An Application for Through-Vial Impedance Spectroscopy (TVIS) in the Qualification of the Pirani-Gauge Assessment of the Ice Sublimation Endpoint

Background/Objectives: All the industry standard methods for monitoring the freeze-drying process, from the single-vial assessment using temperature probes, such as thermocouples, to batch assessments using comparative pressure measurements, have poorly defined transitions marking the end of ice sublimation. In this study, through-vial impedance spectroscopy (TVIS) is used to characterise and validate the point on the Pirani curve that corresponds to the end of ice sublimation. The impact of the solution composition in relation to its propensity to form crystalline and amorphous domains and the impact of the batch size were investigated. Methods: Individual TVIS vials were placed at specific positions across the shelf, in order to represent the core and edge vials of the batch. The unique features of the high-frequency real part capacitance, with its precise sublimation endpoint-defining plateau, were then used to map the individual-vial sublimation endpoints onto the Pirani profile, with a view to predicting the batch sublimation endpoint. Results: TVIS vial endpoints enabled a key observation that the shape of the Pirani profile may be analysed in terms of two phases, the first being largely associated with ice sublimation and the second being associated with water desorption. Moreover, by identifying the transition point more precisely, even in the small to intermediate scale systems, we provide a scientific basis for predicting the sublimation endpoint for production-scale dryers, where Pirani sensors are already in place. Conclusions: Such qualification of batch sublimation endpoints would allow for earlier, confident switching to the secondary drying stage without unnecessary delay, leading to shorter cycles, reduced energy consumption, and improved utilisation of costly freeze-drying infrastructure.