(470g) Sensitivity Analysis and Identification of Feasible Region of a Wet Granulation Continuous Pharmaceutical Manufacturing Process
- Conference: AIChE Annual Meeting
- Year: 2018
- Proceeding: 2018 AIChE Annual Meeting
- Group: Pharmaceutical Discovery, Development and Manufacturing Forum
- Time: Wednesday, October 31, 2018 - 10:06am-10:27am
Sensitivity analysis is the study of how uncertainty in a model output can be assigned to different sources of uncertainty in the model input2. Sources of uncertainty exist through potential variability in raw material quality, operating conditions and production rate demands. As flowsheet models have several input and output variables, it is important to identify the variables that have a significant effect on the properties of interest. This allows prioritization of the input factors and simplification of the high dimensional problem that aids in further applications such as feasibility analysis. Feasibility analysis is used to identify the feasible region of a process that is characterized by the range of input variables within which the process meets equipment, quality and production constraints3. Traditional methods to identify feasible regions incur large sampling costs which is prohibitive for a wet granulation flowsheet model. In addition, some constraints are not available in closed form expression. Alternatively, they may be available but expensive to evaluate4.
Current work utilizes surrogate based feasibility analysis method5 that is based on building surrogate models used to approximate the function of interest. In this work, a reduced order model is built for feasibility function, which characterizes the maximum constraint violation. The surrogate model accuracy is improved through selection of new samples that are identified using an adaptive sampling strategy. The strategy uses a modified Expected improvement function to direct search towards feasible region boundaries and unexplored regions6. The developed approach is utilized to identify feasible regions for an integrated wet granulation line that simulates a plant scale operation.
- Boukouvala F, Chaudhury A, Sen M, et al. Computer-Aided Flowsheet Simulation of a Pharmaceutical Tablet Manufacturing Process Incorporating Wet Granulation. J Pharm Innov. 2013;8(1):11-27.
- Saltelli A, Annoni P, Azzini I, Campolongo F, Ratto M, Tarantola S. Variance based sensitivity analysis of model output. Design and estimator for the total sensitivity index. Computer Physics Communications. 2010;181(2):259-270.
- Wang Z, Escotet-Espinoza MS, Ierapetritou M. Process analysis and optimization of continuous pharmaceutical manufacturing using flowsheet models. Computers & Chemical Engineering.
- Rogers A, Ierapetritou M. Feasibility and flexibility analysis of black-box processes Part 1: Surrogate-based feasibility analysis. Chem Eng Sci. 2015;137:986-1004.
- Wang Z, Ierapetritou M. A novel feasibility analysis method for blackâbox processes using a radial basis function adaptive sampling approach. Aiche J. 2017;63(2):532-550.
- Boukouvala F, Ierapetritou MG. Derivativeâfree optimization for expensive constrained problems using a novel expected improvement objective function. Aiche J. 2014;60(7):2462-2474.