Recently, attention has been drawn to microwave-assisted freeze-drying (MFD), as it drastically reduces the typically long drying times of biopharmaceuticals in conventional freeze-drying (CFD). Nevertheless, previously described prototype machines lack important attributes such as in-chamber freezing and stoppering, not allowing for the performance of representative vial freeze-drying processes. In this study, we present a new technical MFD setup, designed with GMP processes in mind. It is based on a standard lyophilizer equipped with flat semiconductor microwave modules. The idea was to enable the retrofitting of standard freeze-dryers with a microwave option, which would reduce the hurdles of implementation. We aimed to collect process data with respect to the speed, settings, and controllability of the MFD processes. Moreover, we studied the performance of six monoclonal antibody (mAb) formulations in terms of quality after drying and stability after storage for 6 months. We found drying processes to be drastically shortened and well controllable and observed no signs of plasma discharge. The characterization of the lyophilizates revealed an elegant cake appearance and remarkably good stability in the mAb after MFD. Furthermore, overall storage stability was good, even when residual moisture was increased due to high concentrations of glass-forming excipients. A direct comparison of stability data following MFD and CFD demonstrated similar stability profiles. We conclude that the new machine design is highly advantageous, enabling the fast-drying of excipient-dominated, low-concentrated mAb formulations in compliance with modern manufacturing technology.
Primary containers made of cyclic olefin polymer (COP) have recently gained attention since they may overcome several risks and shortcomings of glass containers as they exhibit a high break resistance, biocompatibility, and homogeneous heat transfer during lyophilization. On the downside, COP is more permeable for gases, which can lead to an ingress of oxygen into the container over time. Since oxidation is an important degradation pathway for monoclonal antibodies (mAbs), the continuous migration of oxygen into drug product containers should be avoided overall. To date, no long-term stability studies regarding lyophilizates in polymer vials have been published, potentially because of the unbearable gas permeability. In this study, we demonstrate that after lyophilization in COP vials and storage of these vials in aluminum pouches together with combined oxygen and moisture absorbers (“smart packaging”), oxidation of two lyophilized therapeutic antibodies was as low as in glass vials due to the deoxygenated environment in the pouch. Nevertheless, active removal of oxygen from the primary container below the initial level over time during storage in such “smart” secondary packaging was not achieved. Furthermore, residual moisture was controlled. Overall, the smart packaging reveals a promising approach for long-term stability of biopharmaceuticals; in addition to COP’s known benefits, stable, low oxygen and moisture levels as well as the protection from light and cushioning against mechanical shock by the secondary packaging preserve the sensitive products very well.
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