Skip to main content
Log in

A Systematic Approach of Employing Quality by Design Principles: Risk Assessment and Design of Experiments to Demonstrate Process Understanding and Identify the Critical Process Parameters for Coating of the Ethylcellulose Pseudolatex Dispersion Using Non-Conventional Fluid Bed Process

AAPS PharmSciTech Aims and scope Submit manuscript

Cite this article


The goal of this study was to utilize risk assessment techniques and statistical design of experiments (DoE) to gain process understanding and to identify critical process parameters for the manufacture of controlled release multiparticulate beads using a novel disk-jet fluid bed technology. The material attributes and process parameters were systematically assessed using the Ishikawa fish bone diagram and failure mode and effect analysis (FMEA) risk assessment methods. The high risk attributes identified by the FMEA analysis were further explored using resolution V fractional factorial design. To gain an understanding of the processing parameters, a resolution V fractional factorial study was conducted. Using knowledge gained from the resolution V study, a resolution IV fractional factorial study was conducted; the purpose of this IV study was to identify the critical process parameters (CPP) that impact the critical quality attributes and understand the influence of these parameters on film formation. For both studies, the microclimate, atomization pressure, inlet air volume, product temperature (during spraying and curing), curing time, and percent solids in the coating solutions were studied. The responses evaluated were percent agglomeration, percent fines, percent yield, bead aspect ratio, median particle size diameter (d50), assay, and drug release rate. Pyrobuttons® were used to record real-time temperature and humidity changes in the fluid bed. The risk assessment methods and process analytical tools helped to understand the novel disk-jet technology and to systematically develop models of the coating process parameters like process efficiency and the extent of curing during the coating process.

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

Access this article

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
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12


  1. Sakr A, Alanazi F. Oral solid dosage forms. In: Felton L, editor. Remington essentials of pharmaceutics. London: Pharmaceutical Press; 2012. pp. 581–610.

  2. Tang ES, Wang L, Liew CV, Chan LW, Heng PW. Drying efficiency and particle movement in coating-impact on particle agglomeration and yield. Int J Pharm. 2008;350(1–2):172–80.

    Article  CAS  PubMed  Google Scholar 

  3. Tabasi SH, Fahmy R, Bensley D, O’Brien C, Hoag SW. Quality by design, part III: study of curing process of sustained release coated products using NIR spectroscopy. J Pharm Sci. 2008;97(9):4067–86.

    Article  CAS  PubMed  Google Scholar 

  4. Howland H, Hoag SW. Analysis of curing of a sustained release coating formulation by application of NIR spectroscopy to monitor changes physical-mechanical properties. Int J Pharm. 2013;452:82–91.

    Article  CAS  PubMed  Google Scholar 

  5. Bodmeier R, Paeratakul O. The effect of curing on drug release and morphological properties of ethylcellulose pseudolatex-coated beads. Drug Dev Ind Pharm. 1994;20(9):1517–33.

    Article  CAS  Google Scholar 

  6. Hutchings D, Kuzmak B, Sakr A. Processing considerations for an EC latex coating system: influence of curing time and temperature. Pharm Res. 1994;11(10):1474–8.

    Article  CAS  PubMed  Google Scholar 

  7. Williams Iii RO, Liu J. Influence of processing and curing conditions on beads coated with an aqueous dispersion of cellulose acetate phthalate. Eur J Pharm Biopharm. 2000;49(3):243–52.

    Article  Google Scholar 

  8. Korber M, Hoffart V, Walther M, Macrae RJ, Bodmeier R. Effect of unconventional curing conditions and storage on pellets coated with Aquacoat ECD. Drug Dev Ind Pharm. 2010;36(2):190–9.

    Article  CAS  PubMed  Google Scholar 

  9. Yang QW, Flament MP, Siepmann F, et al. Curing of aqueous polymeric film coatings: importance of the coating level and type of plasticizer. Eur J Pharm Biopharm. 2010;74(2):362–70.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. U.S. Department of Health and Human Services, Food and Drug Administration, International Conference on Harmonization Q8 (R2) Pharmaceutical Development, Guidance for Industry. FDA document Silver, MD, USA; 2009.

  12. U.S. Department of Health and Human Services, Food and Drug Administration, International Conference on Harmonization Q9 Quality Risk Management. FDA document Silver, MD, USA; 2005.

  13. Moltgen CV, Puchert T, Menezes JC, Lochmann D, Reich G. A novel in-line NIR spectroscopy application for the monitoring of tablet film coating in an industrial scale process. Talanta. 2012;92:26–37.

    Article  PubMed  Google Scholar 

  14. Hansuld EM, Briens L, Sayani A, McCann JAB. An investigation of the relationship between acoustic emissions and particle size. Powder Technol. 2012;219:111–7.

    Article  CAS  Google Scholar 

  15. Lee MJ, Seo DY, Lee HE, et al. In line NIR quantification of film thickness on pharmaceutical pellets during a fluid bed coating process. Int J Pharm. 2011;403(1–2):66–72.

    Article  CAS  PubMed  Google Scholar 

  16. De Beer T, Burggraeve A, Fonteyne M, Saerens L, Remon JP, Vervaet C. Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes. Int J Pharm. 2011;417(1–2):32–47.

    Article  PubMed  Google Scholar 

  17. El-Hagrasy AS, Drennen 3rd JK. A process analytical technology approach to near-infrared process control of pharmaceutical powder blending. Part III: quantitative near-infrared calibration for prediction of blend homogeneity and characterization of powder mixing kinetics. J Pharm Sci. 2006;95(2):422–34.

    Article  CAS  PubMed  Google Scholar 

  18. Fahmy R, Kona R, Dandu R, Xie W, Claycamp G, Hoag SW. Quality by design I: application of failure mode effect analysis (FMEA) and Plackett-Burman design of experiments in the identification of “main factors” in the formulation and process design space for roller-compacted ciprofloxacin hydrochloride immediate-release tablets. AAPS PharmSciTech. 2012;13(4):1243–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gressel MG, Gideon JA. An overview of process hazard evaluation techniques. Am Ind Hyg Assoc J. 1991;52(4):158–63.

    Article  CAS  PubMed  Google Scholar 

  20. Anderson MJ, Whitcomb PJ., DOE simplified: practical tools for effective experimentation. 3rd ed. Portland: Productivity Press, Inc.; 2015.

  21. Mathews PG, Design of experiments with MNITAB. Mathews Malnar and Bailey, Inc: ASQ Quality Press; 2012. p. 9

  22. Olivera ME, Manzo RH, Junginger HE, et al. Biowaiver monographs for immediate release solid oral dosage forms: ciprofloxacin hydrochloride. J Pharm Sci. 2011;100(1):22–33.

    Article  CAS  PubMed  Google Scholar 

  23. Breda SA, Jimenez-Kairuz AF, Manzo RH, Olivera ME. Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives. Int J Pharm. 2009;371(1–2):106–13.

    Article  CAS  PubMed  Google Scholar 

  24. Turel I, Bukovec P. Comparison of the thermal stability of ciprofloxacin and its compounds. Thermochim Acta. 1996;287(2):311–8.

    Article  CAS  Google Scholar 

  25. Donnelly RF. Stability of ciprofloxacin in polyvinylchloride minibags. Can J Hosp Pharm. 2011;64(4):252–6.

    PubMed  PubMed Central  Google Scholar 

  26. Siepmann F, Siepmann J, Walther M, MacRae RJ, Bodmeier R. Polymer blends for controlled release coatings. J Control Rel : Off J Control Rel Soc. 2008;125(1):1–15.

    Article  CAS  Google Scholar 

  27. Dixit R, Puthli S. Fluidization technologies: aerodynamic principles and process engineering. J Pharm Sci. 2009;98(11):3933–60.

    Article  CAS  PubMed  Google Scholar 

  28. Torrado JJ, Augsburger LL. Tableting of multipariculate modified release systems. In: Hoag SW, Augsburger LL, editors. Pharmaceutical dosage forms: Tablets vol II, 3rd Ed. New York: Informa Healthcare; 2008. p. 509–532.

  29. Keddie J. Film formation of latex. Mater Sci Eng. 1997;21:101–70.

    Article  Google Scholar 

Download references


The authors would like to thank Dr. Brian Carlin and Dr. Rina Choksi from FMC Corp. for their valuable input in the project, Oystar Huttlin, Germany for providing the fluid bed Mycrolab at the University of Maryland, and Bela Janscik from OPULUS for supplying the Pyrobutton package. We would also like to thank the U.S. Food and Drug Administration (FDA) for funding the project under grant no. HHSF223201110076A. The content of this paper was part of the graduate thesis dissertation submitted by Bhaveshkumar H. Kothari to the faculty of the School of Pharmacy, University of Maryland, Baltimore in partial fulfillment of the requirements for the doctorate degree in pharmaceutical sciences—2014.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Stephen W. Hoag.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kothari, B.H., Fahmy, R., Claycamp, H.G. et al. A Systematic Approach of Employing Quality by Design Principles: Risk Assessment and Design of Experiments to Demonstrate Process Understanding and Identify the Critical Process Parameters for Coating of the Ethylcellulose Pseudolatex Dispersion Using Non-Conventional Fluid Bed Process. AAPS PharmSciTech 18, 1135–1157 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: