title: Quality-by-Design II: Application of Quantitative Risk Analysis to the Formulation of Ciprofloxacin Tablets.
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.
authors.affiliation: Office of Compliance, FDA Center for Drug Evaluation and Research, Silver Spring, MD, USA.|Office of New Animal Drug Evaluation, Food and Drug Administration, Rockville, MD, USA.
authors.forename: H Gregg
authors.initials: HG
authors.lastname: Claycamp
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA.
authors.forename: Ravikanth
authors.initials: R
authors.lastname: Kona
authors.affiliation: Office of New Animal Drug Evaluation, Food and Drug Administration, Rockville, MD, USA.
authors.forename: Raafat
authors.initials: R
authors.lastname: Fahmy
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA. shoag@rx.umaryland.edu.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Hoag
mesh_terms: D001499:Bayes Theorem; D002626:Chemistry, Pharmaceutical / Q000379:methods* / Q000592:standards*; D002939:Ciprofloxacin / Q000737:chemistry* / Q000592:standards*; D011786:Quality Control; D012107:Research Design; D018570:Risk Assessment / Q000379:methods; D013607:Tablets / Q000737:chemistry* / Q000592:standards*; D013678:Technology, Pharmaceutical / Q000379:methods / Q000592:standards
chemical_list: D013607:Tablets; D002939:Ciprofloxacin
keywords: Bayesian Monte Carlo simulation; ciprofloxacin and granulation; ciprofloxacin hydrochloride; qualitative risk assessment; quality-by-design (QbD); roller compaction