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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

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ABSTRACT

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.

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ACKNOWLEDGMENTS

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.

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Correspondence to Stephen W. Hoag.

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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). https://doi.org/10.1208/s12249-016-0569-0

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