Impact of Primary Container Closure System on PS80 Oxidation and the Mechanistic Understanding.

Abstract

Polysorbate oxidation can potentially lead to protein degradation and loss of potency, which has been a challenge for the pharmaceutical industry for decades. Many factors have been reported to impact polysorbate oxidation rate, including types of elemental impurities, peroxide content, pH, light exposure, grades of polysorbate, etc. Even though there are many publications in this field, the impact of primary container closure system on PS80 oxidation has not been systematically studied or reported. The purpose of the current study is to close this gap. Placebo PS80 formulations were prepared and filled into different container-closure systems (CCS), including different types of glass vials and polymer vials. Oleic acid content was monitored on stability as a surrogate value for PS80 content, which will decline upon oxidation. ICP-MS analysis and metal spiking studies were carried out to correlate the PS80 oxidation rate with metals leached from primary containers. PS80 degrades via oxidation at the fastest rate in glass vials with high coefficient of expansion (COE), followed by glass vials with low coefficient of expansion, while polymer vials minimized the oxidation of PS80 in most formulation conditions explored in this paper. ICP-MS analysis demonstrated that 1) 51 COE glass has more metal leachables than 33 COE glass in this study; and 2) More metal leachables correlates with faster PS80 oxidation. Metal spiking studies confirmed the hypothesis that aluminum and iron have a synergistic catalysis effect on PS80 oxidation. Primary containers of drug products play a significant role in the rate of PS80 oxidation. This study revealed a new major contributor to PS80 oxidation and potential mitigation strategy for biological drug products.