The most important observation underpinning our understanding of contamination is called the "plateau" effect (Roark, 1972; Sykes, 1970). If an inert surface is left in a microbiologically contaminated environment, one might reasonably expect a gradual and continuous increase of microorganisms recoverable from the surfaces. This is not the case. The microbial count per unit area increases and then equilibrates (the plateau) for an indefinite period thereafter (Figure 1.1).
The plateau effect has led to the development of theories of contamination. Figure 1.2 shows a pictorial model of how a sterile item may become microbiologically contaminated when placed in a nonsterile environment. This model proposes two mechanisms of contamination: deposition and contact.
Deposition Contact ^ ( Departure
Deposition recognizes that microorganisms present in environmental air are likely to settle out on surfaces of items, as a result of any one or more of several mechanisms. Contact describes contamination by means of transfer of microorganisms from one surface to another by physical proximity. The contribution from these two mechanisms to the contamination of items will differ according to individual circumstances.
The extent of contamination from deposition will differ according to the concentration of microorganisms in air; this will differ from one type of environment to another, and within any one environment it will differ from one time to another. The outstanding feature of the design of pharmaceutical clean rooms used for the manufacture of sterile products is the extent of control of the microbiological quality of environmental air, particularly around areas where the product is exposed.
Air is filtered, often recirculated and refiltered. It is maintained in constant turbulence or is used in laminar flow devices to "sweep" contaminants away from exposed items. In a well-designed process operating in a well-designed, well-maintained clean room, contamination by deposition of microorganisms from environmental air is intended to be controlled to a "steady state," where it is not likely to be a significant persistent mechanism of product contamination.
The vulnerability of product contamination from deposition increases when the steady state is disturbed. Personnel are the most significant cause of disturbance.
The reality of clean rooms is that no matter how skilled, well-trained or well-garbed, the concentration of microorganisms and nonviable particles in air around personnel is inevitably higher than in air in unmanned areas.
If it is accepted that personnel are necessarily present in or around areas where product is exposed, for instance to start up the process, make adjustments, take samples, monitor etc., it should be accepted that the amount of contamination from deposition will then increase.
Bernuzzi et al. (1997) summarized these views by stating that contamination in aseptic filling of pharmaceutical products is mainly the result of two different stochastic processes.
The first contribution to contamination is from airborne particles, while the second is from personnel line intervention. The first spans the whole filling operation, the second occurs randomly when human intervention takes place.
Sometimes asepsis is referred to as a "no-touch" technique, thereby reducing contamination by contact to the minimum. Primary sources are personnel and water, but equipment, machine surfaces and even integral components of the pharmaceutical presentation may be vectors for contact contamination.
Contamination could occur in a pharmaceutical product in a vial from contact with a rubber closure, which has in turn been contaminated by contact with the production operator while transferring the sterilized closures from the autoclave to the hopper on the filling machine. Contamination by contact is intermittent, erratic and largely unpredictable.
The second important consideration illustrated by this model (Figure 1.2) is that contamination is not synonymous with loss of sterility. Sterility is defined as the absence of all viable life forms from an item. Clearly, the plateau effect illustrates that an item may become contaminated, but the fate of its contaminants may thereafter follow three courses, only one of which necessarily leads to nonsterility.
The microorganisms that have been transferred to the item by physical forces may as well be removed by physical forces; they may fall off, fall out or be blown off the item. The microorganisms may die on the item; death rates of microorganisms are particular to species and to the nature of the material they find themselves to be in or on, and to the surrounding environmental conditions. Desiccation-resistant types have a greater potential for survival on inert surfaces.
It is important to understand this distinction between contamination and nonsterility.
Experimental work has been done to develop and support views, theories and mathematical models of aseptic manufacture developed from techniques involving the recovery of microorganisms in liquid nutrient media (media fills), or on solidified nutrient media (active and passive microbiological air monitoring).
The conditions in microbiological media are, with respect to the survival potential of microorganisms, quite different from the conditions existing in "inert" materials used in aseptic manufacture. These include glass vials, rubber stoppers and stainless steel hoppers, as well as aseptically manufactured pharmaceutical products (e.g., nonneutral pH, antimicrobial preservative content, hypotonicity, hypertonicity, etc.).
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