Scale-Up Strategy in Quality by Design Approach for Pharmaceutical Blending Process with Discrete Element Method Simulation.

An approach combining quality by design (QbD) and the discrete element method (DEM) is proposed to establish an effective scale-up strategy for the blending process of an amlodipine formulation prepared by the direct compression method. Critical process parameters (CPPs) for intermediate critical quality attributes (IQAs) were identified using risk assessment (RA) in the QbD approach. A Box-Behnken design was applied to obtain the operating space for a laboratory-scale. A DEM model was developed by the input parameters for the amlodipine formulation; blending was simulated on a laboratory-scale V-blender (3 L) at optimal settings. The efficacy and reliability of the DEM model was validated through a comparison of simulation and experimental results. Change of operating space was evaluated using the validated DEM model when scaled-up to pilot-scale (10 L). Pilot-scale blending was simulated on a V-blender and double-cone blender at the optimal settings derived from the laboratory-scale operating space. Both pilot-scale simulation results suggest that blending time should be lower than the laboratory-scale optimized blending time to meet target values. These results confirm the change of operating space during the scale-up process. Therefore, this study suggests that a QbD-integrated DEM simulation can be a desirable approach for an effective scale-up strategy.

Application of the Discrete Element Method for Manufacturing Process Simulation in the Pharmaceutical Industry.

Process simulation using mathematical modeling tools is becoming more common in the pharmaceutical industry. A mechanistic model is a mathematical modeling tool that can enhance process understanding, reduce experimentation cost and improve product quality. A commonly used mechanistic modeling approach for powder is the discrete element method (DEM). Most pharmaceutical materials have powder or granular material. Therefore, DEM might be widely applied in the pharmaceutical industry. This review focused on the basic elements of DEM and its implementations in pharmaceutical manufacturing simulation. Contact models and input parameters are essential elements in DEM simulation. Contact models computed contact forces acting on the particle-particle and particle-geometry interactions. Input parameters were divided into two types-material properties and interaction parameters. Various calibration methods were presented to define the interaction parameters of pharmaceutical materials. Several applications of DEM simulation in pharmaceutical manufacturing processes, such as milling, blending, granulation and coating, were categorized and summarized. Based on this review, DEM simulation might provide a systematic process understanding and process control to ensure the quality of a drug product.