Van Bockstal Pieter-Jan, Mortier Séverine Thérèse F C, De Meyer Laurens, Corver Jos, Vervaet Chris, Nopens Ingmar, De Beer Thomas
Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; BIOMATH, Department of Mathematical Modelling, Statistics and Bioinformatics, Faculty of Bioscience Engingeering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.
Eur J Pharm Biopharm. 2017 May;114:11-21. doi: 10.1016/j.ejpb.2017.01.001. Epub 2017 Jan 12.
Conventional pharmaceutical freeze-drying is an inefficient and expensive batch-wise process, associated with several disadvantages leading to an uncontrolled end product variability. The proposed continuous alternative, based on spinning the vials during freezing and on optimal energy supply during drying, strongly increases process efficiency and improves product quality (uniformity). The heat transfer during continuous drying of the spin frozen vials is provided via non-contact infrared (IR) radiation. The energy transfer to the spin frozen vials should be optimised to maximise the drying efficiency while avoiding cake collapse. Therefore, a mechanistic model was developed which allows computing the optimal, dynamic IR heater temperature in function of the primary drying progress and which, hence, also allows predicting the primary drying endpoint based on the applied dynamic IR heater temperature. The model was validated by drying spin frozen vials containing the model formulation (3.9mL in 10R vials) according to the computed IR heater temperature profile. In total, 6 validation experiments were conducted. The primary drying endpoint was experimentally determined via in-line near-infrared (NIR) spectroscopy and compared with the endpoint predicted by the model (50min). The mean ratio of the experimental drying time to the predicted value was 0.91, indicating a good agreement between the model predictions and the experimental data. The end product had an elegant product appearance (visual inspection) and an acceptable residual moisture content (Karl Fischer).
传统的药物冷冻干燥是一种低效且昂贵的分批过程，存在诸多缺点，导致最终产品的变异性无法控制。所提出的连续替代方法，基于在冷冻过程中旋转小瓶以及在干燥过程中提供最佳能量供应，极大地提高了过程效率并改善了产品质量（均匀性）。旋转冷冻小瓶连续干燥过程中的热传递是通过非接触式红外（IR）辐射实现的。应优化向旋转冷冻小瓶的能量传递，以在避免冻块塌陷的同时最大化干燥效率。因此，开发了一个机理模型，该模型能够根据一次干燥进程计算最佳动态红外加热器温度，进而也能够基于所应用的动态红外加热器温度预测一次干燥终点。通过按照计算出的红外加热器温度曲线干燥含有模型配方（10R小瓶中3.9mL）的旋转冷冻小瓶对该模型进行了验证。总共进行了6次验证实验。通过在线近红外（NIR）光谱法实验确定了一次干燥终点，并与模型预测的终点（50分钟）进行了比较。实验干燥时间与预测值的平均比值为0.91，表明模型预测与实验数据之间具有良好的一致性。最终产品具有良好的外观（目视检查）和可接受的残留水分含量（卡尔费休法）。
