Department of Clinical Pharmacy, Division Laboratory and Pharmacy, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX, Utrecht, The Netherlands.
Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Pharm Res. 2018 Feb 5;35(2):42. doi: 10.1007/s11095-017-2341-x.
To measure aggregate and particle formation in tumor necrosis factor-alpha (TNF-α) inhibitors etanercept, adalimumab and certolizumab pegol product samples after exposure to freezing temperature conditions similar to storage conditions previously observed in patients' homes.
TNF-α inhibitors in their original primary and secondary packaging were exposed to 32 freeze-thaw cycles (-10°C for 120min/5°C for 60 min) or continuous low storage temperature (-20°C for 96 h) before thawing at 2-8°C. Non-stressed products were used as controls. The products were analyzed by high pressure size exclusion chromatography (HP-SEC), dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), micro-flow imaging (MFI) and second derivative ultraviolet (UV) spectroscopy.
Ten out of twenty-one stressed product samples (47.6%) showed increased particle numbers in the submicron and micron size range when compared to controls. For each product, DLS, MFI and NTA detected an increase in particle level in at least one stressed syringe (both continuous freezing and freeze-thaw), whereas HP-SEC and UV spectroscopy showed no differences between stressed and non-stressed products.
TNF-α inhibitors are relatively resistant to freezing temperatures similar to storage conditions previously observed in patients' homes. However, almost half of the stressed product samples showed formation of particles in the submicron and micron size range.
测量肿瘤坏死因子-α（TNF-α）抑制剂依那西普、阿达木单抗和培塞利珠单抗在产品样品经历类似于先前在患者家中观察到的储存条件的冷冻温度条件后，聚集物和颗粒形成情况。
TNF-α抑制剂在其原始的初级和次级包装中经历 32 次冻融循环（-10°C 持续 120min/5°C 持续 60min）或连续低温储存（-20°C 持续 96h），然后在 2-8°C 下解冻。未受压力的产品用作对照。通过高压尺寸排阻色谱法（HP-SEC）、动态光散射（DLS）、纳米颗粒跟踪分析（NTA）、微流成像（MFI）和二阶导数紫外（UV）光谱法对产品进行分析。
与对照相比，21 个受压力产品样品中的 10 个（47.6%）在亚微米和微米尺寸范围内显示出颗粒数量增加。对于每种产品，DLS、MFI 和 NTA 在至少一个受压力注射器中检测到颗粒水平的增加（连续冷冻和冻融），而 HP-SEC 和 UV 光谱法显示受压力和未受压力产品之间没有差异。
TNF-α抑制剂对类似于先前在患者家中观察到的储存条件的冷冻温度相对具有抗性。然而，几乎一半的受压力产品样品在亚微米和微米尺寸范围内显示出颗粒形成。
