Digital Twin for Continuous Production of Virus-like Particles toward Autonomous Operation.

Lentiviral vector and virus-like particle (VLP) manufacturing have been published in fed-batch upstream and batch downstream modes before. Batch downstream and continuous upstream in perfusion mode were reported as well. This study exemplifies development and validation steps for a digital twin combining a physical-chemical-based mechanistic model for all unit operations with a process analytical technology strategy in order to show the efforts and benefits of autonomous operation approaches for manufacturing scale.

Pressurized Hot Water Extraction as Green Technology for Natural Products as Key Technology with Regard to Hydrodistillation and Solid-Liquid Extraction.

Hydrodistillation and solid-liquid extraction with organic solvents or supercritical CO are standard technologies for natural product manufacturing. Within this technology, portfolio pressurized hot water technology is ranked as a green, sustainable, resilient, kosher and halal manufacturing process. Essential for sustainability is energy integration for heating and cooling the auxiliary water as well as product concentration without evaporation but with the aid of low energy consuming ultra- and nanofiltration membrane technology.

Digital Twin for Centrifugal Extractors Exemplified for pDNA Clarification Process after Lysis.

Plasmid DNA is an important substance for the pharmaceutical industry. A major challenge in its production is the clarification of the lysate after harvesting. In this work, a novel process for this is demonstrated in an annular centrifugal contactor (ACC) with an aqueous two-phase extraction.

Resource-Efficient Use of Residues from Medicinal and Aromatic Plants for Production of Secondary Plant Metabolites.

Although people's interest in green and healthy plant-based products and natural active ingredients in the cosmetic, pharmaceutical, and food industries is steadily increasing, medicinal and aromatic plants (MAPs) represent a niche crop type.It is possible to increase cultivation and sales of MAPs, by utilizing plant components that are usually discarded. This chapter provides an overview of studies concerning material flows and methods used for sustainable production of valuable metabolites from MAPs between 2018 and 2023.

Digital Twin Fundamentals of mRNA Transcription in Variable Scale Toward Autonomous Operation.

The COVID-19 pandemic caused the rapid development of mRNA (messenger ribonucleic acid) vaccines and new RNA-based therapeutic methods. However, the approval rate for candidates has the potential to be increased, with a significant number failing so far due to efficacy, safety, and manufacturing deficiencies, hindering equitable vaccine distribution during pandemics. This study focuses on optimizing the production of mRNA, a critical component of mRNA-based vaccines, using a scalable machine by investigating the key mechanisms of mRNA transcription.

Green Manufacturing for Herbal Remedies with Advanced Pharmaceutical Technology.

Herbal remedies are in most cases still manufactured with traditional equipment installations and processes. Innovative chemical process engineering methods such as modeling and process intensification with green technology could contribute to the economic and ecologic future of those botanicals. The integration of modern unit operations such as water-based pressurized hot water extraction and inline measurement devices for process analytical technology approaches in traditional extraction processes is exemplified.

Model-Based Product Temperature and Endpoint Determination in Primary Drying of Lyophilization Processes.

Lyophilization process design still relies mainly on empirical studies with high experimental loads. In the regulatory demanded Quality by Design approach, process modeling is a key aspect. It allows process design, optimization and process control to ensure a safe process and product quality.

Digital Twins in Biomanufacturing.

In recent years process modelling has become an established method which generates digital twins of manufacturing plant operation with the aid of numerically solved process models. This article discusses the benefits of establishing process modelling, in-house or by cooperation, in order to support the workflow from process development, piloting and engineering up to manufacturing. The examples are chosen from the variety of botanicals and biologics manufacturing thus proving the broad applicability from variable feedstock of natural plant extracts of secondary metabolites to fermentation of complex molecules like mAbs, fragments, proteins and peptides.

Integrated Clarification and Purification of Monoclonal Antibodies by Membrane Based Separation of Aqueous Two-Phase Systems.

Therapeutic monoclonal antibodies (mAb) are used for the treatment of numerous serious diseases, which have led to an increasing demand over the last decades. Increased cell density and mAb titer of the cultivation broth lead to great challenges for the subsequent clarification and capture operations in the downstream process. As an alternative approach to the conventional downstream process, a selective mAb extraction via an aqueous two-phase system (ATPS) directly from the cultivation broth of a mAb producing industrial relevant chinese hamster ovary (CHO) cell line was investigated.

Process Engineering Accelerating an Economic Industrialization Towards a Bio-Based World.

The transition towards a bio-based world is a challenging undertaking. This perspective paper, from an engineering point of view, aims to provide an overview of existing projects and academic disciplines highlighting the potential benefit of increased interdisciplinary exchanges. Furthermore, the current utilization of biomass to produce biogas is discussed, including an economic assessment, showing the need for new strategies of biomass valorization.

Process Analytical Technology for Advanced Process Control in Biologics Manufacturing with the Aid of Macroscopic Kinetic Modeling.

Productivity improvements of mammalian cell culture in the production of recombinant proteins have been made by optimizing cell lines, media, and process operation. This led to enhanced titers and process robustness without increasing the cost of the upstream processing (USP); however, a downstream bottleneck remains. In terms of process control improvement, the process analytical technology (PAT) initiative, initiated by the American Food and Drug Administration (FDA), aims to measure, analyze, monitor, and ultimately control all important attributes of a bioprocess.

Evaluation of Continuous Membrane Chromatography Concepts with an Enhanced Process Simulation Approach.

Modern biopharmaceutical products strive for small-scale, low-cost production. Continuous chromatography has shown to be a promising technology because it assures high-capacity utilization, purity and yield increases, and lower facility footprint. Membrane chromatography is a fully disposable low-cost alternative to bead-based chromatography with minor drawbacks in terms of capacity.

Development of a Scale-up Tool for Pervaporation Processes.

In this study, an engineering tool for the design and optimization of pervaporation processes is developed based on physico-chemical modelling coupled with laboratory/mini-plant experiments. The model incorporates the solution-diffusion-mechanism, polarization effects (concentration and temperature), axial dispersion, pressure drop and the temperature drop in the feed channel due to vaporization of the permeating components. The permeance, being the key model parameter, was determined via dehydration experiments on a mini-plant scale for the binary mixtures ethanol/water and ethyl acetate/water.

Process Analytical Approach towards Quality Controlled Process Automation for the Downstream of Protein Mixtures by Inline Concentration Measurements Based on Ultraviolet/Visible Light (UV/VIS) Spectral Analysis.

Downstream of pharmaceutical proteins, such as monoclonal antibodies, is mainly done by chromatography, where concentration determination of coeluting components presents a major problem. Inline concentration measurements (ICM) by Ultraviolet/Visible light (UV/VIS)-spectral data analysis provide a label-free and noninvasive approach to significantly speed up the analysis and process time. Here, two different approaches are presented.

Integration of Aqueous Two-Phase Extraction as Cell Harvest and Capture Operation in the Manufacturing Process of Monoclonal Antibodies.

Substantial improvements have been made to cell culturing processes (e.g., higher product titer) in recent years by raising cell densities and optimizing cultivation time.

Purification of Monoclonal Antibodies Using a Fiber Based Cation-Exchange Stationary Phase: Parameter Determination and Modeling.

Monoclonal antibodies (mAb) currently dominate the market for protein therapeutics. Because chromatography unit operations are critical for the purification of therapeutic proteins, the process integration of novel chromatographic stationary phases, driven by the demand for more economic process schemes, is a field of ongoing research. Within this study it was demonstrated that the description and prediction of mAb purification on a novel fiber based cation-exchange stationary phase can be achieved using a physico-chemical model.

Host Cell Proteins in Biologics Manufacturing: The Good, the Bad, and the Ugly.

Significant progress in the manufacturing of biopharmaceuticals has been made by increasing the overall titers in the USP (upstream processing) titers without raising the cost of the USP. In addition, the development of platform processes led to a higher process robustness. Despite or even due to those achievements, novel challenges are in sight.

Preparation and characterization of high capacity, strong cation-exchange fiber based adsorbents.

Motivated by the demand for more economical capture and polishing steps in downstream processing of protein therapeutics, a novel strong cation-exchange chromatography stationary phase based on polyethylene terephthalate (PET) high surface area short-cut fibers is presented. The fiber surface is modified by grafting glycidyl methacrylate (GMA) via surface-initiated atom transfer radical polymerization (SI-ATRP) and a subsequent derivatization leading to sulfonic acid groups. The obtained cation-exchange fibers have been characterized and compared to commercially available resin and membrane based adsorbers.

Infrared and Raman spectroscopic methods for characterization of Taxus baccata L.--Improved taxane isolation by accelerated quality control and process surveillance.

Different yew species contain poisonous taxane alkaloids which serve as resources for semi-synthesis of anticancer drugs. The highly variable amounts of taxanes demand new methods for fast characterization of the raw plant material and the isolation of the target structures during phyto extraction. For that purpose, applicability of different vibrational spectroscopy methods in goods receipt of raw plant material and in process control was investigated and demonstrated in online tracking isolation and purification of the target taxane 10-deacetylbaccatin III (10-DAB) during solvent extraction.

Trends in Upstream and Downstream Process Development for Antibody Manufacturing.

A steady increase of product titers and the corresponding change in impurity composition represent a challenge for development and optimization of antibody production processes. Additionally, increasing demands on product quality result in higher complexity of processes and analytics, thereby increasing the costs for product work-up. Concentration and composition of impurities are critical for efficient process development.

Extraction of polyphenols from black tea--conventional and ultrasound assisted extraction.

Products from plant raw materials gain increasing importance in food-, cosmetics and pharmaceutical industry. By way of contrast, due to lack of detailed physico-chemical fundamentals, existing production processes are economically not optimal designed. This leads to a need for deeper understanding of the processes and furthermore a systematic process and equipment design for the potentially applicable extraction techniques.

Generic method for systematic phase selection and method development of biochromatographic processes. Part I. Selection of a suitable cation-exchanger for the purification of a pharmaceutical protein.

Even if the first protein therapeutics are now for more than 20 years on the market the selection of suitable adsorbents for the preparative downstream processing (DSP) of these biomolecules as well as the method development towards process conditions are still based mainly on 'trial and error'. Therefore, theses processes are not perfectly efficient, but indeed very time consuming and laborious. In this study a novel systematic method is introduced to find a suitable adsorbent (not necessarily the best one) with appropriate separation parameters for a specific separation with reduced effort.