(660d) Water Activity As Indicator for Antibody Stability in Lyophilized Formulations

Freeze-drying (lyophilization) still is one of the state-of-the-art formulation strategies, when it comes to hard to formulate biopharmaceuticals. It is generally accepted, that two mechanisms are responsible for the stabilization of the biopharmaceutical in the final product: (1) water replacement and (2) vitrification. In case of water replacement, stabilization is achieved by preferential interactions of excipients and the biopharmaceuticals in the freeze-dried formulation. In case of vitrification, stabilization is achieved by limiting the mobility of the biopharmaceuticals in a viscous amorphous phase. Although investigated extensively, no general/universal method to predict composition and concentration of excipients in the amorphous phase for an optimal stabilization of the biopharmaceutical exists. Screening for appropriate formulation conditions is mainly based on heuristic decisions and experimental screening.

In this work, we used the water activity within the amorphous phase as a quick and easy indicator of monoclonal antibody (mAb) storage stability. The water activity (coefficient) reflects and gives access to the interactions of water within the amorphous phase and enables the quantification of interaction. The PC-SAFT equation-of-state was used to predict the water activity (in the amorphous phase) for different excipient mixtures, containing sucrose, cyclodextrins, rHA, PVP, arginine, and ectoine with various residual moistures. It was shown that adjusting to a specific range in water activity in the amorphous phase after drying improved stability and thus mAb monomer retention during storage. Historically suspected but insufficiently proven and recently rediscovered was the concept of optimal residual moisture. Meaning that a higher residual moisture may lead to better stability, which was supported by stability studies. In combination with selected measurements, predicting water activity (coefficients) might serve as a valuable tool for an initial excipient/formulation screening for lyophilization processes.