Abstract QbD is considered an important, fundamental, and integral part of dosage form development. Despite its significance in drug formulations, the knowledge, reference, and guidance for using QbD in analytical science have not been thoroughly documented in the literature. The present study is aimed at bridging the gap between its generated data and the unexplored terrain in formulation science. This study is novel because, for the first time, an exclusive shorter run time UHPLC method for estimating degradation products was developed through the QbD approach, validated, and proved stability indicative. Five degradation impurities were separated and well characterized. Further, the degradation pathway of the anticancer drug nintedanib (NIN) was explored for the first time in the soft gel formulation using tandem quadrupole MS abetted mass identification, and ESI/MS/MS aided structure elucidation was performed. By carefully demonstrating the step-by-step procedure for QbD-based optimization, parameters such as the analytical target profile (ATP) and critical quality attributes (CQAs) were assessed. The risk assessment was performed using failure mode effect analysis (FMEA). Critical method attributes and critical method parameters were identified based on the magnitude of the calculated risk priority number (RPN) value. Designed experiments using 4-factor two-level factorial design monitored three critical quality attributes to arrive at a method operable design space (MODS). The effect of individual method attributes was also analyzed using half-normal and Pareto charts. Control strategies design and RPN values were recalculated based on the DOE output. This RPN value is eventually identified to be significantly smaller and satisfactory within the allowable limit.

中文翻译：

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QbD 介导的 RP-UPLC 方法开发调用基于 FMEA 的风险评估来估计尼达尼布降解产物及其途径

摘要 QbD 被认为是剂型开发的重要、基础和不可或缺的部分。尽管 QbD 在药物配方中具有重要意义，但在分析科学中使用 QbD 的知识、参考和指导尚未在文献中完整记录。本研究旨在弥合其生成的数据与配方科学中未开发的领域之间的差距。这项研究是新颖的，因为首次通过 QbD 方法开发了一种用于估计降解产物的专属较短运行时间的 UHPLC 方法，并经过验证并证明了稳定性指示。五种降解杂质被分离并得到很好的表征。更多，首次使用串联四极杆质谱辅助质谱鉴定在软凝胶制剂中探索了抗癌药物尼达尼布 (NIN) 的降解途径，并进行了 ESI/MS/MS 辅助结构解析。通过仔细演示基于 QbD 的优化的分步程序，评估了分析目标曲线 (ATP) 和关键质量属性 (CQA) 等参数。使用故障模式影响分析 (FMEA) 进行风险评估。根据计算出的风险优先级数 (RPN) 值的大小确定关键方法属性和关键方法参数。使用 4 因子两水平因子设计的设计实验监测三个关键质量属性，以得出方法可操作设计空间 (MODS)。还使用半正态图和帕累托图分析了各个方法属性的影响。根据 DOE 输出重新计算控制策略设计和 RPN 值。该 RPN 值最终被确定为在允许的范围内明显更小且令人满意。