Pharmaceutical Technology and Biopharmaceutics, Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
Technical Research and Development, Novartis Pharma AG, 4002 Basel, Switzerland.
Eur J Pharm Biopharm. 2024 Oct;203:114418. doi: 10.1016/j.ejpb.2024.114418. Epub 2024 Jul 28.
Silicone oil (SO) migration into the drug product of combination products for biopharmaceuticals during storage is a common challenge. As the inner barrel surface is depleted of SO the extrusion forces can increase compromising the container functionality. In this context we investigated the impact of different formulations on the increase in gliding forces in a spray-on siliconized pre-filled syringe upon storage at 2-8 °C, 25 °C and 40 °C for up to 6 months. We tested the formulation factors such as surfactant type, pH, and ionic strength in the presence of one monoclonal antibody (mAb) as well as compared three mAbs in one formulation. After 1 month at 40 °C, the extrusion forces were significantly increased due to SO detachment dependent on the fill medium. The storage at 40 °C enhanced the SO migration process but it could also be observed at lower storage temperatures. Regarding the formulation factors the tendency for SO migration was predominantly dependent on the presence and type of surfactant. Interestingly, when varying the mAb molecules, one of the proteins showed a rather stabilizing effect on the SO layer resulting into higher container stability. In contrast to the formulation factors, those different stability outcomes could not be explained by interfacial tension (IFT) measurements at the SO interface. Further characterization of the mAb molecules regarding interfacial rheology and conformational stability were not adequately able to explain the observed difference. Solely a hydrophobicity ranking of the molecules correlated to the stability outcome. Further investigations are needed to clarify the role of the protein in the SO detachment process and to understand the cause for the stabilization. However, the study clearly demonstrated that the protein itself plays a critical role in the SO detachment process and underlined the importance to include verum for container stability.
硅油 (SO) 在储存过程中向生物制药组合产品药物制剂中的迁移是一个常见的挑战。由于内筒表面的 SO 耗尽，挤出力会增加，从而影响容器的功能。在这种情况下，我们研究了不同配方在储存于 2-8°C、25°C 和 40°C 长达 6 个月时对喷雾硅化预充注射器中滑动力增加的影响。我们测试了配方因素，如表面活性剂类型、pH 值和离子强度，以及在存在一种单克隆抗体 (mAb) 的情况下以及在一种配方中比较三种 mAb 的情况下。在 40°C 储存 1 个月后，由于填充介质的 SO 脱落，挤出力显著增加。在 40°C 下储存会加速 SO 迁移过程，但也可以在较低的储存温度下观察到。关于配方因素，SO 迁移的趋势主要取决于表面活性剂的存在和类型。有趣的是，当改变 mAb 分子时，其中一种蛋白质对 SO 层表现出相当稳定的作用，从而使容器更稳定。与配方因素不同，这些不同的稳定性结果不能用 SO 界面的界面张力 (IFT) 测量来解释。进一步对 mAb 分子的界面流变学和构象稳定性进行表征，也无法充分解释观察到的差异。仅分子的疏水性排序与稳定性结果相关。需要进一步的研究来阐明蛋白质在 SO 脱落过程中的作用，并了解稳定的原因。然而，该研究清楚地表明，蛋白质本身在 SO 脱落过程中起着关键作用，并强调了在容器稳定性研究中包含真实药物的重要性。
