Yang Samuel H, Wang Jenny, Zhang Kelly
Small Molecule Pharmaceutical Sciences, Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
Small Molecule Pharmaceutical Sciences, Genentech, 1 DNA Way, South San Francisco, CA 94080, United States.
J Chromatogr A. 2017 Apr 7;1492:89-97. doi: 10.1016/j.chroma.2017.02.074. Epub 2017 Mar 1.
Despite the advantages of 2D-LC, there is currently little to no work in demonstrating the suitability of these 2D-LC methods for use in a quality control (QC) environment for good manufacturing practice (GMP) tests. This lack of information becomes more critical as the availability of commercial 2D-LC instrumentation has significantly increased, and more testing facilities begin to acquire these 2D-LC capabilities. It is increasingly important that the transferability of developed 2D-LC methods be assessed in terms of reproducibility, robustness and performance across different laboratories worldwide. The work presented here focuses on the evaluation of a heart-cutting 2D-LC method used for the analysis of a pharmaceutical material, where a key, co-eluting impurity in the first dimension (D) is resolved from the main peak and analyzed in the second dimension (D). A design-of-experiments (DOE) approach was taken in the collection of the data, and the results were then modeled in order to evaluate method robustness using statistical modeling software. This quality by design (QBD) approach gives a deeper understanding of the impact of these 2D-LC critical method attributes (CMAs) and how they affect overall method performance. Although there are multiple parameters that may be critical from method development point of view, a special focus of this work is devoted towards evaluation of unique 2D-LC critical method attributes from method validation perspective that transcend conventional method development and validation. The 2D-LC method attributes are evaluated for their recovery, peak shape, and resolution of the two co-eluting compounds in question on the D. In the method, linearity, accuracy, precision, repeatability, and sensitivity are assessed along with day-to-day, analyst-to-analyst, and lab-to-lab (instrument-to-instrument) assessments. The results of this validation study demonstrate that the 2D-LC method is accurate, sensitive, and robust and is ultimately suitable for QC testing with good method transferability.
尽管二维液相色谱（2D-LC）具有诸多优势，但目前几乎没有工作来证明这些二维液相色谱方法适用于药品生产质量管理规范（GMP）测试的质量控制（QC）环境。随着商用二维液相色谱仪器的可用性显著增加，越来越多的测试机构开始具备二维液相色谱分析能力，这一信息匮乏的问题变得愈发关键。在全球不同实验室中，根据重现性、稳健性和性能来评估已开发的二维液相色谱方法的可转移性变得越来越重要。本文介绍的工作重点是评估一种用于药物分析的中心切割二维液相色谱方法，其中第一维（D1）中的关键共洗脱杂质与主峰分离，并在第二维（D2）中进行分析。在数据收集过程中采用了实验设计（DOE）方法，然后使用统计建模软件对结果进行建模，以评估方法的稳健性。这种设计质量（QBD）方法能更深入地理解这些二维液相色谱关键方法属性（CMA）的影响以及它们如何影响整体方法性能。尽管从方法开发的角度来看可能有多个参数至关重要，但这项工作的一个特别重点是从方法验证的角度评估超越传统方法开发和验证的独特二维液相色谱关键方法属性。对二维液相色谱方法属性在回收率、峰形以及D1上两种共洗脱化合物的分离度方面进行评估。在该方法中，还评估了线性、准确度、精密度、重复性和灵敏度，以及不同日期、不同分析人员和不同实验室（不同仪器）之间的评估。这项验证研究的结果表明，二维液相色谱方法准确、灵敏且稳健，最终适用于具有良好方法可转移性的质量控制测试。
