A deeper understanding of the biological events occurring when bioprocess parameters changed will be of great value in improving the monoclonal antibodies (mAbs) production. Design of experiment (DoE) was applied to i...A deeper understanding of the biological events occurring when bioprocess parameters changed will be of great value in improving the monoclonal antibodies (mAbs) production. Design of experiment (DoE) was applied to investigate the effect of process parameters (pH, temperature shift and dissolve oxygen (DO)) on protein titer. The key metabolites connecting the critical process parameters (CPPs) with monoclonal antibody production were identified by different chemometrics tools. Finally, the biological events of marker metabolites relating with titer improvement were concluded. pH and temperature shift were identified as CPPs that affect the target protein titer. A series of metabolites influenced by the altered CPPs and correlated with protein titer were screened by principal component analysis (PCA) and Pearson' correlation test. The marker metabolites and their pathways linking CPPs to target protein titer in different culture phases were summarized. Metabolomics and chemometrics are promising data-driven tools to shine light into the biological black box between the bioprocess parameters and process performance.展开更多
The quality standards for Fructus Comi have been established based on the effects of the manufacturing processes.Three critical process parameters(CPPs)of extraction,filtration,and concentration to prepare Fructus Com...The quality standards for Fructus Comi have been established based on the effects of the manufacturing processes.Three critical process parameters(CPPs)of extraction,filtration,and concentration to prepare Fructus Comi concentrate were identified by Plackett-Burman design with a single batch of Fructus Corni,which were heating medium temperature,extraction time,and water addition.Morroniside yield,loganin yield,and dry matter yield were process critical quality attributes(CQAs).CPPs arranged with a Box-Behnken design were applied to treat different batches of Fructus Comi After constructing a model that included CPPs,material propertie s,and process CQAs,loganin content was found to be the critical material attribute(CMA).The design space was calculated with a probability method.According to the limits of process CQAs,the minimum content of loganin in Fructus Corni was calculated with an error propagation method,which was 6.92 mg·g^(-1).When the content of loganin in Fructus Corni reaches up to 6.92 mg·g^(-1),the material is considered high-quality and is most suitable for the process.High-quality material can be used for production of Fructus Comi concentrate.This method can also be used to set material quality standards for other Chinese medicines.展开更多
Pharmaceutical production is changing from batch production to continuous production,during which granulation is one of the most important unit operations.The quality of mass-produced products is traditionally guarant...Pharmaceutical production is changing from batch production to continuous production,during which granulation is one of the most important unit operations.The quality of mass-produced products is traditionally guaranteed by conducting off-line testing,which cannot meet the demand of continuous production for real-time monitoring of critical process parameters and critical quality attributes(CQAs)of the pharmaceutical granulation technology.Since the U.S.Food and Drug Administration proposed process analytical technology(PAT)in 2004,many PAT tools have been developed to monitor the granulation process and provide information regarding the granulation operation conditions and endpoint determination.In this article,we review the recent research and application of two PAT modes in the granulation process,namely,single CQA and multi-CQA PAT,with the aim to provide references for comprehensively improving the technological level of the pharmaceutical granulation process.Furthermore,the potential applications in traditional Chinese Medicine are discussed.展开更多
目的基于质量源于设计(quality by design,QbD)理念,剖析对照药的处方组成及关键工艺参数(CPPs),运用星点设计-效应面法优化蜡骨架缓释片的处方。方法以氯化钾为模型药物,运用失败模式和影响分析法(failure mode and effect analysis,FM...目的基于质量源于设计(quality by design,QbD)理念,剖析对照药的处方组成及关键工艺参数(CPPs),运用星点设计-效应面法优化蜡骨架缓释片的处方。方法以氯化钾为模型药物,运用失败模式和影响分析法(failure mode and effect analysis,FMEA)进行风险评估,确定CPPs,并采用星点设计-效应面法对CPPs进行优化,建立统计模型,得到最优的处方工艺。结果基于QbD理念,通过星点设计-效应面法对CPPs进行优化,以粉衣层明胶比例、粉衣层增重、隔离层层数、糖衣层增重为自变量,以0.25、0.5、1、2、4、6和8 h的累积释放百分率为因变量,绘制优化模型的效应面图,最终得到了最优的包衣工艺。建立了CPPs与CQAs的关联,并对最优包衣工艺进行验证,释放结果与预测值基本一致,自制片与参比制剂的体外释放行为一致。结论基于QbD理念,得到了优化模型的产品,符合预期的QTPP且质量稳定、可控。展开更多
基金Supported by the Science and Technology Development Program of Zhejiang Province(2017C03003)
文摘A deeper understanding of the biological events occurring when bioprocess parameters changed will be of great value in improving the monoclonal antibodies (mAbs) production. Design of experiment (DoE) was applied to investigate the effect of process parameters (pH, temperature shift and dissolve oxygen (DO)) on protein titer. The key metabolites connecting the critical process parameters (CPPs) with monoclonal antibody production were identified by different chemometrics tools. Finally, the biological events of marker metabolites relating with titer improvement were concluded. pH and temperature shift were identified as CPPs that affect the target protein titer. A series of metabolites influenced by the altered CPPs and correlated with protein titer were screened by principal component analysis (PCA) and Pearson' correlation test. The marker metabolites and their pathways linking CPPs to target protein titer in different culture phases were summarized. Metabolomics and chemometrics are promising data-driven tools to shine light into the biological black box between the bioprocess parameters and process performance.
基金Supported by the Open Fund of Key Laboratory of Modern Chinese Medicine Preparations,Ministry of Education,Jiangxi University of Traditional Chinese Medicine and First-class Discipline Construction Project of Jiangxi Province(JXSYLXK-ZHYAO009,JXSYLXK-ZHYAO010)。
文摘The quality standards for Fructus Comi have been established based on the effects of the manufacturing processes.Three critical process parameters(CPPs)of extraction,filtration,and concentration to prepare Fructus Comi concentrate were identified by Plackett-Burman design with a single batch of Fructus Corni,which were heating medium temperature,extraction time,and water addition.Morroniside yield,loganin yield,and dry matter yield were process critical quality attributes(CQAs).CPPs arranged with a Box-Behnken design were applied to treat different batches of Fructus Comi After constructing a model that included CPPs,material propertie s,and process CQAs,loganin content was found to be the critical material attribute(CMA).The design space was calculated with a probability method.According to the limits of process CQAs,the minimum content of loganin in Fructus Corni was calculated with an error propagation method,which was 6.92 mg·g^(-1).When the content of loganin in Fructus Corni reaches up to 6.92 mg·g^(-1),the material is considered high-quality and is most suitable for the process.High-quality material can be used for production of Fructus Comi concentrate.This method can also be used to set material quality standards for other Chinese medicines.
基金the National Natural Sciences Foundation of China(No.82074276)Tianjin Science and Technology project(No.20ZYJDJC00090).
文摘Pharmaceutical production is changing from batch production to continuous production,during which granulation is one of the most important unit operations.The quality of mass-produced products is traditionally guaranteed by conducting off-line testing,which cannot meet the demand of continuous production for real-time monitoring of critical process parameters and critical quality attributes(CQAs)of the pharmaceutical granulation technology.Since the U.S.Food and Drug Administration proposed process analytical technology(PAT)in 2004,many PAT tools have been developed to monitor the granulation process and provide information regarding the granulation operation conditions and endpoint determination.In this article,we review the recent research and application of two PAT modes in the granulation process,namely,single CQA and multi-CQA PAT,with the aim to provide references for comprehensively improving the technological level of the pharmaceutical granulation process.Furthermore,the potential applications in traditional Chinese Medicine are discussed.
文摘目的基于质量源于设计(quality by design,QbD)理念,剖析对照药的处方组成及关键工艺参数(CPPs),运用星点设计-效应面法优化蜡骨架缓释片的处方。方法以氯化钾为模型药物,运用失败模式和影响分析法(failure mode and effect analysis,FMEA)进行风险评估,确定CPPs,并采用星点设计-效应面法对CPPs进行优化,建立统计模型,得到最优的处方工艺。结果基于QbD理念,通过星点设计-效应面法对CPPs进行优化,以粉衣层明胶比例、粉衣层增重、隔离层层数、糖衣层增重为自变量,以0.25、0.5、1、2、4、6和8 h的累积释放百分率为因变量,绘制优化模型的效应面图,最终得到了最优的包衣工艺。建立了CPPs与CQAs的关联,并对最优包衣工艺进行验证,释放结果与预测值基本一致,自制片与参比制剂的体外释放行为一致。结论基于QbD理念,得到了优化模型的产品,符合预期的QTPP且质量稳定、可控。
