对2016年至2020年之间批准的93种治疗性蛋白质的生物许可申请(BLA)进行了分析,以使用质谱(MS)作为先前研究的后续研究,该研究评估了2000年至2015年在BLA中使用MS的情况。这些BLAs中有30%是生物仿制药,而在2016年之前,只有一种生物类似药BLA获得批准。该分析评估了各种MS技术和仪器的使用。根据MS使用随时间的关系进一步解释结果,在药物类型之间,在新药和生物仿制药之间。MS数据包括在所检查的93个BLAs中。按等级排序,MS评估最多的前8个质量属性是氨基酸序列,分子量,氧化,二硫键,脱酰胺,糖基化,N端序列变体,和C端序列变体。这些属性与以前从2000年至2015年批准的BLAs中看到的最高属性相同,并且使用MS分析它们通常在新的时间框架内继续增加。在21年的延长时间范围内,每个BLAMS分析的平均属性数也继续增加。高分辨率,精确的质量仪器,如Orbitrap和飞行时间(TOF)的使用随着时间的推移而增加,所有评估的属性,而基质辅助激光解吸/电离(MALDI)-TOF/(TOF)使用率下降。从最高等级到最低等级,前11个属性是抗体药物缀合物(ADC)表征(即,载药量分布/药物抗体比(DAR),ADC和链接站点,和合成接头),异构化,折叠/高阶结构(HOS),截断,宿主细胞蛋白(HCP),序列变异(氨基酸取代),琥珀酰亚胺,糖化,聚乙二醇化,电荷变体,和氧化。
Biologic license applications (BLAs) for 93 therapeutic proteins approved between 2016 and 2020 were analyzed for use of mass spectrometry (MS) as a follow up to a previous study that assessed MS use in BLAs from 2000 to 2015. Thirty percent of these BLAs were biosimilars, while only one biosimilar BLA was approved prior to 2016. This analysis evaluated the use of a variety of MS techniques and instrumentation. Results were further interpreted based on the relationship of MS use over time, between drug types, and between new drugs and biosimilars. MS data were included in 93 BLAs examined. The top eight quality attributes most assessed by MS in rank order were amino acid sequence, molecular mass, oxidation, disulfide bonds, deamidation, glycosylation, N-terminal sequence variants, and C-terminal sequence variants. These attributes were the same top attributes seen previously from BLAs approved between 2000 and 2015, and the use of MS to analyze them generally continued to increase across the new time frame. The average number of attributes analyzed by MS per BLA also continued to increase over the extended time frame of 21 years. High-resolution, accurate mass instrumentation such as the Orbitrap and time-of-flight (TOF) usage increased over time for all assessed attributes, while matrix-assisted laser desorption/ionization (MALDI)-TOF/(TOF) usage decreased. From highest to lowest rank, the top 11 attributes were antibody drug conjugate (ADC) characterization (i.e., drug load distribution/drug to antibody ratio (DAR), ADC and linkage site, and synthetic linker), isomerization, folding/higher-order structure (HOS), truncation, host cell proteins (HCPs), sequence variants (amino acid substitutions), succinimidation, glycation, PEGylation, charge variants, and oxidation.