These microorganisms comprise an often ill-defined group referred to as objectionable microorganisms. 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. Pumps should be of sanitary design with seals that prevent contamination of the water. This chapter provides an overview of the concepts and equations that are relevant to solubility measurements. Conclusions derived from trend analysis of the microbiological data should be used as the alert mechanism for maintenance.The frequency of sanitization should be established in such a way that the system operates in a state of microbiological control and does not routinely exceed alert levels (see. In these single sample and mixed data use situations, the worst-case scenario should be utilized. Unrealistically high action levels allow systems to grow well out of control before action is taken, when their intent should be to catch a system imbalance before it goes wildly out of control. The frequency of sanitization should be supported by, if not triggered by, the results of system microbial monitoring. These are all bulk waters, with names given for descriptive purposes only. Similar to RO, successful performance is dependent upon pretreatment of the water by upstream unit operations. However, these alternatives do not function by the same mechanisms as activated carbon, may not be as effective at removing disinfectants and some organics, and have a different set of operating concerns and control measures that may be nearly as troublesome as activated carbon beds. Ceramic ultrafilters are self supporting and extremely durable, backwashable, chemically cleanable, and steam sterilizable. ); and (6) developing a prospective PQ stage to confirm the appropriateness of critical process parameter operating ranges (During this phase of validation, alert and action levels for key quality attributes and operating parameters are verified. Control and validation concerns include volume and duration of use, flow rate, water conductivity and purity, and constancy and concentration of endotoxin levels being removed. Alert and action levels should be derived from an evaluation of historic monitoring data called a trend analysis. Sufficient care should be given to system design and maintenance in order to minimize microbial contamination from these exogenous sources. Microbiological requirements of drinking water ensure the absence of coliforms, which, if determined to be of fecal origin, may indicate the potential presence of other potentially pathogenic microorganisms and viruses of fecal origin. Microorganisms in biofilms represent a continuous source of contamination and are difficult to directly sample and quantify. Organic scavenging devices use macroreticular weakly basic anion-exchange resins capable of removing organic material and endotoxins from the water. 1. Alert and action levels may be both quantitative and qualitative. All of these factors may have to be evaluated and challenged prior to using this approach, making this a difficult-to-validate application. Valves should have smooth internal surfaces with the seat and closing device exposed to the flushing action of water, such as occurs in diaphragm valves. Sanitization steps require validation to demonstrate the capability of reducing and holding microbial contamination at acceptable levels. ); (9) instituting a schedule for periodic review of the system performance and requalification, and (10) completing protocols and documenting Steps 1 through 9. Design and operational issues that may impact performance of depth filters include channeling of the filtering media, blockage from silt, microbial growth, and filtering-media loss during improper backwashing. For the determination of apparent s… In-house remedial actions may or may not also be needed, but could include performing additional coliform testing on the incoming water and pretreating the water with either additional chlorination or UV light irradiation or filtration or a combination of approaches. The free form of endotoxins may be released from cell surfaces of the bacteria that colonize the water system, or from the feed water that may enter the water system. As it passes through the resin, it is deionized to become product water. Gram-negative bacteria that form biofilms can become a source of endotoxins in pharmaceutical waters. A specification excursion may trigger an extensive finished product impact investigation, substantial remedial actions within the water system that may include a complete shutdown, and possibly even product rejection. Product quality requirements should dictate water quality specifications. Therefore, optimal biocide control is achieved by frequent biocide use that does not allow significant biofilm development between treatments. Because routine microbial monitoring is performed for the same transfer process and components (e.g., hoses and heat exchangers) as that of routine water use (see, Validation is the process whereby substantiation to a high level of assurance that a specific process will consistently produce a product conforming to an established set of quality attributes is acquired and documented.