Accelerated Aggregation Studies of Monoclonal Antibodies: Considerations for Storage Stability

• Published in: Journal of pharmaceutical sciences 2020-01, Vol.109 (1), p.595-602
• Main Authors: Wälchli, Ruben, Vermeire, Pieter-Jan, Massant, Jan, Arosio, Paolo
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - chemistry; antibody(s); developability; Drug Compounding; Drug Stability; Drug Storage; Immunoglobulin G - chemistry; Kinetics; mechanistic modeling; monoclonal antibody(s); Particle Size; Protein Aggregates; protein aggregation; Protein Stability; stability; Temperature
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2019.10.048

Aggregation of mAbs is a crucial concern with respect to their safety and efficacy. Among the various properties of protein aggregates, it is emerging that their size can potentially impact their immunogenicity. Therefore, stability studies of antibody formulations should not only evaluate the rate of monomer loss but also determine the size distribution of the protein aggregates, which in turn depends on the aggregation mechanism. Here, we study the aggregation behavior of different formulations of 2 monoclonal immunoglobulins (IgGs) in the temperature range from 5°C to 50°C over 52 weeks of storage. We show that the aggregation kinetics of both antibodies follow non-Arrhenius behavior and that the aggregation mechanisms change between 40°C and 5°C, leading to different types of aggregates. Specifically, for a given monomer conversion, dimer formation dominates at low temperatures, while larger aggregates are formed at higher temperatures. We further show that the stability ranking of different molecules as well as of different formulations is drastically different at 40°C and 5°C while it correlates better between 30°C and 5°C. Our findings have implications for the level of information provided by accelerated aggregation studies with respect to protein stability under storage conditions.