Possibilities and limitations of α-relaxation data of amorphous freeze-dried cakes to predict long term IgG antibody stability.

The value of correlating global α-relaxations with long term protein stability after freeze-drying is inconsistently reported. This study aims to clarify whether and to what extend the long term stability of a freeze-dried protein formulation can be predicted with this method. For this purpose, the α-relaxation parameter τ [h] of freshly prepared freeze-dried products is obtained by isothermal microcalorimetry. The concept is, that molecular movements in the amorphous matrix are strongly reduced in cakes with longer relaxation time and the product should therefore be more resistant against aggregation. To increase τ in comparison to a conventional freeze-drying cycle, aggressive drying cycles including structural collapse of the product as well as tempering protocols after freeze-drying are applied. The τ values are correlated with the aggregation rate of a freeze-dried IgG monoclonal antibody measured with high performance size exclusion chromatography. The antibody was used in its market formulation and 6 further compositions. A weak correlation between α-relaxation times and IgG aggregation was found. A higher mobility level through increased residual moisture helped to improve the correlation.