Introduction
This paper discusses microbiology in the pharmaceutical quality control environment and the opportunities for development and application of new microbiology methods. Many new methods use technologies developed for space research [1], clinical studies [2], and the food industry [3]. While it may seem odd that the pharmaceutical industry lags behind in implementing new microbiological technologies, it can be readily explained as a resistance to change spawned, in part, by assay complexity and regulatory pressures.
In a regulated environment, once a method is accepted, there is significant corporate pressure to maintain procedures the same, thereby avoiding delays associated with regulatory scrutiny. As such, “accepted methods” are used repetitively, and often without question. Therefore, unfortunately, without critical evaluation, pharmaceutical microbiology and process understanding fail to advance and serve only to satisfy regulatory requirements.
Quality Control and Quality Assurance
Established standards for “quality control” are required by the Food, Drug and Cosmetic Act (FD&C) and the Code of Federal Regulations (CFR). For new drug products, FD&C section 505(b)(1)(D) requires full descriptions of manufacturing controls in a drug application. Regulations [21 CFR 314.50(d)(1)] require that in-process control tests and specifications be described in the chemistry, manufacturing, and controls (CMC) technical section of a new drug application submitted for review. Analogous requirements exist for generic drugs, animal drugs, biologics, and devices. Furthermore, current good manufacturing practice (CGMP) regulations (21 CFR 211) establish minimum practices to assure that products meet quality and purity expectations. The QA program has the responsibility of assuring the product meets these requirements, and the QC program assures the reliability of data used in that determination [4].
There is sufficient overlap in the roles of QA and QC that the responsibilities are often blended. In fact, there is no specified distinction between QA and QC within the CFR. The regulations (21 CFR 211.22) stipulate the requirement and responsibilities of a “quality control unit.” In general, it is up to individual companies to determine how the functions of the “quality control unit” will be apportioned between QA and QC. However it is done, the roles and responsibilities of QA and QC units should be clearly described in the company’s SOPs. The roles of the pharmaceutical engineers, chemists, and microbiologists should provide seamless support to the overall function of the quality unit, and that can only be done when each technical unit is led by technically independent managers with appropriate decision-making authority.
FDA representatives view quality assurance as a system of activities to assure a product meets its defined standards with a level of assurance [5]. For example, in producing a parenteral product, the defined standard of “sterile” requires a greater level of assurance than that afforded by a compendial sterility test. For that reason, the FDA’s 1994 guidance for submitting documentation for sterilization process validation stated, “The efficacy of a given sterilization process for a specific drug product is evaluated on the basis of a series of protocols and scientific experiments designed to demonstrate that the sterilization process and associated control procedures can reproducibly deliver a sterile product” [6]. This approach overcomes the inherent variability in sterility testing with an overall quality control program that uses process design and process control tests to assure product sterility.
Pharmaceutical products and processes use fewer microbiology tests than chemistry tests, so microbiology resources (personnel, funding, and space) are proportionally less. As awareness of microbiology principles becomes proportionally less, the managers of quality units are less likely to understand microbiology data and conclusions. This is a historical trend and one not limited to the pharmaceutical industry. For example, environmental microbiology suffered similarly during the era of EPA’s “superfund” as Quality Assurance (QA) programs focused predominantly on chemical assays were managed by chemists [4]. Under these conditions, pharmaceutical microbiologists build quality measures based on chemistry measurement principles, which is not a good fit.
However, microbiology plays a critical role in pharmaceutical quality control, specifically evaluating raw materials, process controls, product release tests and product stability tests. The quality and interpretation of these tests’ data critically impacts product safety. It is the Quality Control (QC) unit which assures that data from these tests are meaningful (reliable and precise) and have a minimum of error. QA units must evaluate the suitability for use of microbiology tests, the limitations of their applicability and measurements, and whether acceptance criteria were met. Therefore, to understand a process and product’s microbiological attributes, the overall quality unit (QC and QA) must understand both the nature of the tests and the data derived from them
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