Process Understanding in Freeze-Drying Cycle Development: Applications for Through-Vial Impedance Spectroscopy (TVIS) in Mini-pilot Studies
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The freeze-drying cycle comprises three stages: (1) freezing, to form ice and to crystallise out any solutes with a propensity to crystallise, (2) primary drying to remove the ice phase by sublimation and (3) secondary drying to remove the remaining unfrozen water which is bound to the remaining matrix of crystalline and amorphous solids. Given the impact of scale on the process outcomes, any freeze-drying cycle developed based on mini-pilot studies will inevitably require measurement technologies for characterising each stage of the cycle at each scale of the process. However, there are inherent challenges in the development of reliable mini-piloting studies, with the first being the fact that no single PAT technology for freeze drying may be implemented across all levels of scale, and the second being the inherent changes in process characteristics (process parameters that result from scale-up).
Here, we present a new approach for process understanding in freeze-drying cycle development, which uses a through-vial impedance measurement.
The technique has been used to characterise a broad range of features of the process, including, ice onset times, the completion of ice solidification, the glass transition and the structural relaxation of the amorphous solid, a surrogate for primary drying rate and the primary drying end point.
The on-going development of this technology may see the application with microtitre plate technologies for formulation screening (microscale down) and for scale-up into production by using a non-contact probes for monitoring problematic regions within the dryer.
KeywordsFreeze drying In-line process control PAT QbD Critical process parameters
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