Abstract
PurposePolysorbate excipients are commonly used as surfactants to stabilize therapeutic proteins in formulations. Degradation of polysorbates could lead to particle formation and instability of the drug formulation. We investigated how the fatty acid composition of polysorbate 80 impacts the degradation profile, particle formation, and product stability under stress conditions.MethodsTwo polysorbate 80-containing therapeutic protein formulations were reformulated with either Polysorbate 80 NF synthesized from a fatty acid mixture that contains mainly oleic acid (≥58%) or a version of polysorbate 80 synthesized with high oleic acid (>98%). Stress conditions, including high temperature and esterase spiking, were applied and changes to both the polysorbate and the therapeutic protein product were investigated for stability, purity, innate immune response and biological activity.ResultsThe addition of esterase and storage at 37°C led to significant hydrolysis of the polysorbate and increases in sub-visible particle formation for both polysorbates tested. The fatty acid composition of polysorbate 80 did not directly alter the stability profile of either therapeutic protein as measured by size exclusion chromatography, or significantly impact innate immune response or biological activity. However, formulations with Polysorbate 80 NF showed greater propensity for sub-visible particle formation under stress conditions.ConclusionsThese results suggest that composition of fatty acids in polysorbate 80 may be a promoter for sub-visible particulate formation under the stress conditions tested but may not impact protein aggregation or biological activity.
Highlights
Polysorbates are a family of excipients that function as surfactants
Formulations with Polysorbate 80 NF showed greater propensity for sub-visible particle formation under stress conditions. These results suggest that composition of fatty acids in polysorbate 80 may be a promoter for sub-visible particulate formation under the stress conditions tested but may not impact protein aggregation or biological activity
Homogenous all-oleate PS80 to be less prone to free fatty acid (FFA) particle formation compared to heterogenous PS80 [30]. In alignment with these previous studies, we found that treatment of both types of polysorbate 80 used in this study with an esterase led to rapid hydrolysis as indicated by similar increases in FFA consistent with the composition of fatty acids in the two types of polysorbate we studied, and PS-80 HOA showed less susceptibility to particle formation compared to PS-80 NF (Fig. 3 E and 3G)
Summary
Polysorbates are a family of excipients that function as surfactants. These non-ionic amphipathic surfactants are composed of polyethoxylated sorbitan fatty acid monoesters in which the fatty acid composition is heterogeneous. Polysorbates are commonly used in therapeutic protein formulations where they act as stabilizers to prevent protein adsorption at surface interfaces. Each Polysorbate NF monograph specifies a range for each of the various fatty acid constituents to accommodate variation in naturally occurring oils serving as the source of fatty acids used to synthesize this excipient. This tendency for natural variation results in a heterogeneous fatty acid composition and the potential for significant lot-to-lot variability of the fatty acid composition in polysorbate excipients found in therapeutic protein formulations. Improved understanding about how the variability of the fatty acid content in polysorbate excipients impact the stability of therapeutic protein formulations will enable manufacturers to optimize quality and safety of protein drug formulations
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