4D Micro-Computed X-ray Tomography as a Tool to Determine Critical Process and Product Information of Spin Freeze-Dried Unit Doses

Abstract

Maintaining chemical and physical stability of the product during freeze-drying is important but challenging. In addition, freeze-drying is typically associated with long process times. Therefore, mechanistic models have been developed to maximize drying efficiency without altering the chemical or physical stability of the product. Dried product mass transfer resistance ( R p ) is a critical input for these mechanistic models. Currently available techniques to determine R p only provide an estimation of the mean R p and do not allow measuring and determining essential local (i.e., intra-vial) R p differences. In this study, we present an analytical method, based on four-dimensional micro-computed tomography (4D- μ CT), which enables the possibility to determine intra-vial R p differences. Subsequently, these obtained R p values are used in a mechanistic model to predict the drying time distribution of a spin-frozen vial. Finally, this predicted primary drying time distribution is experimentally verified via thermal imaging during drying. It was further found during this study that 4D- μ CT uniquely allows measuring and determining other essential freeze-drying process parameters such as the moving direction(s) of the sublimation front and frozen product layer thickness, which allows gaining accurate process knowledge. To conclude, the study reveals that the variation in the end of primary drying time of a single vial could be predicted accurately using 4D- μ CT as similar results were found during the verification using thermal imaging.

Model-based optimization of the primary drying phase of oral lyophilizates

“…Sharp angles in the shape would otherwise result in a rupture of the blister foil. However, this will lead to more exotic product shapes than the cylinders who are typically described in parenteral freeze-drying ( Pikal, 2002 ; Vanbillemont et al, 2020b ). A mechanistic description of the product shape using a sliced horizontal cylinder with spherical caps model was proposed and implemented in the heat and mass balances of the primary drying phase (i.e.…”

In-Situ X-ray Imaging Of Sublimating Spin-Frozen Solutions

“…As a reference, the third sample was plain deionised water without dissolved substance. The two solutions have a high collapse temperature ( ) (−9 °C for BSA and −2 °C for mannitol) [ 36 ], which minimizes the risk of (micro-)collapse during the dynamic imaging experiments. These solutions were chosen for their different structure in solid state, being amorphous for the BSA formulation and mainly crystalline for mannitol.…”

“…Hence the resulting spin-frozen layer has a nearly cylindrical shape, with minor variations due to gravitational effects and the local composition during freezing. The projection series consisting of multiple full rotations was reconstructed to a time sequence of 3D volumes in a cylindrical coordinate system following the vial's symmetry axis in order to ease further analysis [36]. Each single reconstruction depicts the state of the object within the quasi-static time frame in the sliding projection window.…”

Spin Freezing and Its Impact on Pore Size, Tortuosity and Solid State

“…A load-lock ensures the transfer of the vial between two chambers with different process conditions without disturbing the process. The product temperature is continuously controlled by an infrared heater in front of every vial in combination with a thermal camera [23][24][25]. Finally, a stable dry product is obtained.…”

“…In contrast, batch freeze-drying is associated with complex re-validation procedures since, among others, heat transfer in a small lab-scale freeze-dryer is not comparable to the heat transfer in a production scale freeze-dryer [18,22]. The drying step of this continuous spin freeze-dry technology is currently extensively described in the literature [18,19,22,23,[25][26][27]. However, little is known about the impact of the spin-freezing step on the subsequent process steps and critical quality attributes.…”