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


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 (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.


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 Tg.
Duddu
S P
SP
Department of Pharmaceutical Technologies, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Sarma_P_Duddu@sbphrd.com
Dal Monte
P R
PR
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002850:Chromatography, Gel; D003460:Crystallization; D004563:Electrochemistry; D005612:Freeze Drying; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013395:Sucrose / Q000737:chemistry; D013696:Temperature; D014199:Trehalose / Q000737:chemistry
D000911:Antibodies, Monoclonal; D011993:Recombinant Fusion Proteins; D013395:Sucrose; D014199:Trehalose