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AAPS PharmSciTech. 2016 Apr;17(2):233-44. doi: 10.1208/s12249-015-0349-2. Epub 2015 Jul 23.

Quality-by-Design II: Application of Quantitative Risk Analysis to the Formulation of Ciprofloxacin Tablets.

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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.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA.
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA.


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.


Bayesian Monte Carlo simulation; ciprofloxacin and granulation; ciprofloxacin hydrochloride; qualitative risk assessment; quality-by-design (QbD); roller compaction

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