AAPS PharmSciTech

, Volume 18, Issue 4, pp 1135–1157 | Cite as

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

  • Bhaveshkumar H. Kothari
  • Raafat Fahmy
  • H. Gregg Claycamp
  • Christine M. V. Moore
  • Sharmista Chatterjee
  • Stephen W. Hoag
Research 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.


design of experiments and Pyrobutton® ethylcellulose fluid bed technology quality by design risk assessment 



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.


  1. 1.
    Sakr A, Alanazi F. Oral solid dosage forms. In: Felton L, editor. Remington essentials of pharmaceutics. London: Pharmaceutical Press; 2012. pp. 581–610.Google Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 10.
    Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25(4):781–91.CrossRefPubMedGoogle Scholar
  11. 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.Google Scholar
  12. 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.Google Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gressel MG, Gideon JA. An overview of process hazard evaluation techniques. Am Ind Hyg Assoc J. 1991;52(4):158–63.CrossRefPubMedGoogle Scholar
  20. 20.
    Anderson MJ, Whitcomb PJ., DOE simplified: practical tools for effective experimentation. 3rd ed. Portland: Productivity Press, Inc.; 2015.Google Scholar
  21. 21.
    Mathews PG, Design of experiments with MNITAB. Mathews Malnar and Bailey, Inc: ASQ Quality Press; 2012. p. 9Google Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 24.
    Turel I, Bukovec P. Comparison of the thermal stability of ciprofloxacin and its compounds. Thermochim Acta. 1996;287(2):311–8.CrossRefGoogle Scholar
  25. 25.
    Donnelly RF. Stability of ciprofloxacin in polyvinylchloride minibags. Can J Hosp Pharm. 2011;64(4):252–6.PubMedPubMedCentralGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 27.
    Dixit R, Puthli S. Fluidization technologies: aerodynamic principles and process engineering. J Pharm Sci. 2009;98(11):3933–60.CrossRefPubMedGoogle Scholar
  28. 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.Google Scholar
  29. 29.
    Keddie J. Film formation of latex. Mater Sci Eng. 1997;21:101–70.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  • Bhaveshkumar H. Kothari
    • 1
    • 2
  • Raafat Fahmy
    • 3
  • H. Gregg Claycamp
    • 3
  • Christine M. V. Moore
    • 4
    • 5
  • Sharmista Chatterjee
    • 4
  • Stephen W. Hoag
    • 1
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyUniversity of MarylandBaltimoreUSA
  2. 2.Amneal PharmaceuticalsBrookhavenUSA
  3. 3.Office of New Animal Drug Evaluation, Center for Veterinary MedicineUS Food and Drug AdministrationRockvilleUSA
  4. 4.Office of Process and Facilities, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  5. 5.Merck Research LaboratoriesWest PointUSA

Personalised recommendations