Optimizing lyophilization primary drying: A vaccine case study with experimental and modeling techniques

In this study, we present the lyophilization process development efforts for a vaccine formulation aimed at optimizing the primary drying time (hence, the total cycle length) through comprehensive evaluation of its thermal characteristics, temperature profile, and critical quality attributes (CQAs). Differential scanning calorimetry (DSC) and freeze-drying microscopy (FDM) were used to experimentally determine the product-critical temperatures, viz., the glass transition temperature (T_g') and the collapse temperature (T_c). Initial lyophilization studies indicated that the conventional approach of targeting product temperature (T_p) below the T_c (determined from FDM) resulted in long and sub-optimal drying times. Interestingly, aggressive drying conditions where the product temperature reached the total collapse temperature did not result in macroscopic collapse but, instead, reduced the drying time by ∼ 45 % while maintaining product quality requirements. This observation suggests the need for a more reliable measurement of the macroscopic collapse temperature for product in vials. The temperature profiles from different lyophilization runs showed a drop in product temperature following the primary drying ramp, of which the magnitude was correlated to the degree of macroscopic collapse. The batch-average product resistance, R_p, determined using the manometric temperature measurement (MTM), decreased with increasing dried layer thickness for aggressive primary drying conditions. A quantitative analysis of the product temperature and resistance profiles combined with qualitative assessment of cake appearance attributes was used to determine a more representative macro-collapse temperature, T_cm, for this vaccine product. A primary drying design space was generated using first principles modeling of heat and mass transfer to enable selection of optimum process parameters and reduce the number of exploratory lyophilization runs. Overall, the study highlights the importance of accurate determination of macroscopic collapse in vials, pursuing aggressive drying based on individual product characteristics, and leveraging experimental and modeling techniques for process optimization.