Modelling the primary drying step for the determination of the optimal dynamic heating pad temperature in a continuous pharmaceutical freeze-drying process for unit doses

Abstract

In the pharmaceutical industry, traditional freeze-drying of unit doses is a batch-wise process associated with many disadvantages. To overcome these disadvantages and to guarantee a uniform product quality and high process efficiency, a continuous freeze-drying process is developed and evaluated. The main differences between the proposed continuous freeze-drying process and traditional freeze-drying can be found firstly in the freezing step during which the vials are rotated around their longitudinal axis (spin freezing), and secondly in the drying step during which the energy for sublimation and desorption is provided through the vial wall by conduction via an electrical heating pad. To obtain a more efficient drying process, the energy transfer has to be optimised without exceeding the product and process limits (e.g. cake collapse, choked flow). Therefore, a mechanistic model describing primary drying during continuous lyophilisation of unit doses based on conduction via heating pads was developed allowing the prediction of the optimal dynamic power input and temperature output of the electric heating pads. The model was verified by experimentally testing the optimal dynamic primary drying conditions calculated for a model formulation. The primary drying endpoint of the model formulation was determined via in-line NIR spectroscopy. This endpoint was then compared with the predicted model based endpoint. The mean ratio between the experimental and model based predicted drying time for six verification runs was 1.05±0.07, indicating a good accordance between the model and the experimental data.

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

“…An electric heating pad was tightly wrapped around the spin-frozen vial to provide the heat required for sublimation. An in-house scripted LabVIEW 2017 (National Instruments, Austin, TX, USA) application was used to keep the electric heating pad around the spin frozen vial at a fixed temperature of 40 • C and the pressure level at 5 Pa using proportional-integral-derivative (PID) controllers [4]. In addition, a low attenuating insulating fabric was put over the spin-frozen vial to shield it from uncontrolled energy from the environment.…”

“…A reduction in production cost and process time can be achieved by shifting from batch freeze-drying to continuous freeze-drying. An innovative continuous freeze-drying process was recently developed [4][5][6][7][8]. The freezing step used in this continuous freeze-drying process is modified compared to traditional batch freeze-drying, as glass vials filled with a liquid formulation are rotated around their longitudinal axis while cooled and frozen with a cold, sterile and inert gas (i.e., spin freezing) [4][5][6][7][8].…”

“…An innovative continuous freeze-drying process was recently developed [4][5][6][7][8]. The freezing step used in this continuous freeze-drying process is modified compared to traditional batch freeze-drying, as glass vials filled with a liquid formulation are rotated around their longitudinal axis while cooled and frozen with a cold, sterile and inert gas (i.e., spin freezing) [4][5][6][7][8]. This approach reduces the product layer thickness and increases the surface area, resulting in much higher sublimation rates and thus much shorter production times.…”

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

“…(13) describes the temperature difference over the frozen product layer. This system of equations is already thoroughly described in literature ( De Meyer et al, 2017 ; Leys et al, 2020 ; Mortier et al, 2015 ; Vanbillemont et al, 2020c ). …”

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

“…By accurately controlling the heat transfer and pressure, water is separated from an aqueous solution in three consecutive steps to achieve a dry stable cake: Freezing, primary drying and secondary drying [ 1 , 2 , 3 ]. While freeze-drying in industry is typically approached as a batch process, spin-freeze-drying is a promising technique for continuous freezing of unit doses in pharmaceutical sciences [ 4 , 5 ]. Single cylindrical vials are spun rapidly around their longitudinal axis while a stream of cold sterile gas is sent around the vial.…”