Effect of formulation composition on trastuzumab stability

For monoclonal antibody drug products as for other biologics, while the innovator drug products first becomes commercially available, they are often followed by one or more biosimilar products. These biosimilars often differ from the innovator product, as well as from each other, in their formulation composition. However, the impact of the formulation composition on the stability of the active pharmaceutical ingredient subjected to different ‘stresses’ is still not understood. We have evaluated the effect of different formulations on structural stability and aggregation behavior of a monoclonal antibody, trastuzumab (both the drug substance and the final drug product), against three most common stresses encountered during production, storage, and formulation into a lyophilized product − freeze–thaw, freeze-drying, and agitation. Irrespective of the stabilizer used, the formulations exhibited good conformational stability against all three stresses. However, the freeze-drying process caused a significant increase in the number of soluble aggregates, but only in sucrose containing formulations. On the other hand, agitation in sorbitol containing formulation led to a significant increase in insoluble aggregates. This effect could also be attributed to the absence of surfactant in this formulation composition. The stabilizing effect of trehalose appeared to be independent of its concentration. Therefore, the effect of formulation composition is more pronounced for aggregation of trastuzumab than for its conformational stability. Our findings suggest that formulation design warrants consideration of both conformational stability and aggregation behavior of the active ingredient.