La contribución de las fórmulas existentes de cooperación intermunicipal en la equidad territorial: el caso de la Mancomunitat de la Ribera Alta

Good governance is considered, both politically, geographically and economically, a key element for territorial and urban competitiveness. This article presents a critical and alternative point of view to this formulation, considering governance as a key factor of the objective of territorial balance. For this, two key concepts are considered: polycentrism (not morphological but functional and urban-rural) and territorial cooperation (of variable geometries) as the most efficient way to provide services and apply policies with territorial impact. The idea of territorial cohesion, as configured from the European Union, and the Territorial Strategy of the Comunitat Valenciana, which put emphasis on the key elements of territorial management, are taken as reference. After this contextualization, this paper presents the analysis of the predominant form of inter-city cooperation in the Valencian territory, the commonwealth, through a case study: the Mancomunitat de la Ribera Alta.La buena gobernanza está considerada, tanto desde el punto de vista político como geográfico y económico, como un elemento clave para la competitividad territorial y urbana. El artículo presenta un punto de vista crítico y alternativo a esta formulación, entendiendo la gobernanza como factor del objetivo de equilibrio territorial. Para ello, se consideran dos conceptos clave: policentrismo (no morfológico, sino funcional y urbanorural) y cooperación territorial (de geometrías variables), como forma más eficiente de dotar servicios y aplicar políticas con impacto territorial. Para todo ello se toman como referencia la idea de cohesión territorial, configurada principalmente desde la Unión Europea, y la Estrategia Territorial de la Comunitat Valenciana, que pone énfasis en los elementos de gestión territorial. Tras esta contextualización, el artículo presenta el análisis de la forma de cooperación intermunicipal predominante en el territorio valenciano, la mancomunidad, mediante un estudio de caso: la Mancomunitat de la Ribera Alta.valenciano, la mancomunidad, mediante un estudio de caso: la Mancomunitat de la Ribera Alta

Implementation of membrane models on a CAPE-OPEN tool to simulate a process including RO membranes

Process simulators are a useful tool for evaluating different configurations of chemical processes and developing new ones. Although these programs include many standard units like reactor or distillation towers, membrane units are not usually included. In this paper, it is shown the possibility to implement a reverse osmosis (RO) membrane unit in the free process simulator COCO, using input membrane parameters. The RO modeling is based on the coupling of the solution diffusion model with a model for concentration polarization. The model was implemented as a Matlab CAPE-OPEN unit operation. In order to show the functionality of the developed application, a rinsing process adapted from literature was implemented to test different configurations. In this way, the combined use of the COCO simulator and the model of a reverse osmosis unit proved to be a useful tool for comparing the performance of different process configurations.The Spanish Ministry of Economy and Competitiveness is kindly acknowledged (Project CTM 2010-20248).Gozálvez Zafrilla, JM.; Santafé Moros, MA.; Sanchis Sebastiá, M.; Gomis Fons, J. (2014). Implementation of membrane models on a CAPE-OPEN tool to simulate a process including RO membranes. Desalination and Water Treatment. 1-7. https://doi.org/10.1080/19443994.2014.995718S17Sharaf Eldean, M. A., & Soliman, A. M. (2013). A new visual library for modeling and simulation of renewable energy desalination systems (REDS). Desalination and Water Treatment, 51(37-39), 6905-6920. doi:10.1080/19443994.2013.777369Choi, Y.-J., Hwang, T.-M., Oh, H., Nam, S.-H., Lee, S., Jeon, J., … Chung, Y. (2011). Development of a simulation program for the forward osmosis and reverse osmosis process. Desalination and Water Treatment, 33(1-3), 273-282. doi:10.5004/dwt.2011.2652Karabelas, A. J., Kostoglou, M., & Koutsou, C. P. (2015). Modeling of spiral wound membrane desalination modules and plants – review and research priorities. Desalination, 356, 165-186. doi:10.1016/j.desal.2014.10.002Peshev, D., & Livingston, A. G. (2013). OSN Designer, a tool for predicting organic solvent nanofiltration technology performance using Aspen One, MATLAB and CAPE OPEN. Chemical Engineering Science, 104, 975-987. doi:10.1016/j.ces.2013.10.033Testard, L., & Belaud, J.-P. (2005). A CAPE-OPEN based framework for process simulation solutions integration. European Symposium on Computer-Aided Process Engineering-15, 38th European Symposium of the Working Party on Computer Aided Process Engineering, 607-612. doi:10.1016/s1570-7946(05)80223-8Morales-Rodríguez, R., Gani, R., Déchelotte, S., Vacher, A., & Baudouin, O. (2008). Use of CAPE-OPEN standards in the interoperability between modelling tools (MoT) and process simulators (Simulis® Thermodynamics and ProSimPlus). Chemical Engineering Research and Design, 86(7), 823-833. doi:10.1016/j.cherd.2008.02.022Guria, C., Bhattacharya, P. K., & Gupta, S. K. (2005). Multi-objective optimization of reverse osmosis desalination units using different adaptations of the non-dominated sorting genetic algorithm (NSGA). Computers & Chemical Engineering, 29(9), 1977-1995. doi:10.1016/j.compchemeng.2005.05.002Senthilmurugan, S., Ahluwalia, A., & Gupta, S. K. (2005). Modeling of a spiral-wound module and estimation of model parameters using numerical techniques. Desalination, 173(3), 269-286. doi:10.1016/j.desal.2004.08.034Chilyumova, E., & Thöming, J. (2007). Dynamic simulation of rinsing and regeneration networks based on high pressure RO. Desalination, 207(1-3), 45-58. doi:10.1016/j.desal.2006.07.00

Pilot-scale integrated continuous biomanufacturing for monoclonal antibodies including mild pH

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Toolbox for efficient development of high cell density perfusion process, integrated with continuous DSP

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Optimization study on periodic counter-current chromatography integrated in a monoclonal antibody downstream process

An optimization study of an integrated periodic counter-current chromatography (PCC) process in a monoclonal antibody (mAb) downstream process at lab scale, is presented in this paper. The optimization was based on a mechanistic model of the breakthrough curve in the protein-A capture step. Productivity and resin utilization were the objective functions, while yield during the loading of the capture column was set as a constraint. Different integration approaches were considered, and the effect of the feed concentration, yield and the protein-A resin was studied. The breakthrough curve and the length of the product recovery, which depended on the integration approach, determined the process scheduling. Several optimal Pareto solutions were obtained. At 0.5 mg mL−1 and 99% yield, a maximum productivity of 0.38 mg mL−1 min−1 with a resin utilization of 60% was obtained. On the other hand, the maximum resin utilization was 95% with a productivity of 0.10 mg mL−1 min−1. Due to the constraint of the process scheduling, a lower productivity could be achieved in the integration approaches with higher recovery time, which was more remarkable at higher concentrations. Therefore, it was shown that a holistic approach, where all the purification steps are considered in the process optimization, is needed to design a PCC in a downstream process

Smart platform for development of small-scale integrated continuous downstream processes

This chapter presents and discuss a platform for small-scale drug candidate production, process development and performance studies of integrated continuous downstream processes. The main idea of the platform methodology is to use common available equipment and reconfigure them for advanced downstream processing. Five different industrial case studies are discussed. The resulting processes are automated and controlled by the external supervisory controller, called Orbit. Orbit communicate with the local equipment control system, resulting in a minimum of adjustment in the laboratory infrastructure. Orbit is implemented in python, making it an open, flexible, and extendable control system. Orbit give support for integration of multiple chromatography columns, operate downstream processes on multiple parallel setups, integrated online analytics, use of advanced feedback control and batch-to-batch control. This functionality is presented in ten examples. The platform has successful been used in number of industrial case studies, particular in early drug and process development and for efficient small-scale drug candidate production

An automated buffer management system for small-scale continuous downstream bioprocessing

Buffer management for biopharmaceutical purification processes include buffer preparation, storage of buffers and restocking the buffers when needed. This is usually performed manually by the operators for small scale operations. However, buffer management can become a bottleneck when running integrated continuous purification processes for prolonged times, even at small scale. To address this issue, a buffer management system for the application in continuous lab-scale bioprocessing is presented in this paper. For this purpose, an ÄKTA™ explorer chromatography system was reconfigured to perform the buffer formulation. The system formulated all buffers from stock solutions and water according to pre-specified recipes. A digital twin of the physical system was introduced in the research software Orbit, written in python. Orbit was also used for full automation and control of the buffer system, which could run independently without operator input and handle buffer management for one or several connected buffer-consuming purification systems. The developed buffer management system performed automatic monitoring of buffer volumes, buffer order handling as well as buffer preparation and delivery. To demonstrate the capability of the developed system, it was integrated with a continuous downstream process and supplied all 9 required buffers to the process equipment during a 10-day operation. The buffer management system processed 55 orders and delivered 38 L of buffers, corresponding to 20% of its capacity. The pH and conductivity profiles observed during the purification steps were consistent across the cycles. The deviation in conductivity and pH from the measured average value was within ±0.89% in conductivity and ±0.045 in pH, well within the typical specification for buffer release, indicating that the prepared buffers had the correct composition. The operation of the developed buffer management system was robust and fully automated, and provides one solution to the buffer management bottleneck on lab scale for integrated continuous downstream bioprocessing

Optimal loading flow rate trajectory in monoclonal antibody capture chromatography

In this paper, we determined the optimal flow rate trajectory during the loading phase of a mAb capture column. For this purpose, a multi-objective function was used, consisting of productivity and resin utilization. Several general types of trajectories were considered, and the optimal Pareto points were obtained for all of them. In particular, the presented trajectories include a constant-flow loading process as a nominal approach, a stepwise trajectory, and a linear trajectory. Selected trajectories were then applied in experiments with the state-of-the-art protein A resin mAb Select PrismATM, running in batch mode on a standard single-column chromatography setup, and using both a purified mAb solution as well as a clarified supernatant. The results show that this simple approach, programming the volumetric flow rate according to either of the explored strategies, can improve the process economics by increasing productivity by up to 12% and resin utilization by up to 9% compared to a constant-flow process, while obtaining a yield higher than 99%. The productivity values were similar to the ones obtained in a multi-column continuous process, and ranged from 0.23 to 0.35 mg/min/mL resin. Additionally, it is shown that a model calibration carried out at constant flow can be applied in the simulation and optimization of flow trajectories. The selected processes were scaled up to pilot scale and simulated to prove that even higher productivity and resin utilization can be achieved at larger scales, and therefore confirm that the trajectories are generalizable across process scales for this resin

Automated quality analysis in continuous downstream processes for small-scale applications

Development of integrated, continuous biomanufacturing (ICB) processes brings along the challenge of streamlining the acquisition of data that can be used for process monitoring, product quality testing and process control. Manually performing sample acquisition, preparation, and analysis during process and product development on ICB platforms requires time and labor that diverts attention from the development itself. It also introduces variability in terms of human error in the handling of samples. To address this, a platform for automatic sampling, sample preparation and analysis for use in small-scale biopharmaceutical downstream processes was developed. The automatic quality analysis system (QAS) consisted of an ÄKTA Explorer chromatography system for sample retrieval, storage, and preparation, as well as an Agilent 1260 Infinity II analytical HPLC system for analysis. The ÄKTA Explorer system was fitted with a superloop in which samples could be stored, conditioned, and diluted before being sent to the injection loop of the Agilent system. The Python-based software Orbit, developed at the department of chemical engineering at Lund university, was used to control and create a communication framework for the systems.To demonstrate the QAS in action, a continuous capture chromatography process utilizing periodic counter-current chromatography was set up on an ÄKTA Pure chromatography system to purify the clarified harvest from a bioreactor for monoclonal antibody production. The QAS was connected to the process to collect two types of samples: 1) the bioreactor supernatant and 2) the product pool from the capture chromatography. Once collected, the samples were conditioned and diluted in the superloop before being sent to the Agilent system, where both aggregate content and charge variant composition were determined using size-exclusion and ion-exchange chromatography, respectively. The QAS was successfully implemented during a continuous run of the capture process, enabling the acquisition of process data with consistent quality and without human intervention, clearing the path for automated process monitoring and data-based control

Integration of a complete downstream process for the automated lab-scale production of a recombinant protein

In this work, an automated downstream process for the purification and formulation of a recombinant protein was integrated at lab scale in a single chromatography unit. The purification chain consists of three bind-and-elute chromatography columns, a flow-through membrane chromatography step, and a final ultrafiltration-diafiltration (UFDF) step to concentrate and formulate the sample. An integrated downstream process increases productivity and decreases process time and hold-up volume. In addition, the automation of the process allows reducing the manual work and increases reproducibility. To integrate the downstream steps, all the intermediate tanks are removed, and the eluate of a column is loaded directly onto the next one. This makes it necessary to design the process in order to minimize the column volumes and the process time. A research software called Orbit was used to automate the purification process and implement a UFDF step in the chromatography unit. The whole downstream sequence was successfully implemented at lab scale, getting a pure concentrated and formulated product with a productivity of 1.09 mg mL−1 h−1, achieving a time reduction from almost two to one working day, while getting a similar yield and purity. Regarding the UFDF operation, the sample was concentrated 10 times, and 97% of the old buffer was exchanged by the formulation buffer with a sequential diafiltration