Abstract
Accelerated degradation studies are frequently used to screen for formulation conditions that confer adequate shelf life for therapeutic proteins. To speed development cycles, degradation is often accelerated by application of conditions that expose proteins to elevated temperatures, dynamic air-water interfaces created by agitation, or stresses induced by freeze-thaw cycling. The purpose of this case study was to compare freeze-thaw- and agitation-induced aggregations with aggregation previously studied at elevated temperatures (Fast J, Cordes AA, Carpenter JF, Randolph TW. 2009. Biochemistry 48:11724-11736) using the therapeutic fusion protein abatacept as a model. The stability of abatacept against aggregation induced by the freeze-thaw and agitation degradation methods was assessed by size-exclusion chromatography (SEC) and microflow imaging (MFI) analysis. pH conditions that were previously found to increase conformational stability of abatacept and reduce aggregation during incubation at elevated temperature (Fast J, Cordes AA, Carpenter JF, Randolph TW. 2009. Biochemistry 48:11724-11736) also reduced aggregation induced by freeze-thaw cycling and by agitation in this study. Especially in the case of the freeze-thaw cycling, wherein the formation of aggregates was not readily detectable by SEC, MFI proved to be a useful method to characterize the stability of the formulations against aggregation.
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