基于过程分析技术和设计空间的金银花醇沉加醇过程终点检测

建立了一种新的基于过程分析技术(PAT)和质量源于设计(QbD)设计空间的中药制药过程终点分析与控制方法.以近红外(NIR)光谱技术为PAT工具, 采集正常操作条件下制药过程的多批次NIR光谱; 采用主成分分析结合移动块相对标准偏差(PCA-MBRSD)法, 确定每一批次过程的理想终点样本(DEPs), 由多批DEPs的光谱信息构成过程终点设计空间; 在过程终点设计空间确定的范围内, 建立多变量统计过程控制(MSPC)模型, 利用多变量Hotelling T²和SPE控制图对过程终点进行判断.应用上述方法, 进行了金银花醇沉加醇过程终点检测研究, 结果表明该方法灵敏、准确, 适宜于中药制药过程终点检测.     

Batch process monitoring using on-line MIR spectroscopy

Many high quality products are produced in a batch wise manner. One of the characteristics of a batch process is the recipe driven nature. By repeating the recipe in an identical manner a desired end-product is obtained. However, in spite of repeating the recipe in an identical manner, process differences occur. These differences can be caused by a change of feed stock supplier or impurities in the process. Because of this, differences might occur in the end-product quality or unsafe process situations arise. Therefore, the need to monitor an industrial batch process exists. An industrial process is usually monitored by process measurements such as pressures and temperatures. Nowadays, due to technical developments, spectroscopy is more and more used for process monitoring. Spectroscopic measurements have the advantage of giving a direct chemical insight in the process. Multivariate statistical process control (MSPC) is a statistical way of monitoring the behaviour of a process. Combining spectroscopic measurements with MSPC will notice process perturbations or process deviations from normal operating conditions in a very simple manner. In the following an application is given of batch process monitoring. It is shown how a calibration model is developed and used with the principles of MSPC. Statistical control charts are developed and used to detect batches with a process upset.     

中药注射剂荧光光谱法的快速鉴别和热稳定性研究

红外光谱指纹图谱技术应用中药注射剂的快速鉴别中，某些试样因难于成膜造成制样困难，为此，直接或仅经水稀释后测定了12种21批次的常用中药注射剂的荧光光谱。结果表明：由于中药注射剂常含荧光性物质，但因不同注射剂所含具体荧光性物质不同，同种注射剂又因厂家的具体配方的差异或制备工艺条件的波动，均会使其特征的荧光激发、发射光谱不同或其强度呈现差异；从而可充分利用荧光分析的高灵敏度，使其作为中药整体红外指纹识别的一种辅助手段，根据注射剂的荧光图谱的差异达到快速鉴别、认定和控制配方、工艺的目的。比较而言，荧光法表现出来的差异更为一目了然，易于判断。此外，荧光光谱法还可用于中药注射液的热稳定性的研究。     

NIR analysis for batch process of ethanol precipitation coupled with a new calibration model updating strategy

Ethanol precipitation plays a major role in the pretreatment of Flos Lonicerae Japonicae of Qingkailing injection, and is also one of the most popular purification techniques in Chinese herbal medicines. In order to monitor and have a better understanding of the ethanol precipitation process, a PLS model was built based on NIR spectroscopy and HPLC analysis of chlorogenic acid content within the framework of FDA's PAT initiative. Nevertheless, due to the complex mechanism of and the raw materials’ natural variability introduced into the ethanol precipitation process, it was unable to foresee the variations in new batches which may jeopardize the robustness of the established model. Therefore, based on the simple interval calculation (SIC) theory, a new model expansion updating strategy which could continuously expand the variation coverage of the calibration model along with the batch proceeding of ethanol precipitation process was proposed. Effects of model updating were validated by an individual batch with 60 samples. After two times of updating, the root mean squared error of prediction (RMSEP) decreased from 0.268 mg mL⁻¹ to 0.199 mg mL⁻¹, while the insiders in the object status plot (OSP) increased from 44 to 58, demonstrating the good performance of the proposed approach.     

A batch modelling approach to monitor a freeze-drying process using in-line Raman spectroscopy

Freeze-drying or lyophilisation is a batch wise industrial process used to remove water from solutions, hence stabilizing the solutes for distribution and storage. The objective of the present work was to outline a batch modelling approach to monitor a freeze-drying process in-line and in real-time using Raman spectroscopy. A 5% (w/v) d-mannitol solution was freeze-dried in this study as model. The monitoring of a freeze-drying process using Raman spectroscopy allows following the product behaviour and some process evolution aspects by detecting the changes of the solutes and solvent occurring during the process. Herewith, real-time solid-state characterization of the final product is also possible.The timely spectroscopic measurements allowed the differentiation between batches operated in normal process conditions and batches having deviations from the normal trajectory. Two strategies were employed to develop batch models: partial least squares (PLS) using the unfolded data and parallel factor analysis (PARAFAC). It was shown that both strategies were able to developed batch models using in-line Raman spectroscopy, allowing to monitor the evolution in real-time of new batches. However, the computational effort required to develop the PLS model and to evaluate new batches using this model is significant lower compared to the PARAFAC model. Moreover, PLS scores in the time mode can be computed for new batches, while using PARAFAC only the batch mode scores can be determined for new batches.     

指纹图谱法在参麦注射液质控中的应用

 中医药理论和实践要求综合评价中药的质量 ,指纹图谱法是对中药制剂进行综合宏观分析的可行手段之一 ,因此采用反相高效液相建立了参麦注射液的特征指纹图谱。条件 :Hypersil C18(4 6mmi d × 2 5 0mm ,5 μm)反相柱 ,流动相由水 (A)和乙腈 (B)组成 ,B的体积分数在 5 0min内由 5 %线性增长到 95 % ,流速为1 0mL/min ;紫外检测 ,波长为 2 0 2nm。 2 3个特征指纹峰与内标 (联苯 )的峰面积比作为指标 ,结合主成分分析 投影判别法比较了同一厂家不同批次产品和不同厂家同类产品的化学指纹差异。     

中药材提取物的混批勾兑研究

采用非线性最小二乘拟合计算中药材提取物的勾兑系数,不同批的中药材提取物经过勾兑后与参照样品的差异减小,各成分含量稳定。采用数据预处理的方法,并对数据预处理方法进行改进,使峰面积较小的色谱峰可以实现较小的相对差异。引入误差控制系数,可实现对特定色谱峰的控制要求。实验结果表明,非线性最小二乘拟合可以用于计算中药材提取物的勾兑系数。     

Quality fluctuation detection of an herbal injection based on biological fingerprint combined with chemical fingerprint

Herbal injection is one of the most important preparations of traditional Chinese medicine. More than 130 types of herbal injections are used clinically for 400 million patients annually with total sales of over four billion US dollars per year. However, the current quality control (QC) methods relying mainly on chemical fingerprints (CF) can hardly ensure quality and safety of the herbal injections with complex chemical composition and have resulted in an increase in serious adverse drug reactions. In this study, a comprehensive approach for the QC of a controversial herbal injection Shuang-Huang-Lian lyophilized powder (SHL) was established based on the quality fluctuation detection by a combination of CF and biological fingerprint (BF). High-performance liquid chromatography and the impedance-based xCELLigence system were applied to establish the CF and BF, respectively. In addition, multivariate analysis was performed to evaluate the discriminant ability of the two methods. The results showed that being subjected to environmental influence like oxygen/air, high temperature, and extreme illumination could lead to quality fluctuation of SHL. The combination of chemical and biological fingerprint method is a more powerful tool for the QC of SHL because it can clearly discriminate different groups of abnormal samples. This method can be used for the detection of quality fluctuation of SHL and can provide reference for the quality control of other herbal injections.     

高效液相色谱-电感耦合等离子体质谱(ICP-MS)法测定中药材中无机汞、甲基汞、乙基汞

为准确测定中药材中不同形态的汞含量,通过选用人工胃液作为提取液,经水浴加热提取后,以甲醇-乙酸铵为流动相,采用C18反相色谱柱对样品溶液进行分离,最后经电感耦合等离子体质谱(ICP-MS)法测定3种汞形态化合物的含量。建立了中药材中无机汞、甲基汞、乙基汞的高效液相色谱-电感耦合等离子体质谱(HPLC-ICP-MS)法的测定方法,结果表明,3种汞形态化合物在0.5～5 ng/mL范围内均获得良好的线性关系,相关系数均大于0.999。通过加标回收的方法进行准确性评价,加标回收率为75.5%～118%,相对标准偏差RSD为2.4%～9.7%。测定的106批次中药材中,均未检出甲基汞、乙基汞。无机汞检出率为88.7%,合格率为100%。方法能够准确、高效地测定中药材中3种汞形态化合物的含量。106批次中药材中的汞存在形态主要是以无机汞为主。考察的106批次根及根茎类中药材中3种汞形态化合物的含量,积累了基础数据,为中药饮片的质量安全性监管提供技术支撑。     

基于三波长融合谱的系统指纹定量法鉴定龙胆泻肝丸的真实质量

建立了龙胆泻肝丸(Longdanxiegan pill,LDXGP)三波长融合高效液相色谱(HPLC)指纹图谱,以系统指纹定量法全面鉴定LDXGP的质量。采用反相高效液相色谱法(RP-HPLC),运用多波长融合指纹图谱技术对色谱图进行处理,以黄芩苷为参照物峰,确立了63个共有指纹峰,以宏定性相似度为参量对12个厂家的12批LDXGP进行聚类分析,确定用其中10批生成对照指纹图谱(RFP),以此RFP为标准用系统指纹定量法评价12批LDXGP的质量。结果鉴别出9批质量完全合格,1批含量明显偏高,2批化学成分数量和分布比例不合格。基于多波长融合技术的系统指纹定量法是评价中药真实质量的可靠方法。     

OPLS in batch monitoring – Opens up new opportunities

In batch statistical process control (BSPC), data from a number of “good” batches are used to model the evolution (trajectory) of the process and they also define model control limits, against which new batches may be compared. The benchmark methods used in BSPC include partial least squares (PLS) and principal component analysis (PCA).     

In‐Line Monitoring of Vinyl Chloride Suspension Polymerization with Near Infrared Spectroscopy, 2 ‐ Design of an Advanced Control Strategy

Near infrared spectroscopy (NIRS) may constitute a powerful tool for in‐line monitoring of morphological properties of PVC particles in suspension polymerizations. It is shown that dynamic trajectories of morphological properties, as predicted with NIR‐based calibration models, change smoothly along the batch; thus, these trajectories can be used as references for process monitoring and control. It is also shown that modification of operation variables during the batch leads to modification of the final morphological properties of the powder. This indicates that the morphology of PVC grains can be manipulated along the batch and that advanced NIR‐based control procedures can be implemented for control of the morphological properties of PVC resins, as illustrated through simulation.

     

Quality evaluation of Hypericum ascyron extract by two‐dimensional high‐performance liquid chromatography coupled with the colorimetric 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide method

In this paper, a heart‐cutting two‐dimensional high‐performance liquid chromatography coupled with the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) method was established for controlling the quality of different batches of Hypericum ascyron extract for the first time. In comparison with the common one‐dimensional fingerprint, the second‐dimensional fingerprint compiled additional spectral data and was hence more informative. The quality of H. ascyron extract was further evaluated by similarity measures and the same results were achieved, the correlation coefficients of the similarity of ten batches of H. ascyron extract were ＞0.99. Furthermore, we also evaluated the quality of the ten batches of H. ascyron extract by antibacterial activity. The result demonstrated that the quality of the ten batches of H. ascyron extract was not significantly different by MTT. Finally, we demonstrated that the second‐dimensional fingerprint coupled with the MTT method was a more powerful tool to characterize the quality of samples of batch to batch. Therefore the proposed method could be used to comprehensively conduct the quality control of traditional Chinese medicines.     

Fantastic plastic? An image-based test method to detect aesthetic defects in batches based on reference samples

The production of high-end manufactured products requires Aesthetic Quality Control (AQC) in the form of human visual inspection. Manufactures can reduce AQC costs by incorporating semi-automated visual defect detection in units with the existing 3D metrology scans. This paper demonstrates how an image-based test method for defect detection can reduce the workload related to human visual inspection by proposing a median master comparison of batch image series. Our contribution consist of a) contrast enhancing and sorting batch image series for human visual inspection and b) providing a quality index (nQI) incorporated into statistical process control (SPC) for monitoring and controlling the AQC process. Our data shows that the median master differencing together with the nQI is great for classification of defects in batch images series. We introduce a SPC design proposal where individual batches as well as aggregated data can be inspected in synergy with the principles of Six Sigma. Based on Six Sigma control limits we have reduced the number of images in need of review by AQC assessors by a factor of 13.     

能量色散X射线荧光光谱法测定中草药中的Cd元素

利用能量散射X射线荧光光谱（ED-XRF）法快速测定中草药中的Cd元素.方法对中草药进行简单预处理（粉碎）,使用X射线荧光光谱法建立中草药中Cd元素含量与相对强度的校正工作曲线,分析中草药样品中的Cd元素.Cd元素的检出限为0.083 mg/kg,定量限为0.207 mg/kg,定量限低于国家控制标准0.3 mg/kg.测量定量限以上的中草药样品时,其准确性与化学分析结果相当,重复性和稳定性等结果完全满足GB/T 4889-2008数据的统计处理标准.方法预处理时间不超过5 min,完成一个样品的检测时间不超过15 min,可应用于中草药生产企业中的重金属监控.     

Evaluation of capillary zone electrophoresis for the quality control of complex biologic samples: Application to snake venoms

Snake venoms constitute a very promising resource for the development of new medicines. They are mainly composed of very complex peptide and protein mixtures, which composition may vary significantly from batch to batch. This latter consideration is a challenge for routine quality control (QC) in the pharmaceutical industry. In this paper, we report the use of capillary zone electrophoresis for the development of an analytical fingerprint methodology to assess the quality of snake venoms. The analytical fingerprint concept is being widely used for the QC of herbal drugs but rarely for venoms QC so far. CZE was chosen for its intrinsic efficiency in the separation of protein and peptide mixtures. The analytical fingerprint methodology was first developed and evaluated for a particular snake venom, Lachesis muta . Optimal analysis conditions required the use of PDADMAC capillary coating to avoid protein and peptide adsorption. Same analytical conditions were then applied to other snake venom species. Different electrophoretic profiles were obtained for each venom. Excellent repeatability and intermediate precision was observed for each batch. Analysis of different batches of the same species revealed inherent qualitative and quantitative composition variations of the venoms between individuals.     

Quality assessment of Cinnamomi Ramulus by the simultaneous analysis of multiple active components using high‐performance thin‐layer chromatography and high‐performance liquid chromatography

A novel and improved method for the quality assessment of Cinnamomi Ramulus was developed and completely validated. The method was established using fingerprint technology and simultaneous quantitative determination of six main marker compounds including coumarin, cinnamic alcohol, cinnamic acid, 2‐methoxy cinnamic acid, cinnamaldehyde, and 2‐methoxy cinnamaldehyde in the herbal medicine for the first time. A newly developed high‐performance thin‐layer chromatography method, which achieved simultaneous definition of five marker components by comparing the colors and retardation factor values of the bands in high‐performance thin‐layer chromatography, was first used for the authentication of Cinnamomi Ramulus. The fingerprints of 26 batches of herbal samples from different regions of China showed very similar chromatographic patterns that were evaluated by similarity analysis and hierarchical clustering analysis. In addition, six marker compounds were simultaneously determined using single standard to determine multiple components by the relative response factors. Compared with the external standard method, the new quantitative method was validated to determine multiple compounds in 26 batches of Cinnamomi Ramulus samples. All results demonstrated that the simple and rapid method could be effectively utilized for the quality control of Cinnamomi Ramulus.     

Using Unfold‐PCA for batch‐to‐batch start‐up process understanding and steady‐state identification in a sequencing batch reactor

In chemical and biochemical processes, steady‐state models are widely used for process assessment, control and optimisation. In these models, parameter adjustment requires data collected under nearly steady‐state conditions. Several approaches have been developed for steady‐state identification (SSID) in continuous processes, but no attempt has been made to adapt them to the singularities of batch processes. The main aim of this paper is to propose an automated method based on batch‐wise unfolding of the three‐way batch process data followed by a principal component analysis (Unfold‐PCA) in combination with the methodology of Brown and Rhinehart 2 for SSID. A second goal of this paper is to illustrate how by using Unfold‐PCA, process understanding can be gained from the batch‐to‐batch start‐ups and transitions data analysis. The potential of the proposed methodology is illustrated using historical data from a laboratory‐scale sequencing batch reactor (SBR) operated for enhanced biological phosphorus removal (EBPR). The results demonstrate that the proposed approach can be efficiently used to detect when the batches reach the steady‐state condition, to interpret the overall batch‐to‐batch process evolution and also to isolate the causes of changes between batches using contribution plots. Copyright © 2007 John Wiley & Sons, Ltd.     

近红外光谱法快速测定附子中6个生物碱的含量

应用近红外光谱(NIRS)技术结合偏最小二乘(PLS)和最小二乘支持向量机(LS-SVM)建立了附子中多指标成分的快速无损检测方法.选取38批样品建立了同时测定附子样品中6种成分含量的高效液相色谱(HPLC)方法;通过采集附子样品的NIRS图,分别采用PLS和LS-SVM建立了各个成分HPLC测定值与NIRS图的定量校...     

Method to evaluate the quality of herbal medicines based on the dynamic changes of chemical compounds and pharmacological activity

Quality control has been one of the key scientific issues in the modernization of traditional Chinese medicine. This study explored a novel method for quality evaluation of herbal medicines. High‐performance liquid chromatography fingerprints and the osteoblast proliferation activity of 18 batches of Achyranthes bidentata, which were prepared with salt, were determined to establish a chromatographic database and an activity database. Correlation analyses of these databases were performed using partial least squares to obtain regression coefficients (positive and negative correlation coefficients). Then, the sums of the products of the positive and negative correlation peak areas and the corresponding coefficients, respectively, were calculated for each sample. The absolute value of the ratios of the sums of the positive and negative products were calculated, our studies showed that this ratio was significantly correlated with the proliferation activity, particularly when the activity was in the best and worst ranges. Therefore, we developed a parameter that was used to evaluate the quality of samples osteoblast proliferation activity. The quality of another ten batches of samples was assessed to verify this method. The results indicated that this method can be used for quality evaluation of herbal medicines according to the dynamic changes in the chemical compounds and activity.