(89g) Modeling API Crystal Surface Degradation Processes in Drug Product Formulations

Modeling the packaged stability of active pharmaceutical ingredient (API) drug product (DP) is critical for predicting the shelf life of DP formulations. The most common modeling approach is to assume the DP degradation rate is only a function of the temperature and relative humidity (RH). The temperature and RH dependencies determined from experiments are then combined with a model for package moisture uptake to predict long term shelf stability. Recently, an API in development was discovered to have a degradation rate that depends on the specific surface area (SSA) of the API drug substance (DS), suggesting that the degradation mechanism is driven by processes on the surface of the API. To capture this experimental observation, a mechanistic model for DP degradation due to surface reactions was developed. Open dish stability experiments were leveraged to fit the model and comparisons between model predictions and packaged stability experiments validated the model. Model predictions were then leveraged to inform decisions including the choice of desiccant loading in bottles and API DS impurity and SSA specifications. Finally, potential improvements to the model, including application to other SSA-dependent degradation processes, will be discussed.