Evaluation of a PAT-based in-line control system for a continuous spin freeze-drying process

Continuous spin freeze-drying provides a range of opportunities regarding the implementation of several in-line process analytical technologies (PAT) to control and optimize the freeze-drying process at the individual vial level. In this work, two methods were developed to (1) control the freezing phase by separately controlling the cooling and freezing rate and (2) control the drying phase by controlling the vial temperature (and hence the product temperature) to setpoint values and monitoring the residual moisture content. During the freezing phase, the vial temperature closely followed the decreasing setpoint temperature during the cooling phases, and the crystallization phase was reproducibly controlled by regulating the freezing rate. During both primary and secondary drying, vial temperature could be maintained on the setpoint temperature which resulted in an elegant cake structure after every run. By being able to accurately control the freezing rate and the vial temperature, a homogeneous drying time (SD = 0.07-0.09 h) between replicates was obtained. Applying a higher freezing rate significantly increased primary drying time. On the other hand, fast freezing rates increased the desorption rate. Finally, the residual moisture of the freeze-dried formulation could be monitored in-line with a high accuracy providing insight on the required length of the secondary drying phase.