或水壓測(cè)試，噴球功能測(cè)試和流動(dòng)湍流。
- 應(yīng)提供在線測(cè)量總有機(jī)碳（TOC）、電導(dǎo)率和溫度的措施。
- 文件應(yīng)提供系統(tǒng)組成和資格證明。這些包括適用的圖紙、建筑材料合格證書(shū)的原始或經(jīng)認(rèn)證的副本、現(xiàn)場(chǎng)測(cè)試記錄、焊接/連接記錄、校準(zhǔn)證書(shū)、系統(tǒng)壓力測(cè)試記錄和鈍化記錄。
第 8 章：系統(tǒng)消毒和生物負(fù)荷控制主要變化：修訂8.2小節(jié)，增加應(yīng)考慮的其它控制技術(shù)8.2 Controls may include using chemical and/or thermal sanitization procedures as appropriate (e.g. production, storage and distribution). The procedure and conditions used, such as times and temperatures, as well as the frequency, should be defined and proven to be effective for sanitizing all relevant parts of the system. The techniques employed should be considered during the design stage of the system as the procedure and technique may impact on the components and materials of construction.
8.2控制措施可包括酌情使用化學(xué)和/或熱消毒程序（例如生產(chǎn)，儲(chǔ)存和分配）。應(yīng)該定義所使用的程序和條件（例如時(shí)間和溫度以及頻率），并證明對(duì)消毒系統(tǒng)的所有相關(guān)部分均有效。在系統(tǒng)的設(shè)計(jì)階段應(yīng)考慮采用的技術(shù)，因?yàn)槌绦蚝图夹g(shù)可能會(huì)影響構(gòu)造的組件和材料。10.4 Where heat exchangers are employed to heat or cool WPU within a system, precautions should be taken in order to prevent the heating or cooling utility from contaminating the water.如果使用了熱交換器加熱或冷卻系統(tǒng)中的WPU，則應(yīng)采取預(yù)防措施防止加熱或冷卻系統(tǒng)對(duì) 水產(chǎn)生污染。10.5 Secure types of heat exchangers, such as double tube plate, double plate and frame, or tube and shell configuration, should be considered. Where these types are not used, an alternative approach whereby the utility is maintained and monitored at a lower pressure than the WPU may be considered. The latter approach is not usually appropriate in BWFI systems.應(yīng)考慮使用安全型的熱交換器，如雙管板、雙板和雙框，或管殼設(shè)計(jì)的熱交換器。如果不是 使用此類熱交換器，則應(yīng)考慮維持公用系統(tǒng)的壓力低于WPU并進(jìn)行監(jiān)測(cè)。后一種方法通常 不合適用于BWFI系統(tǒng)。第11章：運(yùn)行考量，包括一些確認(rèn)和驗(yàn)證原則刪除原第 11 章“生物污染控制技術(shù)“（11. Biocontamination control techniques）的內(nèi)容。原 12 章運(yùn)行考量（Operational considerations）修改為11章：運(yùn)行考量，包括一些確認(rèn)和驗(yàn)證原則（Operational considerations including some qualification and validation principles）12.2 There should be documented evidence of consideration and execution of stages of qualification including, as appropriate, URS, factory acceptance testing (FAT), site acceptance testing (SAT), design qualification (DQ), IQ, OQ and PQ.應(yīng)有書(shū)面證據(jù)證明考慮和執(zhí)行了不同階段的確認(rèn)，包括（適當(dāng)時(shí)）URS、工廠接收測(cè)試 （FAT）、現(xiàn)場(chǎng)接收測(cè)試（SAT）、設(shè)計(jì)確認(rèn)（DQ）、IQ、OQ和 PQ。刪除原15.4-15.9的內(nèi)容，即“工藝和制劑應(yīng)考慮使用特定類型水”及其相關(guān)要求。刪除原16.3的內(nèi)容，即審計(jì)或檢查中可包括的具體項(xiàng)目。Ref.: [WHO][2020-07-30]Good manufacturing practices: water for pharmaceutical use
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