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    Evaluating the Combined Impact of Temperature and Application of Interfacial Dilatational Stresses on Surface-mediated Protein Particle Formation in Monoclonal Antibody Formulations

    Year: 2022

    Journal: J. Pharm. Sci., Volume 111, MAR, page 680–689

    Authors: Griffin, Valerie P.; Merritt, Kimberly; Vaclaw, Coleman; Whitaker, Neal; Volkin, David B.; Ogunyankin, Maria Olu; Pace, Samantha; Dhar, Prajnaparamita

    Organizations: Bristol Myers Squibb, North Brunswick, NJ

    Keywords: Surface induced sub-visible particle formation; Surface pressure; Dilatational stresses; Monoclonal antibody(s); Temperature

    Formation of submicron and subvisible protein particles (0.1-100 mm) present a major obstacle during processing and storage of therapeutic proteins. While protein aggregation resulting in particle formation is wellunderstood in bulk solution, the mechanisms of aggregation due to interfacial stresses is less understood. Particularly, in this study, we focus on understanding the combined effect of temperature and application of interfacial dilatational stresses, on interface-induced protein particle formation, using two industrially relevant monoclonal antibodies (mAbs). The surface activity of Molecule C (MC) and Molecule B (MB) were measured at room temperature (RT) and 4 degrees C in the absence and presence of interfacial dilatation stress using a Langmuir trough. These results were correlated with Micro-flow imaging (MFI) to characterize formation of subvisible protein particles at the interface and in the bulk solution. Our results show that the surface activity for both proteins is temperature dependent. However, the extent of the impact of temperature on the mechanical properties of the monomolecular protein films when subjected to dilatational stresses is protein dependent. Protein particle analysis provided evidence that protein particles formed in bulk solution originate at the interface and are dependent on both application of thermal stresses and interfacial dilatational stresses. In the absence of any interfacial stresses, more and larger protein particles were formed at the interface at RT than at 4 degrees C. When mAb formulations are subjected to interfacial dilatational stresses, protein particle formation in bulk solution was found to be temperature dependent. Together our results validate that mAb solutions maintained at 4 degrees C can lower the surface activity of proteins and reduce their tendency to form interface-induced protein particles both in the absence and presence of interfacial dilatational stresses. (c) 2021 Published by Elsevier Inc. on behalf of American Pharmacists Association.
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