Environmental Monitoring in Pharmaceutical Manufacturing - A Product Risk Issue

The objective of a risk-based approach is to use scientific data and principles to assess the relative risk/benefit value of specific control measures. In the case of aseptically-filled parenteral products, the current standards require environmental controls producing results at stated levels or better, including monitoring, process simulations (media fills) and sterility testing of finished, packaged product. Of the evaluation measures listed, the only test of the actual product is the sterility test. For obvious reasons, 100% sterility testing is not yet feasible with current technology. The end result is that a manufacturer must use the preponderance of the available data to decide if the product meets the sterility requirements for release. The fact that a product lot ?passes? a sterility test is one piece of data. The sterility test, like any other microbiological test, is limited in its ability to detect every conceivable microbial contaminant. For a product lot to ?fail? a sterility test, there likely was a significant, up-stream contamination event involving a high percentage of the production units. Otherwise, the likelihood of picking the small percentage of test units out of thousands containing at least one contaminated unit is very slim. This fact is acknowledged in the sterility testing procedures where a repeat test is not permitted without first invalidating the original test.
Additional data to be considered when evaluating the sterility assurance level of an aseptically-filled product is the environmental monitoring data from that particular production run and the data from previous runs. The previous run data provides a basis for comparison in which the same monitoring methods were used in the same controlled environment. A change in the magnitude of the results can be an indication of changing conditions that may affect the risk to the product. This type of evaluation is referred to as trending. The Centers for Disease Control (CDC) published an article in 2002 comparing various methods of recovering microorganisms from contaminated surfaces. This study, along with other previous work, shows that the ability to quantitatively evaluate surface contamination levels is highly variable with common methodology [4]. The consistent use of specific sampling methods, as well as a defined sampling plan based on risk analysis, somewhat overcomes the variability factors of the methods. This enables an assessment of the overall contamination level based on a qualitative interpretation of the data. In simpler terms, a ?hit rate? determination or number of contaminated samples out of all samples taken can be very useful. This approach recognizes that standard viable environmental monitoring methods are more reliable as qualitative methods than quantitative ones. This is a recognized data evaluation method in the new aseptic guidance. ?Because false negatives can occur, consecutive growth results are only one type of adverse trend. Increased incidence of contamination over a given period is an equal or more significant trend to be tracked? [2].
The factors that make most viable environmental monitoring methods more qualitative than quantitative also pose challenges for using the evolving rapid methods for these purposes. In particular, very few organisms exist in nature as single cells. They are usually in cell groupings such as grape-like clusters, strings of beads or other configurations and in biofilm structures. This is why organism counts on plates are recorded in CFUs (colony-forming units). A cfu can be 1 or 1001+ separate organism cells. Many of the emerging methods can identify separate cells. However, the limitations of sampling methods will affect conventional and new detection methods equally in that an organism must be recovered from the sample point before it can be detected unless a direct method can be used on the host surface.
Theoretically, a single cell can cause an infection in a susceptible host. Before this single cell can be a problem it must survive in the product and enter the host. The product itself has risk factors. Media fills use an artificial product (media) that has significant risk factors for allowing the survival and growth of potential contaminants. In particular, general-purpose growth media incubated for extended time periods at variable temperatures. The media is also shown to support the growth of common environmental isolates. Most aseptically-filled parenteral products do not have the ideal survival and growth conditions provided by media. Many products are preserved or have other formulation conditions that provide a hostile environment for microbial growth and survival. Before the advent of modern clean rooms, product formulation and packaging were the predominant protection for the product. Where these factors should not be considered when deciding on the potential risk posed by adverse environmental conditions, they do provide a degree of product protection though very difficult to quantify. Lyophilized products illustrate this concept very well. Lyophilization is a common method of preserving microorganisms but it is also a common method of preserving food products. Low water activity levels (ratio of bound vs. unbound moisture) are a very effective microbial control method. The lyophilization process will definitely not allow microorganisms to increase in number but it may or may not kill them. The greatest risk to a lyophilized product is prior to lyophilization.
Environmental risk is not confined to viable microorganisms. There have been FDA- requested recalls based on the level of non-viable particulates. Viable particulates are unique in that they have the ability to reproduce themselves and to go where no ?bug? has gone before. Non-viable particulates can affect the particulate level of a product but the correlation is very tenuous. Most clean room standards were and are based on non-viable particulate levels. The control of these particles is more a function of the air-handling filtration systems than any other factor. In the early days of clean rooms, the emphasis was on electronics and not pharmaceuticals. Viable contaminants were not considered a real concern for electronic applications. When clean rooms were adopted for pharmaceutical use, the then existing standards were also adopted. There were studies in the early 1960?s where attempts were made to correlate viable and nonviable particulates. What came out of those studies was a paradigm that a 5-micron particle was the smallest non-viable particle that could support a viable ?hitch hiker.? Consequently, the 5-micron particle could thus be used as an indicator of the possible presence of viable organisms without actually doing viable determinations. Other environmental risk factors are cleaning agent residues or vapors, temperature fluctuations, vibration levels, light levels, and other such variables. Depending primarily on product characteristics, these may or may not be potential or actual concerns.
Environmental monitoring in the pharmaceutical industry, particularly in aseptic manufacturing, is a somewhat unique activity for determining product quality. It is assumed that increased levels of microorganisms in proximity to open product can and will render that product adulterated. A close examination of this assumption shows a better term to be paradigm (a commonly held belief). There is the regulatory concern that is not required to be based on scientific principals and there is the now required scientific justification. The basis of the scientific approach is to postulate a theory and to either prove or disprove that theory with appropriate experiments. A sterile product that is not exposed to viable microorganisms will remain sterile. The theory of spontaneous generation (life arising from non-life) was disproved many years ago. Where it is not possible to render a finished, packaged product sterile, every reasonable effort should be made to minimize the potential level of contamination in that product. Possible sources of contamination include the environment to which that product is exposed. Using scientific logic, the way to limit the potential contamination risk is to limit exposure. Conventional clean rooms provide an aseptic and not sterile environment. Risk assessment, as per the current guidance documents, is based on an arbitrary number of media fill units produced under the conditions of the process being simulated would be exposed. To increase the risk, known and foreseeable interventions are to be used. In the great majority of runs, media fills are clean. When there is the occasional one or maybe two units found contaminated, concurrent environmental contaminants are rarely involved. Many times, similar types of organisms routinely found, such as those associated with people (?people bugs?) are the cause, but identifying the exact organism and relating that to a specific source is more desire than reality. In other words, it is very difficult to correlate specific environmental data to actual product failures with conventional methodology. The scientific approach says that other methods of assessing risk should be evaluated. The new regulatory initiatives mandate alternative approaches and, in particular, a thorough understanding of the product and manufacturing process. A part of this should be environmental controls. The scientific method for risk assessment is not based on monitoring but on a thorough understanding of the control measures, potential failure modes, and early detection. The recovery of organisms in an aseptic environment is not the real issue. The real issue is how the presence of this organism can affect the product.
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