The quality by design approach was introduced to the biopharmaceutical industry over 15 years ago. This principle is widely implemented in the characterization of monoclonal antibody production processes. Anyway, the early process phase, namely the inoculum expansion, was not yet investigated and characterized for most processes. In order to increase the understanding of early process parameter interactions and their influence on the later production process, a risk assessment followed by a design of experiments approach was conducted. The DoE included the critical parameters methotrexate (MTX) concentration, initial passage viable cell density and passage duration. Multivariate data analysis led to mathematical regression models and the establishment of a designated design space for the studied parameters. It was found that the passage duration as well as the initial viable cell density for each passage during the inoculum expansion have severe effects on the growth rate and viability of the early process phase. Furthermore, the variations during the inoculum expansion directly influenced the production process responses. This carry‐over of factor effects highlights the crucial impact of early process failures and the importance of process analysis and control during the first part of mAb production processes.

中文翻译：

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在 mAb 生产过程的接种量扩展中实施 QbD 策略


15 年前，生物制药行业就引入了质量源于设计的方法。这一原理广泛应用于单克隆抗体生产过程的表征中。无论如何，大多数过程的早期过程阶段，即接种物扩展，尚未被研究和表征。为了加深对早期工艺参数相互作用及其对后期生产工艺的影响的理解，进行了风险评估，然后进行了实验方法设计。 DoE 包括关键参数甲氨蝶呤 (MTX) 浓度、初始传代活细胞密度和传代持续时间。多元数据分析产生了数学回归模型，并为研究参数建立了指定的设计空间。研究发现，传代持续时间以及接种物扩增期间每次传代的初始活细胞密度对早期过程阶段的生长速率和活力有严重影响。此外，接种物扩增过程中的变化直接影响生产过程的响应。这种因素效应的延续凸显了早期工艺失败的关键影响以及单克隆抗体生产工艺第一部分中工艺分析和控制的重要性。