生物制药
设计质量
关键质量属性
计算机科学
水准点(测量)
药物发现
过程(计算)
结合
质量(理念)
亲水作用色谱法
组合化学
化学
生化工程
色谱法
数学
高效液相色谱法
工程类
生物技术
物理化学
哲学
认识论
粒径
生物
生物化学
地理
数学分析
操作系统
大地测量学
作者
Sebastian Andris,Jürgen Hubbuch
标识
DOI:10.1016/j.jbiotec.2020.04.018
摘要
Antibody-drug conjugates (ADCs) are hybrid molecules based on monoclonal antibodies (mAbs) with covalently attached cytotoxic small-molecule drugs. Due to their potential for targeted cancer therapy, they form part of the diversifying pipeline of various biopharmaceutical companies, in addition to currently seven commercial ADCs. With other new modalities, ADCs contribute to the increasing complexity of biopharmaceutical development in times of growing costs and competition. Another challenge is the implementation of quality by design (QbD), which receives a lot of attention. In order to answer these challenges, mechanistic models are gaining interest as tools for enhanced process understanding and efficient process development. The drug-to-antibody ratio (DAR) is a critical quality attribute (CQA) of ADCs. After the conjugation reaction, the DAR can still be adjusted by including a hydrophobic interaction chromatography (HIC) step. In this work, we developed a mechanistic model for the preparative separation of cysteine-engineered mAbs with different degrees of conjugation with a non-toxic surrogate drug. The model was successfully validated for varying load compositions with linear and optimized step gradient runs, applying conditions differing from the calibration runs. In two in silico studies, we then present scenarios for how the model can be applied profitably to ensure a more robust achievement of the target DAR and for the efficient characterization of the design space. For this, we also used the model in a linkage study with a kinetic reaction model developed by us previously. The combination of the two models effectively widens system boundaries over two adjacent process steps. We believe this work has great potential to help advance the incorporation of digital tools based on mechanistic models in ADC process development by illustrating their capabilities for efficient process development and increased robustness. Mechanistic models can support the implementation of QbD and eventually might be the basis for digital process twins able to represent multiple unit operations.
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