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 program should include (1) procedures for operating the system, (2) monitoring programs for critical quality attributes and operating conditions including calibration of critical instruments, (3) schedule for periodic sanitization, (4) preventive maintenance of components, and (5) control of changes to the mechanical system and to operating conditions. 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. These include method sensitivity, range of organisms types or species recovered, sample processing throughput, incubation period, cost, and methodological complexity. Pumps should be designed to deliver fully turbulent flow conditions to facilitate thorough heat distribution (for hot water sanitized systems) as well as thorough chemical sanitant distribution. Unit and system configurations vary widely in type of filtering media and location in the process. ); (9) instituting a schedule for periodic review of the system performance and requalification, and (10) completing protocols and documenting Steps 1 through 9. However, because some attributes may not continuously be monitored or have a long delay in data availability (like microbial monitoring data), properly established, As process control indicators, alert and action levels are designed to allow remedial action to occur that will prevent a system from deviating completely out of control and producing water unfit for its intended use. However, it must be noted that these are not referee methods nor are they necessarily optimal for recovering microorganisms from all water systems. Samples containing chemical sanitizing agents require neutralization prior to microbiological analysis. Should chemicals or additives be used to clean, control, or sanitize the system, materials resistant to these chemicals or additives must be utilized. Water systems with these levels should unarguably be considered out of control. Microorganisms that are known to be problematic could include opportunistic or overt pathogens, nonpathogenic indicators of potentially undetected pathogens, or microorganisms known to compromise a process or product, such as by being resistant to a preservative or able to proliferate in or degrade a product. It is important to note that the use of steam for carbon bed sanitization is often incompletely effective due to steam channeling rather than even permeation through the bed. The “pores” of RO membranes are actually intersegmental spaces among the polymer molecules. Microorganisms present in feed water may adsorb to carbon bed, deionizer resins, filter membranes, and other unit operation surfaces and initiate the formation of a biofilm. Because pharmaceutical waters are generally produced by continuous processes and used in products and manufacturing processes soon after generation, the water is likely to have been used well before definitive test results are available. By the end of this period, a relatively steady state microbial population (microorganism types and levels) will have been allowed or promoted to develop as a result of the collective effects of routine system maintenance and operation, including the frequency of unit operation rebeddings, backwashings, regenerations, and sanitizations. Generally, some form of microbial isolate characterization, if not full identification, may be a required element of water system monitoring. It is invalid to apply alert and action level criteria to test results generated by a different test method. 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. High-nutrient media such as plate count agar (TGYA) and m-HPC agar (formerly m-SPC agar), are intended as general media for the isolation and enumeration of heterotrophic or “copiotrophic” bacteria. A current understanding of the mechanisms involved in microbial retention and the variables that can affect those mechanisms has yielded a far more complex interaction of phenomena than previously understood. In the latter application, sterilizing grade filters are generally considered to have an assigned rating of 0.2 or 0.22 µm. This microbial population will typically be higher than was seen when the water system was new, so it should be expected that the data trends (and the resulting alert and action levels) will increase over this “maturation” period and eventually level off. The contents will help users to better understand pharmaceutical water issues and some of the microbiological and chemical concerns unique to water. For the determination of apparent s… Classical culture approaches for microbial testing of water include but are not limited to pour plates, spread plates, membrane filtration, and most probable number (MPN) tests. The following waters are typically produced in large volume by a multiple-unit operation water system and distributed by a piping system for use at the same site. Valve installation attitude should promote gravity drainage. This was a major philosophical change and allowed major savings to be realized by industry.