Esfandiary Reza, Gattu Shravan K, Stewart John M, Patel Sajal M
Department of Formulation Sciences, Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland 20878.
Department of Formulation Sciences, Biopharmaceutical Development, MedImmune, Gaithersburg, Maryland 20878.
J Pharm Sci. 2016 Apr;105(4):1427-33. doi: 10.1016/j.xphs.2016.02.003.
This study highlights the significance of the freezing step and the critical role it can play in modulating process performance and product quality during freeze-drying. For the model protein formulation evaluated, the mechanism of freezing had a significant impact on cake appearance, a potential critical product quality attribute for a lyophilized drug product. Contrary to common knowledge, a freezing step with annealing resulted in 20% increase in primary drying time compared to without annealing. In addition, annealing resulted in poor cake appearance with shrinkage, cracks, and formation of a distinct skin at the top surface of the cake. Finally, higher product resistance (7.5 cm(2).Torr.hr/g) was observed in the case of annealing compared to when annealing was not included (5 cm(2).Torr.hr/g), which explains the longer primary drying time due to reduced sublimation rates. An alternative freezing option using controlled ice nucleation resulted in reduced primary drying time (i.e., 30% reduction compared to annealing) and a more homogenous batch with elegant uniform (i.e., significantly improved) cake appearance. Here, a mechanistic understanding of the distinct differences in cake appearance as a function of freezing mechanism is proposed within the context of ice nucleation temperature, ice crystal growth, and presumed solute distribution within the frozen matrix.
本研究强调了冷冻步骤的重要性及其在冷冻干燥过程中对调节工艺性能和产品质量所起的关键作用。对于所评估的模型蛋白质制剂，冷冻机制对冻干药品潜在的关键产品质量属性——饼状外观有显著影响。与常识相反，与未进行退火的冷冻步骤相比，进行退火的冷冻步骤使一次干燥时间增加了20%。此外，退火导致饼状外观不佳，出现收缩、裂缝以及在饼的顶面形成明显的表皮。最后，与未进行退火（5 cm²·Torr·hr/g）相比，进行退火时观察到更高的产品阻力（7.5 cm²·Torr·hr/g），这解释了由于升华速率降低导致一次干燥时间更长的原因。使用受控冰核化的另一种冷冻方法可缩短一次干燥时间（即与退火相比减少30%），并得到批次更均匀、外观优雅一致（即显著改善）的饼状外观。在此，在冰核化温度、冰晶生长以及冷冻基质中假定的溶质分布的背景下，提出了对作为冷冻机制函数的饼状外观明显差异的机理理解。
