| 1. |
- Andersson, Niklas, et al.
(författare)
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Methodology for fast development of digital solutions in integrated continuous downstream processing
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Ingår i: Biotechnology and Bioengineering. - 0006-3592.
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Tidskriftsartikel (refereegranskat)abstract
- The methodology for production of biologics is going through a paradigm shift from batch-wise operation to continuous production. Lot of efforts are focused on integration, intensification, and continuous operation for decreased foot-print, material, equipment, and increased productivity and product quality. These integrated continuous processes with on-line analytics become complex processes, which requires automation, monitoring, and control of the operation, even unmanned or remote, which means bioprocesses with high level of automation or even autonomous capabilities. The development of these digital solutions becomes an important part of the process development and needs to be assessed early in the development chain. This work discusses a platform that allows fast development, advanced studies, and validation of digital solutions for integrated continuous downstream processes. It uses an open, flexible, and extendable real-time supervisory controller, called Orbit, developed in Python. Orbit makes it possible to communicate with a set of different physical setups and on the same time perform real-time execution. Integrated continuous processing often implies parallel operation of several setups and network of Orbit controllers makes it possible to synchronize complex process system. Data handling, storage, and analysis are important properties for handling heterogeneous and asynchronous data generated in complex downstream systems. Digital twin applications, such as advanced model-based and plant-wide monitoring and control, are exemplified using computational extensions in Orbit, exploiting data and models. Examples of novel digital solutions in integrated downstream processes are automatic operation parameter optimization, Kalman filter monitoring, and model-based batch-to-batch control.
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| 2. |
- Espinoza, Daniel, et al.
(författare)
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Automatic procedure for modelling, calibration, and optimization of a three-component chromatographic separation
- 2024
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Ingår i: Journal of Chromatography A. - 0021-9673. ; 1720
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Tidskriftsartikel (refereegranskat)abstract
- The current landscape of biopharmaceutical production necessitates an ever-growing set of tools to meet the demands for shorter development times and lower production costs. One path towards meeting these demands is the implementation of digital tools in the development stages. Mathematical modelling of process chromatography, one of the key unit operations in the biopharmaceutical downstream process, is one such tool. However, obtaining parameter values for such models is a time-consuming task that grows in complexity with the number of compounds in the mixture being purified.In this study, we tackle this issue by developing an automated model calibration procedure for purification of a multi-component mixture by linear gradient ion exchange chromatography. The procedure was implemented using the Orbit software (Lund University, Department of Chemical Engineering), which both generates a mathematical model structure and performs the experiments necessary to obtain data for model calibration. The procedure was extended to suggest operating points for the purification of one of the components in the mixture by means of multi-objective optimization using three different objectives. The procedure was tested on a three-component protein mixture and was able to generate a calibrated model capable of reproducing the experimental chromatograms to a satisfactory degree, using a total of six assays. An additional seventh experiment was performed to validate the model response under one of the suggested optimum conditions, respecting a 95 % purity requirement. All of the above was automated and set in motion by the push of a button. With these results, we have taken a step towards fully automating model calibration and thus accelerating digitalization in the development stages of new biopharmaceuticals.
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| 3. |
- Löfgren, Anton, et al.
(författare)
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Optimization of integrated chromatography sequences for purification of biopharmaceuticals
- 2019
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Ingår i: Biotechnology Progress. - : Wiley. - 8756-7938 .- 1520-6033. ; 35:6
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Tidskriftsartikel (refereegranskat)abstract
- With continued development of integrated and continuous downstream purification processes, tuning and optimization become increasingly complicated with additional parameters and codependent variables over the sequence. This article offers a novel perspective of nonlinear optimization of integrated sequences with regard to individual column sizes, flow rates, and scheduling. The problem setup itself is a versatile tool to be used in downstream design which is demonstrated in two case studies: a four-column integrated sequence and a continuously loaded twin-capture setup with five columns.
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| 4. |
- Tallvod, Simon, et al.
(författare)
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A novel process design for automated quality analysis in an integrated biopharmaceutical platform
- 2022
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Ingår i: 32nd European Symposium on Computer Aided Process Engineering. - 1570-7946. - 9780323958790 ; 51, s. 619-624
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Bokkapitel (refereegranskat)abstract
- This contribution describes a novel process design consisting of the implementation of a high performance liquid chromatography (HPLC) system into an existing integrated biopharmaceutical purification platform in order to extend the possibilities of analysis. This setup is controlled by a custom-made set of software tools, namely the combination of Orbit along with a C# based program called Satellite, which is used to link the HPLC system to Orbit. By using this process design, automated analysis of the continuous process flow is made possible, generating full wavelength spectra, and automated pool quality analysis. These spectra contain at least an order of magnitude more data compared to a standard chromatogram, which can be utilized for further analysis, while the pool quality analyses can be used for making decisions regarding how to proceed with a particular pool. The results of the study show the successful implementation of automated analytic tools to the purification process, which also indicates that the process carries promise as a generalizable platform for Orbit-controlled designs for different analysis purposes.
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| 5. |
- Tallvod, Simon, et al.
(författare)
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Automated quality analysis in continuous downstream processes for small-scale applications
- 2023
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Ingår i: Journal of chromatography. A. - 1873-3778. ; 1702
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Tallvod, Simon, et al.
(författare)
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Automation of Modeling and Calibration of Integrated Preparative Protein Chromatography Systems
- 2022
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Ingår i: Processes. - : MDPI AG. - 2227-9717. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- With the increasing global demand for precise and efficient pharmaceuticals and the biopharma industry moving towards Industry 4.0, the need for advanced process integration, automation, and modeling has increased as well. In this work, a method for automatic modeling and calibration of an integrated preparative chromatographic system for pharmaceutical development and production is presented. Based on a user-defined system description, a system model was automatically generated and then calibrated using a sequence of experiments. The system description and model was implemented in the Python-based preparative chromatography control software Orbit.
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| 7. |
- Tallvod, Simon
(författare)
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Tools for digital twins in continuous downstream processing
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Biopharmaceuticals are of ever-growing importance for human health. The development and production of biopharmaceuticals has the potential for efficiency improvements by switching from batch-wise to continuous production. This change demands more advanced process control in the form of automation and digital tools such as digital twins, which in turn need adequate mathematical models and accessible process data.This thesis discusses the concept of digital twins as well as the automation of modelling and data acquisition in integrated continuous downstream processes for the development and production of biopharmaceuticals. Utilizing in-house supervisory control software for chromatographic systems enables automation of modeling, calibration, sampling, and analysis in integrated downstream processes, advancing the development of digital twins.
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