127 research outputs found

    A Comprehensive Study of Sequential Simulated Moving Bed: Purification of Xylo-oligosaccharides and fructose-glucose

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    Chromatographic separation is a promising alternative for separation and purification of sugars in industry. Simulated moving bed (SMB) technique has been proven as an efficient chromatographic separation method due to its enhanced productivity and purity, reduced solvent consumption, convenient operating control, and improved separation performance for some systems with low resolution and selectivity. The sequential simulated moving bed (SSMB) is a modification of the conventional SMB process, which currently has some applications for sugar separation due to its low solvent consumption. This work mainly investigates the design strategy of the innovative SSMB process and explore its advantages and disadvantages over the SMB process based on the xylo-oligosaccharides (XOSs) and fructose-glucose systems. SSMB separation of XOSs, a functional food additive in the form of a oligomeric saccharide, was firstly conducted. DOWEX MONOSPHERETM 99/310 resin ionized with K+, which has better selectivity compared with Ca2+ and Na+ was used as the stationary phase.Breakthrough experiments showed that XOSs and the two major industrial impurities, xylose and arabinose, all exhibit linear isotherms. Transport-dispersive (TD) model parameters were determined by pulse experiments carried out at various flowrates. Finally, both the averaged and individual parameters of XOSs and XOS2-XOS7 were obtained. Lab-scale SSMB experiments and the corresponding simulations were carried out to validate the acquired TD model parameters and adsorption isotherms. After that, in order to investigate the optimal operating conditions of this process, the multi-objective optimizations were carried out for three cases with various objectives and constraints. It was found that, for a given SSMB unit, there exist a pareto curve for simultaneous maximization of purity and unit throughput. The flowrate ratios (m values), however, exhibit some trends that are different from those of conventional SMB and cannot be explained by the direct use of Triangle Theory with averaged m values. According to the literature, the fructose-glucose system is representative and have linear isotherms over a wide concentration range, which makes it an excellent example system to conduct some basic analysis and performance prediction. Therefore, the multi-objective optimization of SMB and SSMB processes was conducted and compared based on the fructose-glucose system. The results show that the solvent consumption of SSMB is always less than that of SMB unit

    Theoretical Analysis and Experimental Investigation of Simulated Moving Bed Chromatography for the Purification of Protein Mixtures

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    Stepwise-Elution Simulated Moving Bed Chromatography (SE-SMB) is a promising method for ‘intensification’ of polishing chromatographic processes in downstream bioprocessing. This is because SE-SMB systems are continuous, capable of high-resolution separations, efficient in their utilization of chromatographic resins, well-suited to non-isocratic proteinaceous separation problems operated under high feed-loading conditions, and highly productive. However, there are a number of theoretical and practical problems which have impeded industrial interest in the adoption of SE-SMB separations into downstream processes. Fundamental phenomena, such as the modulator dynamics of SE-SMB systems, have yet to be theoretically analysed. Consequently, important practical questions – such as how productive and high-resolution separations may be best achieved through SE-SMB systems – remain unanswered. Furthermore, the complexity and operational fragility of SE-SMB systems require much improvement in their ‘robustness’ before any consideration of their application to industrial purification of therapeutic proteins may be entertained. This thesis constitutes an initial investigation of the theoretical and practical issues which arise concerning the application of SE-SMB to industrial bioseparations. Regarding the theoretical issues, an analysis of modulator dynamics in SE-SMB systems is presented. This provides new insights into how such systems – both for binary and ternary separations - should be designed for productive and robust operations. Furthermore, the behaviour of SE-SMB systems under high feedloading conditions is also investigated. Regarding practical issues, experimental SMB separations of a challenging proteinaceous mixture are demonstrated, and simulated comparisons are used to investigate the comparative performance of various intensified processes. Finally, an exploration of SE-SMB fault detection and diagnosis methods is undertaken. The results suggest that SE-SMB chromatography may be ‘de-risked’ to such an extent that, with future development, it becomes an attractive option for incorporation into industrial bioprocesses

    Compact simulated countercurrent chromatography for downstream processing of (bio)pharmaceuticals

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    Dissertação para obtenção do Grau de Doutor em Engenharia Química e BioquímicaFundação para a Ciência e Tecnologia - PhD gran

    Single-Column Chromatography with Recycle Lag Analog to Simulated Moving Bed Processes

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    The chromatography steps dominate the Downstream Processing (DSP) costs of a new biopharmaceutical, which has propelled the biopharmaceutical industry to invest a lot of effort on their improvement in order to reduce the costs of the biopharmaceutical production. Liquid chromatography (LC) is currently the core technique within the DSP strategy for the purification of biopharmaceuticals. Although single-column batch chromatography is simpler to operate than continuous (multicolumn) chromatography, the latter has many advantages over the former, including improved purity, yield, and productivity. The main objective of this thesis is the development of a new chromatographic platform based on a novel single-column device that mimics the operation of multicolumn chromatography through ingenious management and recycling of the mixed fractions exiting the chromatographic column. The platform shares the benefits of the Simulated- Moving-Bed (SMB) technology. However, the newly developed process uses only a single chromatographic column. The conceptual design of the set-up and its mathematical model were successfully established. The laboratory prototype was built focusing on a simple, compact, and versatile design with small footprint. The binary separation of nucleosides by reversedphase chromatography was experimentally realized as proof of concept of the new system. An effort was made in 3D manufacturing of flow distributors and internals to ensure the proper operation of the recycle device and the improvement of its efficiency. A second case study—the capture step of monoclonal antibodies by affinity chromatography on protein A—was successfully used as a demonstration of the applicability of the newly developed process. The new system offers a more compact, less expensive, and simpler-to-operate alternative to multicolumn SMB chromatography. Depending on the efficiency of the recycle device, the single-column process can achieve the same purities as the analogous SMB unit while keeping the specific productivity constant. Moreover, the single-column chromatograph can be easily integrated into the existing downstream processing platforms of complex biopharmaceuticals

    Analysis and design of center-cut separations using 8-zone simulated moving bed chromatography

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    Preparative gradient chromatography

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    During a chromatographic separation, it is convenient to keep the essential operating parameters like temperature, pressure, mobile phase flow-rate, and mobile phase composition constant. Though, it is well known that in contrast to this isocratic operation the intelligent modulation of certain operating parameters can improve the separation performance significantly. Such gradient approaches are widely applied in analytical (linear) chromatography to reduce the time of analysis and to enhance the selectivity. In contrast, the extent of application of these gradients is still rather limited in the field of preparative (nonlinear) chromatography. The first part of this paper is devoted to the discussion of the principal differences between linear and nonlinear and isocratic and gradient chromatography. The second part focuses on introducing a countercurrent process that allows separation in a continuous manner, efficiently exploiting a two-step solvent composition gradient. Copyright © 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim [accessed February 8th 2013

    Towards continuous biomanufacturing a computational approach for the intensification of monoclonal antibody production

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    Current industrial trends encourage the development of sustainable, environmentally friendly processes with reduced energy and raw material consumption. Meanwhile, the increasing market demand as well as the tight regulations in product quality, necessitate efficient operating procedures that guarantee products of high purity. In this direction, process intensification via continuous operation paves the way for the development of novel, eco-friendly processes, characterized by higher productivity compared to batch (Nicoud, 2014). The shift towards continuous operation could advance the market of high value biologics, such as monoclonal antibodies (mAbs), as it would lead to shorter production times, decreased costs, as well as significantly less energy consumption (Konstantinov and Cooney, 2015, Xenopoulos, 2015). In particular, mAb production comprises two main steps: the culturing of the cells (upstream) and the purification of the targeted product (downstream). Both processes are highly complex and their performance depends on various parameters. In particular, the efficiency of the upstream depends highly on cell growth and the longevity of the culture, while product quality can be jeopardized in case the culture is not terminated timely. Similarly, downstream processing, whose main step is the chromatographic separation, relies highly on the setup configuration, as well as on the composition of the upstream mixture. Therefore, it is necessary to understand and optimize both processes prior to their integration. In this direction, the design of intelligent computational tools becomes eminent. Such tools can form a solid basis for the: (i) execution of cost-free comparisons of various operating strategies, (ii) design of optimal operation profiles and (iii) development of advanced, intelligent control systems that can maintain the process under optimal operation, rejecting disturbances. In this context, this work focuses on the development of advanced computational tools for the improvement of the performance of: (a) chromatographic separation processes and (b) cell culture systems, following the systematic PAROC framework and software platform (Pistikopoulos et al., 2015). In particular we develop model-based controllers for single- and multi-column chromatographic setups based on the operating principles of an industrially relevant separation process. The presented strategies are immunized against variations in the feed stream and can successfully compensate for time delays caused due to the column residence time. Issues regarding the points of integration in multi-column systems are also discussed. Moreover, we design and test in silico model-based control strategies for a cell culture system, aiming to increase the culture productivity and drive the system towards continuous operation. Challenges and potential solutions for the seamless integration of the examined bioprocess are also investigated at the end of this thesis.Open Acces

    Optimization of Chiral Separation of Nadolol by Simulated Moving Bed Technology

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    Simulated Moving Bed (SMB) technology has gained increasing attention as one of the most powerful techniques for chromatographic separations due to its cost-effectiveness and efficiency. Application of SMB technology is especially important in the pharmaceutical industry for production of enantiopure drugs, as required under strict FDA regulations, to avoid possible adverse effects of racemic drugs. In this study, the performance of the SMB process in separation of racemic nadolol on a perphenyl carbamoylated beta cyclodextrin (β-CD) stationary phase was investigated. The equilibrium dispersive model coupled with bi-Langmuir adsorption isotherm and lumped kinetic approximation, constitute the mathematical model used to simulate the dynamic behavior of SMB. Multi-objective optimization was carried out using a robust state-of-the-art optimization technique, non-dominated sorting genetic algorithm (NSGA). Two optimization problems were solved to simultaneously maximize productivity and purity of the product and minimize consumption of desorbent. The generated Pareto optimal solutions showed that selection of operating conditions can significantly affects the performance of SMB to meet the desired objectives

    Chromatographic purification of virus particles for advanced therapy medicinal products

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    The increasing number of cancer diagnoses in the last decades is associated with behavioral risks, in addition with those genetically originated. The fight against the disease usually relapses in not selective mechanisms like chemotherapy or radiotherapy, that induce the organism in deep alterations and side effects. One of the alternative strategies relies on the use of advanced therapies medicinal products suchlike viruses, to carry out the treatment in each cell taking advantage of their invading abilities. The cost of producing this oncolytic virus directly influences process engineering, and thus, numerous efforts have been made to improve each purification step. The development of the downstream process begins with the clarification of the viruses harvested from the bioreactor with two depth-filtration steps. This allows a gradual removal of larger impurities like cell debris with a complete virus recovery. Afterwards, a tangential flow filtration step enables volume reduction. After concentration, the retentate is subjected to diafiltration which allows not only the permeation of impurities but also the formulation of the concentrated product for the next processing step. The following step in the purification train is anion exchange chromatography. The chromatographic media used was selected after successive screening tests with a library of resins and membranes. The conditions used reflect the study carried out, in the sense that the load employed corresponds to the DBC10% obtained of 6.2 x 1011 (TP/ml) particles per millilitre and the elution of the viruses is preceded by a low salt concentration elution (200 mM) in order to remove impurities. The yield obtained is 85%. The purification process ends with polishing and sterile filtration to achieve the specified conditions, through a size-exclusion chromatography and membrane filters, respectively, obtaining a total yield of 53%. The study also opens perspectives on innovation and future development with the performance of multi-column chromatography assays and automated filtration tests, both in specialized equipment
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