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In order to overcome the downside of long conventional freeze-drying (CFD) process times for monoclonal antibody formulations, microwave-assisted freeze-drying (MFD) was introduced. Recently, the general applicability and potential shortening of drying times were shown. However, little is known about the storage stability of MFD products compared to CFD references. Additionally, batch homogeneity issues were seen within MFD in the past. In this study, we examined four different formulations of two different monoclonal antibodies using three different glass-forming excipients: sucrose, trehalose, and arginine phosphate. These formulations were freeze-dried with two different drying protocols (CFD and MFD), stored for 24 weeks, and analyzed for solid-state and protein-related quality attributes. Moreover, a new microwave generator setup was investigated for its potential to improve batch homogeneity. In all investigated formulations, comparable stability profiles were found, although the classical magnetron generator led to inferior batch homogeneity with respect to residual moisture distribution. In contrast, the new MFD setup indicated the potential to approximate batch homogeneity to the level of CFD. However, for future applications, there is an unabated need for new machine designs to comply with pharmaceutical manufacturing requirements.Pharmaceutics 2019, 11, 674 2 of 21 be frozen. In a second step, the drying itself takes place. In contrast to CFD, the main heat transfer mechanism is radiation rather than convection and conduction. Especially polar substances, e.g., water, sugars, and amino acids, show good absorption of electromagnetic waves of wavelengths of 12.2 cm and frequencies of 2.45 GHz [15,16]. In brief, the heating mechanism in pharmaceutics occurs due to dipolar and ionic mechanisms. When such a polar compound is placed in an oscillating field, dipoles or ions try to realign in the direction of the electric field. Due to the ultra-rapid change in the direction of the electric field, internal friction of the molecules is caused, leading to heating within the material, i.e., volumetric heating. In the case of ions, a charge-driven migration is discussed [16][17][18]. MFD has clear advantages over conventional drying processes, like significantly shorter process times [19,20], and in the field of food processing, in the maintenance of shape, color, taste, odor, and texture [14,[21][22][23]. In the transition area between food and pharmaceutical technology, MFD was used for the gentle drying of bacteria suspensions. Ambros et al. [19] investigated the survival rate and viability of different bacterial cultures. They found comparable survival rates of the investigated cultures produced by MFD compared to conventional freeze-drying but were able to shorten process times by up to 80%. The first usage in pharmaceutical freeze-drying was presented by Evans et al. [24] at the CPPR Freeze Drying of Pharmaceuticals & Biologics Conference in 2014, showing the general applicability to monoclonal antibodies a...

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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.