Protein Aggregation in Biopharmaceuticals: Control Strategies and Recent Trends

Abstract:

The importance of managing protein aggregation in the biopharmaceutical industry has been highlighted by the increasing demand for high-concentration Subcutaneous (SC) formulations and Intravenous (IV) injections, as well as the emergence of complex novel modalities such as bispecific antibodies. Protein aggregation can cause serious problems, such as inducing immunogenicity, reducing drug efficacy, and lowering process efficiency, so it must be strictly managed as a Critical Quality Attribute (CQA) of pharmaceuticals. This review aims to comprehensively cover the mechanisms of aggregation, the analytical characterization of aggregates across the entire aggregate size spectrum, and practical formulation strategies. To this end, the impact of protein aggregation on pharmaceutical development, the thermodynamic and kinetic mechanisms that induce aggregation, and various stress factors are examined in detail. The review comparatively analyzes the principles, advantages, and disadvantages of the latest techniques for analyzing aggregates of diverse sizes, from soluble aggregates to insoluble particulates. It proposes strategies for complementarily utilizing these techniques. The review also provides comprehensive information for successful biopharmaceutical development, discussing the stabilization mechanisms of major excipients, such as buffers, surfactants, and amino acids, early candidate selection through developability assessment, and the recently emerging Artificial Intelligence (AI) and automation-based formulation optimization approaches.