As previously covered on Eureka, compounding pharmacies often act more like drug manufacturers than pharmacies, and as such, ought to abide by the same rules – the cGMPs – that pharmaceutical companies comply with to assure that the medicines they produce are safe and pure.
A key part of cGMPs is the establishment of a robust environmental monitoring (EM) program. Even if compounding pharmacies are not formally required to adhere to cGMPs, they should put in place an EM program that achieves these three goals:
- Know the flora of the compounding environment
- Know what is in and around ingredients and components
- Know what is in or around the finished products
An EM program does not just detect the presence or absence of contamination. It should also establish the identity of microorganisms that are found. Accurately identifying organisms to the species, and many times the strain, level permits tracking of the potential origin of the contamination and avoids delays in product release and completion of investigations.
The identification of microorganisms can be achieved through various methods, each with its own level of accuracy and reproducibility.
- Genotypic identification involves sequencing of ribosomal RNA regions of bacterial and fungal genomes. It can provide identification at the species and occasionally subspecies level, and has been shown to be more accurate and precise than traditional biochemical and phenotypic techniques (see below).
- Proteotypic identification is achieved through matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. This technique analyzes a small amount of sample to produce a protein spectrum based primarily on ribosomal proteins, which is then compared to a validated database. This method has been shown to yield a high level of species discrimination.
- Phenotypic identification differentiates between organisms based on the results of biochemical tests, such as sugar fermentation, or physiological properties, such as salt or pH tolerance. Subjective interpretation of results contributes to a higher rate of inaccurate identifications compared to other methods. Additionally, it is often the case that microorganisms isolated from manufacturing environments are physiologically stressed and may not fully express their phenotypic and biochemical characteristics, resulting in erroneous (or lack of) identification.
No matter what method of identification is used, the quality of the reference library to which the results of analysis are compared is paramount. Libraries must be built in a quality environment and validated to ensure consistent performance and accuracy, and library coverage must be reflective of the organisms observed in the environment being tested. This last point is especially germane in the context of systems which are traditionally used in clinical settings and are therefore dominated by skewed reference libraries not ideal for EM of compounding pharmacies.
An EM program is a surveillance system that provides a baseline profile of a manufacturing environment; acts as an early warning system to detect possible environmental contaminants that are out of limits and that may impact the product; and promptly identifies the sites in the manufacturing environment at risk of contaminating the product. The data gathered in a well-designed and executed EM program provide critical information for tracking and trending on a routine basis. Accurate and consistent species-level identifications result in more confidence in this tracking and trending information.
Detailed analysis of the state of environmental control within a manufacturing area can detect the emergence of indicator organisms and allow excursions from normal operating conditions to be identified quickly and reliably. Accurate identifications aid in root cause determination and help determine the appropriate mitigation steps. All of this together ultimately minimizes risk and provides brand protection through product assurance.