Evaluation of a Combined MHE-NMPC Approach to Handle Plant-Model Mismatch in a Rotary Tablet Press

The transition from batch to continuous processes in the pharmaceutical industry has been driven by the potential improvement in process controllability, product quality homogeneity, and reduction of material inventory. A quality-by-control (QbC) approach has been implemented in a variety of pharmaceutical product manufacturing modalities to increase product quality through a three-level hierarchical control structure. In the implementation of the QbC approach it is common practice to simplify control algorithms by utilizing linearized models with constant model parameters. Nonlinear model predictive control (NMPC) can effectively deliver control functionality for highly sensitive variations and nonlinear multiple-input-multiple-output (MIMO) systems, which is essential for the highly regulated pharmaceutical manufacturing industry. This work focuses on developing and implementing NMPC in continuous manufacturing of solid dosage forms. To mitigate control degradation caused by plant-model mismatch, careful monitoring and continuous improvement strategies are studied. When moving horizon estimation (MHE) is integrated with NMPC, historical data in the past time window together with real-time data from the sensor network enable state estimation and accurate tracking of the highly sensitive model parameters. The adaptive model used in the NMPC strategy can compensate for process uncertainties, further reducing plant-model mismatch effects. The nonlinear mechanistic model used in both MHE and NMPC can predict the essential but complex powder properties and provide physical interpretation of abnormal events. The adaptive NMPC implementation and its real-time control performance analysis and practical applicability are demonstrated through a series of illustrative examples that highlight the effectiveness of the proposed approach for different scenarios of plant-model mismatch, while also incorporating glidant effects

Advanced control strategies for bioprocess chromatography: Challenges and opportunities for intensified processes and next generation products

Recent advances in process analytical technologies and modelling techniques present opportunities to improve industrial chromatography control strategies to enhance process robustness, increase productivity and move towards real-time release testing. This paper provides a critical overview of batch and continuous industrial chromatography control systems for therapeutic protein purification. Firstly, the limitations of conventional industrial fractionation control strategies using in-line UV spectroscopy and on-line HPLC are outlined. Following this, an evaluation of monitoring and control techniques showing promise within research, process development and manufacturing is provided. These novel control strategies combine rapid in-line data capture (e.g. NIR, MALS and variable pathlength UV) with enhanced process understanding obtained from mechanistic and empirical modelling techniques. Finally, a summary of the future states of industrial chromatography control systems is proposed, including strategies to control buffer formulation, product fractionation, column switching and column fouling. The implementation of these control systems improves process capabilities to fulfil product quality criteria as processes are scaled, transferred and operated, thus fast tracking the delivery of new medicines to market

High-Performance Integrated Window and Façade Solutions for California

The researchers developed a new generation of high-performance façade systems and supporting design and management tools to support industry in meeting California’s greenhouse gas reduction targets, reduce energy consumption, and enable an adaptable response to minimize real-time demands on the electricity grid. The project resulted in five outcomes: (1) The research team developed an R-5, 1-inch thick, triplepane, insulating glass unit with a novel low-conductance aluminum frame. This technology can help significantly reduce residential cooling and heating loads, particularly during the evening. (2) The team developed a prototype of a windowintegrated local ventilation and energy recovery device that provides clean, dry fresh air through the façade with minimal energy requirements. (3) A daylight-redirecting louver system was prototyped to redirect sunlight 15–40 feet from the window. Simulations estimated that lighting energy use could be reduced by 35–54 percent without glare. (4) A control system incorporating physics-based equations and a mathematical solver was prototyped and field tested to demonstrate feasibility. Simulations estimated that total electricity costs could be reduced by 9-28 percent on sunny summer days through adaptive control of operable shading and daylighting components and the thermostat compared to state-of-the-art automatic façade controls in commercial building perimeter zones. (5) Supporting models and tools needed by industry for technology R&D and market transformation activities were validated. Attaining California’s clean energy goals require making a fundamental shift from today’s ad-hoc assemblages of static components to turnkey, intelligent, responsive, integrated building façade systems. These systems offered significant reductions in energy use, peak demand, and operating cost in California

Model Predictive Control of an Integrated Continuous Pharmaceutical Manufacturing Pilot Plant

This paper considers the model predictive control (MPC) of critical quality attributes (CQAs) of products in an end-to-end continuous pharmaceutical manufacturing pilot plant, which was designed and constructed at the Novartis-MIT Center for Continuous Manufacturing. Feedback control is crucial for achieving the stringent regulatory requirements on CQAs of pharmaceutical products in the presence of process uncertainties and disturbances. To this end, a key challenge arises from complex plant-wide dynamics of the integrated process units in a continuous pharmaceutical process, that is, dynamical interactions between several process units. This paper presents two plant-wide MPC designs for the end-to-end continuous pharmaceutical manufacturing pilot plant using the quadratic dynamic matrix control algorithm. The plant-wide MPC designs are based on different modeling approaches - subspace identification and linearization of nonlinear differential-algebraic equations that yield, respectively, linear low-dimensional and high-dimensional state-space models for the plant-wide dynamics. The closed-loop performance of the plant-wide MPC designs is evaluated using a nonlinear plant simulator equipped with a stabilizing control layer. The closed-loop simulation results demonstrate that the plant-wide MPC systems can facilitate effective regulation of CQAs and flexible process operation in the presence of uncertainties in reaction kinetics, persistent drifts in efficiency of filtration units, temporary disturbances in purity of intermediate compounds, and set point changes. The plant-wide MPC allows for incorporating quality-by-design considerations into the control problem through input and output constraints to ensure regulatory compliant process operation

Development of advanced monitoring and control tools for rAAV production in the insect cell system

"Since the first publication introducing the concept in 1972, gene therapy has had a series of success stories and setbacks. However, the recent rise of awareness, public interest, promising results in clinical trials and recent market approvals indicate that gene therapy has come to stay. Currently there is a growing interest from the biopharmaceutical industry in gene and cell therapy, mostly using viral vectors. (...)

Expanding the Horizons of Manufacturing: Towards Wide Integration, Smart Systems and Tools

This research topic aims at enterprise-wide modeling and optimization (EWMO) through the development and application of integrated modeling, simulation and optimization methodologies, and computer-aided tools for reliable and sustainable improvement opportunities within the entire manufacturing network (raw materials, production plants, distribution, retailers, and customers) and its components. This integrated approach incorporates information from the local primary control and supervisory modules into the scheduling/planning formulation. That makes it possible to dynamically react to incidents that occur in the network components at the appropriate decision-making level, requiring fewer resources, emitting less waste, and allowing for better responsiveness in changing market requirements and operational variations, reducing cost, waste, energy consumption and environmental impact, and increasing the benefits. More recently, the exploitation of new technology integration, such as through semantic models in formal knowledge models, allows for the capture and utilization of domain knowledge, human knowledge, and expert knowledge toward comprehensive intelligent management. Otherwise, the development of advanced technologies and tools, such as cyber-physical systems, the Internet of Things, the Industrial Internet of Things, Artificial Intelligence, Big Data, Cloud Computing, Blockchain, etc., have captured the attention of manufacturing enterprises toward intelligent manufacturing systems

Trajectory planning based on adaptive model predictive control: Study of the performance of an autonomous vehicle in critical highway scenarios

Increasing automation in automotive industry is an important contribution to overcome many of the major societal challenges. However, testing and validating a highly autonomous vehicle is one of the biggest obstacles to the deployment of such vehicles, since they rely on data-driven and real-time sensors, actuators, complex algorithms, machine learning systems, and powerful processors to execute software, and they must be proven to be reliable and safe. For this reason, the verification, validation and testing (VVT) of autonomous vehicles is gaining interest and attention among the scientific community and there has been a number of significant efforts in this field. VVT helps developers and testers to determine any hidden faults, increasing systems confidence in safety, security, functional analysis, and in the ability to integrate autonomous prototypes into existing road networks. Other stakeholders like higher-management, public authorities and the public are also crucial to complete the VTT process. As autonomous vehicles require hundreds of millions of kilometers of testing driven on public roads before vehicle certification, simulations are playing a key role as they allow the simulation tools to virtually test millions of real-life scenarios, increasing safety and reducing costs, time and the need for physical road tests. In this study, a literature review is conducted to classify approaches for the VVT and an existing simulation tool is used to implement an autonomous driving system. The system will be characterized from the point of view of its performance in some critical highway scenarios.O aumento da automação na indústria automotiva é uma importante contribuição para superar muitos dos principais desafios da sociedade. No entanto, testar e validar um veículo altamente autónomo é um dos maiores obstáculos para a implantação de tais veículos, uma vez que eles contam com sensores, atuadores, algoritmos complexos, sistemas de aprendizagem de máquina e processadores potentes para executar softwares em tempo real, e devem ser comprovadamente confiáveis e seguros. Por esta razão, a verificação, validação e teste (VVT) de veículos autónomos está a ganhar interesse e atenção entre a comunidade científica e tem havido uma série de esforços significativos neste campo. A VVT ajuda os desenvolvedores e testadores a determinar quaisquer falhas ocultas, aumentando a confiança dos sistemas na segurança, proteção, análise funcional e na capacidade de integrar protótipos autónomos em redes rodoviárias existentes. Outras partes interessadas, como a alta administração, autoridades públicas e o público também são cruciais para concluir o processo de VTT. Como os veículos autónomos exigem centenas de milhões de quilómetros de testes conduzidos em vias públicas antes da certificação do veículo, as simulações estão a desempenhar cada vez mais um papel fundamental, pois permitem que as ferramentas de simulação testem virtualmente milhões de cenários da vida real, aumentando a segurança e reduzindo custos, tempo e necessidade de testes físicos em estrada. Neste estudo, é realizada uma revisão da literatura para classificar abordagens para a VVT e uma ferramenta de simulação existente é usada para implementar um sistema de direção autónoma. O sistema é caracterizado do ponto de vista do seu desempenho em alguns cenários críticos de autoestrad