| 1. |
- Löfgren, Anton, et al.
(författare)
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Designing an Autonomous Integrated Downstream Sequence From a Batch Separation Process − An Industrial Case Study
- 2018
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Ingår i: Biotechnology Journal. - : Wiley. - 1860-6768.
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Tidskriftsartikel (refereegranskat)abstract
- This work is a proof of concept of how a sequence of industrial batch separation steps together are used to form an integrated autonomous downstream process. The sequence in this case study consisted of an anion chromatography step, virus inactivation and finally a hydrophobic chromatography step. Moving from batch to integrated separation minimizes hold‐up times, storage tanks, and required equipment. The conversion from batch to integrated mode is achieved by extracting operating points and separation data from batch chromatograms. The integrated separation process is realized on an ÄKTA Pure controlled by an open research software called Orbit, making it possible to operate complex process configurations including multiple steps. The results from this case study is the principle and method of the steps taken to automation, achieving a more continuous and efficient downstream process.
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| 2. |
- Andersson, Niklas, et al.
(författare)
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Design and control of integrated chromatography column sequences
- 2017
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Ingår i: Biotechnology Progress. - : Wiley. - 1520-6033 .- 8756-7938. ; 00:00
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Tidskriftsartikel (refereegranskat)abstract
- To increase the productivity in biopharmaceutical production, a natural step is to introduce integrated continuous biomanufacturing which leads to fewer buffer and storage tanks, smaller sizes of integrated unit operations, and full automation of the operation. The main contribution of this work is to illustrate a methodology for design and control of a downstream process based on integrated column sequences. For small scale production, for example, pre-clinical studies, integrated column sequences can be implemented on a single chromatography system. This makes for a very efficient drug development platform. The proposed methodology is composed of four steps and is governed by a set of tools, that is presented, that makes the transition from batch separations to a complete integrated separation sequence as easy as possible. This methodology, its associated tools and the physical implementation is presented and illustrated on a case study where the target protein is separated from impurities through an integrated four column sequence. This article shows that the design and control of an integrated column sequence was successfully implemented for a tertiary protein separation problem.
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| 3. |
- Sellberg, Anton, et al.
(författare)
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Multi-flowrate Optimization of the Loading Phase of a Preparative Chromatographic Separation
- 2018
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Ingår i: Computer Aided Chemical Engineering. - 1570-7946. - 9780444642356 ; 43, s. 1619-1624
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Bokkapitel (refereegranskat)abstract
- This contribution consists of a multi-flow rate optimization method to maximize the key performance indicators, yield, degree of resin utilization and productivity for a chromatographic loading step. The protein adsorption to the resin is modeled using a mechanistic column model with a steric mass action adsorption isotherm. The model was used to optimize the flow rate trajectories and the loading duration by using a simultaneous method where the controls and state variables were discretized using a direct and local collocation method on finite elements in the temporal dimension and a finite volume weighted essentially non-oscillatory scheme in the spatial dimension. The discretized nonlinear program was solved using an interior point method. The two and three dimensional pareto fronts for the multi-objective optimization are presented and the multi-flow rate strategy showed considerable improvement in all objectives at different points on the pareto front.
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| 4. |
- Gomis-Fons, Joaquín, et al.
(författare)
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Integration of a complete downstream process for the automated lab-scale production of a recombinant protein
- 2019
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Ingår i: Journal of Biotechnology. - : Elsevier BV. - 0168-1656. ; 301, s. 45-51
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Löfgren, Anton, et al.
(författare)
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An integrated continuous downstream process with real-time control : A case study with periodic countercurrent chromatography and continuous virus inactivation
- 2021
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Ingår i: Biotechnology and Bioengineering. - : Wiley. - 0006-3592 .- 1097-0290. ; 118:4, s. 1645-1657
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Tidskriftsartikel (refereegranskat)abstract
- Integrated continuous downstream processes with process analytical technology offer a promising opportunity to reduce production costs and increase process flexibility and adaptability. In this case study, an integrated continuous process was used to purify a recombinant protein on laboratory scale in a two-system setup that can be used as a general downstream setup offering multiproduct and multipurpose manufacturing capabilities. The process consisted of continuous solvent/detergent virus inactivation followed by periodic countercurrent chromatography in the capture step, and a final chromatographic polishing step. A real-time controller was implemented to ensure stable operation by adapting the downstream process to external changes. A concentration disturbance was introduced to test the controller. After the disturbance was applied, the product output recovered within 6 h, showing the effectiveness of the controller. In a comparison of the process with and without the controller, the product output per cycle increased by 27%, the resin utilization increased from 71.4% to 87.9%, and the specific buffer consumption was decreased by 21% with the controller, while maintaining a similar yield and purity as in the process without the disturbance. In addition, the integrated continuous process outperformed the batch process, increasing the productivity by 95% and the yield by 28%.
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| 6. |
- Löfgren, Anton, et al.
(författare)
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An integrated continuous downstream process with real-time control: A case study with periodic countercurrent chromatography and continuous virus inactivation
- 2021
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Integrated continuous downstream processes with process analytical technology offer a promising opportunity to reduce production costs and increase process flexibility and adaptability. In this case study, an integrated continuous process was used to purify a recombinant protein on laboratory scale in a two-system setup that can be used as a general downstream setup offering multi-product and multi-purpose manufacturing capabilities. The process consisted of continuous solvent/detergent virus inactivation followed by periodic countercurrent chromatography in the capture step, and a final chromatographic polishing step. A real-time controller was implemented to ensure stable operation by adapting the downstream process to external changes. A concentration disturbance was introduced to test the controller. After the disturbance was applied, the product output recovered within 6 hours, showing the effectiveness of the controller. In a comparison of the process with and without the controller, the product output per cycle increased by 27%, the resin utilization increased from 71.4% to 87.9%, and the specific buffer consumption was decreased by 21% with the controller, while maintaining a similar yield and purity as in the process without the disturbance. In addition, the integrated continuous process outperformed the batch process, increasing the productivity by 95% and the yield by 28%.
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| 7. |
- Löfgren, Anton
(författare)
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Developing integrated downstream processes for next-generation biologics
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Manufacturing of biopharmaceuticals is a costly and time consuming process due to its inherent complexity and variability. The downstream process is the most expensive part and it involves multiple non-trivial steps. Continuous integrated manufacturing is a new concept that is encouraged by authorities. The advantages include uninterrupted operation, automation, consistent product quality, lower residence times and decreased capital and operational costs. Novel techniques and concepts require a holistic process understanding as well as a technical competence to implement them, and to do that, there are multiple practical challenges that must be overcome. There is a growing need to rapidly adjust to market demands and also to decrease costs as the industry gets increasingly competitive. The ability to adjust a facility or production line, to manufacture a variety of biopharmaceuticals, must be taken into consideration when developing integrated systems. It is also important to be aware of how to monitor critical quality attributes to properly ensure product quality. Another important attribute of integrated systems is intuitive and how easy to use they are.The aim of the thesis is to demonstrate, based on a selection of case studies, how some of the presented challenges can be overcome. The case studies have integrated systems that are flexible and have advanced process analytical technology. One of the papers in this thesis also focuses on the optimization of coupled columns sequences with the purpose of reducing costs. Overall, the results of this thesis shows the potential of continuous integrated designs for purification of biopharmaceuticals while simultaneously increasing both performance and product quality.
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| 8. |
- Löfgren, Anton, et al.
(författare)
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Nerve Function Impairment after Acute Vibration Exposure
- 2020
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Ingår i: Journal of Occupational and Environmental Medicine. - : Lippincott Williams & Wilkins. - 1076-2752 .- 1536-5948. ; 62:2, s. 124-129
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study was to investigate the acute effects of hand-arm vibrations on the nerve functions of the hands, and the impact of the grip force applied to the vibrating tool during exposure.METHODS: Grip strength and perception of vibration, touch, and temperature were evaluated using QST before and after vibration exposure in 21 occupationally unexposed individuals. The procedure was performed twice, with a higher grip force being applied during exposure on the second occasion.RESULTS: Vibration perception was significantly impaired after both exposures. Grip strength, perception of touch and temperature were only significantly affected after the high grip force exposure.CONCLUSIONS: Exposure to hand-arm vibrations has acute effects on hand nerve function that are sensitive to the grip force applied during exposure.
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| 9. |
- 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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| 10. |
- Yamanee-Nolin, Mikael, et al.
(författare)
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Single-shooting optimization of an industrial process through co-simulation of a modularized Aspen Plus Dynamics model
- 2019
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Ingår i: Computer Aided Chemical Engineering. - 1570-7946. - 9780128186343 ; 2019
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Tidskriftsartikel (refereegranskat)abstract
- The Python Module Coupler (PyMoC) is a tool for co-simulation of Aspen Plus Dynamics modules that together make up an overall process flowsheet. The tool requires only user input in the form of file paths to Aspen Plus Dynamics modules, and it is able to automatically make the required connections there between, and keep track of the simulation whilst updating the streams regularly. This contribution briefly discusses the implementation and mechanisms of PyMoC, and then applies it to a multi-module, single-shooting constrained optimization problem, where an industrial set-up consisting of an evaporator system coupled to a distillation column is studied. This serves as a showcase of PyMoC's functionality and usability, as well as its potential in serving as a helpful tool for practitioners of model-based studies who could benefit from modularizing their models. Utilizing PyMoC for this purpose, the optimization results indicate that the operating costs induced from the steam consumption can be reduced by 54% compared to a nominal operating case, but a holistic, full-process study is necessary to understand the full set of possibilities, causes, and effects.
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