In this study, we developed a control strategy for a drug product prepared by high-shear wet granulation and roller compaction using integrated quality by design (QbD). During the first and second stages, we optimized the process parameters through the design of experiments and identified the intermediate quality attributes (IQAs) and critical quality attributes (CQAs) relationship, respectively. In the first stage, we conducted an initial risk assessment by selecting critical process parameters with high impact on IQAs and CQAs and confirmed the correlation between control and response factors. Additionally, we performed Monte Carlo simulations by optimizing the process parameters to deriving and building a robust design space. In the second stage, we identified the IQAs and CQAs relationship for the control strategy, using multivariate analysis (MVA). Based on MVA, in the metformin layer, dissolution at 1 h was significantly correlated with intrinsic dissolution rate and granule size, and dissolution at 3 h was significantly correlated with bulk density and granule size. In dapagliflozin layer, dissolution at 10 min and 15 min was significantly correlated with granule size. Our results suggest that the desired drug quality may result through IQAs monitoring during the process and that the integrated QbD approach utilizing MVA can be used to develop a control strategy for producing high-quality drug products.

中文翻译：

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高剪切湿法制粒和压路机压制工艺的控制策略，通过设计综合质量来制备混合药物

在这项研究中，我们通过设计综合质量（QbD），开发了通过高剪切湿法制粒和辊压成型制备的药品的控制策略。在第一和第二阶段，我们通过实验设计优化了工艺参数，并分别确定了中间质量属性（IQA）和关键质量属性（CQAs）的关系。在第一阶段，我们通过选择对IQA和CQAs有高影响的关键过程参数进行了初步风险评估，并确认了控制因素和响应因素之间的相关性。此外，我们通过优化工艺参数来进行蒙特卡洛仿真，以推导并构建强大的设计空间。在第二阶段，我们确定了控制策略的IQA和CQA关系，使用多元分析（MVA）。基于MVA，在二甲双胍层中，1 h的溶出度与固有溶出度和颗粒大小显着相关，3 h的溶出度与堆积密度和颗粒大小显着相关。在达格列净层中，在10分钟和15分钟时的溶出度与颗粒大小显着相关。我们的结果表明，在过程中通过IQA监控可能会达到所需的药品质量，利用MVA的集成QbD方法可用于开发生产高质量药品的控制策略。10分钟和15分钟时的溶出度与颗粒大小显着相关。我们的结果表明，在过程中通过IQA监控可能会达到所需的药品质量，利用MVA的集成QbD方法可用于开发生产高质量药品的控制策略。10分钟和15分钟时的溶出度与颗粒大小显着相关。我们的结果表明，在过程中通过IQA监控可能会达到所需的药品质量，利用MVA的集成QbD方法可用于开发生产高质量药品的控制策略。