(365d) Characterizing and Understanding Protein Stability at High Concentration

With the growing number of therapeutic proteins formulated at high concentration, i.e. > 50 mg/mL, understanding and controlling their real time stability is drawing increasing attention from the biopharmaceutical industry and regulatory agencies. Although stability prediction is typically made at low concentrations for formulation screening purposes through parameters such as B₂₂ or k_D, real-time measurements at formulation conditions are still highly desired for formulated drug products. Conventional techniques suffer from the low concentration requirements and excipient interferences. In this study, Raman spectroscopy combined with the nanoscale physical properties derived from DLS provide unique insights into the optimum solvent (formulation) conditions required for stability. In particular the Raman measurements provide insights into the secondary and tertiary structural changes as well as the conformations around the disulfide linkages. In addition, a number of kinetic and thermodynamic parameters can also be obtained through temperature studies and/or the use of deuterium exchange experiments. Data on mAbs and model proteins will be presented to demonstrate that this tool may be utilized for early validation of the existing stability protocols and also for providing novel insights into protein stability under the influence of various stresses and at high concentrations