| The quality of Chinese herbal medicine is affected by various aspects of manufacturing process which is considered as a complex system.With the extensive application of modern information technology,analytical technology and sensor technology in the Chinese herbal medicine manufacturing process,the establishment of the comprehensive quality control system from raw materials to products is the key to ensure the quality target,to deliver substance,energy and efficacy stably,and to maintain the quality consistent of intra and inter batches,At present,the quality control of the Chinese herbal medicine manufacturing process was mainly based on analytical and statistical methodologies.On one hand,results of analytical test on the raw materials,intermediates and products were used to determine whether the quality was compliant according to the established quality standards in the manufacturing process.On the other hand,the statistical process control models were built based on the quality-related information,and the control limits and the process capability index were calculated to real time monitor the quality.However,with the implementation of the "Made in China 2025”and"Guidance for Pharmaceutical industry development",the Chinese herbal medicine manufacturing enterprises have expressed a strong desire to apply the efficient and intelligent pharmaceutical equipment,and to implement the advanced quality management and control technologies.The current quality control of Chinese herbal medicine based on analytical and statistical methodologies has been unable to meet the requirement in the future.In order to increase the transparency of the Chinese herbal medicine manufacturing process and improve the intelligence,efficiency and reliability of the quality control,this article was focused on the Chinese herbal medicine quality design and control methodology under the guidance of Quality by Design(QbD)concept.The relationships among the critical materials attributes,the critical process parameters and critical quality attributes were established with the process system modeling method.The product quality could be predicted and the significant variables affecting the product quality were also identified.Then the feedforward and feedback control strategy,and the real time release testing could be implemented.This methodology promote the quality control of Chinese medicine changed from passive to active,from empirical control to scientific decision-making.The thesis was organized as the following four sections.1.System model on Chinese herbal medicine manufacturing processUnder the holistic view of TCM and theory of system science,this section was focused on the system modeling method of Chinese herbal medicine manufacturing process in order to improve the interpretation of manufacturing process.The manufacturing process of Panax notoginseng saponins tablet was taken as a research object.The data were collected from experiments conducted based on design of experiment.In order to understand the correlations among the variables and the distribution of samples in each unit,the exploratory analysis was conducted with principle component analysis(PCA)method.On the basis,the path modeling method which contained the internal structure of process was applied to build the system model.The Q2 of the path model was 63.5%which indicated that the model predictive performance was good and it was suitable for quantitative analysis of the complex system.The path model was useful to interpret the connection among the process unit and quality transfer direction,to improve the understandings on the process system.2.Analyzing the characteristics of Chinese medicine manufacturing processIn this section,the characteristics of Chinese herbal medicine manufacturing process were analyzed from two viewpoints of input raw materials and process.There is a biggest difference between raw materials of Chinese medicine and chemical medicine.Different batches of the Panax notoginseng saponins extracts were collected.Both the chemical components and the physical properties of the Panax notoginseng saponins extracts were evaluated.The granules and tablets were produced under the same operation conditions.The properties of granules and tablets were also measured.The impacts of raw materials variations on the properties of the granules and tablets were analyzed with both the intuitive comparison and the statistical modeling method.The results show that the physical properties had great effects on the quality of the product(BIP>1).Among them,the particle size,bulk density and tap density of Panax notoginseng extract are the critical material attributes.One batch of Panax notoginseng saponins extracts was selected and was prepared based on the experimental design.The partial least squares(PLS),orthogonal partial least squares(OPLS)and multiblock partial least squares(MBPLS)were combined and applied to analyze the relationships among the process parameters,granule physical properties and the product quality.The results showed that the different model can improve understandings on the Chinese medicine manufacturing process from different view point.It was very useful to evaluate the influence of process parameters on product quality and identify the critical process parameters and the critical process units comprehensively.3.Feedforward control strategy of Chinese herbal medicine manufacturing processLarge quantities of the uncertainty factors coming from Chinese medicine manufacturing process mainly lead to worse quality consistency of Chinese medicine preparations.In order to reduce the batch-to-batch variation,in this section,taking manufacturing process of Panax notoginseng saponins tablet as an example,the feedforward control strategy was presented for the Chinese herbal medicine manufacturing process.The performance of feedforward control strategy was validated by the Monte Carlo simulation using the existed experimental data.The results demonstrated that the predictive performance of the model was good by the expanding PLS method.With the accumulation of process quality,the R2 and Q2 of the PLS model were gradually improved.Constraints in the original variable space and the latent variable space were both used to optimize at the same time.Compared with the optimization using constraints in the original variable space alone,the obtained optimization results not only met the requirements of the original variables,but also got lower Hotelling T2 and SPE,indicating it was closer to the center of the latent variable space,that is,closer to the original operation mode and finally acquired higher reliability.4.Real time release testing control of Chinese herbal medicine manufacturing processUsing the process data of Chinese herbal medicine manufacturing process,this section established the real-time release testing control strategy of PNS tablet manufacturing process.The results showed that the descision based on the real-time release testing was consistent with the end point testing.It was indicated that the real-time release testing control strategy can be a substitute of the end point testing in order to reduce the frequency of the end point testing and to reduce costs of quality control.In this section,the real time release testing methods of critical quality attributes of intermediate and product from the manufacturing process of Panax notoginseng saponins tablet were built based on the process analytical technology.The predictive models of D10 and bulk density(Db)of Panax notoginseng saponins granules were established by using near infrared(NIR)spectra and process parameters,respectively.Results demonstrated that the performance of predictive models of D10 was all perfect,and the performance of predictive models of Db was good.More importantly,the real-time release test model with NIR spectrum was more accurate for both D10 and Db.It was confident that NIR spectrum can reflect the information of granules more comprehensively.Different API contents of Panax notoginseng saponins tablets were produced through a design of experiment.The NIR spectra of tablets were collected and the real time release testing model of APIs was established.Based on β-ETI,the total error was calculated for the quantitative analysis of the NIR and the quality control limits of APIs in Panax notoginseng saponins tablets were also determined.Results showed that the range of quality control calculated from β-ETI was significantly narrowed compared with the origin,which effectively decreased the release risk and improved the reliability of real time release.In this thesis,the process system modeling method,the feedforward control and the real time release testing were put forward to overcome several key problems of predictive quality control in the Chinese herbal medicine manufacturing process.These proposed methods were useful to increase the understanding on the causal relationships among different variables in the process system,to identify critical process unit,to enhance the process robustness,to improve the reliability of release decision-making,and to promote the development of intelligent quality control in the Chinese medicine manufacturing process. |
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