Skip to main content
SpringerLink
Log in

Application of Quality by Design to the Process Development of Botanical Drug Products: A Case Study

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

This paper was designed to assess the value of quality by design (QbD) to improve the manufacturing process understanding of botanical drug products. Ethanol precipitation, a widely used unit operation in the manufacture of botanical drug products was employed to illustrate the use of QbD, taking the process of danshen (the dry root of Salvia miltiorrhiza Bunge) as an example. The recovery of four active pharmaceutical ingredients (APIs) and the removal of saccharides were used to represent the performance of ethanol precipitation. Potentially critical variables, including density of concentrate, ethanol consumption, and settling temperature were identified through risk assessment methods. Design of experiments (DOE) was used to evaluate the effects of the potentially critical factors on the performance of ethanol precipitation. It was observed that higher density of concentrate leads to higher removal of saccharides, but results in lower recovery of APIs. With the rise of ethanol consumption, the recovery of different APIs behaves in different ways. A potential design space of ethanol precipitation operation was established through DOE studies. The results in this work facilitate the enhanced understanding of the relationships between multiple factors (material attributes and process parameters) and the performance of ethanol precipitation. This case study demonstrated that QbD is a powerful tool to develop manufacturing process of botanical drug products.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Yang L, Wang Y, Wang L, Xiao H, Wang Z, Hu Z. Rapid quantification of iridoid glycosides analogues in the formulated Chinese medicine Longdan Xiegan Decoction using high-performance liquid chromatograph coupled with mass spectromentry. J Chromatogr A. 2009;1216:2098–103.

    Article  PubMed  CAS  Google Scholar 

  2. ICH Q8 (R2). Pharmaceutical development. 2009. http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html. Accessed 18 May 2012.

  3. Basalious EB, El-Sebaie W, El-Gazayerly O. Application of pharmaceutical QbD for enhancement of the solubility and dissolution of a class II BCS drug using polymeric surfactants and crystallization inhibitors: development of controlled-release tablets. AAPS Pharm Sci Tech. 2011;12(3):799–810.

    Article  CAS  Google Scholar 

  4. Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25(4):781–91.

    Article  PubMed  CAS  Google Scholar 

  5. Zhang X, Lionberger RA, Davit BM, Yu LX. Utility of physiological based absorption modeling in implementing quality by design in drug development. AAPS J. 2011;13(1):59–71.

    Article  PubMed  Google Scholar 

  6. Al-Hallak MHDK, Azarmi S, Xu Z, Maham Y, Löbenberg R. Isothermal microcalorimetry as a quality by design tool to determine optimal blending sequences. AAPS J. 2010;12(3):417–23.

    Article  PubMed  CAS  Google Scholar 

  7. Chen Y, Jin Y, Cai S, Cheng Y, Qu H. Study Progresses: TCM ethanol precipitation techniques and associated equipment. World Sci Technol. 2007;9(5):16–9.

    Google Scholar 

  8. Gong X, Wang S, Qu H. Comparison of two separation technologies applied in the manufacture of botanical injections: second ethanol precipitation and solvent extraction. Ind Eng Chem Res. 2011;50:7542–8.

    Article  CAS  Google Scholar 

  9. Koh GY, Chou G, Liu Z. Purification of a water extract of Chinese sweet tea plant (Rubus suavissimus S. Lee) by alcohol precipitation. J Agric Food Chem. 2009;57:5000–6.

    Article  PubMed  CAS  Google Scholar 

  10. Schmourlo G, Mendonça-Filho RR, Alviano CS, Costa SS. Screening of antifungal agents using ethanol precipitation and bioautography of medicinal and food plants. J Ethnopharmacol. 2005;96:563–8.

    Article  PubMed  Google Scholar 

  11. Wang X, Morris-Natscbke SL, Lee KH. New developments in the chemistry and biology of the bioactive constituents of Tanshen. Med Res Rev. 2007;27(1):133–48.

    Article  PubMed  Google Scholar 

  12. Li YG, Song L, Liu M, Hu ZB, Wang ZT. Advancement in analysis of Salviae miltiorrhizae Radix et Rhizoma (Danshen). J Chromatogr A. 2009;1216:1941–53.

    Article  PubMed  CAS  Google Scholar 

  13. Zhou L, Zuo Z, Chow MSS. Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol. 2005;45:1345–59.

    Article  PubMed  CAS  Google Scholar 

  14. Lau KM, Lai KK, Liu CL, Tam JCW, To MH, Kwok HF, et al. Synergistic interaction between Astragali Radix and Rehmanniae Radix in a Chinese herbal formula to promote diabetic wound healing. J Ethnopharmacol. 2012;141:250–6.

    Article  PubMed  Google Scholar 

  15. Izumi E, Ueda-Nakamura T, Veiga VF, Pinto AC, Nakamura CV. Terpenes from Copaifera demonstrated in vitro antiparasitic and synergic activity. J Med Chem. 2012;55:2994–3001.

    Article  PubMed  CAS  Google Scholar 

  16. Herranz-Lopez M, Fernandez-Arroyo S, Perez-Sanchez A, Barrajon-Catalan E, Beltran-Debon R, Menedez JA, et al. Synergism of plant-derived polyphenols in adipogenesis: perspectives and implications. Phytomedicine. 2012;19:253–61.

    Article  PubMed  CAS  Google Scholar 

  17. Li H, Song F, Zheng Z, Liu Z, Liu S. Characterization of saccharides and phenolic acids in the Chinese herb Tanshen by ESI-FT-ICR-MS and HPLC. J Mass Spectrom. 2008;43:1545–52.

    Article  PubMed  CAS  Google Scholar 

  18. Falcone PM, Tagliazucchi D, Verzelloni E, Giudici P. Sugar conversion induced by the application of heat to grape must. J Agric Food Chem. 2010;58:8680–91.

    Article  PubMed  CAS  Google Scholar 

  19. Severin I, Dumont C, Jondeau-Cabaton A, Graillot V, Chagnon MC. Genotoxic activities of the food contaminant 5-hydroxymethylfurfural using different in vitro bioassays. Toxicol Lett. 2010;192:189–94.

    Article  PubMed  CAS  Google Scholar 

  20. Adam S, Suzzi D, Radeke C, Khinast JG. An integrated quality by design (QbD) approach towards design space definition of a blending unit operation by discrete element method (DEM) simulation. Eur J Pharm. 2011;42:106–15.

    Article  CAS  Google Scholar 

  21. ICH Q9. Quality risk management. 2005. http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html. Accessed 18 May 2012.

  22. Commission CP. Chinese Pharmacopoeia. Beijing: China Medical Science Press; 2010. p. 907.

    Google Scholar 

  23. Dubois M, Gilles KA, Hamilton JK, Rebers PA, Smith F. Colorimetric method for determination of sugars and related substances. Anal Chem. 1956;28(3):350–6.

    Article  CAS  Google Scholar 

  24. Lepore J, Spavins J. PQLI design space. J Pharm Innov. 2008;3:79–87.

    Article  Google Scholar 

  25. Boukouvala F, Muzzio FJ, Ierapetritou MG. Design space of pharmaceutical processes using data-driven-based methods. J Pharm Innov. 2010;5:119–37.

    Article  Google Scholar 

  26. Huang J, Kaul G, Cai C, Chatlapalli R, Hernandez-Abad P, Ghosh K, Nagi A. Quality by design case study: an integrated multivariate approach to drug product and process development. Int J Pharm. 2009;382:23–32.

    Article  PubMed  CAS  Google Scholar 

  27. Zhang L, Gong X, Wang Y, Qu H. Solubilities of protocatechuic aldehyde, caffeic acid, d-galactose, and d-raffinose pentahydrate in ethanol-water solutions. J Chem Eng Data. 2012;57:2018–22.

    Article  CAS  Google Scholar 

  28. Alves LA, Silva JBA, Giulietti M. Solubility of d-glucose in water and ethanol/water mixtures. J Chem Eng Data. 2007;52(6):2166–70.

    Article  CAS  Google Scholar 

  29. Bouchard A, Hofland GW, Witkamp GJ. Properties of sugar, polyol, and polysaccharide water-ethanol solutions. J Chem Eng Data. 2007;52(5):1838–42.

    Article  CAS  Google Scholar 

  30. Gong X, Wang S, Qu H. Solid–liquid equilibria of d-glucose, d-fructose and sucrose in the mixture of ethanol water from 273.2 K to 293.2 K. Chin J Chem Eng. 2011;19(2):1–6.

    Article  Google Scholar 

  31. Macedo EA, Peres AM. Thermodynamics of ternary mixtures containing sugars. SLE of d-fructose in pure and mixed solvents. Comparison between modified UNIQUAC and modified UNIFAC. Ind Eng Chem Res. 2001;40(21):4633–40.

    Article  CAS  Google Scholar 

  32. Kapsi SG, Castro LD, Muller FX, Wrzosek TJ. Development of a design space for a unit operation: illustration using compression-mix blending process for the manufacture of a tablet dosage form. J Pharm Innov. 2012;7:19–29.

    Article  Google Scholar 

  33. ICH Q10. Pharmaceutical quality system. 2008. http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html. Accessed 18 May 2012.

  34. Huang H, Qu H. In-line monitoring of alcohol precipitation by near-infrared spectroscopy in conjunction with multivariate batch modeling. Anal Chem Acta. 2011;707:47–56.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the China International Science and Technology Cooperation Project (2010DFB33630) and Zhejiang Provincial Natural Science Foundation of China (LQ12H29004).

Author information

Authors and Affiliations

  1. Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, People’s Republic of China

    Lei Zhang, Binjun Yan, Xingchu Gong & Haibin Qu

  2. Office of Generic Drugs, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD, 20855, USA

    Lawrence X. Yu

Authors
  1. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Binjun Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xingchu Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lawrence X. Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haibin Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haibin Qu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, L., Yan, B., Gong, X. et al. Application of Quality by Design to the Process Development of Botanical Drug Products: A Case Study. AAPS PharmSciTech 14, 277–286 (2013). https://doi.org/10.1208/s12249-012-9919-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-012-9919-8

KEY WORDS

Search

Navigation