Primary drying optimization in pharmaceutical freeze-drying: a multi-vial stochastic modeling framework

Primary drying is the most time-consuming and energy-intensive step of pharmaceutical freeze-drying. Minimizing the duration of this stage is of paramount importance to speed up process development and product manufacturing. In this study, we propose a stochastic modeling framework that can help reaching this target. The framework is composed by five sequential steps: model development, sensitivity analysis, model calibration, model validation, and dynamic optimization. Three critical issues are addressed and accounted for in the model structure, namely: (i) the effect of time-varying operating conditions on the process key performance indicators (KPIs); (ii) the dynamic evolution of the water vapor partial pressure inside the drying chamber; (iii) the impact of drying heterogeneity on the primary drying duration. We cope with the first two issues by introducing macroscopic energy and mass balances within the model formulation. The third issue is addressed by allocating intra-lot variability as parametric...