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ABSTRACT:16 17Spin-freezing as alternative freezing approach was evaluated as part of an innovative 18 continuous pharmaceutical freeze-drying concept for unit doses. The aim of this paper 19 was to compare the sublimation rate of spin-frozen vials versus traditionally frozen vials 20 in a batch freeze-dryer, and its impact on total drying time. 21Five different formulations, each having a different dry cake resistance, were tested. 23After freezing, the traditionally frozen vials were placed on the shelves while the spin-24 frozen vials were placed in aluminium vial holders providing radial energy supply during 25 drying. Different primary drying conditions and chamber pressures were evaluated. 26After two hours of primary drying, the amount of sublimed ice was determined in each 27 vial. Each formulation was monitored in-line using NIR spectroscopy during drying to

Traditional pharmaceutical freeze-drying is an inefficient batch process often applied to improve the stability of biopharmaceutical drug products. The freeze-drying process is regulated by the (dynamic) settings of the adaptable process parameters shelf temperature T and chamber pressure P. Mechanistic modelling of the primary drying step allows the computation of the optimal combination of T and P in function of the primary drying time. In this study, an uncertainty analysis was performed on the mechanistic primary drying model to construct the dynamic Design Space for the primary drying step of a freeze-drying process, allowing to quantitatively estimate and control the risk of cake collapse (i.e., the Risk of Failure (RoF)). The propagation of the error on the estimation of the thickness of the dried layer L as function of primary drying time was included in the uncertainty analysis. The constructed dynamic Design Space and the predicted primary drying endpoint were experimentally verified for different RoF acceptance levels (1%, 25%, 50% and 99% RoF), defined as the chance of macroscopic cake collapse in one or more vials. An acceptable cake structure was only obtained for the verification runs with a preset RoF of 1% and 25%. The run with the nominal values for the input variables (RoF of 50%) led to collapse in a significant number of vials. For each RoF acceptance level, the experimentally determined primary drying endpoint was situated below the computed endpoint, with a certainty of 99%, ensuring sublimation was finished before secondary drying was started. The uncertainty on the model input parameters demonstrates the need of the uncertainty analysis for the determination of the dynamic Design Space to quantitatively estimate the risk of batch rejection due to cake collapse.

Recently, an innovative continuous freeze-drying concept for unit doses was proposed, based on spinning the vials during freezing. An efficient heat transfer during drying is essential to continuously process these spin frozen vials. Therefore, the applicability of non-contact infrared (IR) radiation was examined. The impact of several process and formulation variables upon the mass of sublimed ice after 15 minutes of primary drying (i.e., sublimation rate) and the total drying time was examined. Two experimental designs were performed in which electrical power to the IR heaters, distance between the IR heaters and the spin frozen vial, chamber pressure, product layer thickness and five model formulations were included as factors. A near-infrared (NIR) spectroscopy method was developed to determine the endpoint of primary and secondary drying. The sublimation rate was mainly influenced by the electrical power to the IR heaters and the distance between the IR heaters and the vial. The layer thickness had the largest effect on total drying time. The chamber pressure and the five model formulations had no significant impact on sublimation rate and total drying time, respectively. This study shows that IR radiation is suitable to provide the energy during the continuous processing of spin frozen vials.

The UGent Institutional Repository is the electronic archiving and dissemination platform for all UGent research publications. Ghent University has implemented a mandate stipulating that all academic publications of UGent researchers should be deposited and archived in this repository. Except for items where current copyright restrictions apply, these papers are available in Open Access. This item is the archived peer-reviewed author-version of: Thermal imaging as a noncontact inline process analytical tool for product temperature monitoring during continuous freezedrying of unit dose