Purpose

Small-scale models that simulate large-scale freezing of bulk drug substance of biopharmaceuticals are highly needed to define freezing and formulation parameters based on process understanding. We evaluated a novel scale-down device (SDD), which is based on a specially designed insulation cover, with respect to changes in concentration after freezing, referred to as cryoconcentration, and 3D temperature profiles. Furthermore, the effect of the initial monoclonal antibody (mAb) concentration on cryoconcentration was addressed.

Methods

2 L and 125 mL bottles were utilized. Temperatures were mapped using type T thermocouples. Frozen blocks were cut and mAb and histidine concentrations were analysed by HPLC. In addition, concentration- and temperature-dependent viscosities were measured.

Results

3D freezing profiles in the SDD were comparable to large-scale bottles. The SDD accurately predicted cryoconcentration of both mAb and histidine of large-scale freezing. Concentric changes in concentration were evident as well as an unforeseen diluted core at the last point to freeze. At low initial mAb concentration cryoconcentration was substantial, while high initial mAb concentration suppressed cryoconcentration almost completely.

Conclusion

The novel SDD gives detailed insights into large-scale freezing of mAb solutions using only a fraction of the simulated volume. It is a promising material- and cost-saving tool to understand large-scale freezing processes.

中文翻译：

---

大型PET瓶和新颖的按比例缩小设备中mAb溶液冷冻期间的低温浓度和3D温度曲线。

目的

高度需要模拟大规模生物制药原料药冻结的小规模模型，以基于过程理解来定义冻结和配方参数。我们评估了一种新颖的按比例缩小装置（SDD），该装置基于专门设计的隔热盖，涉及冷冻后的浓度变化（称为低温浓缩）和3D温度曲线。此外，解决了初始单克隆抗体（mAb）浓度对冷冻浓度的影响。

方法

使用2升和125毫升瓶。使用T型热电偶绘制温度图。切下冷冻的块，并通过HPLC分析mAb和组氨酸的浓度。此外，还测量了浓度和温度相关的粘度。

结果

SDD中的3D冻结曲线可与大型瓶子媲美。SDD可以准确预测大规模冷冻中mAb和组氨酸的冷冻浓度。浓度的同心变化明显，并且在冻结的最后一点出现了无法预料的稀释核心。在较低的初始mAb浓度下，冷冻浓度很高，而较高的初始mAb浓度则几乎完全抑制了冷冻浓度。

结论

新颖的SDD仅使用模拟体积的一小部分即可对mAb溶液的大规模冷冻提供详细的见解。它是了解大规模冷冻过程的一种有希望的节省材料和成本的工具。