In my last blog, I reviewed Dr. Bryan Riley's European Pharmaceutical Review article on FDA's perspectives of RMMs. In the same EPR supplement, Baxter's Dr. Youwen Pan provided an overview of the challenges our industry faces when implementing rapid methods, and offers strategies for a successful technical validation and business justification. Here is my review of Dr. Pan's article.
Challenges and Strategies for the Application of Rapid Microbiological Methods in the Pharmaceutical Industry. Youwen Pan. Technology Resources/Sterility Assurance, Baxter Healthcare Corporation. European Pharmaceutical Review. 2011: 16(5), 66-69.
Dr. Pan opens his article by stating that although advances in science and innovation in pharmaceutical manufacturing has promoted an interest in using RMMs, a number of challenges still persist that have made it difficult for companies to implement these new methods. The primary decision faced by the pharmaceutical microbiologist is the choice of precisely which technology to implement, ensuring it fits the purpose of its intended application. For example, choosing a RMM solely based on its technical merits may not be appropriate because the capability of the method may not be applicable with certain tests or samples types. There are critical factors that should be considered wen selecting a RMM, specifically, technical reliability and business benefit.
Key factors in technical reliability include the demonstration of equivalence between the RMM and the conventional method (e.g., with respect to limit of detection, specificity, accuracy and precision), risks in generating false positive or false negative results, ease of use and validation.
The sensitivity of a RMM should be assessed using a wide range of microorganisms, including those that have varied physiological states (e.g., stressed vs. healthy), as well as strains that have been isolated from the manufacturing environment.
False positive or false negative results may occur due to a variety of reasons, including the technical limitations of the RMM system. For example, a false positive in an ATP bioluminescence RMM may be due to background ATP in the sample matrix. Conversely, a false positive result may occur if an insufficient amount of ATP is released from viable cells during the test. Dr. Pan provides a similar example when using PCR-based RMMs. Extracellular nucleic acid fragments that mimic target sequences can cause false positives, while sample residues may affect the PCR reaction, resulting in a false negative result.
When determining the business benefits from a rapid method, detailed evaluation should include capital and consumable cost, labor efficiency, time savings, regulatory authority acceptance, and the ability of the RMM vendor to provide technical support. In fact, the business benefits often are the motivating factors in deciding to implement RMMs.
Dr. Pan concludes that the implementation of a rapid method is a complex project which requires expertise from multiple fields such as finance, regulatory, microbiology, quality assurance, statistics and information technology. Additionally, advice from regulatory agencies and the RMM vendors will aid in the success of your implementation efforts. To read the full article, please visit the RMM Supplement of the European Pharmaceutical Review.