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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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).
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.
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.