Previous articles in this series (1, 2, 3) have examined the difference in focus between the USP/NF requirements for the absence of specific microorganisms in monograph products and that the USP Microbial Limits Tests does not address the legal requirement that non-sterile products be free of “objectionable organisms” as set forth in 21CFR 211.113 and 21 CFR 211.165.
So, since the microbial limits tests do not address themselves to “objectionable” microorganisms, how is the manufacturer to determine if there are “objectionables” in a lot of product awaiting release? One approach is suggested by FDA – once all organisms grown in the total count studies (total aerobic as well as total yeast and mold) are identified, a qualified microbiologist would conduct a risk analysis on the presence of that organism in that medication (4). This risk analysis should incorporate a minimum of four separate analyses: Absolute numbers of organisms seen Microorganism’s Characteristics Product Characteristics Potential Impact on Patients
Although high numbers of non-pathogenic organisms may not pose a health hazard, they may affect product efficacy and/or physical /chemical stability. An unusually high number of organisms seen in the product may also indicate a problem during the manufacturing process, or an issue with a raw material. The high bacterial counts may indicate that the microorganisms are thriving in the product. If a preserved product this could indicate that the product’s preservative system is not functioning or worse, the preservative was missing or incorrectly formulated.
The characteristics of the microorganism can be determined by a search of textbooks, or library work, by internet searches, or a combination of all of these. It is always a good idea to remember that you are interested in the microbiology of the situation – do not restrict the search to pharmaceutical sources as most of the best information will come from food, environmental, clinical and perhaps cosmetic microbiology sources in addition to the pharmaceutical field.
During this search look for synonyms of the organisms current name. With the widespread use of genetic techniques in taxonomy the names of some organisms have undergone multiple changes. The national culture collections are a good source of synonyms and all name variants should be researched.
First of all, determine if the organism is a known pathogen. A good place to start on this search is the FDA web site the “Bad Bug Book.” This is only a guide, but a good one (5). One approach is to do a preliminary evaluation for any organism that appears on the FDA/CFSAN list and immediately classify that organism as “objectionable.” However, it is also important to consider the route of administration and the susceptible population in this evaluation.
A second characteristic of the microorganism that must be taken into account is the potential for the organism to cause spoilage of the product. Make a list of substances used by the microorganism for growth. This can be from the literature, or from the identification equipment. For example, the Vitek 2 Compact will provide an extensive list of compounds the microorganism can metabolize, the Biolog a list of carbohydrates utilized, etc. Use the information gained during the identification of the organism. Compare these to the product formulation for potential issues. A microorganism is also objectionable if it has the potential to degrade the product on stability. Evaluate the microorganism’s tolerance to unusual conditions: low or high pH high salt concentration high sugar concentration (osmotic conditions) Low water activity Growth temperature, etc. It can also be useful to determine if the microorganism has a recognized proclivity for harboring plasmid-mediated antibiotic resistance. This is a special concern in regards to horizontal transmission of the trait within an vulnerable patient population.
The dosage form is important to consider. Is the product anhydrous or water based? This can have an effect on the ability of microorganisms to proliferate. Does it have sufficient free water to support microbial growth (6, 7). Is the container designed to minimize contamination and subsequent spoilage? Closure design can have a major effect on in-use stability of a product. Is the container adequately designed to retard access to the environment, and to prevent contamination from the environment. Give special consideration to the likelihood of an anhydrous medication’s exposure to water, providing the potential for microbial proliferation. The route of administration is also important. A medication orally administered can tolerate some microorganisms that would be disastrous in a medication meant to be applied topically to abraded skin or to rashes. Similarly, some microorganisms that could be tolerated in a topical would cause severe distress to a patient if taken orally. Inhalants, although not required to be sterile, are a particularly sensitive area and great care should be taken in classifying any contaminate as “non-objectionable.” Other product-related considerations should include a review of the production records and the environmental monitoring trends, A review of field complaints is also useful (is this contaminant one that causes eventual returns?).
Finally, a consideration of the targeted patient population is in order. The manufacturer cannot control, and should be held accountable, for patient abuse of a product or off-label use of the product by physicians. However, reasonable use of the product should be considered and part of the risk analysis. Are patient populations that are likely to use this product at increased risk if exposed to the particular microorganism?
The FDA’s concern with non-sterile dosage format is that the product not contain “objectionable” organisms. This FDA concern has been made clear since the 1970’s. However, many companies continue to mistakenly believe that if their non-sterile product meets the requirements in USP, it will be safe from FDA dispute. This not the case. The manufacturer is responsible for all contents of his drug product. Should question arise over the appropriateness of a particular organism, the manufacturer is expected to have a justification for the presence of that organism, preferably as part of the batch release document. Presented here is a brief description of some factors to consider in determining if an organism is objectionable. These considerations include: Absolute number of organisms present Microorganism characteristics Product characteristics Patient Population These are not meant to be a comprehensive listing of all issues, but rather a starting point for the non-sterile manufacturer to use in establishing their program to qualify finished product bioburden.
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