质量源于设计在银杏叶片制粒工艺中的应用(Ⅲ):基于设计空间的过程控制策略  

Application of quality by design in granulation process for Ginkgo leaf tablet(Ⅲ):process control strategy based on design space

作　　者：崔向龙 徐冰[1,2] 孙飞[1] 戴胜云 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1048-1054,共7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：该文在质量源于设计(QbD)理念的指导下,建立基于设计空间的银杏叶片高速剪切湿法制粒工艺控制策略,提高过程质量可控性和产品质量一致性。以颗粒中间体的中值粒径(D_(50))和松装密度(D_a)为关键质量属性(CQAs),采用失败模式和效应分析(FMEA)辨识潜在关键工艺参数(pCPPs)。采用Plackett-Burmann设计对潜在关键工艺参数进行筛选,确定黏合剂用量、湿混时间和湿混搅拌桨转速为关键工艺参数(CPPs)。在关键工艺参数范围内,采用Box-Behnken设计和二次多项式回归模型开发工艺设计空间。ANOVA分析显示回归模型的P<0.05,且失拟值>0.1,表明其可较好地定量描述CQAs和CPPs之间的关系。设计空间内任一CPPs组合均能分别将颗粒D_(50)和D_a控制在170~500μm和0.30~0.44 g·cm^(-3),进而满足银杏叶片机械性质要求。In this paper, under the guidance of quality by design （QbD） concept, the control strategy of the high shear wet granulation process of the ginkgo leaf tablet based on the design space was established to improve the process controllability and product quality consistency. The median granule size （ D50 ） and bulk density （ Da ） of granules were identified as critical quality attributes （CQAs） and potential critical process parameters （pCPPs） were determined by the failure modes and effect analysis （FMEA）. The Plackeet- Burmann experimental design was used to screen pCPPs and the results demonstrated that the binder amount, the wet massing time and the wet mixing impeller speed were critical process parameters （CPPs）. The design space of the high shear wet granulation process was developed within pCPPs range based on the Box-Behnken design and quadratic polynomial regression models. ANOVA analysis showed that the P-values of model were less than 0. 05 and the values of lack of fit test were more than 0. 1, indicating that the relationship between CQAs and CPPs could be well described by the mathematical models. D50could be controlled within 170 to 500 μm, and the bulk density could be controlled within 0. 30 to 0.44 g · cm-3 by using any CPPs combination within the scope of design space. Besides, granules produced by process parameters within the design space region could also meet the requirement of tensile strength of the ginkgo leaf tablet.

关 键 词：高速剪切湿法制粒 设计空间 质量可控性 关键工艺参数 质量风险管理 

分 类 号：R283.6[医药卫生—中药学]