Advanced Control of Continuous Pharmaceutical Tablet Manufacturing Processes

Abstract

A novel manufacturing strategy based on continuous processing, integrated with online/inline monitoring tools, coupled with an advanced automatic feedback control system is highly desired for efficient Quality by Design (QbD)-based manufacturing of the next generation of pharmaceutical products with optimal consumption of time, space and resources. In this work, an advanced hybrid MPC-PID control system as well as a simpler PID controller for a direct compaction continuous tablet manufacturing process has been designed and implemented for a pilot-scale pharmaceutical process. An NIR sensor, an online NIR prediction tool, a PAT data management tool, an OPC communication protocol, a standard control platform and control hardware have been used to close the control loop. A systematic methodology to design and implement the control system has been also proposed. A control framework with features such as the option to run the plant in open-loop as well as in a closed-loop scenario has been developed. Furthermore, within the closed-loop scenario, options for a simpler PID, a dead time compensator (Smith predictor) as well as an advanced model predictive controller have been included. The feature to run the control strategy in simulation mode has been added to the control platform to facilitate virtual control system design and performance evaluation. Two case studies involving a direct compaction continuous tablet manufacturing process have been considered to demonstrate the closed-loop operation. Case Study 1 was completed at Rutgers University and constituted the use of a continuous cylindrical blender with a rotating screw. Case Study 2 was based on a continuous tumble mixer and was completed at the University of Puerto Rico-Mayaguez Campus (UPRM).

Measuring the Particle Packing of l-Glutamic Acid Crystals through X-ray Computed Tomography for Understanding Powder Flow and Consolidation Behavior

“…This proof of concept work also has the potential for characterizing the behavior of formulated pharmaceutical systems, e.g., the impact of varied concentrations of active pharmaceutical ingredients and excipients within a formulation on processing performance, potentially leading to the development of simulation tools and workflows for optimizing, e.g., the content uniformity of formulations in terms of their blending, flow ,and compaction unit operations. The latter is particularly timely regarding current interest in the multiscale design of continuous direct compression manufacturing processes. , Such studies may also benefit from combining laboratory-based XCT for quasistatic analysis coupled with the use of synchrotron radiation based tomographic imaging to study the dynamics of particle processing under representative conditions.…”

Continuous Heterogeneous Crystallization on Excipient Surfaces

“…The downstream process of the drug product manufacturing starts from the crystallization step of the API (drug substance upstream) and often includes many intermediate steps of milling, mixing (with required excipients) and blending, granulation, drying, sieving, and tablet pressing − (Figure a). Many risks, challenges, technical hurdles, and considerations are associated with each of the aforementioned steps. − The precise final dosage, content uniformity, composition, mechanical properties, and critical quality attribute of every single tablet, which are highly regulated, ,− highly depend on the performance of the involved stages, for instance, component segregation, which can be caused by differences in particle size, density, or shape, and segregation in blending, hoppers, transfer lines, or feeders, and results in heterogeneity in tablet compositions. − Significant academic research and industrial development have been invested to overcome drug product line challenges and enable consistent manufacturing of high-quality tablets. − These challenges, and subsequent effects, are more problematic in the continuous manufacturing arena, , where the continuous flow of material, continuous workload of the drug product line, residence time distribution, and validation of “batches” of the final product enter into the design of already complicated processes. ,,,, …”