Abstract: The efficacy of traditional Chinese medicine (TCM) is based on the combined effects of its constituents. Variation in chemical composition between batches of TCM has always been the deterring factor in achieving consistency in efficacy. The batch mixing process can significantly reduce the batch-to-batch quality variation in TCM extracts by mixing them in a well-designed proportion. However, reducing the quality variation without sacrificing too much of the production efficiency is one of the challenges. Accordingly, an innovative and practical batch mixing method aimed at providing acceptable efficiency for industrial production of TCM products is proposed in this work, which uses a minimum number of batches of extracts to meet the content limits. The important factors affecting the utilization ratio of the extracts (URE) were studied by simulations. The results have shown that URE was affected by the correlation between the contents of constituents, and URE decreased with the increase in the number of targets and the relative standard deviations of the contents. URE could be increased by increasing the number of storage tanks. The results have provided a reference for designing the batch mixing process. The proposed method has possible application value in reducing the quality variation in TCM and providing acceptable production efficiency simultaneously.

[1]Efferth, T., Koch, E., 2011. Complex interactions between phytochemicals. The multi-target therapeutic concept of phytotherapy. Curr. Drug Targets, 12(1):122-132.

[2]Fan, X.H., Cheng, Y.Y., Ye, Z.L., Lin, R.C., Qian, Z.Z., 2006. Multiple chromatographic fingerprinting and its application to the quality control of herbal medicines. Anal. Chim. Acta, 555(2):217-224.

[3]Gao, S., Jiang, W., Yin, T.J., Hu, M., 2010. Highly variable contents of phenolics in St. John’s Wort products affect their transport in the human intestinal Caco-2 cell model: pharmaceutical and biopharmaceutical rationale for product standardization. J. Agric. Food. Chem., 58(11):6650-6659.

[4]García-Muñoz, S., Dolph, S., Ward II, H.W., 2010. Handling uncertainty in the establishment of a design space for the manufacture of a pharmaceutical product. Comput. Chem. Eng., 34(7):1098-1107.

[5]Huang, H.X., Qu, H.B., 2011. In-line monitoring of alcohol precipitation by near-infrared spectroscopy in conjunction with multivariate batch modeling. Anal. Chim. Acta, 707(1):47-56.

[6]Huang, J., Goolcharran, C., Utz, J., Hernandez-Abad, P., Ghosh, K., Nagi, A., 2010. A PAT approach to enhance process understanding of fluid bed granulation using in-line particle size characterization and multivariate analysis. J. Pharm. Innov., 5(1):58-68.

[7]ICH (International Conference on Harmonization), 2009. ICH Harmonised Tripartite Guideline: Pharmaceutical Development Q8(R2). Available from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf [Accessed on Apr. 28, 2012].

[8]Kumral, M., 2005. Quadratic programming for the multivariable pre-homogenization and blending problem. J. S. Afr. Inst. Min. Metall., 105(5):317-322.

[9]Kumral, M., 2006. Bed blending design incorporating multiple regression modelling and genetic algorithms. J. S. Afr. Inst. Min. Metall., 106(3):229-236.

[10]Liu, Y.S., Cao, M., Chen, Y.Y., Hu, Y.Z., Wang, Y.M., Luo, G.A., 2006. Study of blending method for the extracts of herbal plants. Chin. J. Chromatogr., 24(2):117-121.

[11]Luo, X.F., Mo, B.Q., Ye, Y.Y., Cheng, Y.Y., Qu, H.B., 2007. Homogenization for quality control of compound Danshen extract. Chin. Tradit. Herb. Drugs, 38(12):1817-1819 (in Chinese).

[12]Michaels, J.N., Bonsignore, H., Hudson-Curtis, B.L., Laurenz, S., Lin, H.R.H., Mathai, T., Pande, G., Sheth, A., Sprockel, O., 2011. Attribute-based design space: materials-science-based quality-by-design for operational flexibility and process portability. J. Pharm. Innov., 6(4):193-201.

[13]Prpich, A., Ende, M.T.A., Katzschner, T., Lubczyk, V., Weyhers, H., Bernhard, G., 2010. Drug product modeling predictions for scale-up of tablet film coating—a quality by design approach. Comput. Chem. Eng., 34(7):1092-1097.

[14]Qu, H.B., Ou, D.L., Cheng, Y.Y., 2006. A new quality control method of Chinese medicinal plant extracts. Chin. Pharm. J., 41(1):57-60 (in Chinese).

[15]Tistaert, C., Dejaegher, B., van der Heyden, Y., 2011. Chromatographic separation techniques and data handling methods for herbal fingerprints: a review. Anal. Chim. Acta, 690(2):148-161.

[16]Wang, S.F., Fang, H.Y., Qu, H.B., 2011. Optimization of micellar electrokinetic capillary chromatography method using central composite design for the analysis of components in Yangwei granule. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 12(3):193-200.

[17]Wang, Y., Yu, L.Y., Zhang, L., Qu, H.B., Cheng, Y.Y., 2010. A novel methodology for multicomponent drug design and its application in optimizing the combination of active components from Chinese medicinal formula Shenmai. Chem. Biol. Drug Des., 75(3):318-324.

[18]Xie, B.G., Gong, T., Tang, M.H., Mi, D.F., Zhang, X., Liu, J., Zhang, Z.R., 2008. An approach based on HPLC-fingerprint and chemometrics to quality consistency evaluation of Liuwei Dihuang Pills produced by different manufacturers. J. Pharm. Biomed. Anal., 48(4):1261-1266.

[19]Yacoub, F., Lautens, J., Lucisano, L., Banh, W., 2011. Application of quality by design principles to legacy drug products. J. Pharm. Innov., 6(2):61-68.

[20]Yang, H.H., Wang, Y., Zhang, H.Y., Liang, Q.L., Wang, Y.M., Luo, G.A., 2007. Optimization method for blending traditional Chinese medicine herbs to ensuring the content stability of multiple indicative constituents. Chem. J. Chin. Univ., 28(10):1863-1868 (in Chinese).

[21]Yang, M., Zhou, Y.M., Chen, J.L., Yu, M.Y., Shi, X.F., Gu, X.J., 2009. Application of genetic algorithm in blending technology for extractions of Cortex Fraxini. China J. Chin. Mater. Med., 34(20):2594-2598.

[22]Zhang, X.P., Feng, G.H., Zhang, J., Cai, Y., Tian, H., Zhang, X.F., Zhou, Y.F., Wang, Z.W., Wang, K.Y., 2009. Protective effects of salvia miltiorrhizae on the hearts of rats with severe acute pancreatits or obstructive jaundice. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 10(3):193-202.