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The Importance of Heat Flow Direction for Reproducible and Homogeneous Freezing of Bulk Protein Solutions

机译：热流向对大体积蛋白质溶液的可复制和均质冷冻的重要性

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Freezing is an important operation in biotherapeutics industry. However, water crystallization in solution, containing electrolytes, sugars and proteins, is difficult to control and usually leads to substantial spatial solute heterogeneity. Herein, we address the influence of the geometry of freezing direction (axial or radial) on the heterogeneity of the frozen matrix, in terms of local concentration of solutes and thermal history. Solutions of hemoglobin were frozen radially and axially using small-scale and pilot-scale freezing systems. Concentration of hemoglobin, sucrose and pH values were measured by ice-core sampling and temperature profiles were measured at several locations. The results showed that natural convection is the major source for the cryoconcentration heterogeneity of solutes over the geometry of the container. A significant improvement in this spatial heterogeneity was observed when the freezing geometry was nonconvective, i.e., the freezing front progression was unidirectional from bottom to top. Using this geometry, less than 10% variation in solutes concentration was obtained throughout the frozen solutions. This result was reproducible, even when the volume was increased by two orders of magnitude (from 30 mL to 3 L). The temperature profiles obtained for the nonconvective freezing geometry were predicted using a relatively simple computational fluid dynamics model. The reproducible solutes distribution, predictable temperature profiles, and scalability demonstrate that the bottom to top freezing geometry enables an extended control over the freezing process. This geometry has therefore shown the potential to contribute to a better understanding and control of the risks inherent to frozen storage.
机译：冷冻是生物治疗工业中的重要操作。但是，含有电解质，糖和蛋白质的溶液中的水结晶难以控制，通常会导致大量的空间溶质异质性。在本文中，我们从溶质的局部浓度和热历史的角度探讨了冻结方向（轴向或径向）几何形状对冻结基质异质性的影响。使用小规模和中试规模的冷冻系统将血红蛋白溶液径向和轴向冷冻。通过冰芯取样测量血红蛋白，蔗糖的浓度和pH值，并在几个位置测量温度曲线。结果表明，自然对流是溶质在容器几何形状上低温浓缩异质性的主要来源。当冻结几何形状是非对流的时，即从底部到顶部，冻结锋的进展是单向的时，可以观察到这种空间异质性的显着改善。使用这种几何形状，在整个冷冻溶液中溶质浓度的变化小于10％。即使体积增加了两个数量级（从30 mL到3 L），该结果也是可重现的。使用相对简单的计算流体动力学模型预测了非对流冻结几何形状获得的温度曲线。可重现的溶质分布，可预测的温度曲线和可扩展性证明，从底部到顶部的冷冻几何形状可以扩展对冷冻过程的控制。因此，这种几何形状显示了潜在的潜力，可有助于更好地理解和控制冷冻存储所固有的风险。

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