Model-Based Monitoring and Control of Industrial Freeze-Drying Processes: Effect of Batch Nonuniformity

Abstract

This article deals with the monitoring and control of the freeze drying of pharmaceuticals in vials taking into account batch heterogeneity. Firstly, the problem of nonuniformity of the batch is addressed: the vials in the chamber of the freeze dryer can, in fact, exhibit different time evolutions due not only to radiation from the wall of the chamber, but also to temperature gradients on the heating shelf, vapor fluid dynamics, and nonuniform inert distribution, as it has been evidenced by means of computational fluid dynamics simulations. Then, the effect of batch heterogeneity on the performance of the monitoring and control system is discussed and a new tool is presented, based on an advanced algorithm, the Dynamic Parameters Estimation, that estimates the state of the system (product temperature and residual ice content) by using the results of the pressure rise test, coupled with a controller (LyoDriver) that changes the shelf temperature in order to maintain product temperature below the maximum allowed value while minimizing the duration of primary drying.