Effect of glass transition temperature on the stability of lyophilized formulations containing a chimeric therapeutic monoclonal antibody.

Abstract

The purpose of this study is to highlight the importance of knowing the glass transition temperature, Tg, of a lyophilized amorphous solid composed primarily of a sugar and a protein in the interpretation of accelerated stability data. Glass transition temperatures were measured using DSC and dielectric relaxation spectroscopy. Aggregation of protein in the solid state was monitored using size-exclusion chromatography. Sucrose formulation (Tg approximately 59 degrees C) when stored at 60 degrees C was found to undergo significant aggregation, while the trehalose formulation (Tg approximately 80 degrees C) was stable at 60 degrees C. The instability observed with sucrose formulation at 60 degrees C can be attributed to its Tg (approximately 59 degrees C) being close to the testing temperature. Increase in the protein/sugar ratio was found to increase the Tgs of the formulations containing sucrose or trehalose, but to different degrees. Since the formulations exist in glassy state during their shelf-life, accelerated stability data generated in the glassy state (40 degrees C) is perhaps a better predictor of the relative stability of formulations than the data generated at a higher temperature (60 degrees C) where one formulation is in the glassy state while the other is near or above its Tg.