质量源于设计在银杏叶片制粒工艺中的应用(Ⅱ):颗粒关键质量属性辨识  

Application of quality by design in granulation process for ginkgo leaf tablet(Ⅱ):identification of critical quality attributes

作　　者：徐冰[1,2] 崔向龙 杨婵[1] 王馨[1] 史新元[1,2] 乔延江[1,2] 

机构地区：[1]北京中医药大学中药信息工程研究中心,北京100029 [2]北京市科委中药生产过程控制与质量评价北京市重点实验室,北京100029

出　　处：《中国中药杂志》2017年第6期1043-1047,共5页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(81403112);北京市自然科学基金项目(7154217);中药生产过程控制与质量评价北京市重点实验室2015年度科技创新基地培育与发展专项(Z151100001615065);北京中医药大学自主选题项目(2016-JYB-XS051)

摘　　要：质量源于设计(QbD)强调"以终为始",即首先对目标产品质量进行透彻理解,进而指导药品工艺开发和生产质量控制的全过程。该文以银杏叶片颗粒中间体为对象,以片剂抗张强度要求为目标,建立了颗粒物理关键质量属性(CQAs)辨识及其限度范围制定的方法。首先采用正交偏最小二乘法(OPLS)建立29批颗粒粉体学性质和和银杏叶片抗张强度关联模型,以变量投影重要性(VIP)筛选颗粒潜在关键质量属性(pCQAs)。按照VIP由小到大逐一删减OPLS模型中的pCQAs变量,发现模型校正和预测性能无降低趋势,结合pCQAs共线性和易测性,确定颗粒中值粒径(D_(50))和松装密度(D_a)为关键质量属性。采用多元线性回归模型建立D_(50)和D_a与片剂抗张强度的关系模型,基于模型开发颗粒关键质量属性设计空间。由设计空间确定颗粒CQAs目标控制区域为170μm<D_(50)<500μm和0.30 g·cm^(-3)<D_a<0.44 g·cm^(-3),研究结果为银杏叶片湿法制粒工艺控制和优化提供了依据。Quality by design （QbD） highlights the concept of ＂begin with the end＂, which means to thoroughly understand the target product quality first, and then guide pharmaceutical process development and quality control throughout the whole manufacturing process. In this paper, the Ginkgo biloba granules intermediates were taken as the research object, and the requirements of the tensile strength of tablets were treated as the goals to establish the methods for identification of granules＇ critical quality attributes （CQAs） and establishment of CQAs＇ limits. Firstly, the orthogonal partial least square （OPLS） model was adopted to build the relationship between the micromeritic properties of 29 batches of granules and the tensile strength of ginkgo leaf tablets, and thereby the potential critical quality attributes （pCQAs） were screened by variable importance in the projection （VIP） indexes. Then, a series of OPLS models were rebuilt by reducing pCQAs variables one by one in view of the rule of VIP values from low to high in sequence. The model performance results demonstrated that calibration and predictive performance of the model had no decreasing trend after variables reduction. In consideration of the results from variables selection as well as the collinearity test and testability of the pCQAs, the median par- ticle size （Ds0） and the bulk density （D~） were identified as critical quality attributes （CQAs）. The design space of CQAs was developed based on a multiple linear regression model established between the CQAs （Ds0 and Da ） and the tensile strength. The control constraints of the CQAs were determined as 170μm 〈 D50 〈 500 μm and 0. 30 g · cm -3 〈 Da 〈 0. 44 g · cm-3 according to the design space, which provided a basis for controlling and optimizing the wet granulation process of the ginkgo leaf tablet.

关 键 词：关键质量属性 设计空间 正交偏最小二乘法 变量投影重要性 中药湿法制粒 

分 类 号：R283.6[医药卫生—中药学]