Ahmad Aziz, Refaat Hesham, Bhattacharya Sanghati, Gurvich Vadim J, Rathore Anurag S, Nejadnik Reza, Suryanarayanan Raj
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States.
Int J Pharm. 2025 Feb 25;671:125275. doi: 10.1016/j.ijpharm.2025.125275. Epub 2025 Jan 25.
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.
与其他生物制品一样，对于单克隆抗体药物产品，创新药物产品首次上市后，通常会有一个或多个生物类似药产品相继出现。这些生物类似药在制剂组成方面往往与创新产品不同，彼此之间也存在差异。然而，制剂组成对活性药物成分在不同“应激”条件下稳定性的影响仍不明确。我们评估了不同制剂对单克隆抗体曲妥珠单抗（原料药和最终药品）的结构稳定性和聚集行为的影响，该抗体针对生产、储存以及制成冻干产品过程中遇到的三种最常见应激——冻融、冻干和搅拌。无论使用何种稳定剂，这些制剂在面对所有三种应激时均表现出良好的构象稳定性。然而，冻干过程导致可溶性聚集体数量显著增加，但仅在含有蔗糖的制剂中出现这种情况。另一方面，在含有山梨醇的制剂中搅拌会导致不溶性聚集体显著增加。这种效应也可归因于该制剂组成中不存在表面活性剂。海藻糖的稳定作用似乎与其浓度无关。因此，制剂组成对曲妥珠单抗聚集的影响比对其构象稳定性的影响更为显著。我们的研究结果表明，制剂设计需要同时考虑活性成分的构象稳定性和聚集行为。
