Coriolis Pharma Research GmbH, Fraunhoferstr, 18b, 82152 Martinsried, Munich, Germany.
Division of Drug Delivery Technology, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, PO Box 9502, 2300, RA, Leiden, The Netherlands.
Pharm Res. 2017 Dec;34(12):2910-2921. doi: 10.1007/s11095-017-2274-4. Epub 2017 Oct 24.
To investigate the effect of nanoparticulate impurities (NPIs) isolated from pharmaceutical-grade sucrose, on the stability of monoclonal antibodies (mAbs).
NPIs were purified from pharmaceutical-grade sucrose and spiked into trastuzumab, rituximab, infliximab, and cetuximab formulations. The stability of the mAbs as a function of storage time, temperature, and NPI concentration was assessed by visual inspection, flow-imaging microscopy, nanoparticle tracking analysis, size-exclusion chromatography, capillary isoelectric focusing, and intrinsic differential scanning fluorimetry.
NPIs negatively affected the stability of all mAbs, albeit it to different extents. After spiking with NPIs, trastuzumab formulations showed high numbers of μm-sized particles and turbidity, rituximab and cetuximab formulations contained high numbers of nm-sized particles, while infliximab formed nm- and μm-sized particles, and showed turbidity. Low-molecular-weight species were observed for rituximab and infliximab, whereas high-molecular-weight species were detected for cetuximab. Whereas the stability of trastuzumab and infliximab formulations was affected directly after spiking NPIs, degradation of rituximab and cetuximab was observed only after 14 weeks at elevated temperatures. Moreover, the stability of rituximab and infliximab was affected by NPI concentrations that are potentially present in final drug products.
The presence of sucrose-derived NPIs in (bio-)pharmaceutical formulations may pose a threat to the stability of mAbs.
研究从制药级蔗糖中分离出的纳米颗粒杂质（NPIs）对单克隆抗体（mAbs）稳定性的影响。
从制药级蔗糖中纯化 NPIs 并将其掺入曲妥珠单抗、利妥昔单抗、英夫利昔单抗和西妥昔单抗制剂中。通过目视检查、流成像显微镜、纳米颗粒跟踪分析、尺寸排阻色谱、毛细管等电聚焦和内禀差示扫描荧光法评估 mAbs 随储存时间、温度和 NPI 浓度的稳定性。
NPIs 对所有 mAbs 的稳定性都产生了负面影响，尽管影响程度不同。NPIs 掺入后，曲妥珠单抗制剂表现出大量 μm 大小的颗粒和浑浊度，利妥昔单抗和西妥昔单抗制剂含有大量 nm 大小的颗粒，而英夫利昔单抗形成 nm 和 μm 大小的颗粒，并表现出浑浊度。利妥昔单抗和英夫利昔单抗观察到低分子量物质，而西妥昔单抗则检测到高分子量物质。曲妥珠单抗和英夫利昔单抗制剂的稳定性在直接掺入 NPIs 后受到影响，而利妥昔单抗和西妥昔单抗的降解仅在高温下 14 周后才观察到。此外，利妥昔单抗和英夫利昔单抗的稳定性受到潜在存在于最终药物产品中的 NPI 浓度的影响。
（生物）制药制剂中存在蔗糖衍生的 NPIs 可能对 mAbs 的稳定性构成威胁。
