Modeling the Thermal Stability of in vitro Diagnostic Bioassays
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The objective of this work is to develop mathematical models for predicting the thermal stability of commercial diagnostic assays. These assays are a product of the Point of Care division of Abbott laboratories, and are used for analyzing patient blood samples for specific substances. The accuracy of the results from these diagnostic tests relies on the activity of specific biological and/or chemical components of the sensors. Mathematical models that describe the stability of these active components are useful for supporting product shelf-life claims and for the design and implementation of accelerated testing protocols. In the thesis, the stability of two diagnostic assay systems of interest to Abbott Point of Care is investigated using mathematical modeling. For the first assay system investigated, the biosensor associated with the assay is identified as an important factor for product stability. A second-order dynamic model is developed to describe the thermal stability of this biosensor. The model corresponds to a reversible reaction followed by an irreversible reaction, with rate coefficients having Arrhenius temperature dependencies. The second-order dynamic model provides improved predictions relative to a first-order dynamic model, based on a comparison between model fits for two experimental datasets, and a comparison of predictive ability for a validation dataset. The second-order dynamic model is used to extend the concept of Mean Kinetic Temperature concept from the pharmaceutical industry to systems with higher-order dynamics. For the second assay system investigated, the calibration fluid is identified as a key factor in assay stability. A first-order model is developed to describe the stability of the analyte within the calibration fluid. The first-order model captures most of the trend present in the data from calibration fluid incubation experiments. Finally, model predictions are used to investigate the amount of change in assay response that can be attributed to changes in concentration of analyte in the calibration fluid (after storage at elevated temperatures). The results show that the changes observed in assay responses are consistent with the magnitude of changes in calibrant analyte concentrations predicted by the model.