Accelerated Storage for Shelf-Life Prediction of Lyophiles: Temperature Dependence of Degradation of Amorphous Small Molecular Weight Drugs and Proteins

Abstract

Prediction of lyophilized product shelf-life using accelerated stability data requires understanding the temperature dependence of the degradation rate. Despite the abundance of published studies on stability of freeze-dried formulations and other amorphous materials, there are no definitive conclusions on the type of pattern one can expect for the temperature dependence of degradation. This lack of consensus represents a significant gap which may impact development and regulatory acceptance of freeze-dried pharmaceuticals and biopharmaceuticals. Review of the literature demonstrates that the temperature dependence of degradation rate constants in lyophiles can be represented by the Arrhenius equation in most cases. In some instances there is a break in the Arrhenius plot around the glass transition temperature or a related characteristic temperature. The majority of the activation energies (E_a), which are reported for various degradation pathways in lyophiles, falls in the range of 8 to 25 kcal/mol. The degradation E_a values for lyophiles are compared with the E_a for relaxation processes and diffusion in glasses, as wells as solution chemical reactions. Collectively, analysis of the literature demonstrates that the Arrhenius equation represents a reasonable empirical tool for analysis, presentation, and extrapolation of stability data for lyophiles, provided that specific conditions are met.

Keywords: Accelerated stability; Activation energy; Aggregation; Amorphous; Arrhenius; Deamidation; Freeze-drying; Hydrolysis; Molecular mobility; Oxidation; Stability; Stability prediction; Temperature dependence.