Quality-by-Design II: Application of Quantitative Risk Analysis to the Formulation of Ciprofloxacin Tablets |
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Authors: | H Gregg Claycamp Ravikanth Kona Raafat Fahmy Stephen W Hoag |
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Institution: | 1.Office of Compliance,FDA Center for Drug Evaluation and Research,Silver Spring,USA;2.Department of Pharmaceutical Sciences,University of Maryland School of Pharmacy,Baltimore,USA;3.Office of New Animal Drug Evaluation,Food and Drug Administration,Rockville,USA |
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Abstract: | Qualitative risk assessment methods are often used as the first step to determining design space boundaries; however, quantitative assessments of risk with respect to the design space, i.e., calculating the probability of failure for a given severity, are needed to fully characterize design space boundaries. Quantitative risk assessment methods in design and operational spaces are a significant aid to evaluating proposed design space boundaries. The goal of this paper is to demonstrate a relatively simple strategy for design space definition using a simplified Bayesian Monte Carlo simulation. This paper builds on a previous paper that used failure mode and effects analysis (FMEA) qualitative risk assessment and Plackett-Burman design of experiments to identity the critical quality attributes. The results show that the sequential use of qualitative and quantitative risk assessments can focus the design of experiments on a reduced set of critical material and process parameters that determine a robust design space under conditions of limited laboratory experimentation. This approach provides a strategy by which the degree of risk associated with each known parameter can be calculated and allocates resources in a manner that manages risk to an acceptable level. |
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