The peptide coupling reaction is one of the most critical steps in the solid phase synthesis of therapeutic peptides/proteins. Improper reaction conditions can result in several common impurities such as single amino acid deletions, additions, N‐terminus modifications, and D‐isomers, all while potentially impacting the active pharmaceutical ingredient critical quality attributes. In this work, we developed a first‐principle mechanistic reaction kinetics model for the solid‐phase peptide/protein coupling reaction based on well‐established reaction mechanisms and experimental data from literature. Utilizing the reaction kinetics model, we present a systematic, quality by design approach for the coupling reaction control strategy. Critical process parameters are identified via univariate analysis and the design space is designated via multivariate risk assessment. The presented approach provides a novel solution for designing solid‐phase peptide/protein synthesis control strategies and identifying normal operating ranges for each process parameter, as well as the associated design space.

中文翻译：

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通过机械反应动力学建模方法设计固相肽/蛋白质偶联反应的质量

肽偶联反应是治疗性肽/蛋白质固相合成中最关键的步骤之一。不正确的反应条件可能会导致几种常见的杂质，例如单个氨基酸缺失、添加、N 末端修饰和 D 异构体，同时可能影响活性药物成分的关键质量属性。在这项工作中，我们基于成熟的反应机制和文献中的实验数据，开发了固相肽/蛋白质偶联反应的第一原理反应动力学模型。利用反应动力学模型，我们提出了一种系统的、质量源于设计的耦合反应控制策略方法。通过单变量分析确定关键工艺参数，并通过多变量风险评估指定设计空间。所提出的方法为设计固相肽/蛋白质合成控制策略和确定每个工艺参数的正常操作范围以及相关的设计空间提供了一种新颖的解决方案。