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Processes
Special Issues
Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing
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Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing

A special issue of Processes (ISSN 2227-9717). This special issue belongs to the section "Pharmaceutical Processes".

Deadline for manuscript submissions: closed (15 April 2022) | Viewed by 50902

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Ralf Pörtner

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Guest Editor
Institute of Bioprocess and Biosystems Engineering, Hamburg University of Technology, 21073 Hamburg, Germany
Interests: cell culture technology; bioreactor design; modeling and control; tissue engineering
Dr. Johannes Möller

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Guest Editor
Institute of Bioprocess and Biosystems Engineering, Hamburg University of Technology, 21073 Hamburg, Germany
Interests: bioprocess and biosystems engineering; digital revolution; pharmaceutical manufacturing

Special Issue Information

Dear Colleagues,

Biopharmaceutical and pharmaceutical manufacturing are shifting to a modernized mode, built on the application of computer-based methods of process systems engineering. This development is also supported by the process analytical technology initiative (PAT) and quality by design (QbD) methodology for enhancing the understanding of integrated processes. The major goals of this effort can be summarized into developing a mechanistic understanding of a wide range of process steps, including the development of technologies to perform online measurements and real-time control and optimization. Furthermore, minimization of the number of empirical experiments and the model-assisted exploration of the process design space are targeted. Even if tremendous progress has been achieved so far, there is still work to be done in order to realize the full potential of the process systems engineering toolbox.

With this Special Issue of Processes, we aim to give an overview of the current developments of process systems engineering for (bio)pharmaceutical manufacturing processes, including

  • pharmaceutical production processes design/synthesis
  • computer-aided process design
  • modeling and simulation of the pharmaceutical processing unit operation
  • analysis, risk assessment, and sensitivity analysis
  • control and monitoring of pharmaceutical production processes
  • design space identification
  • optimal operation
  • enterprise-wide optimization and supply chain management

Prof. Dr. Ralf Pörtner
Dr. Johannes Möller
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Processes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • process systems engineering
  • process analytical technology
  • computer-aided process design
  • modelling and simulation
  • process monitoring and control
  • computer-based optimization

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Published Papers (10 papers)

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Editorial

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4 pages, 192 KiB  
Editorial
Special Issue “Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing”
by Ralf Pörtner and Johannes Möller
Processes 2022, 10(8), 1634; https://doi.org/10.3390/pr10081634 - 18 Aug 2022
Viewed by 1346
Abstract
Biopharmaceutical and pharmaceutical manufacturing are strongly influenced by the process analytical technology initiative (PAT) and quality by design (QbD) methodologies, which are designed to enhance the understanding of more integrated processes [...] Full article
(This article belongs to the Special Issue Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing)

Research

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19 pages, 6552 KiB  
Article
Seed Train Intensification Using an Ultra-High Cell Density Cell Banking Process
by Jan Müller, Vivian Ott, Dieter Eibl and Regine Eibl
Processes 2022, 10(5), 911; https://doi.org/10.3390/pr10050911 - 5 May 2022
Cited by 12 | Viewed by 4817
Abstract
A current focus of biopharmaceutical research and production is seed train process intensification. This allows for intermediate cultivation steps to be avoided or even for the direct inoculation of a production bioreactor with cells from cryovials or cryobags. Based on preliminary investigations regarding [...] Read more.
A current focus of biopharmaceutical research and production is seed train process intensification. This allows for intermediate cultivation steps to be avoided or even for the direct inoculation of a production bioreactor with cells from cryovials or cryobags. Based on preliminary investigations regarding the suitability of high cell densities for cryopreservation and the suitability of cells from perfusion cultivations as inoculum for further cultivations, an ultra-high cell density working cell bank (UHCD-WCB) was established for an immunoglobulin G (IgG)-producing Chinese hamster ovary (CHO) cell line. The cells were previously expanded in a wave-mixed bioreactor with internal filter-based perfusion and a 1 L working volume. This procedure allows for cryovial freezing at 260 × 106 cells mL−1 for the first time. The cryovials are suitable for the direct inoculation of N−1 bioreactors in the perfusion mode. These in turn can be used to inoculate subsequent IgG productions in the fed-batch mode (low-seed fed-batch or high-seed fed-batch) or the continuous mode. A comparison with the standard approach shows that cell growth and antibody production are comparable, but time savings of greater than 35% are possible for inoculum production. Full article
(This article belongs to the Special Issue Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing)
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28 pages, 29500 KiB  
Article
Designing Robust Biotechnological Processes Regarding Variabilities Using Multi-Objective Optimization Applied to a Biopharmaceutical Seed Train Design
by Tanja Hernández Rodríguez, Anton Sekulic, Markus Lange-Hegermann and Björn Frahm
Processes 2022, 10(5), 883; https://doi.org/10.3390/pr10050883 - 29 Apr 2022
Cited by 8 | Viewed by 2348
Abstract
Development and optimization of biopharmaceutical production processes with cell cultures is cost- and time-consuming and often performed rather empirically. Efficient optimization of multiple objectives such as process time, viable cell density, number of operating steps & cultivation scales, required medium, amount of product [...] Read more.
Development and optimization of biopharmaceutical production processes with cell cultures is cost- and time-consuming and often performed rather empirically. Efficient optimization of multiple objectives such as process time, viable cell density, number of operating steps & cultivation scales, required medium, amount of product as well as product quality depicts a promising approach. This contribution presents a workflow which couples uncertainty-based upstream simulation and Bayes optimization using Gaussian processes. Its application is demonstrated in a simulation case study for a relevant industrial task in process development, the design of a robust cell culture expansion process (seed train), meaning that despite uncertainties and variabilities concerning cell growth, low variations of viable cell density during the seed train are obtained. Compared to a non-optimized reference seed train, the optimized process showed much lower deviation rates regarding viable cell densities (<10% instead of 41.7%) using five or four shake flask scales and seed train duration could be reduced by 56 h from 576 h to 520 h. Overall, it is shown that applying Bayes optimization allows for optimization of a multi-objective optimization function with several optimizable input variables and under a considerable amount of constraints with a low computational effort. This approach provides the potential to be used in the form of a decision tool, e.g., for the choice of an optimal and robust seed train design or for further optimization tasks within process development. Full article
(This article belongs to the Special Issue Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing)
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22 pages, 3360 KiB  
Article
Large-Scale Production of Size-Adjusted β-Cell Spheroids in a Fully Controlled Stirred-Tank Reactor
by Florian Petry and Denise Salzig
Processes 2022, 10(5), 861; https://doi.org/10.3390/pr10050861 - 27 Apr 2022
Cited by 8 | Viewed by 2979
Abstract
For β-cell replacement therapies, one challenge is the manufacturing of enough β-cells (Edmonton protocol for islet transplantation requires 0.5–1 × 106 islet equivalents). To maintain their functionality, β-cells should be manufactured as 3D constructs, known as spheroids. In this study, we investigated [...] Read more.
For β-cell replacement therapies, one challenge is the manufacturing of enough β-cells (Edmonton protocol for islet transplantation requires 0.5–1 × 106 islet equivalents). To maintain their functionality, β-cells should be manufactured as 3D constructs, known as spheroids. In this study, we investigated whether β-cell spheroid manufacturing can be addressed by a stirred-tank bioreactor (STR) process. STRs are fully controlled bioreactor systems, which allow the establishment of robust, larger-scale manufacturing processes. Using the INS-1 β-cell line as a model for process development, we investigated the dynamic agglomeration of β-cells to determine minimal seeding densities, spheroid strength, and the influence of turbulent shear stress. We established a correlation to exploit shear forces within the turbulent flow regime, in order to generate spheroids of a defined size, and to predict the spheroid size in an STR by using the determined spheroid strength. Finally, we transferred the dynamic agglomeration process from shaking flasks to a fully controlled and monitored STR, and tested the influence of three different stirrer types on spheroid formation. We achieved the shear stress-guided production of up to 22 × 106 ± 2 × 106 viable and functional β-cell spheroids per liter of culture medium, which is sufficient for β-cell therapy applications. Full article
(This article belongs to the Special Issue Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing)
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20 pages, 2671 KiB  
Article
Proof-of-Concept of Continuous Transfection for Adeno-Associated Virus Production in Microcarrier-Based Culture
by Brian Ladd, Kevin Bowes, Mats Lundgren, Torbjörn Gräslund and Veronique Chotteau
Processes 2022, 10(3), 515; https://doi.org/10.3390/pr10030515 - 4 Mar 2022
Cited by 4 | Viewed by 5202
Abstract
Adeno-associated virus vectors (AAV) are reported to have a great potential for gene therapy, however, a major bottleneck for this kind of therapy is the limitation of production capacity. Higher specific AAV vector yield is often reported for adherent cell systems compared to [...] Read more.
Adeno-associated virus vectors (AAV) are reported to have a great potential for gene therapy, however, a major bottleneck for this kind of therapy is the limitation of production capacity. Higher specific AAV vector yield is often reported for adherent cell systems compared to cells in suspension, and a microcarrier-based culture is well established for the culture of anchored cells on a larger scale. The purpose of the present study was to explore how microcarrier cultures could provide a solution for the production of AAV vectors based on the triple plasmid transfection of HEK293T cells in a stirred tank bioreactor. In the present study, cells were grown and expanded in suspension, offering the ease of this type of operation, and were then anchored on microcarriers in order to proceed with transfection of the plasmids for transient AAV vector production. This process was developed in view of a bioreactor application in a 200 mL stirred-tank vessel where shear stress aspects were studied. Furthermore, amenability to a continuous process was studied. The present investigation provided a proof-of-concept of a continuous process based on microcarriers in a stirred-tank bioreactor. Full article
(This article belongs to the Special Issue Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing)
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19 pages, 39555 KiB  
Article
New Insights from Locally Resolved Hydrodynamics in Stirred Cell Culture Reactors
by Fabian Freiberger, Jens Budde, Eda Ateş, Michael Schlüter, Ralf Pörtner and Johannes Möller
Processes 2022, 10(1), 107; https://doi.org/10.3390/pr10010107 - 5 Jan 2022
Cited by 13 | Viewed by 3213
Abstract
The link between hydrodynamics and biological process behavior of antibody-producing mammalian cell cultures is still not fully understood. Common methods to describe dependencies refer mostly to averaged hydrodynamic parameters obtained for individual cultivation systems. In this study, cellular effects and locally resolved hydrodynamics [...] Read more.
The link between hydrodynamics and biological process behavior of antibody-producing mammalian cell cultures is still not fully understood. Common methods to describe dependencies refer mostly to averaged hydrodynamic parameters obtained for individual cultivation systems. In this study, cellular effects and locally resolved hydrodynamics were investigated for impellers with different spatial hydrodynamics. Therefore, the hydrodynamics, mainly flow velocity, shear rate and power input, in a single- and a three-impeller bioreactor setup were analyzed by means of CFD simulations, and cultivation experiments with antibody-producing Chinese hamster ovary (CHO) cells were performed at various agitation rates in both reactor setups. Within the three-impeller bioreactor setup, cells could be cultivated successfully at much higher agitation rates as in the single-impeller bioreactor, probably due to a more uniform flow pattern. It could be shown that this different behavior cannot be linked to parameters commonly used to describe shear effects on cells such as the mean energy dissipation rate or the Kolmogorov length scale, even if this concept is extended by locally resolved hydrodynamic parameters. Alternatively, the hydrodynamic heterogeneity was statistically quantified by means of variance coefficients of the hydrodynamic parameters fluid velocity, shear rate, and energy dissipation rate. The calculated variance coefficients of all hydrodynamic parameters were higher in the setup with three impellers than in the single impeller setup, which might explain the rather stable process behavior in multiple impeller systems due to the reduced hydrodynamic heterogeneity. Such comprehensive insights lead to a deeper understanding of the bioprocess. Full article
(This article belongs to the Special Issue Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing)
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16 pages, 2235 KiB  
Article
Digital Twin Application for Model-Based DoE to Rapidly Identify Ideal Process Conditions for Space-Time Yield Optimization
by Benjamin Bayer, Roger Dalmau Diaz, Michael Melcher, Gerald Striedner and Mark Duerkop
Processes 2021, 9(7), 1109; https://doi.org/10.3390/pr9071109 - 25 Jun 2021
Cited by 27 | Viewed by 5737
Abstract
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, [...] Read more.
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. Full article
(This article belongs to the Special Issue Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing)
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Graphical abstract

26 pages, 15423 KiB  
Article
Considerations of the Impacts of Cell-Specific Growth and Production Rate on Clone Selection—A Simulation Study
by Tanja Hernández Rodríguez, Sophie Morerod, Ralf Pörtner, Florian M. Wurm and Björn Frahm
Processes 2021, 9(6), 964; https://doi.org/10.3390/pr9060964 - 28 May 2021
Cited by 4 | Viewed by 3534
Abstract
For the manufacturing of complex biopharmaceuticals using bioreactors with cultivated mammalian cells, high product concentration is an important objective. The phenotype of the cells in a reactor plays an important role. Are clonal cell populations showing high cell-specific growth rates more favorable than [...] Read more.
For the manufacturing of complex biopharmaceuticals using bioreactors with cultivated mammalian cells, high product concentration is an important objective. The phenotype of the cells in a reactor plays an important role. Are clonal cell populations showing high cell-specific growth rates more favorable than cell lines with higher cell-specific productivities or vice versa? Five clonal Chinese hamster ovary cell populations were analyzed based on the data of a 3-month-stability study. We adapted a mechanistic cell culture model to the experimental data of one such clonally derived cell population. Uncertainties and prior knowledge concerning model parameters were considered using Bayesian parameter estimations. This model was used then to define an inoculum train protocol. Based on this, we subsequently simulated the impacts of differences in growth rates (±10%) and production rates (±10% and ±50%) on the overall cultivation time, including making the inoculum train cultures; the final production phase, the volumetric titer in that bioreactor and the ratio of both, defined as overall process productivity. We showed thus unequivocally that growth rates have a higher impact (up to three times) on overall process productivity and for product output per year, whereas cells with higher productivity can potentially generate higher product concentrations in the production vessel. Full article
(This article belongs to the Special Issue Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing)
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Review

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36 pages, 1897 KiB  
Review
Modern Sensor Tools and Techniques for Monitoring, Controlling, and Improving Cell Culture Processes
by Sebastian Juan Reyes, Yves Durocher, Phuong Lan Pham and Olivier Henry
Processes 2022, 10(2), 189; https://doi.org/10.3390/pr10020189 - 18 Jan 2022
Cited by 56 | Viewed by 15436
Abstract
The growing biopharmaceutical industry has reached a level of maturity that allows for the monitoring of numerous key variables for both process characterization and outcome predictions. Sensors were historically used in order to maintain an optimal environment within the reactor to optimize process [...] Read more.
The growing biopharmaceutical industry has reached a level of maturity that allows for the monitoring of numerous key variables for both process characterization and outcome predictions. Sensors were historically used in order to maintain an optimal environment within the reactor to optimize process performance. However, technological innovation has pushed towards on-line in situ continuous monitoring of quality attributes that could previously only be estimated off-line. These new sensing technologies when coupled with software models have shown promise for unique fingerprinting, smart process control, outcome improvement, and prediction. All this can be done without requiring invasive sampling or intervention on the system. In this paper, the state-of-the-art sensing technologies and their applications in the context of cell culture monitoring are reviewed with emphasis on the coming push towards industry 4.0 and smart manufacturing within the biopharmaceutical sector. Additionally, perspectives as to how this can be leveraged to improve both understanding and outcomes of cell culture processes are discussed. Full article
(This article belongs to the Special Issue Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing)
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28 pages, 1642 KiB  
Review
On the Use of Surface Plasmon Resonance-Based Biosensors for Advanced Bioprocess Monitoring
by Jimmy Gaudreault, Catherine Forest-Nault, Gregory De Crescenzo, Yves Durocher and Olivier Henry
Processes 2021, 9(11), 1996; https://doi.org/10.3390/pr9111996 - 9 Nov 2021
Cited by 15 | Viewed by 4611
Abstract
Biomanufacturers are being incited by regulatory agencies to transition from a quality by testing framework, where they extensively test their product after their production, to more of a quality by design or even quality by control framework. This requires powerful analytical tools and [...] Read more.
Biomanufacturers are being incited by regulatory agencies to transition from a quality by testing framework, where they extensively test their product after their production, to more of a quality by design or even quality by control framework. This requires powerful analytical tools and sensors enabling measurements of key process variables and/or product quality attributes during production, preferably in an online manner. As such, the demand for monitoring technologies is rapidly growing. In this context, we believe surface plasmon resonance (SPR)-based biosensors can play a role in enabling the development of improved bioprocess monitoring and control strategies. The SPR technique has been profusely used to probe the binding behavior of a solution species with a sensor surface-immobilized partner in an investigative context, but its ability to detect binding in real-time and without a label has been exploited for monitoring purposes and is promising for the near future. In this review, we examine applications of SPR that are or could be related to bioprocess monitoring in three spheres: biotherapeutics production monitoring, vaccine monitoring, and bacteria and contaminant detection. These applications mainly exploit SPR’s ability to measure solution species concentrations, but performing kinetic analyses is also possible and could prove useful for product quality assessments. We follow with a discussion on the limitations of SPR in a monitoring role and how recent advances in hardware and SPR response modeling could counter them. Mainly, throughput limitations can be addressed by multi-detection spot instruments, and nonspecific binding effects can be alleviated by new antifouling materials. A plethora of methods are available for cell growth and metabolism monitoring, but product monitoring is performed mainly a posteriori. SPR-based biosensors exhibit potential as product monitoring tools from early production to the end of downstream processing, paving the way for more efficient production control. However, more work needs to be done to facilitate or eliminate the need for sample preprocessing and to optimize the experimental protocols. Full article
(This article belongs to the Special Issue Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing)
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