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

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 Ti should be kept below the critical product temperature Ti,crit during primary drying. The static temperature sensors applied in batch freeze-drying provide unreliable Ti 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 Ti 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 Ti 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 ( Rp) 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.