Thermal Imaging as a Noncontact Inline Process Analytical Tool for Product Temperature Monitoring during Continuous Freeze-Drying of Unit Doses

Abstract

Freeze-drying is a well-established technique to improve the stability of biopharmaceuticals which are unstable in aqueous solution. To obtain an elegant dried product appearance, the temperature at the moving sublimation interface T_i should be kept below the critical product temperature T_i,crit during primary drying. The static temperature sensors applied in batch freeze-drying provide unreliable T_i data due to their invasive character. In addition, these sensors are incompatible with the continuous freeze-drying concept based on spinning of the vials during freezing, leading to a thin product layer spread over the entire inner vial wall. During continuous freeze-drying, the sublimation front moves from the inner side of the vial toward the glass wall, offering the unique opportunity to monitor T_i via noncontact inline thermal imaging. Via Fourier's law of thermal conduction, the temperature gradient over the vial wall and ice layer was quantified, which allowed the exact measurement of T_i during the entire primary drying step. On the basis of the obtained thermal images, the infrared (IR) energy transfer was computed via the Stefan-Boltzmann law and the dried product mass transfer resistance ( R_p) profile was obtained. This procedure allows the determination of the optimal dynamic IR heater temperature profile for the continuous freeze-drying of any product. In addition, the end point of primary drying was detected via thermal imaging and confirmed by inline near-infrared (NIR) spectroscopy. Both applications show that thermal imaging is a suitable and promising process analytical tool for noninvasive temperature measurements during continuous freeze-drying, with the potential for inline process monitoring and control.