An Integrated Quality-by-Design (QbD) Approach towards Design Space Definition of Key Unit Operations In the Manufacturing of Solid Dosage Forms by Discrete Element Method (DEM) and Computational Fluid Dynamics (CFD) Simulation

Combined Quality-by-Design and computer simulation approaches (discrete element method and computational fluid dynamics) are presented to characterize key unit operations of solid dosage form manufacturing, namely powder blending and tablet coating. The aim is to evaluate the impact of formulation parameters and process variables on process and product quality. Fundamental scientific knowledge is required to develop and optimize pharmaceutical manufacturing processes that yield constantly high quality products and provide most cost efficient manufacturing strategies. Understanding the variability of both the material attributes and process parameters, as well as their overall impact on the three key unit operations are critical elements for QbD. In a first step, the QbD-methodology is systematically used to (1) establish the critical quality attributes representative for the selected dosage forms, (2) identify potentially critical input factors that may affect process and product quality and (3) risk-rank these factors to define activities for process characterization. Subsequently, computer simulation-based characterizations of the three key unit operations are performed. Data are then used to map out three-dimensional knowledge spaces, providing parameters to define a design space as their subset and set up an appropriate control strategy. Powder blending, being one of the key unit operations for solid dosage form manufacturing, strongly impacts the quality of the final product, and therefore, closely relates to safety and efficacy. In this study we develop in-depth understanding of how formulation variables of a model two-component formulation and the blending process parameters affect the blending kinetics, the blending end-point and the final blending quality. A QbD-based model is presented that relates blending time and concentration of the active pharmaceutical ingredient to blending quality [1]. Depending on these two variables, the blending end point and the blend quality can be predicted. Tablet coating is another key unit operation of solid dosage form manufacturing and ensures uniform coating films on solid dosage forms required to, e.g., mask bitter tastes of the core formulation, improve stability of the finished product and modify the drug release profile. Coating processes have already been used for several decades in pharmaceutical manufacturing and their design and operating conditions merely relies on art than on fundamental scientific knowledge. In this study we evaluate the effect of variable coating process parameters on coating process and end product quality [2]. [1] Adam, S., Suzzi, D., Radeke, C., Khinast, J.G., 2010. An Integrated Quality by Design (QbD) Approach towards Design Space Definition of a Blending Unit Operation by Discrete Element Method (DEM) Simulation. Submitted to Europ. J. Pharm. Sci. [2] Suzzi, D., Radl, S., Khinast, J.G., 2010. Local Analysis of the Tablet Coating Process: Impact of Operation Conditions on Film Quality. Submitted to Chem. Eng. Sci.