Special Issue "Processes Accelerating Biologics Manufacturing by Modelling"

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

Deadline for manuscript submissions: closed (15 September 2020).

Special Issue Editors

Prof. Dr. Jochen Strube
E-Mail Website
Guest Editor
Institute for Separation and Process Technology, Clausthal University of Technology, Leibnizstraße 15, 38678 Clausthal-Zellerfeld, Germany
Interests: sustainable manufacturing technologies for biologics and botanicals; key enabling technologies to industrialize innovative manufacturing technologies under QbD-demands; upstream and downstream process integration; model-based process design; quality by design (QbD); continuous bioprocessing (CBP); big data; hybrid models
Special Issues, Collections and Topics in MDPI journals
Dr. Steffen Zobel-Roos
E-Mail Website
Guest Editor
Institute for Separation and Process Technology, Clausthal University of Technology, 38678 Clausthal-Zellerfeld, Germany

Special Issue Information

Dear Colleagues,

Biologics are increasingly dominating the pharmaceutical market. In addition, due to the recent rise of mAbs, a broader molecular variety of fragments, exosomes and VLPs, etc., as well as recombinant peptides and proteins, are back in early product development. As no platform technology established for mAbs manufacturing is available, no solution for fast and efficient process development under the regulatory constraints of QbD and PAT approaches has been seen.

Model-based methods are increasingly used in all areas of biotechnology. They can be applied along the entire workflow of product development, process development and the design, piloting, engineering and manufacturing operation including life cycle management. Nevertheless, the molecular complexity of biologics has been a challenge for the accuracy and precision of model-based predictions. Any digital twin of any manufacturing process under the strict regulation of QbD and PAT approaches must already be defined and validated in early process development, when first test amounts are supplied for approval, because the process including its natural interactions with a digital twin are fixed. Post-approval changes are organized by guidelines, but the benefit of any modification must be clearly quantitatively documented in order to evaluate the benefits and risks to taking data-driven decisions. The variety of modeling methods is broad, ranging from molecular dynamics in drug development to statistical and regression models, as well as artificial intelligence tools like neuronal networks or data mining, machine learning algorithms for rigorous process modeling, and model-based advanced process control concepts.

This Special Issue on “Accelerating Biologics Manufacturing by Modelling” intends to curate novel advances in the development and application of model-based tools to address ever-present challenges of traditional pharmaceutical manufacturing practices. Topics include, but are not limited to:

  • Development of new modeling concepts for biologics manufacturing at different steps of the workflow (phenomena, unit operation, and plant-wide);
  • Design and optimization of biological processes based on the derived models based on the QbD-approach;
  • Process intensification, robustification, and flexibilization of multipurpose manufacturing as well as dedicated continuous bioprocessing CBP;
  • Hybrid modeling combining classical first-principles models with (big) data-driven concepts
  • Process control, monitoring and fault detection in the biologics industry

Prof. Dr. Jochen Strube
Dr. Steffen Zobel-Roos
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 papers will be 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 2000 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

  • upstream and downstream process integration
  • model-based process design
  • quality by design (QbD)
  • continuous bioprocessing (CBP)
  • big data
  • hybrid models

Published Papers (13 papers)

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Research

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Article
Towards Autonomous Operation by Advanced Process Control—Process Analytical Technology for Continuous Biologics Antibody Manufacturing
Processes 2021, 9(1), 172; https://0-doi-org.brum.beds.ac.uk/10.3390/pr9010172 - 18 Jan 2021
Cited by 8 | Viewed by 1816
Abstract
Continuous manufacturing opens up new operation windows with improved product quality in contrast to documented lot deviations in batch or fed-batch operations. A more sophisticated process control strategy is needed to adjust operation parameters and keep product quality constant during long-term operations. In [...] Read more.
Continuous manufacturing opens up new operation windows with improved product quality in contrast to documented lot deviations in batch or fed-batch operations. A more sophisticated process control strategy is needed to adjust operation parameters and keep product quality constant during long-term operations. In the present study, the applicability of a combination of spectroscopic methods was evaluated to enable Advanced Process Control (APC) in continuous manufacturing by Process Analytical Technology (PAT). In upstream processing (USP) and aqueous two-phase extraction (ATPE), Raman-, Fourier-transformed infrared (FTIR), fluorescence- and ultraviolet/visible- (UV/Vis) spectroscopy have been successfully applied for titer and purity prediction. Raman spectroscopy was the most versatile and robust method in USP, ATPE, and precipitation and is therefore recommended as primary PAT. In later process stages, the combination of UV/Vis and fluorescence spectroscopy was able to overcome difficulties in titer and purity prediction induced by overlapping side component spectra. Based on the developed spectroscopic predictions, dynamic control of unit operations was demonstrated in sophisticated simulation studies. A PAT development workflow for holistic process development was proposed. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Digital Twin for Lyophilization by Process Modeling in Manufacturing of Biologics
Processes 2020, 8(10), 1325; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8101325 - 21 Oct 2020
Cited by 4 | Viewed by 1313
Abstract
Lyophilization stabilizes formulated biologics for storage, transport and application to patients. In process design and operation it is the link between downstream processing and with final formulation to fill and finish. Recent activities in Quality by Design (QbD) have resulted in approaches by [...] Read more.
Lyophilization stabilizes formulated biologics for storage, transport and application to patients. In process design and operation it is the link between downstream processing and with final formulation to fill and finish. Recent activities in Quality by Design (QbD) have resulted in approaches by regulatory authorities and the need to include Process Analytical Technology (PAT) tools. An approach is outlined to validate a predictive physical-chemical (rigorous) lyophilization process model to act quantitatively as a digital twin in order to allow accelerated process design by modeling and to further-on develop autonomous process optimization and control towards real time release testing. Antibody manufacturing is chosen as a typical example for actual biologics needs. Literature is reviewed and the presented procedure is exemplified to quantitatively and consistently validate the physical-chemical process model with aid of an experimental statistical DOE (design of experiments) in pilot scale. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Digital Twin for Extraction Process Design and Operation
Processes 2020, 8(7), 866; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8070866 - 17 Jul 2020
Cited by 4 | Viewed by 1349
Abstract
Traditional extraction processes of natural product are widespread, especially in regulated industries. Possibilities of extraction development and manufacturing optimization in regulated industries is limited. Regulatory approvals are often based on traditional preparations of phyto-pharmaceuticals. The dependence on traditional processes can result in sub-optimal [...] Read more.
Traditional extraction processes of natural product are widespread, especially in regulated industries. Possibilities of extraction development and manufacturing optimization in regulated industries is limited. Regulatory approvals are often based on traditional preparations of phyto-pharmaceuticals. The dependence on traditional processes can result in sub-optimal extraction parameters causing unnecessary costs and product variability. Innovative methods like Quality-by-Design (QbD), including process analytical technology (PAT), open opportunities for manufacturers to cope with regulatory demanded, narrow batch-to-batch variability. In addition, such validated process models represent perfect digital twins which could be utilized for advanced process control and life cycle analysis. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Technical Potential for Energy and GWP Reduction in Chemical–Pharmaceutical Industry in Germany and EU—Focused on Biologics and Botanicals Manufacturing
Processes 2020, 8(7), 818; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8070818 - 11 Jul 2020
Cited by 3 | Viewed by 979
Abstract
European policy demands climate neutrality by the year 2050. Therefore, any manufacturing optimization needs to be achieved in the well-known pareto of global warming potential (GWP) reduction combined with cost of goods (COG) reduction at increasing product amounts, while still being able to [...] Read more.
European policy demands climate neutrality by the year 2050. Therefore, any manufacturing optimization needs to be achieved in the well-known pareto of global warming potential (GWP) reduction combined with cost of goods (COG) reduction at increasing product amounts, while still being able to compete in the world market. The chemical–pharmaceutical industry is one of the most energy-intensive industries. The pharmaceutical industry operates with low batch sizes, but high margins. This study analyzes, based on the literature and Bundesministerium für Wirtschaft und Energie (BMWi; English: Federal Ministry for Economic Affairs and Energy)-funded project results, the technical potentials for energy and GWP reduction, while focusing on biologics and botanicals, because those are already widely based on natural raw material resources. The potential impact for green technologies is pointed out in relation to climate-neutral manufacturing. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Distinct and Quantitative Validation for Predictive Process Modelling in Steam Distillation of Caraway Fruits and Lavender Flower Following a Quality-By-Design (QbD) Approach
Processes 2020, 8(5), 594; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8050594 - 16 May 2020
Cited by 6 | Viewed by 1308
Abstract
A quality by design (QbD) approach as part of process development in the regulated, pharmaceutical industry requires many experiments. Due to the large number, process development is time consuming and cost intensive. A key to modern process development to reduce the number of [...] Read more.
A quality by design (QbD) approach as part of process development in the regulated, pharmaceutical industry requires many experiments. Due to the large number, process development is time consuming and cost intensive. A key to modern process development to reduce the number of required experiments is a predictive simulation with a validated physico-chemical model. In order to expand the process expertise of steam distillation through maximum information, a model development workflow is used in this paper, which focuses on implementation, verification, parametrization and validation of a physico-chemical model. Process robustness and sensitivity of target values can be determined from the developed general model and design of experiments with statistical evaluations. The model validation is exemplified by two different types of plant systems, caraway fruits (Carum Carvi) and lavender flowers (Lavandula). Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Accelerating Biologics Manufacturing by Modeling: Process Integration of Precipitation in mAb Downstream Processing
Processes 2020, 8(1), 58; https://0-doi-org.brum.beds.ac.uk/10.3390/pr8010058 - 02 Jan 2020
Cited by 14 | Viewed by 2644
Abstract
The demand on biologics has been constantly rising over the past decades and has become crucial in modern medicine. Promising approaches to cope with widespread diseases like cancer and diabetes are gene therapy, plasmid DNA, virus-like particles, and exosomes. Due to progress that [...] Read more.
The demand on biologics has been constantly rising over the past decades and has become crucial in modern medicine. Promising approaches to cope with widespread diseases like cancer and diabetes are gene therapy, plasmid DNA, virus-like particles, and exosomes. Due to progress that has been made in upstream processing (USP), difficulties arise in downstream processing and demand for innovative solutions. This work focuses on the integration of precipitation using a quality by design (QbD) approach for process development. Selective precipitation is achieved with PEG 4000 resulting in an HCP depletion of ≥80% respectively to IgG. Dissolution was executed with a sodium phosphate buffer (pH = 5/50 mM) reaching an IgG recovery of ≥95%. However, the central challenge in process development is still an optimal process design, which is transferable for a broad molecular variety of new products. This is where rigorous modeling becomes vital in order to generate digital twins to support early-stage process development and reduce the experimental overhead. Therefore, a model development and validation concept for construction of a process model for precipitation is also presented. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Model Validation and Process Design of Continuous Single Pass Tangential Flow Filtration Focusing on Continuous Bioprocessing for High Protein Concentrations
Processes 2019, 7(11), 781; https://0-doi-org.brum.beds.ac.uk/10.3390/pr7110781 - 01 Nov 2019
Cited by 8 | Viewed by 1234
Abstract
In this study, the continuous Single-Pass Tangential Flow Filtration (SPTFF) concept is adapted for high protein concentrations. The work is based on the previously validated physico-chemical model for low concentrations and high viscosities. The model contains the Stagnant Film Model for concentration polarization, [...] Read more.
In this study, the continuous Single-Pass Tangential Flow Filtration (SPTFF) concept is adapted for high protein concentrations. The work is based on the previously validated physico-chemical model for low concentrations and high viscosities. The model contains the Stagnant Film Model for concentration polarization, as well as the Boundary Layer Model for the mass transfer through the membrane. The pressure drop is calculated as a function of the Reynolds number. By performing preliminary experiments with a single ultrafiltration (UF) cassette, the model parameter are determined. The presented model is validated for a multi-step Single-Pass Tangential Flow Filtration. With subsequent simulation studies, an optimized process is found and confirmed by experiments. The outcome of this work shows the potential to optimize this multi-parameter dependent unit operation. This is reached by a model-based optimization allowing significant reduction of experimental efforts and applying the Quality by Design approach consistently. Furthermore, a comparison between the experimental setup and a commercial module is examined. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Distinct and Quantitative Validation Method for Predictive Process Modelling in Preparative Chromatography of Synthetic and Bio-Based Feed Mixtures Following a Quality-by-Design (QbD) Approach
Processes 2019, 7(9), 580; https://0-doi-org.brum.beds.ac.uk/10.3390/pr7090580 - 02 Sep 2019
Cited by 9 | Viewed by 1416
Abstract
Process development, especially in regulated industries, where quality-by-design approaches have become a prerequisite, is cost intensive and time consuming. A main factor is the large number of experiments needed. Process modelling can reduce this number significantly by replacing experiments with simulations. However, this [...] Read more.
Process development, especially in regulated industries, where quality-by-design approaches have become a prerequisite, is cost intensive and time consuming. A main factor is the large number of experiments needed. Process modelling can reduce this number significantly by replacing experiments with simulations. However, this requires a validated model. In this paper, a process and model development workflow is presented, which focuses on implementing, parameterizing, and validating the model in four steps. The presented methods are laid out to gain, create, or generate the maximum information and process knowledge needed for successful process development. This includes design of experiments and statistical evaluations showing process robustness, sensitivity of target values to process parameters, and correlations between process and target values. Two case studies are presented. An ion exchange capture step for monoclonal antibodies focusing on high accuracy and low feed consumption; and one case study for small molecules focusing on rapid process development, emphasizing speed of parameter determination. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Accelerating Biomanufacturing by Modeling of Continuous Bioprocessing—Piloting Case Study of Monoclonal Antibody Manufacturing
Processes 2019, 7(8), 495; https://0-doi-org.brum.beds.ac.uk/10.3390/pr7080495 - 01 Aug 2019
Cited by 11 | Viewed by 3124
Abstract
An experimental feasibility study on continuous bioprocessing in pilot-scale of 1 L/day cell supernatant, that is, about 150 g/year product (monoclonal antibody) based on CHO (Chinese hamster ovary) cells for model validation is performed for about six weeks including preparation, start-up, batch, and [...] Read more.
An experimental feasibility study on continuous bioprocessing in pilot-scale of 1 L/day cell supernatant, that is, about 150 g/year product (monoclonal antibody) based on CHO (Chinese hamster ovary) cells for model validation is performed for about six weeks including preparation, start-up, batch, and continuous steady-state operation for at least two weeks stable operation as well as final analysis of purity and yield. A mean product concentration of around 0.4 g/L at cell densities of 25 × 106 cells/mL was achieved. After perfusion cultivation with alternating tangential flow filtration (ATF), an aqueous two-phase extraction (ATPE) followed by ultra-/diafiltration (UF/DF) towards a final integrated counter-current chromatography (iCCC) purification with an ion exchange (IEX) and a hydrophobic interaction (HIC) column prior to lyophilization were successfully operated. In accordance to prior studies, continuous operation is stable and feasible. Efforts of broadly-qualified operation personal as well as the need for an appropriate measurement and process control strategy is shown evidently. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Model-Based Design and Process Optimization of Continuous Single Pass Tangential Flow Filtration Focusing on Continuous Bioprocessing
Processes 2019, 7(6), 317; https://0-doi-org.brum.beds.ac.uk/10.3390/pr7060317 - 28 May 2019
Cited by 18 | Viewed by 3417
Abstract
In this study the Single-Pass-Tangential-Flow-Filtration (SPTFF) concept for continuous ultrafiltration in bioprocessing is investigated. Based on a previously validated physico-chemical model for a single ultrafiltration cassette, the transfer to a multistage SPTFF is predicted and validated experimentally by concentration steps for bovine serum [...] Read more.
In this study the Single-Pass-Tangential-Flow-Filtration (SPTFF) concept for continuous ultrafiltration in bioprocessing is investigated. Based on a previously validated physico-chemical model for a single ultrafiltration cassette, the transfer to a multistage SPTFF is predicted and validated experimentally by concentration steps for bovine serum albumin (BSA) and the monoclonal antibody immunoglobulin G (IgG) are compared. The model applied for the ultrafiltration membrane contains the Stagnant Film Model (SFM) for concentration polarization, as well as the Osmotic Pressure Model (OPM) and the Boundary Layer Model (BLM) for the mass transfer through the membrane. In addition, pressure drop correlations as a function of the Reynolds number are included to describe the development of the transmembrane pressure over the length of the module. The outcome of this study shows the potential to improve this multi-parameter dependent unit operation by a model-based optimization allowing significant reduction of experimental efforts and applying the Quality by Design (QbD) approach consistently. Consequently, a versatile tool for conceptual process design is presented and further application is discussed. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Distinct and Quantitative Validation Method for Predictive Process Modeling with Examples of Liquid-Liquid Extraction Processes of Complex Feed Mixtures
Processes 2019, 7(5), 298; https://0-doi-org.brum.beds.ac.uk/10.3390/pr7050298 - 19 May 2019
Cited by 11 | Viewed by 2740
Abstract
As of today, industrial process development for liquid-liquid extraction and scale-up of extraction columns is based on an experimental procedure that requires tests in pilot-scale. This methodology consumes large amounts of material and time and the utilized scale-up equations are crude estimates including [...] Read more.
As of today, industrial process development for liquid-liquid extraction and scale-up of extraction columns is based on an experimental procedure that requires tests in pilot-scale. This methodology consumes large amounts of material and time and the utilized scale-up equations are crude estimates including considerable safety margins. This approach is practical for well-known systems or low-value products coupled with high production scale, where such a scale-up methodology has less impact on the overall profitability. However, for new high-value products in biologics manufacturing, a process development based on process understanding and the use of validated process models is imperative. Therefore, a distinct and quantitative validation workflow for liquid-liquid extraction modeling is presented on the example of two complex feed mixtures. Monte-Carlo simulations based on the presented model parameter determination concept result for both examples in prediction accuracy comparable to the experiments and prediction precision within the deviation of the respective experiments. Identification of statistically significant parameters is demonstrated. The presented methodology for model validation will support the implementation of liquid-liquid extraction in the manufacturing of new high value biological products in regulated industries by providing a workflow to derive a Quality-by-Design compatible process model. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Article
Accelerating Biologics Manufacturing by Upstream Process Modelling
Processes 2019, 7(3), 166; https://0-doi-org.brum.beds.ac.uk/10.3390/pr7030166 - 21 Mar 2019
Cited by 19 | Viewed by 3100
Abstract
Intensified and accelerated development processes are being demanded by the market, as innovative biopharmaceuticals such as virus-like particles, exosomes, cell and gene therapy, as well as recombinant proteins and peptides will possess no available platform approach. Therefore, methods that are able to accelerate [...] Read more.
Intensified and accelerated development processes are being demanded by the market, as innovative biopharmaceuticals such as virus-like particles, exosomes, cell and gene therapy, as well as recombinant proteins and peptides will possess no available platform approach. Therefore, methods that are able to accelerate this development are preferred. Especially, physicochemical rigorous process models, based on all relevant effects of fluid dynamics, phase equilibrium, and mass transfer, can be predictive, if the model is verified and distinctly quantitatively validated. In this approach, a macroscopic kinetic model based on Monod kinetics for mammalian cell cultivation is developed and verified according to a general valid model validation workflow. The macroscopic model is verified and validated on the basis of four decision criteria (plausibility, sensitivity, accuracy and precision as well as equality). The process model workflow is subjected to a case study, comprising a Chinese hamster ovary fed-batch cultivation for the production of a monoclonal antibody. By performing the workflow, it was found that, based on design of experiments and Monte Carlo simulation, the maximum growth rate µmax exhibited the greatest influence on model variables such as viable cell concentration XV and product concentration. In addition, partial least squares regressions statistically evaluate the correlations between a higher µmax and a higher cell and product concentration, as well as a higher substrate consumption. Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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Review

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Review
Accelerating Biologics Manufacturing by Modeling or: Is Approval under the QbD and PAT Approaches Demanded by Authorities Acceptable without a Digital-Twin?
Processes 2019, 7(2), 94; https://0-doi-org.brum.beds.ac.uk/10.3390/pr7020094 - 13 Feb 2019
Cited by 39 | Viewed by 4247
Abstract
Innovative biologics, including cell therapeutics, virus-like particles, exosomes, recombinant proteins, and peptides, seem likely to substitute monoclonal antibodies as the main therapeutic entities in manufacturing over the next decades. This molecular variety causes a growing need for a general change of methods as [...] Read more.
Innovative biologics, including cell therapeutics, virus-like particles, exosomes, recombinant proteins, and peptides, seem likely to substitute monoclonal antibodies as the main therapeutic entities in manufacturing over the next decades. This molecular variety causes a growing need for a general change of methods as well as mindset in the process development stage, as there are no platform processes available such as those for monoclonal antibodies. Moreover, market competitiveness demands hyper-intensified processes, including accelerated decisions toward batch or continuous operation of dedicated modular plant concepts. This indicates gaps in process comprehension, when operation windows need to be run at the edges of optimization. In this editorial, the authors review and assess potential methods and begin discussing possible solutions throughout the workflow, from process development through piloting to manufacturing operation from their point of view and experience. Especially, the state-of-the-art for modeling in red biotechnology is assessed, clarifying differences and applications of statistical, rigorous physical-chemical based models as well as cost modeling. “Digital-twins” are described and efforts vs. benefits for new applications exemplified, including the regulation-demanded QbD (quality by design) and PAT (process analytical technology) approaches towards digitalization or industry 4.0 based on advanced process control strategies. Finally, an analysis of the obstacles and possible solutions for any successful and efficient industrialization of innovative methods from process development, through piloting to manufacturing, results in some recommendations. A central question therefore requires attention: Considering that QbD and PAT have been required by authorities since 2004, can any biologic manufacturing process be approved by the regulatory agencies without being modeled by a “digital-twin” as part of the filing documentation? Full article
(This article belongs to the Special Issue Processes Accelerating Biologics Manufacturing by Modelling)
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