中药制剂生产过程全程优化方法学研究
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摘要
中药生产过程是中药产品固有质量的具体形成阶段,中药制药过程的每一单元环节都会对中药质量产生影响。随着现代信息技术、分析技术、控制技术和传感器技术的广泛应用,一批先进的中药制剂新技术、新工艺、新方法,离线／在线质量分析与检测手段被应用与中药制药过程,若干企业实施并建立了中药生产自动化和一体化控制系统,不仅提高了中药制剂生产的效率和水平,也极大地提高了中药产品的内在质量。
然而,在中药生产过程信息化、自动化和控制水平不断提高的同时,某些与中药产品质量密切相关的若干关键基础问题还没有得到较好的解决,表现在：(1)中药质量控制多采用各种离线或在线分析的方法,而较少地从生产过程的角度考虑中药质量在各工艺单元之间的传递规律,当中药材质量出现波动,或者正常生产过程出现扰动时,会发生质量变异及其在整个生产链条中的传播,导致中间体和终产品质量的波动。(2)中药制药过程优化技术,包括单元优化技术和系统集成优化技术,发展滞后,与生产过程的集成化和自动化不匹配。
为解决上述问题,本课题创新性地提出中药制剂生产“全程优化”的概念和方法,是在中医药理论和系统科学理论的指导下,从中药制剂生产过程全局角度考虑质量传递变化规律,应用先进的信息技术、分析技术、制剂技术和工程技术,研究适宜于中药制剂生产的全程建模与仿真方法、中药制药全流程优化控制方法、以及风险控制策略,实现中药生产过程的安全平稳运行和工艺参数的优化操作,保证中药生产过程朝着确定的方向发展,稳定终产品质量,达到“过程控制-过程优化-质量控制-安全有效”的统一,为实现中药生产全过程质量优化控制奠定理论和方法学基础。具体研究内容包括以下四个部分：
1中药生产过程全程优化理论初步研究
中药制剂生产全程优化属于多学科交叉领域,阐释“全程优化”理论的内涵、地位和意义的阐释,将有利于指导全程优化的生产实践。该部分研究了“全程优化”与传统中医药理论的关系,以及如何在中药制剂生产全程优化中体现中医药理论的指导作用；研究“全程优化”与现代系统科学理论的关系,以及如何在中药制剂生产全程优化中应用系统科学的思想；通过探讨中药制剂核心理论的有关内容,明确了“全程优化”在现代中药制剂研究中的地位和作用。在上述探讨的基础上,提出了“全程优化”的实现途径和本课题的研究方案。
2中药生产过程单元典型特征研究
以中药制药典型工艺单元——醇沉为研究对象,采用以近红外(NIR)为主的过程分析技术(PAT),从定量分析和定性分析两个方面对中药制药过程单元的特征进行研究。定量分析采用偏最小二乘(PLS)模型,可以选择性提取过程NIR光谱中与响应变量有关的信息；定性分析采用基于主成分分析(PCA)分析的多变量统计过程控制(MSPC)模型,可以提取过程NIR光谱中的主要模式和特征。结果表明,在相同的工艺参数下,中药制药单元过程的批次间并不稳定一致,存在一定不确定性。定量分析模型和定性分析模型需要不断更新才能应对新的过程变异。PAT技术有助于发现单元批间差异,但在中药制药单元内部控制变异的能力有限。
3中药生产过程质量传递规律研究
借鉴ICH质量源于设计(QbD)的理念,提出了在中药制剂生产工艺中建立设计空间的构想。设计空间代表对中药制药过程的深入理解,其开发需要建立过程模型,该部分研究了四种数据驱动型近似建模技术,即多项式回归、最小二乘支持向量机(LS-SVM)、径向基人工神经网络(RBFNN)和Kriging建模,在栀子提取和醇沉过程单元中的应用。其中,LS-SVM、 RBFNN和Kriging模型采用遗传算法(GA)和自适应建模策略计算最优超参数。基于各单元的工艺模型,采用响应曲面分析、不确定性分析法(UA)和灵敏度分析法(SA),研究了过程单元输入和输出之间的关系,分析了在不同条件下关键工艺参数对关键质量属性的影响。在单元模型建立的基础上,应用系统科学思想,采用“分块-集成”的建模方法建立了栀子“提取-浓缩-醇沉”过程单元组合模型。通过蒙特卡罗仿真(MCS),基于过程单元组合模型,研究了中药制药单元组合设计空间的建立和可视化方法。基于设计空间探讨了栀子苷和京尼平龙胆双糖苷在三个子系统之间的传递规律。
4中药生产过程全程优化策略研究
该部分创新性的将递进PLS建模技术和贝叶斯优化技术集成,建立了适宜于中药多阶段间歇生产过程的全程优化策略——目标导向全程优化(TOPO),包括4个部分(目标定义、数据预处理、递进PLS过程建模、过程优化实施)和10个步骤。以清开灵注射液中金银花和栀子前处理工艺为研究对象,利用企业实际生产数据,进行了TOPO仿真实验,结果表明TOPO可用以稳定终产品质量。首次提出概率轨迹的概念,并将其应用于多阶段间歇生产过程的理解和监控。TOPO充分利用并挖掘隐含在工业生产过程数据中的信息,为中药生产过程全程优化提供了系统的解决方案。
上述四个方面的内容,将单元研究与多单元研究相结合,实验规模研究与生产规模研究相结合,理论研究与实际应用相结合,逐步深入、层层递进,所形成的中药生产过程“全程优化”方法和技术将有助于提高中药制剂生产全过程质量控制水平、促进中药制药产业的核心竞争力的提升。
The quality of traditional Chinese medicine (TCM) products is formed during their pharmaceutical production process, each unit of which has more or less impact on the final product. Along with the development and wide application of modern information technology, analytical technology, sensor and control technology, a number of advanced pharmaceutical innovations has been applied in the manufacturing process of TCM products. Some enterprises built and implemented the automatic and integrated control systems. All these works have greatly increased the level and efficiency of TCM production process, as well as the inner quality of the products.
However, with the good development trend of TCM industry, there still exist some quality related and key problems that have been not solved properly. Firstly, variations from the raw herbal materials and the manufacturing process could propagate during the production, leading to the variability of the intermediate and the product. The quality control of Chinese medicine often emphasizes on the analytical aspect. Conventional analytical techniques are able to capture the phenomenon of process variation, but are insufficient to maintain the quality consistence across herbal products. Secondly, the optimization technologies, including the unit and system optimization, don't match up with the automatic and integrated production systems.
In order to solve the above mentioned problems, the new concept and methodology named overall process optimization (OPO) of the TCM production is proposed in this thesis. The OPO methodology inherits the guidance from the TCM theory and system science theory. The most important character of OPO methodology is that it considers the transfer of products'quality from the overall production process point of view. The advanced information technology, analytical technology, pharmaceutical and engineering technology will be adapted and integrated in the implementation of OPO methodology. The main contents of OPO are to research the overall process modeling and simulation methods, the overall process optimization and control methods, and the risk evaluation and control methods. The goals of OPO are to realize the safe, smooth and optimized manufacture of the TCM product, to assure the predefined target of the TCM production, to stabilize the quality of the final products, and to accomplish the unity of "process control, process optimization, quality control, safety and efficacy". It is hoped that the OPO methodology will lay the foundation for the quality control of the overall process of TCM production. Around the content and aim of OPO. four parts are organized in this thesis.
1. Preliminarily theoretical study of overall process optimization of TCM production
The study of overall process optimization of TCM production belongs to the multidisciplinary research area. Therefore, a clear interpretation of the OPO theory will help to guide the production practice. In this part of the thesis, the relationship between the OPO theory and the TCM theory is analyzed, and the guiding role of TCM theory is established. The relationship between the OPO theory and the modern system science theory is also discussed, and how to apply the system science theory to the overall process optimization is investigated. The core theory of TCM pharmaceutics is investigated, and the position and function of OPO theory in the theory of TCM pharmaceutics is clarified. Based on the theoretical studies, the possible ways to realize the OPO methodology in actual production process as well as the research plan of this thesis are brought forward.
2. Characteristic study of the unit process of TCM production
In this part, the popular TCM production unit, i.e. alcohol precipitation, is taken as the research object. And with the help the near infrared (NIR) spectroscopy, a process analytical technology (PAT) tool, the character of TCM production unit is analyzed from both the quantitative and qualitative aspects. The process NIR spectra could reflect the whole feature and fingerprint of the pharmaceutical process. In the quantitative analysis, the PLS model is utilized to extract the response variable related information from the process NIR spectra. In qualitative analysis, the PCA algorithm and multivariate statistical process control (MSPC) model is used to extract the main pattern from the process NIR spectra. Results revealed that there was batch-to-batch variation in the TCM production, and such variation could be due to the process uncertainty. The quantitative and qualitative models need to be updated to cope with the process variations. The PAT methods are helpful to observe the phenomena of batch-to-batch variations, but deserve the limited competence of control within the production unit.
3. Study of the quality transferring law of TCM production
By applying the concept of ICH's Quality by Design (QbD), the establishment of design space for the TCM production process is proposed. Design space stands for a higher level and deep understanding of the TCM production process, and its development is based on process models. In this part, four kinds of data-driven approximation models, i.e. polynomial model, least square support vector machine (LS-SVM), radical basis function neural network (RBFNN) and Kriging model, are used to build surrogates for the water extraction and alcohol precipitation process of gardenia fruit. The hyperparameters of LS-SVM, RBFNN and Kriging models are optimized by a combination of genetic algorithm (GA) and adaptive modeling technique. Based on the process models, the relationships between the critical process parameters and critical quality attributes of the process unit are investigated by the response surface methodology, uncertainty analysis and sensitivity analysis.
With the established process unit models and the help from the system science theory, a "partition-integration" modeling method is used to develop the multi-unit combinational model for the "extraction-concentration-alcohol precipitation" processes of gardenia fruit. Based on the multi-unit combinational model, the Monte Carlo simulation (MCS) is applied to approximate the multi-unit combinational design space, which is visualized by the parallel coordinate plot. Through the multi-unit combinational design space, the quality transfer laws of Geniposide and Genipin-1-β-D-gentiobioside are studied.
4. Study of the strategy for the overall process optimization of TCM production
This part presents a new strategy, target-oriented overall process optimization (TOPO), which can be used to assure the consistent quality in TCM products. The methodology of TOPO includes four parts, target definition, data pretreatment, process modeling and overall process optimization. The Bayesian approach is integrated into the optimization step. The mechanism of TOPO involves optimizing multiple units of the production system step by step, giving each unit optimal operating conditions consistent with the quality target. The probability trajectory is adjusted to monitor and optimize the production process. The proposed TOPO strategy was successfully applied to seven-unit manufacturing process used to produce Lonicerae Japonicae extract and six-unit production process of gardenia extract. Results demonstrated that TOPO could keep the production process in line with the predefined target and reduce the variability of the final products. In general, TOPO explores the full potential of legacy batch production data with respect to understanding and optimizing the herbal production process, and provides systematic ways to the overall process optimization of the TCM production.
All in all, this thesis integrates the process unit research and multi-unit research, the laboratory scale research and production scale research, the theoretical study and practical application together. The proposed OPO methodologies and technologies for TCM production will help to enhance the level of quality control of TCM products as well as core competiveness of TCM industry.
然而,在中药生产过程信息化、自动化和控制水平不断提高的同时,某些与中药产品质量密切相关的若干关键基础问题还没有得到较好的解决,表现在：(1)中药质量控制多采用各种离线或在线分析的方法,而较少地从生产过程的角度考虑中药质量在各工艺单元之间的传递规律,当中药材质量出现波动,或者正常生产过程出现扰动时,会发生质量变异及其在整个生产链条中的传播,导致中间体和终产品质量的波动。(2)中药制药过程优化技术,包括单元优化技术和系统集成优化技术,发展滞后,与生产过程的集成化和自动化不匹配。
为解决上述问题,本课题创新性地提出中药制剂生产“全程优化”的概念和方法,是在中医药理论和系统科学理论的指导下,从中药制剂生产过程全局角度考虑质量传递变化规律,应用先进的信息技术、分析技术、制剂技术和工程技术,研究适宜于中药制剂生产的全程建模与仿真方法、中药制药全流程优化控制方法、以及风险控制策略,实现中药生产过程的安全平稳运行和工艺参数的优化操作,保证中药生产过程朝着确定的方向发展,稳定终产品质量,达到“过程控制-过程优化-质量控制-安全有效”的统一,为实现中药生产全过程质量优化控制奠定理论和方法学基础。具体研究内容包括以下四个部分：
1中药生产过程全程优化理论初步研究
中药制剂生产全程优化属于多学科交叉领域,阐释“全程优化”理论的内涵、地位和意义的阐释,将有利于指导全程优化的生产实践。该部分研究了“全程优化”与传统中医药理论的关系,以及如何在中药制剂生产全程优化中体现中医药理论的指导作用；研究“全程优化”与现代系统科学理论的关系,以及如何在中药制剂生产全程优化中应用系统科学的思想；通过探讨中药制剂核心理论的有关内容,明确了“全程优化”在现代中药制剂研究中的地位和作用。在上述探讨的基础上,提出了“全程优化”的实现途径和本课题的研究方案。
2中药生产过程单元典型特征研究
以中药制药典型工艺单元——醇沉为研究对象,采用以近红外(NIR)为主的过程分析技术(PAT),从定量分析和定性分析两个方面对中药制药过程单元的特征进行研究。定量分析采用偏最小二乘(PLS)模型,可以选择性提取过程NIR光谱中与响应变量有关的信息；定性分析采用基于主成分分析(PCA)分析的多变量统计过程控制(MSPC)模型,可以提取过程NIR光谱中的主要模式和特征。结果表明,在相同的工艺参数下,中药制药单元过程的批次间并不稳定一致,存在一定不确定性。定量分析模型和定性分析模型需要不断更新才能应对新的过程变异。PAT技术有助于发现单元批间差异,但在中药制药单元内部控制变异的能力有限。
3中药生产过程质量传递规律研究
借鉴ICH质量源于设计(QbD)的理念,提出了在中药制剂生产工艺中建立设计空间的构想。设计空间代表对中药制药过程的深入理解,其开发需要建立过程模型,该部分研究了四种数据驱动型近似建模技术,即多项式回归、最小二乘支持向量机(LS-SVM)、径向基人工神经网络(RBFNN)和Kriging建模,在栀子提取和醇沉过程单元中的应用。其中,LS-SVM、 RBFNN和Kriging模型采用遗传算法(GA)和自适应建模策略计算最优超参数。基于各单元的工艺模型,采用响应曲面分析、不确定性分析法(UA)和灵敏度分析法(SA),研究了过程单元输入和输出之间的关系,分析了在不同条件下关键工艺参数对关键质量属性的影响。在单元模型建立的基础上,应用系统科学思想,采用“分块-集成”的建模方法建立了栀子“提取-浓缩-醇沉”过程单元组合模型。通过蒙特卡罗仿真(MCS),基于过程单元组合模型,研究了中药制药单元组合设计空间的建立和可视化方法。基于设计空间探讨了栀子苷和京尼平龙胆双糖苷在三个子系统之间的传递规律。
4中药生产过程全程优化策略研究
该部分创新性的将递进PLS建模技术和贝叶斯优化技术集成,建立了适宜于中药多阶段间歇生产过程的全程优化策略——目标导向全程优化(TOPO),包括4个部分(目标定义、数据预处理、递进PLS过程建模、过程优化实施)和10个步骤。以清开灵注射液中金银花和栀子前处理工艺为研究对象,利用企业实际生产数据,进行了TOPO仿真实验,结果表明TOPO可用以稳定终产品质量。首次提出概率轨迹的概念,并将其应用于多阶段间歇生产过程的理解和监控。TOPO充分利用并挖掘隐含在工业生产过程数据中的信息,为中药生产过程全程优化提供了系统的解决方案。
上述四个方面的内容,将单元研究与多单元研究相结合,实验规模研究与生产规模研究相结合,理论研究与实际应用相结合,逐步深入、层层递进,所形成的中药生产过程“全程优化”方法和技术将有助于提高中药制剂生产全过程质量控制水平、促进中药制药产业的核心竞争力的提升。
The quality of traditional Chinese medicine (TCM) products is formed during their pharmaceutical production process, each unit of which has more or less impact on the final product. Along with the development and wide application of modern information technology, analytical technology, sensor and control technology, a number of advanced pharmaceutical innovations has been applied in the manufacturing process of TCM products. Some enterprises built and implemented the automatic and integrated control systems. All these works have greatly increased the level and efficiency of TCM production process, as well as the inner quality of the products.
However, with the good development trend of TCM industry, there still exist some quality related and key problems that have been not solved properly. Firstly, variations from the raw herbal materials and the manufacturing process could propagate during the production, leading to the variability of the intermediate and the product. The quality control of Chinese medicine often emphasizes on the analytical aspect. Conventional analytical techniques are able to capture the phenomenon of process variation, but are insufficient to maintain the quality consistence across herbal products. Secondly, the optimization technologies, including the unit and system optimization, don't match up with the automatic and integrated production systems.
In order to solve the above mentioned problems, the new concept and methodology named overall process optimization (OPO) of the TCM production is proposed in this thesis. The OPO methodology inherits the guidance from the TCM theory and system science theory. The most important character of OPO methodology is that it considers the transfer of products'quality from the overall production process point of view. The advanced information technology, analytical technology, pharmaceutical and engineering technology will be adapted and integrated in the implementation of OPO methodology. The main contents of OPO are to research the overall process modeling and simulation methods, the overall process optimization and control methods, and the risk evaluation and control methods. The goals of OPO are to realize the safe, smooth and optimized manufacture of the TCM product, to assure the predefined target of the TCM production, to stabilize the quality of the final products, and to accomplish the unity of "process control, process optimization, quality control, safety and efficacy". It is hoped that the OPO methodology will lay the foundation for the quality control of the overall process of TCM production. Around the content and aim of OPO. four parts are organized in this thesis.
1. Preliminarily theoretical study of overall process optimization of TCM production
The study of overall process optimization of TCM production belongs to the multidisciplinary research area. Therefore, a clear interpretation of the OPO theory will help to guide the production practice. In this part of the thesis, the relationship between the OPO theory and the TCM theory is analyzed, and the guiding role of TCM theory is established. The relationship between the OPO theory and the modern system science theory is also discussed, and how to apply the system science theory to the overall process optimization is investigated. The core theory of TCM pharmaceutics is investigated, and the position and function of OPO theory in the theory of TCM pharmaceutics is clarified. Based on the theoretical studies, the possible ways to realize the OPO methodology in actual production process as well as the research plan of this thesis are brought forward.
2. Characteristic study of the unit process of TCM production
In this part, the popular TCM production unit, i.e. alcohol precipitation, is taken as the research object. And with the help the near infrared (NIR) spectroscopy, a process analytical technology (PAT) tool, the character of TCM production unit is analyzed from both the quantitative and qualitative aspects. The process NIR spectra could reflect the whole feature and fingerprint of the pharmaceutical process. In the quantitative analysis, the PLS model is utilized to extract the response variable related information from the process NIR spectra. In qualitative analysis, the PCA algorithm and multivariate statistical process control (MSPC) model is used to extract the main pattern from the process NIR spectra. Results revealed that there was batch-to-batch variation in the TCM production, and such variation could be due to the process uncertainty. The quantitative and qualitative models need to be updated to cope with the process variations. The PAT methods are helpful to observe the phenomena of batch-to-batch variations, but deserve the limited competence of control within the production unit.
3. Study of the quality transferring law of TCM production
By applying the concept of ICH's Quality by Design (QbD), the establishment of design space for the TCM production process is proposed. Design space stands for a higher level and deep understanding of the TCM production process, and its development is based on process models. In this part, four kinds of data-driven approximation models, i.e. polynomial model, least square support vector machine (LS-SVM), radical basis function neural network (RBFNN) and Kriging model, are used to build surrogates for the water extraction and alcohol precipitation process of gardenia fruit. The hyperparameters of LS-SVM, RBFNN and Kriging models are optimized by a combination of genetic algorithm (GA) and adaptive modeling technique. Based on the process models, the relationships between the critical process parameters and critical quality attributes of the process unit are investigated by the response surface methodology, uncertainty analysis and sensitivity analysis.
With the established process unit models and the help from the system science theory, a "partition-integration" modeling method is used to develop the multi-unit combinational model for the "extraction-concentration-alcohol precipitation" processes of gardenia fruit. Based on the multi-unit combinational model, the Monte Carlo simulation (MCS) is applied to approximate the multi-unit combinational design space, which is visualized by the parallel coordinate plot. Through the multi-unit combinational design space, the quality transfer laws of Geniposide and Genipin-1-β-D-gentiobioside are studied.
4. Study of the strategy for the overall process optimization of TCM production
This part presents a new strategy, target-oriented overall process optimization (TOPO), which can be used to assure the consistent quality in TCM products. The methodology of TOPO includes four parts, target definition, data pretreatment, process modeling and overall process optimization. The Bayesian approach is integrated into the optimization step. The mechanism of TOPO involves optimizing multiple units of the production system step by step, giving each unit optimal operating conditions consistent with the quality target. The probability trajectory is adjusted to monitor and optimize the production process. The proposed TOPO strategy was successfully applied to seven-unit manufacturing process used to produce Lonicerae Japonicae extract and six-unit production process of gardenia extract. Results demonstrated that TOPO could keep the production process in line with the predefined target and reduce the variability of the final products. In general, TOPO explores the full potential of legacy batch production data with respect to understanding and optimizing the herbal production process, and provides systematic ways to the overall process optimization of the TCM production.
All in all, this thesis integrates the process unit research and multi-unit research, the laboratory scale research and production scale research, the theoretical study and practical application together. The proposed OPO methodologies and technologies for TCM production will help to enhance the level of quality control of TCM products as well as core competiveness of TCM industry.
引文
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