Predicting accelerated aggregation rates for monoclonal antibody formulations, and challenges for low-temperature predictions

Nonnative aggregation is a common degradation route for therapeutic proteins. Control of aggregate levels inherently requires control and/or prediction of aggregation rates at formulation conditions and storage temperatures of practical interest. Additionally, formulation screening often involves generation of accelerated stability data at one or more temperatures. A temperature‐scanning approach for measuring nonnative aggregation rates as a function of temperature is proposed and evaluated here for a monoclonal antibody across different formulation conditions. Observed rate coefficients of aggregation (kobs) were determined from isothermal kinetic studies for a range of pH and salt conditions at several temperatures, corresponding to shelf lives spanning multiple orders of magnitude. Isothermal kobs values were efficiently and quantitatively predicted by the temperature‐scanning monomer loss (TSML) approach at accelerated conditions (half lives of the order 10−1-102 h). At lower temperatures, non‐Arrhenius behavior was apparent in some cases, and was semi‐quantitatively described by nonlinear van't Hoff contributions to monomer unfolding free energies. Overall, the results demonstrate a novel strategy to quantitatively determine aggregation rates at time scales of industrial interest, based on kobs values from TSML, which are sample‐ and time‐sparing as compared with traditional isothermal approaches, and illustrate challenges for shelf‐life prediction with non‐Arrhenius kinetics. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4234-4243, 2011