The criticality of particular areas must be taken into account when determining their environmental monitoring frequencies

• Grade C areas (Table 2.1) are not intended to be aseptic; personnel are generally not required to wear sterile garments; nonsterile vessels are in use for bulk compounding. The reason for their microbiological control is protection and minimization of the microbiological challenge to the aseptic areas (Grades B and A of Table 2.1). There is little immediate need for microbiological environmental monitoring data in Grade C areas. There should, however, be sufficient data to indicate that these measures remain under control when the areas are operational.

Monitoring can be done in these areas without significant risk to the process; however, the value of the data is limited.

Weekly, fortnightly or monthly sampling would be reasonable for facilities in frequent or constant operation, depending on their history of compliance with limits and the variability seen in the measures. More variability in the measures from these areas than in aseptic areas can be expected. Where a facility is used, for example, only four times a year, it is clearly unrealistic to monitor weekly or monthly when there is no activity. Such facilities should be monitored only when operational, when monitoring is done at a greater frequency than more heavily used facilities. There would be only limited value in obtaining, for example, only one Grade C datum point for each measure in a facility that is only used for one month at quarterly intervals.

• The intermediate area between Grade C areas and aseptic filling rooms are the change rooms (often called "white" change rooms). These are required to meet the environmental standards of the area to which they give access (MCA, 2002). However they are exposed to a greater microbiological challenge as a result of personnel entering in nonsterile garments, stripping off and changing

— in other words there is more exposure of the change rooms to microbiological contamination, and possibly a greater level of physical activity to disseminate contaminants. The risk is that the change rooms themselves become a source of contamination, which leads to contamination of the aseptic rooms with the operators as the vectors. Personnel are always trained in changing disciplines but they are never, for clear unarguable personal reasons, routinely supervised. Microbiological environmental monitoring of these areas is critical.

Monitoring can be done in these areas without significant risk to the process

Passive air sampling by settle plates is a good means of evaluating the changing process. The plates may be placed on the floor, on stepover benches, and on table tops over the time that personnel are stripping and changing; there is no value in laying out settle plates in empty change rooms. Surface sampling is also valuable; Rodac plates or swabs are equally applicable. Surface sampling should be concentrated on stepover benches, table tops, walls, in the "clean" side of the rooms after personnel have passed through. Personnel should not touch and contaminate these surfaces. However often the conditions in change rooms are so cramped and poorly designed that surface contact is unavoidable. Managers rarely enter aseptic areas and when they do they most often associate the difficulties they experience with their own awkwardness rather than with the facilities provided. Floor sampling, although supported by the FDA, is relatively meaningless. Passive air and surface sampling should be done in "white" change rooms on every operational day or shift. Active air sampling may give unreliable results in change rooms while personnel are changing. The samplers may upset protective air patterns and there may be insufficient total room-air volume to dilute contamination to a fairly representative level. Active air sampling should be done in change rooms when personnel have left (either to work in the aseptic facility or at the end of the working day).

• Grade A and Grade B aseptic areas should not be microbiologically contaminated. Environmental monitoring data from these areas are likely to be most valuable in diagnosing sterility test or media fill anomalies, and to improving environmental controls. The value of obtaining microbiological monitoring data from these areas is significant, but the risk of contaminating the areas, process or product in obtaining these data is equally important

• The three most valuable measures in these areas are active air sampling, surface sampling by swabbing, and personnel monitoring. The number of air changes in modern, well-designed aseptic filling rooms, and particularly in laminar air flow-protected areas, is likely to counteract the gravitational forces necessary for microorganisms to fall out on settle plates. The extensive use of disinfectants in Grades A and B aseptic areas and the comparative ease of cleaning smooth flat surfaces minimizes the value of the Rodac plate. Data from active air sampling, surface sampling and personnel monitoring should be obtained for every shift or for every batch of product manufactured and at regular, frequent intervals. In a facility operates daily, batch-by-batch data will serve as periodic data. In a facility that is only occasionally used, environmental data from Grade A and Grade B areas should be obtained at daily intervals for at least three days before scheduled production start-up, so that some microbiological measures have completed incubation before routine production begins. The availability of such data may in some facilities be proceduralized as a requirement for allowing production start-up.

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