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The primary function of a mine hoist is the transportation of personnel and equipment, serving as a crucial link between underground and surface systems. The proper functioning of key components such as work braking and safety braking is essential for ensuring the safety of both personnel and equipment, thereby playing a critical role in the safe operation of coal mines. As coal mining operations extend to greater depths, they introduce heightened challenges for safe transportation, compounded by increased equipment loss. Consequently, there is a pressing need to enhance safety protocols to safeguard personnel and materials. Traditional maintenance and repair methods, characterized by routine equipment inspections and scheduled downtime, often fall short in addressing emerging issues promptly, leading to production delays and heightened risks for maintenance personnel. This underscores the necessity of adopting predictive maintenance strategies, leveraging digital twin models to anticipate and prevent potential faults in mine hoists. In summary, the implementation of predictive maintenance techniques grounded in digital twin technology represents a proactive and scientifically rigorous approach to ensuring the continued safe operation of mine hoists amidst the evolving challenges of deepening coal mining operations. In this study, we propose the integration of a CNN-LSTM algorithm within a digital twin framework for predicting faults in mine hoist braking systems. Utilizing software such as AMESim 2019 and MATLAB 2016b, we conduct joint simulations of the hoist braking digital twin system. Subsequently, leveraging the simulation model, we establish a fault diagnosis platform for the hoist braking system. Finally, employing the CNN-LSTM network model, we forecast failures in the mine hoist braking system. Experimental findings demonstrate the effectiveness of our proposed algorithm, achieving a prediction accuracy of 95.35%. Comparative analysis against alternative algorithms confirms the superior performance of our approach. [ABSTRACT FROM AUTHOR]

In the era of rapid technological advancement and evolving industrial landscapes, embracing the concept of the factory of the future (FoF) is crucial for companies seeking to optimize efficiency, enhance productivity, and stay sustainable. This case study explores the concept of the FoF and its role in driving the energy transition and digital transformation within the automotive sector. By embracing advancements in technology and innovation, these factories aim to establish a smart, sustainable, inclusive, and resilient growth framework. The shift towards hybrid and electric vehicles necessitates significant adjustments in vehicle components and production processes. To achieve this, the adoption of lighter materials becomes imperative, and new technologies such as additive manufacturing (AM) and artificial intelligence (AI) are being adopted, facilitating enhanced efficiency and innovation within the factory environment. An important aspect of this paradigm involves the development and utilization of a modular, affordable, safe human–robot interaction and highly performant intelligent robot. The introduction of this intelligent robot aims to foster a higher degree of automation and efficiency through collaborative human–robot environments on the factory floor and production lines, specifically tailored to the automotive sector. By combining the strengths of human and robotic capabilities, the future factory aims to revolutionize manufacturing processes, ultimately driving the automotive industry towards a more sustainable and technologically advanced future. This study explores the implementation of automation and the initial strides toward transitioning from Industry 4.0 to 5.0, focusing on three recognized, large, and automotive companies operating in the north of Portugal. [ABSTRACT FROM AUTHOR]

Digital twins are an emerging technology that can be harnessed for the digitalization of the industry. Steel industry systems contain a large number of electro-hydraulic components as proportional valves. An input–output model for a water proportional cartridge valve was derived from physical modeling based on fluid mechanics, dynamics, and electrical principles. The valve is a two-stage valve with two two/two-way water proportional valves as the pilot stage and a marginally stable poppet-type cartridge valve as the main valve. To our knowledge, this is the first time that an input–output model was derived for a two-stage proportional cartridge valve with a marginally stable main valve. The orifice equation, which is based on Bernoulli principles, was approximated by a polynomial, which made the parameter estimation easier and modeling possible without measuring the pressure of the varying control volume, in contrast with previous studies of similar types of valves situated in the pilot stage part of the valve. This work complements previous studies of similar types of valves in two ways: (1) data were collected when the valve was operating in a closed loop and (2) data were collected when the valve was part of a press mill machine in a steel manufacturing plant. Model parameters were identified from data from these operating conditions. The parameters of the input–output model were estimated by convex optimization with physical constraints to overcome the problems caused by poor system excitation. For comparison, a simple linear model was derived and the least squares method was used for the parameter estimation. A thorough estimation of the parameters' relative errors is presented. The model contains five parameters related to the design parameters of the valve. The modeled position output was in good agreement with experimental data for the training and test data. The model can be used for the real-time monitoring of the valve's status by the model parameters. One of the model parameters varied linearly with the production cycles. Thus, the aging of the valve can be monitored. [ABSTRACT FROM AUTHOR]

Hydrodistillation is traditionally a green technology for the manufacturing of natural products that are volatile. As well as acknowledged process intensification methods such as microwave support for energy efficiency to move towards climate neutral operation, digital twins combined with process analytical technology for advanced process control enables reliable operation of an optimal operation point regarding lowest cost of goods, as well as lowest global warming potential equivalent. A novel process control enabled by digital twin technology has shown to reduce the ecological footprint of the extraction by up to 46.5%, while reducing the cost of extraction by 22.4%. Additionally, skilled operator time is reduced, and the sustainable plant material is utilized most efficiently. The approach is ready to apply, but broad industrialization seems to be held back by unclear business cases and lack of comprehension of decision makers. This is in drastic contrast to the political demand for climate neutrality goals and the cost pressure by worldwide completion. [ABSTRACT FROM AUTHOR]

Digital twins have emerged as a powerful concept for real-time monitoring and analysis, facilitating Quality by Design integration into biopharmaceutical manufacturing. Traditionally, lyophilization processes are developed through trial-and-error, incorporating high security margins and inflexible process set points. Digital twins enable the integration of adaptable operating conditions and implementation of automation through Advanced Process Control (APC) with Process Analytical Technology (PAT) and validated physicochemical models that rely on heat and mass transfer principles, allowing us to overcome the challenges imposed by the lyophilization process. In this study, a digital twin for freeze-drying processes is developed and experimentally validated. Using the digital twin, primary drying conditions were optimized for controlled nucleation and annealing methods by carrying out a few laboratory tests beforehand. By incorporating PAT and modeling, the digital twin accurately predicts the product's temperature and drying endpoint, showing smaller errors than the experiments. The digital twin significantly increases productivity by up to 300% while reducing the costs by 74% and the Global Warming Potential by 64%. [ABSTRACT FROM AUTHOR]

The worldwide demand for customized centrifugal pumps in numerous industries is intensifying steadily, posing significant challenges to the traditional design model characterized by extended design cycles, numerous errors, and elevated development costs. To address these issues, this paper introduces an intelligent collaborative design methodology for industrial centrifugal pumps grounded in digital twin (DT) technology. The methodology aims to handle the diversified types and intricate design requirements of industrial pumps and is specifically tailored to predict pump performance through a detailed multi-physics model. This model encapsulates various physical processes, including fluid dynamics, thermodynamics, and structural mechanics, and incorporates the designer's professional knowledge and experience to support enhanced decision-making. Furthermore, the application of intelligent parametric models has facilitated the interconnected design of pump components. This advancement has led to significant improvements such as shortening production cycles, reducing errors and costs, and enhancing design efficiency and quality. Consequently, the paper demonstrates that adopting this intelligent collaborative design approach can greatly benefit the industrial centrifugal pump sector by meeting the growing customization demands with increased efficiency and precision. These findings underscore the potential of DT technology in revolutionizing traditional pump design methodologies, advancing the intelligent progression of industrial centrifugal pump design and manufacturing, and satisfying the expanding demands of the global manufacturing industry. [ABSTRACT FROM AUTHOR]

This paper presents the design and development of a digital twin to diagnose leaks in water distribution networks. The digital twin allows for the remote operation of the hydraulic system's actuators using embedded microcontrollers integrated with Internet of Things (IoT) capabilities. Pressure head and flow rate measurements are received online in the operator interface, and hydraulic simulations are performed with a well-calibrated EPANET model of the hydraulic system to estimate the pressure head at nodes without sensors. A genetic algorithm was designed to detect and estimate the size of the leaks online. Different experiments were carried out to validate the online application of the method based on the digital twin and under a multi-leak event. [ABSTRACT FROM AUTHOR]

Aimed at the characteristics of multi-source heterogeneity and the rapid generation of data in digital twin workshops, as well as the current situation where communication protocols between equipment within the workshop vary greatly and are difficult to interconnect, a data integration method based on OPC UA is designed. Firstly, combining the process flow and data source characteristics of array antenna assembly, a data collection and transmission scheme based on OPC UA was designed. Secondly, a process information model of array antenna assembly was established to realize data perception and transmission and solve the difficulties of complex data structure, high real-time requirements, and heterogeneous data in digital twin workshop. Finally, the proposed method and model were applied to the performance prediction platform for an array antenna assembly process based on digital twins, achieving perception of process data during the assembly process of array antennas, and achieving performance prediction and visualization for various stages of array antennas based on assembly process data. [ABSTRACT FROM AUTHOR]

This paper proposes an active steering controller for Driven Independently Rotating Wheelset (DIRW) vehicles based on deep reinforcement learning (DRL). For the two-axle railway vehicles equipped with Independently Rotating Wheelsets (IRWs), each wheel connected to a wheel-side motor, the Ape-X DDPG controller, an enhanced version of the Deep Deterministic Policy Gradient (DDPG) algorithm, is adopted. Incorporating Distributed Prioritized Experience Replay (DPER), Ape-X DDPG trains neural network function approximators to obtain a data-driven DIRW active steering controller. This controller is utilized to control the input torque of each wheel, aiming to improve the steering capability of IRWs. Simulation results indicate that compared to the existing model-based H∞ control algorithm and data-driven DDPG control algorithm, the Ape-X DDPG active steering controller demonstrates better curving steering performance and centering ability in straight tracks across different running conditions and significantly reduces wheel–rail wear. To validate the proposed algorithm's efficacy in real vehicles, a 1:5 scale model of the DIRW vehicle and its digital twin dynamic model were designed and manufactured. The proposed control algorithm was deployed on the scale vehicle and subjected to active steering control experiments on a scaled track. The experimental results reveal that under the active steering control of the Ape-X DDPG controller, the steering performance of the DIRW scale model on both straight and curved tracks is significantly enhanced. [ABSTRACT FROM AUTHOR]

Industrial manufacturing processes have evolved and improved since the disruption of the Industry 4.0 paradigm, while energy has progressively become a strategic resource required to maintain industrial competitiveness while maximizing quality and minimizing environmental impacts. In this context of global changes leading to social and economic impact in the short term and an unprecedented climate crisis, Digital Twins for Energy Efficiency in manufacturing processes provide companies with a tool to address this complex situation. Nevertheless, already existing Digital Twins applied for energy efficiency in a manufacturing process lack a flexible structure that easily replicates the real behavior of consuming machines while integrating it in complex upper-level environments. This paper presents a combined multi-paradigm approach to industrial process modeling developed and applied during the GENERTWIN project. The tool allows users to predict energy consumption and costs and, at the same time, evaluates the behavior of the process under certain productive changes to maximize consumption optimization, production efficiency and process flexibility. [ABSTRACT FROM AUTHOR]

New requirements for terminal production and operation have emerged as a result of the increase in container terminal throughput. Traditional terminals' manufacturing capabilities fall short of the expanding service needs. By constructing a digital twin yard for container terminals, the production capacity of terminals can be effectively improved, and the production operation process can be optimized. This paper firstly constructs a digital twin yard system for container terminals, proposing that it is mainly composed of physical space, virtual space, data, services, and intelligent agents. This paper elaborates on the core technologies of digital twin yards and finally takes the container delivery and loading process as an example to solve the production bottlenecks of the yard in the container delivery business by reorganizing the operation process and targeting it, which can improve the terminal production efficiency to a certain extent. [ABSTRACT FROM AUTHOR]

Natural extracts are broadly utilized as remedies, nutrition additives, cosmetics or flavors as well as natural pesticides, fungicides or herbicides. Green manufacturing technologies are of added market value and are sustainable towards the climate neutrality politically demanded for 2045. The concept of digital twins involves experimentally distinct validated process models combined with process analytical technology that is to be adapted to the existing operations. This is a key technology for the autonomous operations in industry 4.0. This paper exemplifies this approach and evaluates the results of the application and implementation efforts of regulated industries. A conductivity sensor for the measurement of the dry residue content and/or Fourier-transformed infrared spectroscopy for marker/lead or reference substance concentration determination are the most feasible and straight forward solutions. Different process control concepts from simple PID controllers (proportional, integral and differential) to advanced process control using digital twin models are evaluated and discussed in terms of industrialization efforts and benefits. The global warming potential CO2 equivalent per kg of natural product could be decreased by a factor of 5–10 as well as the cost of goods, which makes the pay-out time for the industrialization investment less than 1 year and the approach highly competitive. The success rate of the extraction process under regulatory constraints can be raised to 100%, reducing waste, overall solvent consumption, personnel efforts and energy requirements to a minimum. [ABSTRACT FROM AUTHOR]

Aeroengine mainshaft bearings are key components in modern aeroengines, and their main functions are to support the rotation of the main shaft of the aeroengine in harsh environments, such as high temperature, heavy load, high speed and oil break; reduce the friction coefficient during the high-speed rotation of the main shaft; and reliably ensure the rotation accuracy and power transmission of the aeroengine's main shaft during operation. The manufacture of aeroengine mainshaft bearings requires complex processes and precise machining to ensure high performance and reliability, and how to intelligently complete the production and manufacture of mainshaft bearings and ensure the strength and accuracy of the bearings, quickly distinguish the fault types of the bearings and efficiently calculate, analyze and predict the life of the bearings are the current research hotspots. Therefore, building a high-fidelity and computationally efficient digital twin life cycle of aeroengine mainshaft bearings is a valuable solution. This paper summarizes the key manufacturing technology, manufacturing mode and manufacturing process based on digital twins in the life cycle of aeroengine mainshaft bearings, including the metallurgical process, heat treatment process and grinding process of aeroengine mainshaft bearings. It presents a fault diagnosis and life analysis of mainshaft bearings of aeroengines, discussing the key technologies and research directions of the life cycle of mainshaft bearings based on digital twins. [ABSTRACT FROM AUTHOR]

The development and optimization of lipid nanoparticle (LNP) formulations through hydrodynamic mixing is critical for ensuring the efficient and cost-effective supply of vaccines. Continuous LNP formation through microfluidic mixing can overcome manufacturing bottlenecks and enable the production of nucleic acid vaccines and therapeutics. Predictive process models developed within a QbD Biopharma 4.0 approach can ensure the quality and consistency of the manufacturing process. This study highlights the importance of continuous LNP formation through microfluidic mixing in ensuring high-quality, in-specification production. Both empty and nucleic acid-loaded LNPs are characterized, followed by a TFF/buffer exchange to obtain process parameters for the envisioned continuous SPTFF. It is shown that LNP generation by pipetting leads to a less preferable product when compared to continuous mixing due to the heterogeneity and large particle size of the resulting LNPs (86–104 nm). Particle size by continuous formation (71 nm) and the achieved encapsulation efficiency (EE) of 88% is close to the targeted parameters for Pfizer's mRNA vaccine (66–93 nm, 88%EE). With the continuous encapsulation of nucleic acids in LNPs and the continuous production of mRNA in in vitro transcription, the basis for the holistic continuous production of mRNA is now established. We already showed that a fully autonomous process requires the incorporation of digital twins and a control strategy, with predictive process models and state-of-the-art PAT enabling real-time-release testing. This autonomous control can considerably improve productivity by about 15–20% and personnel as well as chemical reduction of about 30%. The results of this work complement this, laying the basis for fully continuous, bottleneck-free production of mRNA and other cell- and gene-therapeutic drug/vaccine candidates in a GMP- and QbD-compliant Biopharma 4.0 facilities on a flexible scale. [ABSTRACT FROM AUTHOR]

Pharmaceutical manufacturing processes are moving towards automation and real-time process monitoring with the help of process analytical technologies (PATs) and predictive process models representing the real system. In this paper, we present a digital twin developed for an adjuvant manufacturing process involving a microfluidic formation of lipid particles. The twin uses a hybrid model for estimating the current state of the process and predicting system behavior in real time. The twin is used to control the adjuvant particle size, a critical quality attribute, by varying process parameters such as the temperature and inlet flow rates. We describe steps in the design and implementation of the twin, starting from the conception of the mechanistic model, up to the generation of its surrogate model used as state estimator, PATs and the setup of the information technology—Operational technology architecture. We demonstrate the performance of the twin by introducing different disturbances in the process and comparing the effect on the product critical quality attributes with and without the control of the digital twin. Finally, we showcase the digital twin implementation for the process in good manufacturing practice, through an engineering run, which demonstrated the robustness of the process when controlled by the digital twin. [ABSTRACT FROM AUTHOR]

The concept of digital twinning is essential for smart manufacturing and cyber-physical systems to be connected to the Metaverse. These digital representations of physical objects can be used for real-time analysis, simulations, and predictive maintenance. A combination of smart manufacturing, Industry 4.0, and the Metaverse can lead to sustainable productivity in industries. This paper presents a practical approach to implementing digital twins of a magnetic forging holder that was designed and manufactured in this project. Thus, this paper makes two important contributions: the first contribution is the manufacturing of the holder, and the second significant contribution is the creation of its digital twin. The holder benefits from a special design and implementation, making it a user-friendly and powerful tool in materials research. More specifically, it can be employed for the thermomechanical influencing of the structure and, hence, the final properties of the materials under development. In addition, this mechanism allows us to produce a new type of creep-resistant composite material based on Fe, Al, and Y. The magnetic forging holder consolidates the powder material to form a solid state after mechanical alloying. We produce bars from the powder components using a suitable forging process in which extreme grain coarsening occurs after the final heat treatment. This is one of the conditions for achieving very high resistance to creep at high temperatures. [ABSTRACT FROM AUTHOR]

Limitations regarding process design, optimization, and control often occur when using particular process simulators. With the implementation of connection methodologies, integrated tools could be made by coupling popular process simulation software with each other or with programming environments. In the current paper, we summarized and categorized the existing research regarding the application of multi-software engineering in the chemical industry, with an emphasis on software connections. CAPE-OPEN, COM, OPC, and native integration were discussed in detail, with the intention to serve as a guide for choosing the most suitable software combination and connection. These hybrid systems can handle complex user-defined problems and can be used for decision support, performing custom unit operations, operator training, process optimization, building control systems, and developing digital twins. In this work, we proposed the use of process simulator Aspen HYSYS linked together with the numeric computing platform MATLAB to solve a reaction kinetic parameter identification problem regarding the production of  γ -valerolactone. [ABSTRACT FROM AUTHOR]

Many fundamental decisions in the process design of a separation task are conducted in an early stage where, unfortunately, process simulation does not have the highest priority. Subsequently, during the setup of the digital twin, dedicated experiments are carried out in the design space that was established earlier. These experiments are most often too complicated to conduct directly. This paper addresses the idea of a combined approach. The early-stage buffer screening and optimization experiments were planned with the Design of Experiments, carried out and then analyzed statistically to extract not only the best buffer composition but also the crucial model parameters, in this case the isotherm dependency on the buffer composition. This allowed the digital twin to predict the best buffer composition, and if the model-predicted control was applied to keep the process at the optimal productivity at a predetermined purity. The methodology was tested with an industrial peptide purification step. [ABSTRACT FROM AUTHOR]

Optimizing or debottlenecking existing production plants is a challenging task. In this case study, an existing reversed phased chromatography polishing step for peptide purification was optimized with the help of a digital twin. The existing batch chromatography was depicted digitally with the general rate model. Model parameter determination and model validation was done with dedicated experiments. The digital twin was then used to identify optimized process variants, especially continuous chromatography steps. MCSGP was found to achieve high purities and yield but at the cost of productivity due to column synchronization. An alternative Continuous Twin Column chromatography process (CTCC) was established that eliminates unnecessary waiting times. Ensuring the same or higher purity compared to the batch process, the continuous process achieved a yield increase of 31% and productivity increase of 27.6%. Experimental long runs confirmed these results. [ABSTRACT FROM AUTHOR]

Most large commercial vessels are propelled by low-speed two-stroke diesel engines due to their fuel economy and reliability. With increasing international concern about emissions and the rise in oil prices, improvements in engine efficiency are urgently needed. In the present work, a zero-dimensional model for a low-speed two-stroke diesel engine is developed that considers the exhaust gas bypass and geometry structures for the gas exchange model. The model was applied to a low-speed two-stroke 7G80 ME-C9 marine diesel engine and validated with engine shop test data, which consisted of the main engine performance parameters and cylinder pressure diagrams at different loads. The simulation results were in good agreement with the experimental data. Thus, the model has the ability to predict engine performance with good accuracy. After model validation, the variations in compression ratio, fuel injection timing, exhaust gas bypass valve opening portion, exhaust valve opening timing, and exhaust valve closing timing effects on engine performance were tested. Finally, the influence level of different parameters on engine performance was summarized, which can be used as a reference to determine the reasons for high fuel consumption in some cases. The developed engine performance model is considerable in digital twins for performance simulation, health management, and optimization. [ABSTRACT FROM AUTHOR]

Smart factories are equipped with Industry 4.0 technologies including smart sensors, digital twin, big data, and embedded software solutions. The application of these technologies contributes to better decision-making, and this real-time decision-making can improve the efficiency of both manufacturing and related logistics processes. In this article, the transformation of conventional milk-run-based in-plant supply solutions into a cyber–physical milk-run supply is described, where the application of Industry 4.0 technologies makes it possible to make real-time decisions regarding scheduling, routing, and resource planning. After a literature review, this paper introduces the structure of Industry 4.0 technologies supported by milk-run-based in-plant supply. A mathematical model of milk-run processes is described including both scheduling and routing problems of in-plant supply. This mathematical model makes it possible to analyze the impact of Industry 4.0 technologies on the efficiency, performance, and flexibility of in-plant supply logistics. The scenarios' analysis validates the mathematical model and shows that significant performance improvement and energy savings can be achieved using Industry 4.0 technologies. This performance improvement can lead to a more cost-efficient and sustainable in-plant supply solution, where not only logistics aspects but also energy efficiency and emissions can be taken into consideration. [ABSTRACT FROM AUTHOR]

The production of messenger ribonucleic acid (mRNA) and other biologics is performed primarily in batch mode. This results in larger equipment, cleaning/sterilization volumes, and dead times compared to any continuous approach. Consequently, production throughput is lower and capital costs are relatively high. Switching to continuous production thus reduces the production footprint and also lowers the cost of goods (COG). During process development, from the provision of clinical trial samples to the production plant, different plant sizes are usually required, operating at different operating parameters. To speed up this step, it would be optimal if only one plant with the same equipment and piping could be used for all sizes. In this study, an efficient solution to this old challenge in biologics manufacturing is demonstrated, namely the qualification and validation of a plant setup for clinical trial doses of about 1000 doses and a production scale-up of about 10 million doses. Using the current example of the Comirnaty BNT162b2 mRNA vaccine, the cost-intensive in vitro transcription was first optimized in batch so that a yield of 12 g/L mRNA was achieved, and then successfully transferred to continuous production in the segmented plug flow reactor with subsequent purification using ultra- and diafiltration, which enables the recycling of costly reactants. To realize automated process control as well as real-time product release, the use of appropriate process analytical technology is essential. This will also be used to efficiently capture the product slug so that no product loss occurs and contamination from the fill-up phase is <1%. Further work will focus on real-time release testing during a continuous operating campaign under autonomous operational control. Such efforts will enable direct industrialization in collaboration with appropriate industry partners, their regulatory affairs, and quality assurance. A production scale-operation could be directly supported and managed by data-driven decisions. [ABSTRACT FROM AUTHOR]

Liquid–liquid extraction has proven to be an aid in biologics manufacturing for cell and component separation. Because distribution coefficients and separation factors can be appropriately adjusted via phase screening, especially in aqueous two-phase systems, one stage is frequently feasible. For biologics separation, aqueous two-phase systems have proven to be feasible and efficient. The simple mixer–settler equipment type is still not standard in biologics manufacturing operations. Therefore, a scalable digital twin would be of aid for operator training, process design under the regulatory demanded quality by design approach for risk analysis, design and control space definition, and predictive maintenance. Autonomous operation is achieved with the aid of process analytical technology to update the digital twin to real time events and to allow process control near any optimal operation point. Autonomous operation is first demonstrated with an experimental feasibility study based on an industrial type example of pDNA manufacturing via lysis from E. coli with and without cell separation performance. [ABSTRACT FROM AUTHOR]

Supply chain disruptions and challenges have and will always exist, but preparing in advance and improving resilience for the upcoming consequences should be the utmost important goal. This paper explores trends that affect innovation in the technological sphere of supply chain systems. More precisely, the research is focused on Digital Twin technology applicability through other logistics IT trends and aims to research the pressing issue of ensuring the visibility and resilience of future supply chain systems. The paper's objective is to produce a conceptual model enabling the investment assessment of the necessary IT resources. Initially, a theoretical confirmation of logistics IT trends' relevance to supply chain systems was established. After, propositions of Digital Twin technology applications to other logistics IT trends were made, which were divided into corresponding constant multitudes of supply chain systems. Lastly, the conceptual model for the investment assessment of the necessary IT resources was derived in the form of a matrix. It considers 16 parameters for investment assessment and applicability to all companies, regardless of their specifics. It also supports the notion of digital IT competencies' fundamental importance to the continuous operation of supply chain systems. [ABSTRACT FROM AUTHOR]

Supply chain management is one of the most prominent areas that needs to incorporate sustainability to achieve responsible consumption and production (SDG 11).It has been identified that there are limited studies that have presented the significance of different Industry 4.0 technologies from the perspective of sustainable SCM. The purpose of this study is to discuss the role of Industry 4.0 technologies in the context of sustainable SCM, as well as to identify important areas for future research. The PRISM framework is followed to discuss the role and significance of sustainable SCM and the integration of Industry 4.0-enabling technologies such as the Internet of Things (IoT), cloud computing, big data, artificial intelligence (AI), blockchain, and digital twin for sustainable SCM. The findings of the study reveal that there are limited empirical studies for developing countries and the majority are emphasized in case studies. Additionally, a few studies have focused on operational aspects, economics, and automation in SCM. The current study is able to contribute to the significance and application of IoT, cloud computing, big data, AI, blockchain, and digital twin in achieving sustainable SCM in the future. The current study can be expanded to discuss the Industry 4.0-enabling technologies in analyzing sustainability performance in any organization using environmental, social, and governance (ESG) metrics. [ABSTRACT FROM AUTHOR]

As part of the European Commission research project DIY4U focused on the development of machinery to be installed in supermarket allowing customers to define their customized detergent according to their needs. These machines will mix the detergent components (surfactant, fatty acid, water, perfume, etc.) already in the detergent canister as sold to consumers. To avoid long waiting times for customers, and to obtain a product with good quality and consistency, mixing must be very efficient. A mixing process with rotation and displacement by means of rotating the canister around an axis below the canister bottom has been checked by means of Computational Fluid Dynamics (CFD) tools after validation of one case with lab results. This is a new approach for liquid detergents, as commonly is a powder detergent production process. The mixing process has been simulated for 39 different combinations of components mass fraction percentages and the mixing quality observed during the mixing period. A response surface obtained from these simulations has been developed to be included in a Digital Twin, this being a task within this DIY4U project. The results show that this system is very efficient, taking a few seconds to develop a complete mixing. Also, the mixing time differences are quite small, requiring all customers to wait just few seconds independently of their detergent formulation. [ABSTRACT FROM AUTHOR]

The smart and resilient transformation of manufacturing firms has flourished in the last decade. This paper investigates the smart and resilient transformation of manufacturing firms with the application of digital services. It uses a Serbian data set of 136 manufacturing firms from the Digital Servitization Survey from 2022 coordinated by IFIP WG5.7. The authors applied a different method approach through social network analysis, correlation analysis, and interviews with representatives from the manufacturing firms. The main results show that manufacturing firms that apply an adequate combination of services and digital technologies have the highest impact on the network of manufacturing firms. Moreover, the results show that applying digital technologies, such as additive manufacturing/3D printing, big data analytics, and digital twin, increases the gross annual turnover of manufacturing firms in the COVID-19 era. Finally, the results show that for a successful smart and resilient transformation, manufacturing firms need to develop a strategy and motivation oriented to profit to be resilient enough to withstand market change. [ABSTRACT FROM AUTHOR]

The CNC machine tool is the passive executor of machining code. It cannot predict the machining accuracy during machining. If the error is found to be out of tolerance after processing, it will not only scrap the parts, but also greatly affect the processing efficiency. This phenomenon is very prominent when machining sculptured surface parts with five-axis machine tools. Therefore, this paper proposes a Digital Twin (DT) modeling method of five-axis machine tools for predicting Continuous Trajectory Contour Error (CTCE) caused by tracking errors and geometric errors. The DT consists of three parts: the Setpoints Trajectory (ST) model, the Actual Trajectory (AT) model considering tracking errors and geometric errors and the CTCE model. For a specific machine tool, according to the basic geometric information of the machine tool (tool length, kinematic chain information, etc.) and 41 geometric errors, the DT can be established. Inputting the Setpoints Positions (SPs) and the Linear Encoder Detection Positions (LEDPs), the DT can be used to predict the Tool-Tip Position Trajectory (TTPT) contour error and the Tool Orientation Trajectory (TOT) contour error. In order to verify the proposed method experimentally, the KMC400S U five-axis machine tool is selected to establish its DT by which the contour error of the S-shaped trajectory are predicted offline. Then, the DMU50 five-axis machine tool is selected to establish its DT to predict the contour error of the circular trajectory in real time. Combined with the deep motion mechanism, this paper proposes a DT modeling method for the vertical application scene of parts machining accuracy prediction, which is of great significance to developing the DT application theory and ensuring the machining accuracy of parts. [ABSTRACT FROM AUTHOR]

Scholars seek to recycle wasted energy to produce electricity by integrating thermoelectric generators (TEGs) with internal combustion engines (ICE), which rely on the electrical conductivity, β, of the thermal conductor strips. The TEG legs are alloyed from iron, aluminum and copper in a strip shape with specific characteristics that guarantee maximum thermo-electric transformation, which has fluctuated between a uniform, Gaussian, and exponential distribution according to the structure of the alloy. The ICE exhaust and intake gates were chosen as the TEG sides. The digital simulator twin model checks the integration efficiency through two sequential stages, beginning with recording the causes of thermal conductivity failure via filming and extracting their data by neural network procedures in the feed of the second stage, which reveal that the cracks are a major obstacle in reducing the TEG-generated power. Therefore, the interest of the second stage is predicting the cracks' positions, Pi,j, and their intensity, QP, based on the ant colony algorithm which recruits imaging data (STTF-NN-ACO) to install the thermal conductors far away from the cracks' positions. The proposed metaheuristic (STTF-NN-ACO) verification shows superiority in the prediction over [Mat-ACO] by 8.2% and boosts the TEGs' efficiency by 32.21%. Moreover, increasing the total generated power by 12.15% and working hours of TEG by 20.39%, reflects reduced fuel consumption by up to 19.63%. [ABSTRACT FROM AUTHOR]

Solutions that aim to reduce water production in heavy oil wells have led to the design of devices known as rate-controlled production (RCP) autonomous inflow-control device (AICD) valves, which are placed in well completions and autonomously open with the oil inflow and close with water by choking the flow. These devices, which are based on Bernoulli's principle, use a levitating disk that chokes the flow of the phase with the lowest flow resistance. This study proposes a numerical model based on computational fluid dynamics (CFD) technology to understand these devices' operations and propose better designs without experimentation. The numerical model was based on dynamic fluid–body interaction (DFBI) and volume of fluid (VOF) models. The model was found to respond as expected depending on the physical properties of the fluids involved in heavy oil production. Finally, some limitations were found in the numerical study that can be improved in future studies. [ABSTRACT FROM AUTHOR]

The concept of the metaverse has gained increasing attention in recent years, and the development of various new technologies, including digital twin technology, has made it possible to see the metaverse coming to pass. Many academics have begun to investigate various problems after realizing the importance of digital twin technology in building the metaverse. However, when utilizing digital twin technology to construct a metaverse, there remains limited research on how to allocate multibase station resources. This research translates a multibase station wireless resource allocation problem into an integer linear programming constraint model when virtual service providers construct a metaverse. In addition, the optimal VCG reverse auction (OPT-VCGRA) mechanism is designed to maximize social welfare and solve the problem of IoT devices competing for base station wireless resources. Specifically, the problem of the optimal allocation of wireless channel resources and payment rule based on the Vickrey–Clarke–Groves mechanism is solved to achieve optimal allocation and calculation of payment prices. Since the optimal allocation problem is NP-hard, this paper also designs a metaverse digital twin resource allocation and pricing (MDTRAP) mechanism based on monotonic allocation and key value theory. The mechanism sends the resource allocation results of multiple base stations to IoT devices and calculates the price payment when building a metaverse in the real world. This paper shows that both auction mechanisms have incentive compatibility and individual rationality properties. Through experiments, this paper compares the two mechanisms in terms of social welfare, the number of winners, and the overall payment. The MDTRAP mechanism performs similarly to the OPT-VCGRA mechanism in terms of social welfare, the number of winners, and channel utilization but is far superior to the OPT-VCGRA mechanism in terms of execution time and total payment. The trustful experiment also verified the truthfulness of the MDTRAP mechanism. The experimental results show that the MDTRAP mechanism can be used to solve the resource allocation problem of multiple base stations to IoT devices when building a metaverse in the real world and can effectively maximize social welfare. [ABSTRACT FROM AUTHOR]

The digital twin has emerged as a crucial technology for smart production. The Asset Administration Shell (AAS) is a standard tool that can support the digital representation of a process plant. We present a method to use AAS coupled with ISO 15926 to facilitate the exchange of maintenance data in process plants. To accomplish this, the operation and maintenance (O&M) system framework employed in process plants is defined. Information requirements are derived based on this framework, and a maintenance data structure is designed. Along with this, reference data are applied to identify the types of equipment and properties of each equipment type using ISO 15926. According to the pre-designed data structure, a neutral format based on AAS is developed to exchange maintenance data among software systems in O&M. The neutral format is verified through a test case of exchanging maintenance data (equipment condition and health status data) in terms of applicability to O&M systems in the field and compliance with the AAS meta-data model. [ABSTRACT FROM AUTHOR]

Despite intensive research over the last three decades, it has not yet been possible to bring an effective vaccine against human immunodeficiency virus (HIV) and the resulting acquired immunodeficiency syndrome (AIDS) to market. Virus-like particles (VLP) are a promising approach for efficient and effective vaccination and could play an important role in the fight against HIV. For example, HEK293 (human embryo kidney) cells can be used to produce virus-like particles. In this context, given the quality-by-design (QbD) concept for manufacturing, a digital twin is of great importance for the production of HIV-Gag-formed VLPs. In this work, a dynamic metabolic model for the production of HIV-Gag VLPs was developed and validated. The model can represent the VLP production as well as the consumption or formation of all important substrates and metabolites. Thus, in combination with already described process analytical technology (PAT) methods, the final step towards the implementation of a digital twin for process development and design, as well as process automation, was completed. [ABSTRACT FROM AUTHOR]

The development and optimization of lipid nanoparticle (LNP) formulations through hydrodynamic mixing is critical for ensuring the efficient and cost-effective supply of vaccines. Continuous LNP formation through microfluidic mixing can overcome manufacturing bottlenecks and enable the production of nucleic acid vaccines and therapeutics. Predictive process models developed within a QbD Biopharma 4.0 approach can ensure the quality and consistency of the manufacturing process. This study highlights the importance of continuous LNP formation through microfluidic mixing in ensuring high-quality, in-specification production. Both empty and nucleic acid-loaded LNPs are characterized, followed by a TFF/buffer exchange to obtain process parameters for the envisioned continuous SPTFF. It is shown that LNP generation by pipetting leads to a less preferable product when compared to continuous mixing due to the heterogeneity and large particle size of the resulting LNPs (86–104 nm). Particle size by continuous formation (71 nm) and the achieved encapsulation efficiency (EE) of 88% is close to the targeted parameters for Pfizer’s mRNA vaccine (66–93 nm, 88%EE). With the continuous encapsulation of nucleic acids in LNPs and the continuous production of mRNA in in vitro transcription, the basis for the holistic continuous production of mRNA is now established. We already showed that a fully autonomous process requires the incorporation of digital twins and a control strategy, with predictive process models and state-of-the-art PAT enabling real-time-release testing. This autonomous control can considerably improve productivity by about 15–20% and personnel as well as chemical reduction of about 30%. The results of this work complement this, laying the basis for fully continuous, bottleneck-free production of mRNA and other cell- and gene-therapeutic drug/vaccine candidates in a GMP- and QbD-compliant Biopharma 4.0 facilities on a flexible scale.

Pharmaceutical manufacturing processes are moving towards automation and real-time process monitoring with the help of process analytical technologies (PATs) and predictive process models representing the real system. In this paper, we present a digital twin developed for an adjuvant manufacturing process involving a microfluidic formation of lipid particles. The twin uses a hybrid model for estimating the current state of the process and predicting system behavior in real time. The twin is used to control the adjuvant particle size, a critical quality attribute, by varying process parameters such as the temperature and inlet flow rates. We describe steps in the design and implementation of the twin, starting from the conception of the mechanistic model, up to the generation of its surrogate model used as state estimator, PATs and the setup of the information technology—Operational technology architecture. We demonstrate the performance of the twin by introducing different disturbances in the process and comparing the effect on the product critical quality attributes with and without the control of the digital twin. Finally, we showcase the digital twin implementation for the process in good manufacturing practice, through an engineering run, which demonstrated the robustness of the process when controlled by the digital twin.

Natural extracts are broadly utilized as remedies, nutrition additives, cosmetics or flavors as well as natural pesticides, fungicides or herbicides. Green manufacturing technologies are of added market value and are sustainable towards the climate neutrality politically demanded for 2045. The concept of digital twins involves experimentally distinct validated process models combined with process analytical technology that is to be adapted to the existing operations. This is a key technology for the autonomous operations in industry 4.0. This paper exemplifies this approach and evaluates the results of the application and implementation efforts of regulated industries. A conductivity sensor for the measurement of the dry residue content and/or Fourier-transformed infrared spectroscopy for marker/lead or reference substance concentration determination are the most feasible and straight forward solutions. Different process control concepts from simple PID controllers (proportional, integral and differential) to advanced process control using digital twin models are evaluated and discussed in terms of industrialization efforts and benefits. The global warming potential CO2 equivalent per kg of natural product could be decreased by a factor of 5–10 as well as the cost of goods, which makes the pay-out time for the industrialization investment less than 1 year and the approach highly competitive. The success rate of the extraction process under regulatory constraints can be raised to 100%, reducing waste, overall solvent consumption, personnel efforts and energy requirements to a minimum.

Digital Twins (DT) as digital representations are increasingly becoming operational design tools in a variety of contexts. Although a common understanding of the concept and the underlying development procedure would facilitate DT applications, only limited information has been published on the essential stages of development and fundamental development activities. This paper examines the extent to which an abstract, and thus generally applicable model for the development of Digital Twins can be identified. In order to come up with such a reference procedure, a structured analysis of published development experiences has been performed. Three major application domains, namely product lifecycle management, manufacturing, and predictive maintenance, could be detailed and cross-checked. For each of these domains, a contextual development model could be derived from empirically valid design and engineering practices. The data also allowed for the determination of which way each model corresponds to existing Digital Twin concepts. The use of a standard modeling notation enabled the integration of the domain-specific models into a single Digital Twin development model. As a result, developers are guided by domain-independent and -dependent development steps. Due to its generic structure, the model can serve for further domain explorations. [ABSTRACT FROM AUTHOR]

In this paper, we propose a framework to implement a fault-tolerant and a reconfigurable distributed control approach in programmable logic controller (PLC) for manufacturing systems (MS). The reconfiguration methodology adopted in this paper is based on supervisory control theory (SCT), and it is triggered following sensor fault detection. The lost information about these sensors is replaced by timed information allowing the MS to continue its operations. The switch from a normal behavior to a degraded behavior when a sensor fault appears is ensured by reconfiguration rules. The main objective of our framework is to implement the obtained control into a PLC. To meet this objective, the distributed controllers of the two operating modes as well as the reconfiguration rules are interpreted into different Grafcet models. The implementation of these different models is verified by a checker-model technique before being tested on a digital twin and validated on a real MS. [ABSTRACT FROM AUTHOR]

The production of messenger ribonucleic acid (mRNA) and other biologics is performed primarily in batch mode. This results in larger equipment, cleaning/sterilization volumes, and dead times compared to any continuous approach. Consequently, production throughput is lower and capital costs are relatively high. Switching to continuous production thus reduces the production footprint and also lowers the cost of goods (COG). During process development, from the provision of clinical trial samples to the production plant, different plant sizes are usually required, operating at different operating parameters. To speed up this step, it would be optimal if only one plant with the same equipment and piping could be used for all sizes. In this study, an efficient solution to this old challenge in biologics manufacturing is demonstrated, namely the qualification and validation of a plant setup for clinical trial doses of about 1000 doses and a production scale-up of about 10 million doses. Using the current example of the Comirnaty BNT162b2 mRNA vaccine, the cost-intensive in vitro transcription was first optimized in batch so that a yield of 12 g/L mRNA was achieved, and then successfully transferred to continuous production in the segmented plug flow reactor with subsequent purification using ultra- and diafiltration, which enables the recycling of costly reactants. To realize automated process control as well as real-time product release, the use of appropriate process analytical technology is essential. This will also be used to efficiently capture the product slug so that no product loss occurs and contamination from the fill-up phase is

Product quality is an important part of enterprise competitiveness. Product processing is the key process of quality formation. In smart factories, the improvement of data acquisition and processing capability provides a basis for data-based quality control. In order to reduce the occurrence of product quality problems, we abstracted the product processing process as a data processing unit, abstracted the process of changing the product quality state as a process of the processing quality characteristics data, divided the measured value of quality characteristics into three states according to the fluctuation of the measured value of product quality characteristics, and then the classification model of process equipment parameters was established. The experimental results show that the error rate of the real-time dynamic prediction of quality characteristics based on equipment parameters was acceptable, and its prediction could be used as a reference in real production. The research could be applied in product quality prediction, production process simulation, digital twin and other fields. [ABSTRACT FROM AUTHOR]

The development and adoption of digital twins (DT) for Quality-by-Design (QbD)-based processes with flexible operating points within a proven acceptable range (PAR) and automation through Advanced Process Control (APC) with Process Analytical Technology (PAT) instead of conventional process execution based on offline analytics and inflexible process set points is one of the great challenges in modern biotechnology. Virus-like particles (VLPs) are part of a line of innovative drug substances (DS). VLPs, especially those based on human immunodeficiency virus (HIV), HIV-1 Gag VLPs, have very high potential as a versatile vaccination platform, allowing for pseudotyping with heterologous envelope proteins, e.g., the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As enveloped VLPs, optimal process control with minimal hold times is essential. This study demonstrates, for the first time, the use of a digital twin for the overall production process of HIV-1 Gag VLPs from cultivation, clarification, and purification to lyophilization. The accuracy of the digital twins is in the range of 0.8 to 1.4% in depth filtration (DF) and 4.6 to 5.2% in ultrafiltration/diafiltration (UFDF). The uncertainty due to variability in the model parameter determination is less than 4.5% (DF) and less than 3.8% (UFDF). In the DF, a prediction of the final filter capacity was demonstrated from as low as 5.8% (9mbar) of the final transmembrane pressure (TMP). The scale-up based on DT in chromatography shows optimization potential in productivity up to a factor of 2. The schedule based on DT and PAT for APC has been compared to conventional process control, and hold-time and process duration reductions by a factor of 2 have been achieved. This work lays the foundation for the short-term validation of the DT and PAT for APC in an automated S7 process environment and the conversion from batch to continuous production. [ABSTRACT FROM AUTHOR]

Quality-by-Design (QbD) is demanded by regulatory authorities in biopharmaceutical production. Within the QbD frame advanced process control (APC), facilitated through process analytical technology (PAT) and digital twins (DT), plays an increasingly important role as it can help to assure to stay within the predefined proven acceptable range (PAR).This ensures high product quality, minimizes failure and is an important step towards a real-time-release testing (RTRT) that could help to accelerate time-to-market of drug substances, which is becoming even more important in light of dynamical pandemic situations. The approach is exemplified on scFv manufacturing in Escherichia coli. Simulation results from digital twins are compared to experimental data and found to be accurate and precise. Harvest is achieved by tangential flow filtration followed by product release through high pressure homogenization and subsequent clarification by tangential flow filtration. Digital twins of the membrane processes show that shear rate and transmembrane pressure are significant process parameters, which is in line with experimental data. Optimized settings were applied to 0.3 bar and a shear rate of 11,000 s−1. Productivity of chromatography steps were 5.3 g/L/d (Protein L) and 2167 g/L/d (CEX) and the final product concentration was 8 g/L. Based on digital twin results, an optimized process schedule was developed that decreased purification time to one working day, which is a factor-two reduction compared to the conventional process schedule. This work presents the basis for future studies on advanced process control and automation for biologics production in microbials in regulated industries. [ABSTRACT FROM AUTHOR]

Process chromatography modelling for process development, design, and optimization as well as process control has been under development for decades. Still, the discussion of scientific potential and industrial applications needs is open to innovation. The discussion of next-generation modelling approaches starting from Langmuirian to steric mass action and multilayer or thermodynamic consistent real and ideal adsorption theory or colloidal particle adsorption approaches is continued. [ABSTRACT FROM AUTHOR]

Liquid–liquid extraction has proven to be an aid in biologics manufacturing for cell and component separation. Because distribution coefficients and separation factors can be appropriately adjusted via phase screening, especially in aqueous two-phase systems, one stage is frequently feasible. For biologics separation, aqueous two-phase systems have proven to be feasible and efficient. The simple mixer–settler equipment type is still not standard in biologics manufacturing operations. Therefore, a scalable digital twin would be of aid for operator training, process design under the regulatory demanded quality by design approach for risk analysis, design and control space definition, and predictive maintenance. Autonomous operation is achieved with the aid of process analytical technology to update the digital twin to real time events and to allow process control near any optimal operation point. Autonomous operation is first demonstrated with an experimental feasibility study based on an industrial type example of pDNA manufacturing via lysis from E. coli with and without cell separation performance.

Process chromatography modelling for process development, design, and optimization as well as process control has been under development for decades. Still, the discussion of scientific potential and industrial applications needs is open to innovation. The discussion of next-generation modelling approaches starting from Langmuirian to steric mass action and multilayer or thermodynamic consistent real and ideal adsorption theory or colloidal particle adsorption approaches is continued.

The Industry 4.0 concept of a Digital Twin will bring many advantages for wind energy conversion systems, e.g., in condition monitoring, predictive maintenance and the optimisation of control or design parameters. A virtual replica is at the heart of a digital twin. To construct a virtual replica, appropriate modelling techniques must be selected for the turbine components. These models must be chosen with the intended use case of the digital twin in mind, finding a proper balance between the model fidelity and computational load. This review article presents an overview of the recent literature on modelling techniques for turbine aerodynamics, structure and drivetrain mechanics, the permanent magnet synchronous generator, the power electronic converter and the pitch and yaw systems. For each component, a balanced overview is given of models with varying model fidelity and computational load, ranging from simplified lumped parameter models to advanced numerical Finite Element Method (FEM)-based models. The results of the literature review are presented graphically to aid the reader in the model selection process. Based on this review, a high-level structure of a digital twin is proposed together with a virtual replica with a minimum computational load. The concept of a multi-level hierarchical virtual replica is presented.

The Industry 4.0 concept of a Digital Twin will bring many advantages for wind energy conversion systems, e.g., in condition monitoring, predictive maintenance and the optimisation of control or design parameters. A virtual replica is at the heart of a digital twin. To construct a virtual replica, appropriate modelling techniques must be selected for the turbine components. These models must be chosen with the intended use case of the digital twin in mind, finding a proper balance between the model fidelity and computational load. This review article presents an overview of the recent literature on modelling techniques for turbine aerodynamics, structure and drivetrain mechanics, the permanent magnet synchronous generator, the power electronic converter and the pitch and yaw systems. For each component, a balanced overview is given of models with varying model fidelity and computational load, ranging from simplified lumped parameter models to advanced numerical Finite Element Method (FEM)-based models. The results of the literature review are presented graphically to aid the reader in the model selection process. Based on this review, a high-level structure of a digital twin is proposed together with a virtual replica with a minimum computational load. The concept of a multi-level hierarchical virtual replica is presented. [ABSTRACT FROM AUTHOR]

The fast exploration of a design space and identification of the best process conditions facilitating the highest space-time yield are of great interest for manufacturers. To obtain this information, depending on the design space, a large number of practical experiments must be performed, analyzed, and evaluated. To reduce this experimental effort and increase the process understanding, we evaluated a model-based design of experiments to rapidly identify the optimum process conditions in a design space maximizing space-time yield. From a small initial dataset, hybrid models were implemented and used as digital bioprocess twins, thus obtaining the recommended optimal experiment. In cases where these optimum conditions were not covered by existing data, the experiment was carried out and added to the initial data set, re-training the hybrid model. The procedure was repeated until the model gained certainty about the best process conditions, i.e., no new recommendations. To evaluate this workflow, we utilized different initial data sets and assessed their respective performances. The fastest approach for optimizing the space-time yield in a three-dimensional design space was found with five initial experiments. The digital twin gained certainty after four recommendations, leading to a significantly reduced experimental effort compared to other state-of-the-art approaches. This highlights the benefits of in silico design space exploration for accelerating knowledge-based bioprocess development, and reducing the number of hands-on experiments, time, energy, and raw materials. [ABSTRACT FROM AUTHOR]

Techniques to provide in vitro tissue culture have undergone significant changes during the last decades, and current applications involve interactions of cells and organoids, three-dimensional cell co-cultures, and organ/body-on-chip tools. Efficient computer-aided and mathematical model-based methods are required for efficient and knowledge-driven characterization, optimization, and routine manufacturing of tissue culture systems. As an alternative to purely experimental-driven research, the usage of comprehensive mathematical models as a virtual in silico representation of the tissue culture, namely a digital twin, can be advantageous. Digital twins include the mechanistic of the biological system in the form of diverse mathematical models, which describe the interaction between tissue culture techniques and cell growth, metabolism, and the quality of the tissue. In this review, current concepts, expectations, and the state of the art of digital twins for tissue culture concepts will be highlighted. In general, DT's can be applied along the full process chain and along the product life cycle. Due to the complexity, the focus of this review will be especially on the design, characterization, and operation of the tissue culture techniques. [ABSTRACT FROM AUTHOR]