【作者】 王璐；

【导师】 瞿海斌；

【作者基本信息】 浙江大学 ， 药物分析学， 2015， 博士

【摘要】 作为药物研发和药品生产过程中重要的药品质量管理理念,质量源于设计(Quality by Design, QbD)在制药工业中的成功实施为药物分析方法的研究提供了借鉴。在质量源于设计理念的指导下,找到能够保证分析质量可靠一致的分析参数操作空间,是提高药物分析方法耐用性和可靠性的有效手段。本文开展了基于质量源于设计理念的中药质量分析方法研究,主要研究内容及创新成果如下：1、提出了基于质量源于设计理念开发并优化中药含量测定方法的新策略。以参芪扶正注射液中九种主要化学成分的定量分析为例,研究确定了固相萃取-高效液相色谱-紫外串联蒸发光散射检测器(SPE-HPLC-UV/ELSD)方法的分析参数操作空间。采用风险评估和因子分析同时考察了样品前处理、色谱分离及分析检测过程中的分析参数对关键质量属性的影响；采用响应曲面分析进一步研究了关键分析参数与分析质量间的关系。方法学验证结果表明,该策略能够有效地提高中药分析方法开发的效率,改善中药分析方法的耐用性,同时保证中药分析数据的质量。2、提出了中药分析过程的一致性评价方法。以参芪扶正注射液的SPE-HPLC-UV/ELSD含量测定方法为例,采集分析参数操作空间内正常分析操作下的SPE-HPLC-UV/ELSD数据,运用主成分分析(Principal Component Analysis,PCA)方法建立了分析过程的Hotelling T2和DModX控制图,用于评价中药分析过程的一致性。结果表明,该方法可以有效识别中药分析过程中的样品异常和分析参数异常,结合变量贡献图还可进一步分析过程异常的原因,为中药分析过程的一致性评价提供了参考。3、提出了基于质量源于设计理念开发实时直接分析质谱(Direct Analysis in Real Time Mass Spectrometry,DART-MS)方法的新策略。以复方苦参注射液为例,采用风险评估和因子分析筛选出了影响DART-MS分析质量的关键分析参数；采用响应曲面分析进一步研究了关键分析参数与DART-MS分析质量间的关系,确定了DART_MS的分析参数操作空间。方法学验证结果表明,在质量源于设计理念的指导下,DART_MS分析中药样品的重复性和耐用性都有了显著的提高,为开发中药质谱分析方法、改善质谱响应提供了指导。4、探讨了DART-MS用于中药生产过程实时监测的可行性。以复方苦参注射液的渗漉提取过程为例,实时采集渗漉提取过程中样品的DART-MS图谱,并通过多变量数据分析技术建立渗漉提取过程的控制轨迹,用于发现和诊断批次运行过程中出现的异常,并结合变量贡献图分析过程异常的原因,为改善中药批次质量和过程一致性研究提供了方法学参考。更多还原

【Abstract】 Since quality by design (QbD) has been introduced as a fundamental pharmaceutical quality model in the development of pharmaceutical products and processes, the opportunities for analytical method developments to follow a similar approach have been discussed. A key component of QbD compliant analytical method is the definition of analytical design space where assurance of quality is provided. Analytical design space is a measure of method robustness, and allows the inclusion of the measurement uncertainty to provide assurance of analytical quality. The aim of this dissertation is thus to study the methodology for quality analysis of traditional Chinese medicine (TCM) using QbD principle. The main innovation and academic contributions of this study are summarized as follows:1 The feasibility of QbD in the development and optimization of a quantitative method was evaluated for a botanical injection. Analytical design space of a solid phase extraction-high performance liquid chromatography-ultraviolet tandem evaportive light scattering detector (SPE-HPLC-UV/ELSD) method to assay nine chemical compounds in Shenqi Fuzheng Injection was defined. The impact of the operating parameters, including sample preparation, chromatographic separation, and compound detection, on the method performance were investigated simultaneously. And the relationships between critical parameters and the analytical quality of SPE-HPLC-UV/ELSD were further studied. Compared with analytical method developed using univariate approach traditionally, the method developed following QbD displayed improved robustness. It is revealed that the analytical reliability and method robustness were ensured by analytical design space. This presented approach provided a tutorial to the development of a robust quantitative method for samples in complex matrics.2 The methodology of consistency evaluation of botanical analysis was presented. SPE-HPLC-UV/ELSD for simultaneous determination of nine chemical compounds in Shenqi Fuzheng Injection was taken as an example. A total of 12 runs within analytical design space were used to develop a principal component analysis (PCA) model. Two kinds of multivariate control charts, including Hotelling T2 and DModX charts, were applied to examine the analytical consistency of the tested runs. The results showed that the presented strategy distinguished the abnormal operation during the analytical procedures successfully. Futher understanding of the analytical processes was achieved by investigating the contribution plots. It is demonstrated that consistency evaluation of analytical quality provided a tutorial to the quality control of analytical procedures for botanical drugs.3 The feasibility and methodology of QbD in the optimization of mass spectrometry response was discussed for a botanical injection. Direct analysis in real time mass spectrometry (DART-MS) was adopted to analyze Compound Kushen Injection. The impact of a number of factors on DART-MS method performance were screened, and the relationships between critical factors and DART-MS response were investigated. The robustness of analytical design space were evaluated through the critical point verification. It is revealed that the analytical reproducibility and robustness of DART-MS were significantly improved by analytical design space. This presented study provided a tutorial to the improvement of DART-MS response and a guidance to the development of a robust QbD compliant MS method for samples in complex matrics.4 The application of DART-MS method, as a promising process analytical technology (PAT) tool, to achieve real-time process monitoring in botanical drug manufacturing was presented. A percolation process with multi-constituent substances for Compound Kushen Injection was taken as an example. Multi-way partial least squares (MPLS) model was established by the obtained multivariate data. A total of eight batches with normal operations were utilized to derive control trajectories, which detected and diagnosed the process faults successfully. It is demonstrated that DART-MS is efficiency for real-time process monitoring in botanical drug manufacturing, and can be potentially used to improve batch quality and process consistency of samples in complex matrices.更多还原