Sun Min-Fei, Liao Jia-Ning, Jing Zhen-Yi, Gao Han, Shen Bin-Bin, Xu You-Fu, Fang Wei-Jie
Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Hangzhou Institute of Innovative Medicine, Zhejiang University, Hangzhou Biopharm Town, Hangzhou, 310016, China.
J Pharm Anal. 2022 Oct;12(5):774-782. doi: 10.1016/j.jpha.2022.03.003. Epub 2022 Mar 24.
Biopharmaceuticals are formulated using a variety of excipients to maintain their storage stability. However, some excipients are prone to degradation during repeated use and/or improper storage, and the impurities generated by their degradation are easily overlooked by end users and are usually not strictly monitored, affecting the stability of biopharmaceuticals. In this study, we evaluated the degradation profile of polyol excipient glycerol during repeated use and improper storage and identified an unprecedented cyclic ketal impurity using gas chromatography with mass spectrometry (GC-MS). The other polyol excipient, mannitol, was much more stable than glycerol. The effects of degraded glycerol and mannitol on the stability of the model biopharmaceutical pentapeptide, thymopentin, were also evaluated. The thymopentin content was only 66.4% in the thymopentin formulations with degraded glycerol, compared to 95.8% in other formulations after the stress test. Most glycerol impurities (i.e., aldehydes and ketones) reacted with thymopentin, affecting the stability of thymopentin formulations. In conclusion, this work suggests that more attention should be paid to the quality changes of excipients during repeated use and storage. Additional testing of excipient stability under real or accelerated conditions by manufacturers would help avoid unexpected and painful results.
生物制药制剂使用多种辅料来维持其储存稳定性。然而，一些辅料在反复使用和/或储存不当的情况下容易降解，其降解产生的杂质容易被终端用户忽视，且通常没有受到严格监测，从而影响生物制药的稳定性。在本研究中，我们评估了多元醇辅料甘油在反复使用和储存不当情况下的降解情况，并使用气相色谱-质谱联用仪（GC-MS）鉴定出一种前所未有的环状缩酮杂质。另一种多元醇辅料甘露醇比甘油稳定得多。我们还评估了降解的甘油和甘露醇对模型生物制药五肽胸腺五肽稳定性的影响。在加速试验后，含降解甘油的胸腺五肽制剂中胸腺五肽含量仅为66.4%，而其他制剂中为95.8%。大多数甘油杂质（即醛类和酮类）与胸腺五肽发生反应，影响胸腺五肽制剂的稳定性。总之，这项工作表明，在反复使用和储存过程中应更加关注辅料的质量变化。制造商在实际或加速条件下对辅料稳定性进行额外测试，将有助于避免意外和不良后果。
