Chemical and physical instabilities in manufacturing and storage of therapeutic proteins.

Development of a robust biologic drug product is accomplished by extensive formulation and process development screening studies; however, even in the most optimal formulation, a protein can undergo spontaneous degradation during manufacture, storage, and clinical use. Chemical changes to amino acid residues, such as oxidation of methionine or tryptophan, or changes in charge such as deamidation or carbonylation, can induce conformational changes in the overall protein structure, potentially leading to changes in physical - in addition to chemical - stability. Oxidation is often caused by light exposure or the presence of metal ions or peroxides. Asparagine deamidation is more likely to occur at higher pH and/or elevated temperature. Mechanical and interfacial stresses during manufacturing can lead to physical instabilities (i.e. various forms of aggregation). A well-defined manufacturing process and effective in-process controls are essential in minimizing chemical and physical instabilities, enabling robust production and distribution of a safe and efficacious drug product. In this work, the authors provide a review of developments in these areas over the past two years, with emphasis on manufacturability of therapeutically relevant proteins and protein-based drug products.