Wu Zhouyi, Xu Gangling, He Wu, Yu Chuanfei, Huang Wanqiu, Zheng Shirui, Kang Dian, Xie Michael H, Cao Xingjun, Wang Lan, Wei Kaikun
Center for Drug Evaluation, National Medical Products Administration, Beijing 100022, China.
Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing 102629, China.
Antib Ther. 2023 Aug 4;6(3):194-210. doi: 10.1093/abt/tbad017. eCollection 2023 Jul.
High-producing cell line could improve the affordability and availability of biotherapeutic products. A post-approval production cell line change, low-titer CHO-K1S to high-titer CHO-K1SV GS-KO, was performed for a China marketed bevacizumab biosimilar IBI305. Currently, there is no regulatory guideline specifically addressing the requirements for comparability study of post-approval cell line change, which is generally regarded as the most complex process change for biological products. Following the quality by design principle and risk assessment, an extensive analytical characterization and three-way comparison was performed by using a panel of advanced analytical methods. Orthogonal and state-of-the-art techniques including nuclear magnetic resonance and high-resolution mass spectrometry were applied to mitigate the potential uncertainties of higher-order structures and to exclude any new sequence variants, scrambled disulfide bonds, glycan moiety and undesired process-related impurities such as host cell proteins. Nonclinical and clinical pharmacokinetics (PK) studies were conducted subsequently to further confirm the comparability. The results demonstrated that the post-change IBI305 was analytically comparable to the pre-change one and similar to the reference product in physicochemical and biological properties, as well as the degradation behaviors in accelerated stability and forced degradation studies. The comparability was further confirmed by comparable PK, pharmacodynamics, toxicological and immunogenicity profiles of nonclinical and clinical studies. The comparability strategy presented here might extend to cell line changes of other post-approval biological products, and particularly set a precedent in China for post-approval cell line change of commercialized biosimilars.
高产细胞系可提高生物治疗产品的可及性和可负担性。针对在中国上市的贝伐珠单抗生物类似药IBI305，进行了一次批准后生产细胞系变更，即从低滴度的CHO-K1S变更为高滴度的CHO-K1SV GS-KO。目前，尚无专门针对批准后细胞系变更可比性研究要求的监管指南，而批准后细胞系变更通常被认为是生物制品最复杂的工艺变更。遵循质量源于设计原则和风险评估，采用一系列先进分析方法进行了广泛的分析表征和三方比较。应用了包括核磁共振和高分辨率质谱在内的正交及先进技术，以减轻高阶结构的潜在不确定性，并排除任何新的序列变体、混乱的二硫键、聚糖部分以及不期望的与工艺相关的杂质，如宿主细胞蛋白。随后进行了非临床和临床药代动力学（PK）研究，以进一步确认可比性。结果表明，变更后的IBI305在分析上与变更前的产品具有可比性，在理化和生物学性质以及加速稳定性和强制降解研究中的降解行为方面与参比产品相似。非临床和临床研究中可比的PK、药效学、毒理学和免疫原性概况进一步证实了可比性。本文提出的可比性策略可能适用于其他批准后生物制品的细胞系变更，尤其在中国为商业化生物类似药的批准后细胞系变更树立了先例。
