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在“文章”那一列，自动倒序的。 5.DESIGN AND OPERATION OF PURIFIED WATER AND WATER FOR INJECTION SYSTEMS纯净水和注水系统用水的设计和操作
The design, installation, and operation of systems to produce Purified Water and Water for Injection include similar components, control techniques, and procedures. The quality attributes of the two waters differ in their bioburden expectation, the presence of a bacterial endotoxin requirement for Water for Injection, and in their methods of preparation. The similarities in the quality attributes provide considerable common ground in the design of water systems to meet either requirement. The critical difference is the degree of control of the system and the final purification steps needed to ensure removal of bacteria and bacterial endotoxins and reductions in opportunities for biofilm re-development within those purification steps that could become in situ sources of bacteria and endotoxin in the finished water.
生产纯净水和注射用水系统的设计、安装和操作包括类似的组成部分、控制技术和程序。这两种水的质量属性在它们的生物负荷期望、对注射用水的细菌内毒素要求的存在以及它们的制备方法方面存在差异。质量属性的相似性为水系统的设计提供了相当多的共同点，以满足任何一种要求。关键的区别在于系统和最终净化步骤的控制程度，这些步骤需要确保去除细菌和细菌内毒素，并减少在这些净化步骤中生物膜重新发育的机会，这些步骤可能成为成品水中细菌和内毒素的原位来源。
Many aspects of system design and operation relate to control and elimination of biofilm. Unit operations can cause the deterioration of water microbial attributes and the formation of biofilm on unit operation surfaces, even when properly maintained (see 8.2 Biofilm Formation in Water Systems).
系统设计和运行的许多方面都与生物膜的控制和消除有关。即使是在适当维护的情况下，机组操作可能导致水微生物属性的恶化，并在机组操作表面形成生物膜 (见8.2水系统生物膜的形成)。
Production of pharmaceutical water involves sequential unit operations (processing steps) that address specific water quality attributes and protect the operation of subsequent treatment steps. A typical evaluation process for selecting an appropriate water quality for a particular pharmaceutical purpose is shown in the decision trees in Figure 2a and Figure 2b. This diagram may be used to assist in defining requirements for specific water uses and in the selection of unit operations. The final unit operation used to produce Water for Injection is limited to distillation or other processes equivalent or superior to distillation in the removal of chemical impurities as well as microorganisms and their components, such as bacterial endotoxins. Distillation coupled with suitable pretreatment technologies has a long history of generally reliable performance (though not completely infallible) and can be validated as a unit operation for the production of Water for Injection. Other combinations of purification technologies may also be suitable in the production of Water for Injection if they can be shown through validation to be as effective and reliable as distillation in the removal of chemicals and microorganisms. The development of new designs and materials of construction for other technologies (such as reverse osmosis, electrodeionization, and ultrafiltration) that allow intermittent or continuous operation at hot bactericidal conditions show promise for a valid use in producing Water for Injection. 制药用水的生产涉及处理特定水质属性并保护后续处理步骤操作的连续单元操作(处理步骤)。图2a和图2b的决策树显示了为特定制药目的选择合适水质的典型评估过程。此图可用于辅助确定特定水使用的要求和单元操作的选择。用于生产注射用水的最终单元操作仅限于蒸馏或在去除化学杂质以及微生物及其组分(如细菌内毒素)方面与蒸馏相当或优于蒸馏的其他工艺。蒸馏结合适当的预处理技术具有长期可靠的性能(尽管不是完全可靠)，可以作为注射用水生产的单元操作进行验证。如果能通过验证证明在去除化学物质和微生物方面与蒸馏一样有效和可靠，其他的净化技术组合也可能适用于注射用水的生产。其他技术(如反渗透、电去离子化和超滤)的新设计和结构材料的开发，使其能够在高温杀菌条件下间断或连续运行，这为生产注射用水提供了有效的前景。
5.1Unit Operations Considerations
To achieve the quality attributes for pharmaceutical waters, multiple-unit operations are required. The design of the water purification system needs to take into consideration different aspects, including the source water quality, sanitization, pharmaceutical water quality attributes, uses of the water, and maintenance programs. Each unit operation contributes specific purification attributes associated with chemical and microbiological parameters.
为了达到制药水的质量属性，需要多单元操作。净水系统的设计需要考虑水源水质、消毒处理、药用水质属性、水的用途、维护方案等多个方面。每个单元操作都贡献了与化学和微生物参数相关的特定净化属性。
The following is a brief description of selected unit operations and the design, installation, operation, maintenance, and monitoring parameter considerations associated with them. Not all unit operations are discussed, nor are all potential shortcomings addressed.
以下是所选单元操作的简要描述，以及与之相关的设计、安装、操作、维护和监测参数的考虑。在本文中，不是所有的单元操作都被讨论，也不是所有潜在的缺点都被解决。
5.1.1PREFILTRATION
The purpose of prefiltration—also referred to as initial, coarse, particulate, or depth filtration—is to remove solid contaminants from the incoming source water supply and protect downstream system components from particulates that can inhibit equipment performance and shorten their effective life. This coarse filtration technology primarily uses sieving effects for particle capture and a depth of filtration medium that has a high “dirt load” capacity. Such filtration units are available in a wide range of designs and for various applications. Removal efficiencies and capacities differ significantly, from granular bed filters such as multimedia or sand for larger water systems, to depth cartridges for smaller water systems. Unit and system configurations vary widely in the type of filtering media and the location in the process. Granular or cartridge prefilters are often situated at the beginning of the water purification system prior to unit operations designed to remove the source water disinfectants.
预过滤(也称为初始、粗过滤、颗粒过滤或深度过滤)的目的是去除来水中的固体污染物，并保护下游系统组件免受颗粒的影响，这些颗粒会抑制设备的性能并缩短其有效寿命。这种粗过滤技术主要使用筛分效果来捕获颗粒和具有高“污垢负荷”能力的深度过滤介质。这种过滤装置具有广泛的设计和各种应用。去除效率和能力显著不同，从大型水系统的颗粒床过滤器(如多介质或沙子)到小型水系统的深度滤池。单元和系统的配置因过滤介质的类型和在工艺中的位置而有很大差异。在单元操作设计用于去除水源消毒剂之前，颗粒状或盒式预过滤器通常安装在水净化系统的开始部分。
Cartridge-type coarse filters may also be used to capture fines released from granular beds such as activated carbon and deionization beds. These locations, however, do not preclude the need for periodic microbial evaluation.
粉盒型粗过滤器也可用于捕获从颗粒床(如活性炭和去离子床)释放的细颗粒。然而，（即使有过滤器）这些位置并不排除定期微生物评价的需要。
Design and operational issues that may impact the performance of depth filters include channeling of the filtering media, blockage from silt, microbial growth, and filtering-media loss during improper backwashing. Control methods involve pressure and flow monitoring during use and backwashing, sanitizing, and replacing filtering media. An important design concern is
sizing of the filter to prevent channeling or media loss resulting from inappropriate water flow rates as well as proper sizing to minimize excessively frequent or infrequent backwashing or cartridge filter replacement.
可能影响深度过滤器性能的设计和操作问题包括过滤介质的窜流、淤泥堵塞、微生物生长和不当反冲洗期间的过滤介质损失。控制方法包括使用期间的压力和流量监测以及反冲洗、消毒和更换过滤介质。一个重要的设计问题是过滤器的尺寸，以防止由于不适当的水流速率导致的通道或介质损失，以及适当的尺寸，以尽量减少过度频繁或不频繁的反冲洗或滤芯更换。
5.1.2ACTIVATED CARBON
Activated carbon beds, depending on the type and placement, are used to adsorb low-molecular-weight organic material, bacterial endotoxins, and oxidizing additives such as chlorine and chloramine compounds, removing them from the water. They are used to achieve certain quality attributes and to protect against reactions with downstream unit operations, stainless steel surfaces, resins, and membranes.
活性炭床，根据类型和位置，用于吸附低分子量有机材料，细菌内毒素和氧化添加剂，如从水中去除氯和氯胺化合物。它们用于达到一定的质量属性，并防止那类成分与下游设备操作、不锈钢表面、树脂和膜发生反应。
The chief operating concerns regarding activated carbon beds include the propensity to support bacterial growth, the potential for hydraulic channeling, the organic adsorption capacity, and insufficient contact time. Operation deficiencies may result in the release of bacteria, endotoxins, organic chemicals, and fine carbon particles.
关于活性炭床的主要操作问题包括支持细菌生长的倾向、可能的受压缝隙、有机吸附能力和接触时间不足。操作缺陷可能导致细菌、内毒素、有机化学物和细碳颗粒的释放。
Control measures may involve monitoring water flow rates and differential pressures, sanitizing with hot water or steam, backwashing, testing for adsorption capacity, and frequent replacement of the carbon bed. Monitoring of carbon bed unit operation may also include microbial loading, disinfectant chemical reduction, and TOC if used for TOC reduction. The use of hot water or steam for carbon bed sanitization is ineffective if there is channeling rather than even permeation through the bed. Channeling can be mitigated through design and proper flow rates during sanitization.
控制措施可能包括监测水流速率和压差，用热水或蒸汽消毒，反冲洗，测试吸附能力，以及经常更换碳床。碳床单元操作的监测还可包括微生物负荷、消毒剂化学物减量和TOC(如果用于TOC减量)。如果有通道，而不是渗透通过床，使用热水或蒸汽消毒碳床是无效的。在消毒过程中，可以通过设计和适当的流速来缓解窜流。
Microbial biofilm development on the surface of the granular carbon particles can cause adjacent bed granules to agglomerate. This may result in ineffective removal of trapped debris and fragile biofilm during backwashing, and ineffective sanitization.
颗粒状碳颗粒表面形成的微生物生物膜可导致相邻床层颗粒团聚。这可能导致反冲洗时无法有效清除滞留的碎片和脆弱的生物膜，以及消毒效果不佳。
Alternative technologies to activated carbon beds can be used to avoid their microbial challenges. These include disinfectant-neutralizing chemical additives and intense ultraviolet (UV) light for removal of chlorine, and regenerable organic scavenging deionizing resins for removal of organics.
活性炭床的替代技术可以用来避免其微生物挑战。其中包括用于去除氯的消毒剂中和化学添加剂和强紫外线(UV)光，以及用于去除有机物的可再生有机清除去离子树脂。
5.1.3ADDITIVES
Chemical additives are used in water systems 1) to control microorganisms by use of sanitizing agents, such as chlorine compounds and ozone; 2) to enhance the removal of suspended solids by use of flocculating agents; 3) to remove chlorine compounds; 4) to avoid scaling on reverse osmosis membranes; and 5) to adjust pH for more effective removal of carbonate and ammonia compounds by reverse osmosis. These additives do not constitute “added substances” as long as they are either removed by subsequent processing steps or are otherwise absent from the finished water. Control of additives to ensure a continuously effective concentration and subsequent monitoring to ensure their removal should be designed into the system and included in the monitoring program.
在水系统中使用化学添加剂1)通过使用消毒剂控制微生物，如氯化合物和臭氧;2)通过使用絮凝剂来提高对悬浮固体的去除;3)去除氯化合物;4)防止反渗透膜结垢;5)通过反渗透调节pH以更有效地去除碳酸和氨化合物。这些添加剂不构成“添加物质”，只要它们被后续处理步骤去除或在成品水中不存在即可。控制添加剂以确保持续有效的浓度，并进行后续监测以确保其去除应设计到系统中，并包括在监测程序中。
5.1.4ORGANIC SCAVENGERS
Organic scavenging devices use macroreticular, weakly basic anion-exchange resins capable of removing negatively charged organic material and endotoxins from the water. Organic scavenger resins can be regenerated with appropriate biocidal caustic brine solutions. Operating concerns are associated with organic scavenging capacity; particulate, chemical, and microbiological fouling of the reactive resin surface; flow rate; regeneration frequency; and shedding of fines from the fragile resins. Control measures include TOC testing of influent and effluent, backwashing, monitoring hydraulic performance, and using downstream filters to remove resin fines.
有机清除装置使用大网状、弱碱性阴离子交换树脂，能够去除水中带负电荷的有机物质和内毒素。有机清除剂树脂可以用适当的去生物碱盐水溶液再生。操作问题与有机清除能力有关;反应性树脂表面的颗粒、化学和微生物污染;流量;再生频率;以及从脆弱的树脂上脱落的微粒。控制措施包括对进水和出水进行TOC测试、反冲洗、监测压差变化以及使用下游过滤器去除树脂细粒【谢谢张功臣老师】。
5.1.5SOFTENERS
Water softeners may be located either upstream or downstream of disinfectant removal units. They utilize sodium-based cation-exchange resins to remove water-hardness ions, such as calcium and magnesium, that could foul or interfere with the performance of downstream processing equipment such as reverse osmosis membranes, deionization devices, and distillation units. Water softeners can also be used to remove other lower affinity cations, such as the ammonium ion, that may be released from chloramine disinfectants commonly used in drinking water. If ammonium removal is one of its purposes, the softener must be located downstream of the disinfectant removal operation. Water softener resin beds are regenerated with concentrated sodium chloride solution (brine).
软水器可以位于消毒剂去除单元的上游或下游。他们利用钠基阳离子交换树脂去除水硬度离子，如钙和镁，这些离子可能会污染或干扰下游处理设备的性能，如反渗透膜，去离子化装置和蒸馏装置。软水剂也可用于去除其他较低亲和力的阳离子，如可能从饮用水中常用的氯胺消毒剂中释放出来的铵离子。如果去除铵是其目的之一，软化剂必须位于消毒剂去除操作的下游。用浓氯化钠溶液(盐水)再生水软化剂树脂床。
Concerns include microorganism proliferation, channeling, appropriate water flow rates and contact time, ion-exchange capacity, organic and particulate resin fouling, organic leaching from new resins, fracture of the resin beads, resin degradation by excessively chlorinated water, and contamination from the brine solution used for regeneration.
需要关注的问题包括微生物增殖、流道、适当的水流速率和接触时间、离子交换能力、有机和颗粒树脂污染、新树脂的有机浸出、树脂珠的破裂、过度氯化水对树脂的降解，以及用于再生的浓盐水溶液的污染。
Control measures involve recirculation of water during periods of low water use; periodic sanitization of the resin and brine system; use of microbial control devices (e.g., UV light and chlorine); locating the unit upstream of the disinfectant removal step (if used only for softening); appropriate regeneration frequency; effluent chemical monitoring (e.g., hardness ions and possibly ammonium); and downstream filtration to remove resin fines. If a softener is used for ammonium removal from chloramine-containing source water, then the capacity, contact time, resin surface fouling, pH, and regeneration frequency are very important.
控制措施包括在用水少的时期使水再循环;树脂和盐水系统的定期消毒;使用微生物控制装置(如紫外线和氯);将单元置于消毒剂去除步骤的上游(如仅用于软化);适当的再生频率;废水化学监测(如硬度离子和可能的铵);并通过下游过滤去除树脂细粒。如果使用软化剂从含氯胺的水源水中去除铵，那么其容量、接触时间、树脂表面污垢、pH值和再生频率是非常重要的。
5.1.6DEIONIZATION
Deionization (DI) and continuous electrodeionization (CEDI) are effective methods of improving the chemical quality attributes of water by removing cations and anions. DI systems have charged resins that require periodic regeneration with an acid and base. Typically, cation resins are regenerated with either hydrochloric or sulfuric acid, which replace the captured positive ions with hydrogen ions. Anion resins are regenerated with sodium hydroxide or potassium hydroxide, which replace captured negative ions with hydroxide ions. Because free endotoxin is negatively charged, some removal of endotoxin is
achieved by the anion resin. The system can be designed so that the cation and anion resins are in separate or “twin” beds, or they can be blended together to form a “mixed” bed.
去离子化(DI)和连续电去离子化(CEDI)是通过去除阳离子和阴离子来改善水的化学质量属性的有效方法。DI系统含有需要周期性酸碱再生的带电树脂。通常，阳离子树脂用盐酸或硫酸再生，用氢离子取代捕获的正离子。阴离子树脂用氢氧化钠或氢氧化钾再生，用氢氧根离子取代捕获的负离子。由于游离内毒素是带负电荷的，因此内毒素的部分清除是通过阴离子树脂 实现的。该系统可以设计成阳离子树脂和阴离子树脂在单独或“双”床中，或者它们可以混合在一起形成“混合”床。
The CEDI system uses a combination of ion-exchange materials such as resins or grafted material, selectively permeable membranes, and an electric charge, providing continuous flow (of product and waste concentrate) and continuous regeneration. Water enters both the resin section and the waste (concentrate) section. The resin acts as a conductor, enabling the electrical potential to drive the captured cations and anions through the resin and appropriate membranes for concentration and removal in the waste water stream. As the water passes through the resin, it is deionized to become product water. The electrical potential also separates the water in the resin (product) section into hydrogen and hydroxide ions. This permits continuous regeneration of the resin without the need for regenerant additives. However, unlike conventional deionization, CEDI units must start with water that is already partially purified because they generally cannot achieve the conductivity attribute of Purified Water when starting with the heavier ion load of source water.
CEDI系统使用了树脂或接枝材料等离子交换材料、选择性渗透膜和电荷的组合，提供了连续流动(产品和废浓缩物)和连续再生。水进入树脂段和废料(浓缩)段。树脂充当导体，使电势驱动捕获的阳离子和阴离子通过树脂和适当的膜浓缩和去除废水流。当水通过树脂时，它被去离子化，成为产物水。电势也将树脂(产品)部分中的水分离成氢和氢氧离子。这允许树脂的连续再生而不需要再生剂添加剂。然而，与传统的去离子化不同，CEDI装置必须从已经部分纯化的水开始，因为当从较重的源水离子负荷开始时，它们通常无法达到纯化水的导电属性。
Concerns for all forms of DI units include microbial and endotoxin control; chemical additive impact on resins and membranes; and loss, degradation, and fouling of resin. Issues of concern specific to DI units include regeneration frequency and completeness; channeling caused by biofilm agglomeration of resin particles; organic leaching from new resins; complete resin separation for mixed bed regeneration; and bed fluidization air contamination (mixed beds).
对所有形式的DI单元的关注包括微生物和内毒素控制;化学添加剂对树脂和膜的影响;以及树脂的流失、降解和污染。DI单元所关注的具体问题包括再生频率和完整性;树脂颗粒生物膜团聚引起的窜流;新树脂有机浸出;完全树脂分离混合床再生;和床流态化空气污染(混合床)。
Control measures may include continuous recirculation loops, effluent microbial control by UV light, conductivity monitoring, resin testing, microporous filtration of bed fluidization air, microbial monitoring, frequent regeneration to minimize and control microorganism growth, sizing the equipment for suitable water flow and contact time, and use of elevated temperatures.
Internal distributor and regeneration piping for DI bed units should be configured to ensure that regeneration chemicals contact all internal bed and piping surfaces and resins.
控制措施可能包括连续循环，通过紫外线光控制出水微生物，电导率监测，树脂测试，床流化空气的微孔过滤，微生物监测，频繁再生以减少和控制微生物生长，调整设备的尺寸以适合的水流和接触时间，以及使用升高的温度。DI床单元的内部分布器和再生管道应配置以确保再生化学品接触所有内床和管道表面和树脂。
Rechargeable canisters can be the source of contamination and should be carefully monitored. Full knowledge of previous resin use, minimum storage time between regeneration and use, and appropriate sanitizing procedures are critical factors for ensuring proper performance.
可再生的软化装置可能是污染源，应该仔细监控【感谢张功臣老师】。充分了解以前的树脂使用情况，在再生和使用之间最短的存储时间，以及适当的消毒程序是确保适当性能的关键因素。
