Purpose

To evaluate a modified high purity polysorbate 20 (RO HP PS20)—with lower levels of stearate, palmitate and myristate esters than the non-modified HP PS20—as a surfactant in biopharmaceutical drug products (DP). RO HP PS20 was designed to provide functional equivalence as a surfactant while delaying the onset of free fatty acid (FFA) particle formation upon hydrolytic degradation relative to HP PS20.

Methods

Analytical characterization of RO HP PS20 raw material included fatty acid ester (FAE) distribution, higher order ester (HOE) fraction, FFA levels and trace metals. Functional assessments included 1) vial and intravenous bag agitation; 2) oxidation via a placebo and methionine surrogate study; and 3) hydrolytic PS20 degradation studies to evaluate FFA particle formation with and without metal nucleation.

Results

Interfacial protection and oxidation propensity were comparable between the two polysorbates. Upon hydrolytic degradation, FFA particle onset was delayed in RO HP PS20. The delay was more pronounced when HOEs of PS20 were preferentially degraded. Furthermore, the hydrolytic degradants of RO HP PS20 formed fewer particles in the presence of spiked aluminum.

Conclusion

This work highlights the criticality of having tighter control on long chain FAE levels of PS20 to reduce the occurrence of FFA particle formation upon hydrolytic degradation and lower the variability in its onset. By simultaneously meeting compendial PS20 specifications while narrowing the allowable range for each FAE and shifting its composition towards the shorter carbon chain species, RO HP PS20 provides a promising alternative to HP PS20 for biopharmaceutical DPs.

中文翻译：

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评估旨在降低游离脂肪酸颗粒形成风险的改性高纯度聚山梨醇酯 20

目的

评估改性的高纯度聚山梨醇酯 20 (RO HP PS20)——其硬脂酸酯、棕榈酸酯和肉豆蔻酸酯的含量低于未改性的 HP PS20——作为生物制药药品 (DP) 中的表面活性剂。RO HP PS20 旨在提供作为表面活性剂的功能等效性，同时相对于 HP PS20 在水解降解时延迟游离脂肪酸 (FFA) 颗粒的形成。

方法

RO HP PS20 原材料的分析表征包括脂肪酸酯 (FAE) 分布、高级酯 (HOE) 分数、FFA 水平和痕量金属。功能评估包括 1) 小瓶和静脉袋搅拌；2) 通过安慰剂和蛋氨酸替代研究进行氧化；3) 水解 PS20 降解研究，以评估有和没有金属成核的 FFA 颗粒形成。

结果

两种聚山梨醇酯之间的界面保护和氧化倾向相当。水解降解后，RO HP PS20 中的 FFA 颗粒开始延迟。当 PS20 的 HOE 优先降解时，延迟更为明显。此外，RO HP PS20 的水解降解物在添加铝的情况下形成的颗粒更少。

结论

这项工作强调了对 PS20 的长链 FAE 水平进行更严格控制的重要性，以减少水解降解时 FFA 颗粒形成的发生并降低其起始的可变性。通过同时满足药典 PS20 规范，同时缩小每种 FAE 的允许范围，并将其成分转向较短的碳链物种，RO HP PS20 为生物制药 DPs 提供了 HP PS20 的有希望的替代品。