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(1)
[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(D50)和松装密度(Da)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PlackettBurmann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BoxBehnken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<005，且失拟值>01，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D50和Da控制在170～500 μm和030～044 g·cm-3，进而满足银杏叶片机械性质要求。
[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
[Abstract]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 PlackeetBurmann 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 BoxBehnken design and quadratic polynomial regression models ANOVA analysis showed that the Pvalues of model were less than 005 and the values of lack of fit test were more than 01， indicating that the relationship between CQAs and CPPs could be well described by the mathematical models D50 could be controlled within 170 to 500 μm， and the bulk density could be controlled within 030 to 044 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
, 百拇医药
[Key words]high shear wet granulation； design space； quality controllability； critical process parameter； quality risk management
設计空间(design space，DS)是质量源于设计(quality by design，QbD)方法体系[1]的核心步骤之一[2]，ICH Q8(R2)中定义设计空间为：“能够保证产品质量符合要求的输入变量(如原料质量属性)和工艺参数的多维组合和相互作用”[3]。当制药过程呈现“黑盒”、“灰盒”、“白盒”特征时，可分别采用统计模型、半机制半统计模型、机制模型描述过程“输入输出”之间的关系。其中过程输入包括关键物料属性(critical material attributes，CMAs)和关键工艺参数(critical process parameter，CPPs)，过程输出即关键质量属性(critical quality attributes，CQAs)。设计空间建立在过程模型基础之上，代表了对制药工艺详细和透彻理解。在设计空间内优化或改变关键工艺参数不属于工艺变更，设计空间可赋予生产操作极大的灵活性和过程稳健性。目前设计空间已应用于提取[4]、干燥[5]、混合[6]、制粒[7]、压片[8]、包衣[9]等工艺过程。, 百拇医药(崔向龙 徐冰 孙飞 戴胜云 史新元 乔延江)
[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
[Abstract]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 PlackeetBurmann 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 BoxBehnken design and quadratic polynomial regression models ANOVA analysis showed that the Pvalues of model were less than 005 and the values of lack of fit test were more than 01， indicating that the relationship between CQAs and CPPs could be well described by the mathematical models D50 could be controlled within 170 to 500 μm， and the bulk density could be controlled within 030 to 044 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
, 百拇医药
[Key words]high shear wet granulation； design space； quality controllability； critical process parameter； quality risk management
設计空间(design space，DS)是质量源于设计(quality by design，QbD)方法体系[1]的核心步骤之一[2]，ICH Q8(R2)中定义设计空间为：“能够保证产品质量符合要求的输入变量(如原料质量属性)和工艺参数的多维组合和相互作用”[3]。当制药过程呈现“黑盒”、“灰盒”、“白盒”特征时，可分别采用统计模型、半机制半统计模型、机制模型描述过程“输入输出”之间的关系。其中过程输入包括关键物料属性(critical material attributes，CMAs)和关键工艺参数(critical process parameter，CPPs)，过程输出即关键质量属性(critical quality attributes，CQAs)。设计空间建立在过程模型基础之上，代表了对制药工艺详细和透彻理解。在设计空间内优化或改变关键工艺参数不属于工艺变更，设计空间可赋予生产操作极大的灵活性和过程稳健性。目前设计空间已应用于提取[4]、干燥[5]、混合[6]、制粒[7]、压片[8]、包衣[9]等工艺过程。, 百拇医药(崔向龙 徐冰 孙飞 戴胜云 史新元 乔延江)