Towards Pharmaceutical Protein Stabilization: Thermodynamic and Kinetic Property Database Generation
Type of DegreePhD Dissertation
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Studies on peptide degradation mechanisms are of interest because of the high demand for protein-based therapeutics in the pharmaceutical industry. However, formulation efficiency is limited by the degradation of the desired products during multiple stages of the pharmaceutical protein manufacturing pipeline. While the use of additives and stabilizers has significantly reduced degradation, determining the most effective additives and stabilizers is accomplished through a “guess and check” approach, instead of understanding the underlying mechanism of the degradation pathway. Therefore, we sought to achieve a fundamental understanding of specific degradation mechanisms present in pharmaceutical proteins. Through the use of density functional theory (DFT), we examined peptide degradation at different points of the pharmaceutical protein manufacturing pipeline to generate the thermodynamic and kinetic property databases associated with the degradation mechanism of interest. Additionally, we classified the degradation mechanisms as either ‘functional’ or ‘structural’ based on the type of impact the reaction of interest had on therapeutic proteins. The propensity of the protein to be impacted by these forms of degradation was found to be dependent on the stage of the manufacturing pipeline, where fragmentation was more likely to occur than deamidation during downstream manufacturing and both deamidation and fragmentation occurred under ambient conditions. Furthermore, the propensity of the succinimide reaction pathway to occur under ambient environmental conditions indicated that the screening of cations to inhibit the reaction pathway was only applicable to the specified reaction pathway.