European Journal of Pharmaceutical Sciences 1 Desember 2025

Title	European Journal of Pharmaceutical Sciences 1 Desember 2025
Edition	1 Desember 2025
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ISBN/ISSN
Author(s)
Subject(s)	Protein stability Protein aggregation Thermal stress
Classification
Series Title
GMD	Jurnal
Language	Indonesia
Publisher
Publishing Year	2025
Publishing Place
Collation
Abstract/Notes	ABSTRACT Mitigating protein aggregation remains a challenge in the development of biopharmaceuticals, and agitation is well known as a stress that can induce protein aggregation. However, the temperature dependence of agitation- induced aggregation is not well understood. In this study, the aggregation of an Fc-fusion protein under agitation stress was investigated at 5, 25, and 40 ◦C. Soluble and insoluble aggregates were quantified by size-exclusion liquid chromatography and flow imaging microscopy, respectively. Both the aggregation level and the aggre- gate clusters were temperature dependent. The threshold for the orbital shaking that induced protein aggregation was temperature independent. Although thermal stress at 40 ◦C increased the number of oligomers, it did not lead to a higher monomer loss in a subsequent agitation at 25 ◦C. The aggregation induced by agitation stress was suppressed by adding a surfactant or removing the vial headspace, indicating that the aggregation occurred via an interface-mediated pathway. Thus, the observed temperature dependence was attributed to the protein adsorption to the interface and the following interfacial unfolding and aggregation was affected by the tem- perature. The results emphasized the importance of temperature control during shipping to ensure the quality of drug products. Agitation stability studies at a controlled temperature also provide a deep understanding of the protein aggregation mechanism, which is important for formulation development.
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