Physical Instabilities of Therapeutic Monoclonal Antibodies: A Critical Review

Abstract

The proteinaceous nature of monoclonal antibodies (mAbs) makes them highly sensitive towards various physical and chemical conditions, thus leading to instabilities which are classified as physical and chemical instabilities. In this review, we are discussing in detail about the physical instability of mAbs because a large number of articles previously published are solely focusing on the chemical aspect of the instability with little coverage on the physical side. The physical instabilities of mAbs are classified into denaturation and aggregation (precipitation, visible and subvisible particles). The mechanism involved in their formation is discussed in the article along with the pathways correlating the denaturation of mAb or formation of aggregates to immunogenicity. Further equations like Gibbs-Helmholtz involved in the detection and quantification of denaturation are discussed along with various factors causing the denaturation. Moreover, questions related to aggregation like the types of aggregates and the pathway involved in their formation are answered in this article. Factors influencing the physical stability of the mAbs by causing denaturation or formation of aggregates involving the structure of protein, concentration of mAbs, pH of the protein and the formulations, excipients involved in the formulations, salts added to the formulations, storage temperature, light and UV radiation exposure and processing factors are mentioned in this article. Finally, the analytical approaches used for detecting and quantifying the physical instability of mAbs at all levels of structural conformation like far and near UV, infrared spectroscopy, capillary electrophoresis, LC-MS, micro flow imagining, circular dichroism and peptide mapping are discussed.

Physicochemical and biological stability of diluted vedolizumab in intravenous infusion bags

“…High acceleration speed and significant impaction can occur in a pneumatic dispatch system. Given the inherent sensitivity of protein drugs to mechanical forces in simulated laboratory settings, causing air–liquid interfaces, foaming and resulting in aggregation,5–7 this form of transportation is often not advised for transporting moAbs 8. However, little published objective and real-life data are currently available to suggest that moAb stability is affected by pneumatic tube system transport 4 5…”

Comparative stability study and aggregate analysis of Bevacizumab marketed formulations using advanced analytical techniques

“…Therefore, regulatory agencies around the world highlight the need to perform real time stability studies, force degradation studies, and accelerated stability studies as part of physicochemical characterization to directly compare the stability of the biosimilar formulation with the innovator product [ 5 ]. The comparative force degradation study should ideally be carried out under a variety of stress conditions including thermal, chemical, and mechanical stressors, all of which can lead to gradual product degradation during processing, packaging, shipping and handling [ 1 , 5 ].…”