The development of a continuous and controlled freeze-drying concept for biopharmaceutical unit doses

Freeze-drying is a well-established formulation technique to improve the stability of biopharmaceuticals which are unstable in aqueous solution. Conventional pharmaceutical freeze-drying is a batch-wise process during which all vials are processed through a sequence of consecutive steps, i.e., freezing, primary drying and secondary drying, until the dried end product is obtained. However, this inefficient batch approach is inherently associated with several disadvantages, leading to an uncontrolled variability in product quality, which goes against the guidelines issued by the regulatory authorities. Therefore, the main objective of this thesis was to develop and evaluate a continuous and controlled freeze-drying concept for pharmaceutical unit doses, resolving the disadvantages related to the current state-of-the-art batch process

Impact of vacuum-induced surface freezing on inter- and intra-vial heterogeneity

This paper aims to study the impact of freezing on both within-batch (inter-vial) and within- product (intra-vial) heterogeneity. This analysis has been carried out using two freezing protocols, the conventional shelf-ramped method and the Vacuum Induced Surface Freezing, and placebo formulations containing both crystallizing (mannitol) and amorphous (lactose and sucrose) excipients. The freezing conditions (i.e., the temperature of freezing, the temperature and time of the equilibration phase, and the filling volume) were found to have a dramatic impact on both the within-batch and the within-product homogeneity. Overall, we observed that the control of freezing can effectively minimize the variability in product characteristics, and moisture content, within the same batch. In addition to more uniform production, the control of freezing was found to be fundamental to achieve a more uniform product than that produced by the shelf-ramped freezing method. The influence of the freezing protocol on the crystallization process of mannitol was also investigated, showing that the temperature of freezing plays a key role in the formation of the mannitol polymorphs

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 T-i should be kept below the critical product temperature T-i,T-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 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