title: Use of mechanistic simulations as a quantitative risk-ranking tool within the quality by design framework.
abstract: The purpose of this study is to evaluate the use of computer simulations for generating quantitative knowledge as a basis for risk ranking and mechanistic process understanding, as required by ICH Q9 on quality risk management systems. In this specific publication, the main focus is the demonstration of a risk assessment workflow, including a computer simulation for the generation of mechanistic understanding of active tablet coating in a pan coater. Process parameter screening studies are statistically planned under consideration of impacts on a potentially critical quality attribute, i.e., coating mass uniformity. Based on computer simulation data the process failure mode and effects analysis of the risk factors is performed. This results in a quantitative criticality assessment of process parameters and the risk priority evaluation of failure modes. The factor for a quantitative reassessment of the criticality and risk priority is the coefficient of variation, which represents the coating mass uniformity. The major conclusion drawn from this work is a successful demonstration of the integration of computer simulation in the risk management workflow leading to an objective and quantitative risk assessment.
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, Graz 8010, Austria.
authors.forename: Elena
authors.initials: E
authors.lastname: Stocker
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, Graz 8010, Austria.
authors.forename: Gregor
authors.initials: G
authors.lastname: Toschkoff
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, Graz 8010, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Sacher
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, Graz 8010, Austria; Institute for Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13, Graz 8010, Austria. Electronic address: khinast@tugraz.at.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Khinast
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D004339:Drug Compounding / Q000379:methods*; D012306:Risk; D018570:Risk Assessment; D012307:Risk Factors; D012308:Risk Management / Q000379:methods
keywords: Computational simulation; Discrete element method; ICH Q9 quality risk management; Process understanding; Quality by design; Tablet coating