Category: Manufacturing and Bioprocessing
Purpose: Innovative process analytical technology (PAT) tools provide numerous benefits to the development of a freeze drying cycle, such as precise monitoring of the process and non-invasive determination of critical product parameters. Entirely in line with the Quality by Design (QbD) philosophy, PAT tools not only enable reliable and reproducible cycle performance but also facilitate successful cycle transfer between different freeze dryers and scale.
This presentation gives insights into the benefits and challenges of Manometric Temperature Measurement (MTM) in miniaturized equipment (LyoCapsule™) with the objective to implement this PAT tool complementary in a small scale of seven vials for optimum data comparability. For a sound understanding of the drying behavior, differences in heat transfer characteristics between the mini-freeze dryer and standard laboratory equipment were quantitatively assessed.
Methods: MTM-SMART™ cycle design is illustrated for several formulations using different wall temperature adjustments. The freeze drying behavior and product characteristics of an amorphous formulation during primary drying were studied. Based on these studies and the comprehensive characterization of heat transfer coefficients as a function of chamber pressure and wall temperature setting, a systematic cycle development approach supported by innovative PAT tools in the mini-freeze dryer is presented.
Results: Calculated product temperatures were similar for all different wall temperature settings during the MTM-SMART™ runs and in good agreement with the temperatures measured by thermocouples (Fig. 1). Product resistance profiles showed uniformity in all the runs conducted in the mini-freeze dryer, but absolute values were slightly lower compared to values determined by MTM in the larger laboratory-scale freeze dryer (Fig. 2). The resulting cakes exhibited homogeneous pore structures, residual moisture content and optical appearance, and these characteristics were directly comparable to those obtained in the products of the larger freeze dryer. SMART™ cycle design and product attributes were reproducible and a minimum load of seven 10R vials was identified for accurate MTM values.
The determination of heat transfer coefficients showed that pressure-independent heat transfer into the vials is strongly influenced by the wall temperature setting. MTM-SMART™ runs and sublimation experiments suggested, that in case of the wall temperature following the product temperature of the center vial, heat transfer coefficients and product temperatures differ only slightly from those in a larger laboratory freeze dryer, particularly at low chamber pressure.
Conclusion: Differences in heat transfer characteristics in mini-freeze dryers, such as atypical drying conditions due to increased radiation effects, impede development of a process that can be easily transferred to larger scales. A comprehensive characterization of vial heat transfer coefficients using different chamber pressures and wall temperature settings revealed a pronounced impact of the wall temperature setting in this miniaturized system. Significantly increased radiation effects were recorded if wall temperature was deactivated or lowered to moderate values. In contrast, a strong reduction of the wall temperature to values equivalent to the product temperature of vials during sublimation led to heat transfer coefficients comparable to those in a larger laboratory-scale freeze dryer, with similar contribution of pressure-dependent and pressure-independent heat transfer mechanisms.
Besides the possibility to reflect the drying behavior of larger-scale equipment through adjustment of the wall temperature setting, systematic cycle development and scale-up is supported by innovative PAT tools. The present study confirms the general applicability of MTM-SMART™ as judged by a reasonable, reproducible cycle development and accurate determination of relevant process and product parameters, such as the product temperature and the sublimation rate. Under consideration of the minimum load requirement of seven 10R vials and a regular testing of the leak rate, this PAT tool can be used in the mini-freeze dryer irrespective of the wall temperature setting for substantial time and resource savings during early development and optimum data comparability during scale-up to larger equipment.