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今年5 月，世衛組織（WHO） 修訂了自 2012 年起生效的制藥用水指南，發布征求意見草案。根據反饋意見，7 月 30 日，WHO發布了該指南草案的修訂稿，用于二次征求意見。

基于第二次征求意見收到的反饋，將形成最終版本，并計劃于今年10 月舉行的第55屆藥物制劑專家委員會（ECSPP）會議上對此進行討論，以通過本指南的定稿。

BLACK
&
WHITE

該版本在初稿的基礎上做了較大的修訂，主要變化的中英對照總結如下：

第2章：水要求和用途背景

主要變化：強調了水的等級應與產品性質、用途、階段相匹配。

修訂內容：描述水的質量標準時，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.
存在有不同級別的水質。應根據目標用途使用符合指定質量標準的水，如參考藥典的要求。
新增內容

2.5 The application of specific types of water to processes and dosage forms should be considered.
2.5應考慮將特定類型的水應用于工藝和劑型。
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制藥商應在 生產API和不同劑型，清洗和清潔的不同階段、以及材料和產品的合成過程中，使用適當級別的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用水等級應考慮中間體或FPP的性質和預期用途、以及 生產過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）應用于生產注射產品，例如注射產品生產過程中溶解或稀釋物質或制劑，以及用于生產注射用水。BWFI還應用于清潔與可注射產品接觸的設備和組件之后的最終沖洗，以及用于清洗過程中的最終沖洗（不進行后續熱或化學去熱原工藝）。

第4章：水的質量標準

新增內容：第 4.2 節“飲用水“增加備注

4.2 Drinking-water飲用水
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：飲用水系統的設計、建造和調試要求通常由當地法規控制。飲用水系統通常未經確認或驗證。
刪除原第 4.4 節“散裝高純水“的內容
4.4 Bulk highly purified water

第 7 章：水系統的良好實踐

主要變化
修訂7.2小節-設計和施工方法（design and construction practices）：該部分進行了分類細化，分別從“飲用水貯存、供應和分配系統”以及“純化水和散裝注射用水系統”，闡述了水系統的良好實踐。
飲用水-修訂

For drinking water storage, supply and distribution systems on-site
Materials 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.
用于現場的飲用水存儲、供應和分配系統
結構材料應根據以下要求進行選擇：
在所需溫度/壓力下運行的能力；
對最終水質沒有影響；
抵抗可能使用的任何消毒化學品；
允許使用螺紋和法蘭連接。
進樣閥最好采用衛生設計。
請注意，系統可能具有設計壽命，應在使用壽命結束時對其進行更換/充分維護。

純化水和散裝注射用水系統 -修訂

For purified water and bulk water for injection systems
Note: 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.
用于純化水和散裝注射用水系統
注意：在整個過程階段，施工標準通常與飲用水標準保持一致。
結構材料應適當。它應該是非浸出、非吸附、非吸收和耐腐蝕的。通常建議使用不銹鋼等級316L或PVDC。材料的選擇應考慮到預期的消毒方法。
不銹鋼系統應進行軌道焊接，并在必要時進行手工焊接。材料之間的可焊接性應通過規定的過程證明保持焊接質量。應保留此類系統的文件，并且至少應包括焊工的資格、焊工的設置、工作階段的試件（焊縫樣品）、所用氣體的質量證明、焊機校準記錄、焊縫識別和加熱編號，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）。
接頭應使用衛生連接制成，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）系統應進行熔接，并進行目視檢查。
對于不銹鋼系統，例如對于未經電拋光的表面（在初次安裝后和進行重大改造后），應考慮鈍化，要按照規定使用溶液，其濃度、溫度和接觸時間按照書面程序進行。
內部光潔度應光滑。
法蘭、活接頭和閥門應設計衛生。閥門應為膜片式鍛造或機械加工閥體，其使用點應構造成可以排放的。樣品閥應為衛生型，用于PW和WFI系統的表面粗糙度為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。應進行適當的檢查，以確保使用正確的密封件和隔膜，并正確安裝和擰緊它們。
應安裝系統以提高排水性，建議的最小斜率為1/100。
在適當的情況下，應考慮對泄漏的壓力或水壓測試，噴球功能測試和流動湍流。
應提供在線測量總有機碳（TOC）、電導率和溫度的措施。
文件應提供系統組成和資格證明。這些包括適用的圖紙、建筑材料合格證書的原始或經認證的副本、現場測試記錄、焊接/連接記錄、校準證書、系統壓力測試記錄和鈍化記錄。

第 8 章：系統消毒和生物負荷控制

主要變化：修訂8.2小節，增加應考慮的其它控制技術
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和/或熱消毒程序（例如生產，儲存和分配）。應該定義所使用的程序和條件（例如時間和溫度以及頻率），并證明對消毒系統的所有相關部分均有效。在系統的設計階段應考慮采用的技術，因為程序和技術可能會影響構造的組件和材料。

第 10 章：水分配

主要變化：刪除了熱交換器使用的一些具體要求。

刪除內容

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中的WPU，則應采取預防措施防止加熱或冷卻系統對 水產生污染。
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，或管殼設計的熱交換器。如果不是 使用此類熱交換器，則應考慮維持公用系統的壓力低于WPU并進行監測。后一種方法通常 不合適用于BWFI系統。

第11章：運行考量，包括一些確認和驗證原則

主要變化
刪除原第 11 章“生物污染控制技術“（11. Biocontamination control techniques）的內容。原 12 章運行考量（Operational considerations）修改為11章：運行考量，包括一些確認和驗證原則（Operational considerations including some qualification and validation principles）
刪除內容

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.
應有書面證據證明考慮和執行了不同階段的確認，包括（適當時）URS、工廠接收測試 （FAT）、現場接收測試（SAT）、設計確認（DQ）、IQ、OQ和 PQ。

第14章（原15章）：系統回顧

主要變化
刪除原15.4-15.9的內容，即“工藝和制劑應考慮使用特定類型水”及其相關要求。

第15章（原16章）：水系統檢查

主要變化
刪除原16.3的內容，即審計或檢查中可包括的具體項目。
Ref.: [WHO][2020-07-30]Good manufacturing practices: water for pharmaceutical use