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

Purpose. The purpose of this study is to highlight the importance of knowing the glass transition temperature, T-g, of a lyophilized amorphous solid composed primarily of a sugar and a protein in the interpretation of accelerated stability data. Methods. Glass transition temperatures were measured using DSC and dielectric relaxation spectroscopy. Aggregation of protein in the solid state was monitored using size-exclusion chromatography. Results. Sucrose formulation (T-g similar to 59 degrees C) when stored at 60 degrees C was found to undergo significant aggregation, while the trehalose formulation (T-g similar to 80 degrees C) was stable at 60 degrees C. The instability observed with sucrose formulation at 60 degrees C can be attributed to its T-g (similar to 59 degrees C) being close to the testing temperature. Increase in the protein/sugar ratio was found to increase the T(g)s of the formulations containing sucrose or trehalose, but to different degrees. Conclusions. 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 T-g.