Casian Tibor, Iurian Sonia, Bogdan Catalina, Rus Lucia, Moldovan Mirela, Tomuta Ioan
a Department of Pharmaceutical Technology and Biopharmacy , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania.
b Department of Dermopharmacy and Cosmetics , Iuliu Hatieganu University of Medicine and Pharmacy , Cluj-Napoca , Romania.
Drug Dev Ind Pharm. 2017 Dec;43(12):1932-1944. doi: 10.1080/03639045.2017.1350702. Epub 2017 Aug 16.
This study proposed the development of oral lyophilisates with respect to pediatric medicine development guidelines, by applying risk management strategies and DoE as an integrated QbD approach.
Product critical quality attributes were overviewed by generating Ishikawa diagrams for risk assessment purposes, considering process, formulation and methodology related parameters. Failure Mode Effect Analysis was applied to highlight critical formulation and process parameters with an increased probability of occurrence and with a high impact on the product performance. To investigate the effect of qualitative and quantitative formulation variables D-optimal designs were used for screening and optimization purposes.
Process parameters related to suspension preparation and lyophilization were classified as significant factors, and were controlled by implementing risk mitigation strategies. Both quantitative and qualitative formulation variables introduced in the experimental design influenced the product's disintegration time, mechanical resistance and dissolution properties selected as CQAs. The optimum formulation selected through Design Space presented ultra-fast disintegration time (5 seconds), a good dissolution rate (above 90%) combined with a high mechanical resistance (above 600 g load).
Combining FMEA and DoE allowed the science based development of a product with respect to the defined quality target profile by providing better insights on the relevant parameters throughout development process. The utility of risk management tools in pharmaceutical development was demonstrated.
本研究根据儿科药物开发指南，通过应用风险管理策略和实验设计（DoE）作为一种综合的质量源于设计（QbD）方法，提出口服冻干制剂的开发。
通过生成石川图进行风险评估，考虑与工艺、配方和方法相关的参数，概述产品关键质量属性。应用失效模式效应分析来突出那些发生概率增加且对产品性能有高影响的关键配方和工艺参数。为研究定性和定量配方变量的影响，采用D-最优设计进行筛选和优化。
与混悬液制备和冻干相关的工艺参数被归类为显著因素，并通过实施风险缓解策略进行控制。实验设计中引入的定量和定性配方变量均影响选定为关键质量属性的产品崩解时间、机械抗性和溶出特性。通过设计空间选择的最佳配方呈现出超快崩解时间（5秒）、良好的溶出速率（90%以上）以及高机械抗性（600克负荷以上）。
结合失效模式效应分析和实验设计能够基于科学开发出符合定义的质量目标概况的产品，通过在整个开发过程中对相关参数提供更好的洞察。证明了风险管理工具在药物开发中的效用。
