Abstract：
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 (Tg\') and the collapse temperature (Tc). Initial lyophilization studies indicated that the conventional approach of targeting product temperature (Tp) below the Tc (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, Rp, 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, Tcm, 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.
摘要：
在这项研究中,我们介绍了旨在优化初级干燥时间的疫苗制剂的冻干工艺开发工作(因此，总循环长度)通过综合评估其热特性，温度曲线,和关键质量属性(CQA)。差示扫描量热法（DSC）和冷冻干燥显微镜（FDM）用于实验确定产品的临界温度，viz.,玻璃化转变温度(Tg')和塌陷温度(Tc)。初始冻干研究表明,靶向产物温度(Tp)低于Tc(由FDM确定)的常规方法导致长的和次优的干燥时间。有趣的是,产品温度达到总塌陷温度的剧烈干燥条件不会导致宏观塌陷，但是，相反，将干燥时间减少45%，同时保持产品质量要求。该观察表明需要更可靠地测量小瓶中产品的宏观塌陷温度。来自不同冻干运行的温度曲线显示在初级干燥斜坡之后产品温度下降,其大小与宏观崩溃的程度相关。批量平均产品电阻，Rp,使用测压温度测量(MTM)确定，在激进的初级干燥条件下，随着干燥层厚度的增加而减少。对产品温度和电阻曲线进行定量分析，并结合对蛋糕外观属性的定性评估，以确定更具代表性的宏观塌陷温度，Tcm,这种疫苗产品。使用传热和传质的第一原理建模生成初级干燥设计空间,以使得能够选择最佳工艺参数并减少探索性冻干运行的数量。总的来说,该研究强调了准确确定小瓶中宏观塌陷的重要性，追求基于单个产品特性的激进干燥，并利用实验和建模技术进行工艺优化。
