Metal-catalyzed oxidation (MCO) of biologic drug products can cause aggregation, formation of low molecular weight species, charge variants, and site-specific oxidation or oxidative carbonylation of various amino acid residues. MCO can result from binding of redox-active metals to the protein itself or to buffers and other excipients in solution. The resulting metal complexes can lead to Fenton chemistry, which generates hydroxyl radicals and/or iron IV oxo species that cause protein oxidation and degradation. Because metal ions can be introduced into drug products from many sources, including water, excipients, and leaching from stainless steel during manufacture, chelators are often added to formulations in order to mitigate the risk of metal-catalyzed oxidation. The chelators EDTA and DTPA are commonly used; however, the structure and properties of the resulting metal-EDTA and metal-DTPA complexes are different. The primary coordination sphere around the metal center dictates reactivity, where metal-EDTA complexes are particularly reactive. Thus, while DTPA is able to fully protect many BMS compounds against metal-catalyzed oxidation, EDTA performance is very protein specific and may not fully protect against MCO. Here, we compare EDTA and DTPA performance against MCO for five BMS compounds under accelerated stability conditions.

Excipient choice for protection against metal-catalyzed oxidation: Impact of chelator on stability of biologic drug products

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.