Thomas Wucherpfennig

Boehringer Ingelheim Pharma GmbH und Co. KG · Biopharma Development

Aerated stirred tank reactors are widely used in the biopharmaceutical industry for cell culture applications due to their flexibility and broad range of uses. This book chapter provides an overview of the main characterization methods for aerated stirred tank reactors in the context of cell culture processes. The methods described include mechanic...

Process intensification aims to increase productivity in biologics manufacturing. Significant progress has been made in academia, the biopharmaceutical industry, and by the regulatory guidance since the 2000s. Process intensification can include all unit operations of a drug substance manufacturing process. The applied upstream concepts have conseq...

The robust scale up of perfusion systems requires comparable conditions over all scales to ensure equivalent cell culture performance. As cells in continuous processes circulate outside the bioreactor, performance losses may arise if jet flow and stirring cause a direct connection between perfusion feed and return. Computational fluid dynamics can...

The application of Process Analytical Technology (PAT) for biotherapeutic development and manufacturing has been employed owing to technological, economic, and regulatory advantages across the industry. Typically, chromatographic, spectroscopic and/or mass spectrometric sensors are integrated into upstream and downstream unit operations in in-line,...

During the cell culture in stirred aerated vessels, both stirring and sparging is required for proper homogenization of a mixture and oxygen delivery. Quality by design (QbD) in biopharmaceutical industry aims at identification of the impact of mass transfer, dissolved oxygen, pH and hydrodynamic stress on the cell behavior, productivity and produc...

Detailed process and equipment knowledge is crucial for the successful production of biopharmaceuticals. An essential part is the characterization of equipment for which Computational Fluid Dynamics (CFD) is an important tool. While the steady, Reynolds-averaged Navier–Stokes (RANS) k − ε approach has been extensively reviewed in the literature and...

The calculation of temporally varying upstream process outcomes is a challenging task. Over the last years, several parametric, semi-parametric as well as non-parametric approaches were developed to provide reliable estimates for key process parameters. We present generic and product-specific recurrent neural network (RNN) models for the computatio...

Stirred tank reactors are frequently used for mixing as well as heat- and mass transfer processes in chemical and biochemical engineering due to their robust operation and extensive experiences in the past. However, for cell culture processes like mammalian cell expression systems, special requirements have to be met to ensure optimal cell growth a...

Process intensification by application of perfusion mode in pre‐stage bioreactors and subsequent inoculation of cell cultures at high seeding densities (HSD) has the potential to meet the increasing requirements of future manufacturing demands. However, process development is currently restrained by limited understanding of the cell's requirements...

Mit der Expansion der Industriezweige Biotechnologie und Umwelttechnik bildete sich die Bioverfahrenstechnik (Biochemical Engineering) als eigenständige Ingenieurdisziplin aus. Um biologische und biochemische Stoffumwandlungsprozesse aus dem Labor in den industriellen Maßstab übertragen und technisch realisieren zu können, sind für den Bioverfahren...

The 3rd Modeling Workshop focusing on bioprocess modeling was held in Kenilworth, NJ in May 2019. A summary of these Workshop proceedings is captured in this manuscript. Modeling is an active area of research within the biotechnology community, and there is a critical need to assess the current state and opportunities for continued investment to re...

The focus of the current study is the modeling of UF/DF mixing equipment with a focus on mixing performance. When jet flow and stirring are combined, a spatially resolved computational model can be very helpful, as it makes it possible to predict the flow field and thus the mixing behavior of such tanks. In order to evaluate a particular geometry a...

Despite the fact that aerated stirred tank reactors are widely used in industry and often studied, their design and scale‐up still remains challenging. Especially the specific power input is a crucial and geometry‐dependent scale‐up parameter, usually calculated with the dimensionless power number Po. Within the scope of this study, the power numbe...

Microtiter plates are a common tool for clone selection in biopharmaceutical development. A way of visualizing and evaluating these systems and key processes parameters is the application of Computational Fluid Dynamics (CFD). CFD is a powerful tool for the modelling of hydrodynamics and mass transfer parameters. In this work, CFD was used to deter...

Mit der Expansion der Industriezweige Biotechnologie und Umwelttechnik bildete sich die Bioverfahrenstechnik (Biochemical Engineering) als eigenständige Ingenieurdisziplin aus. Um biologische und biochemische Stoffumwandlungsprozesse aus dem Labor in den industriellen Maßstab übertragen und technisch realisieren zu können, sind für den Bioverfahren...

Aerated stirred tank reactors are widely used in chemical industry and bioprocess engineering. One major parameter to characterize the heat- and mass transfer performance of such aerated stirred tank reactors is the mixing time necessary to homogenize the reactor volume. Despite its importance, the prediction of the mixing time is still challenging...

Predictability of k L a in stirred tank reactors under multiple operating conditions using an Euler–Lagrange approach In industrial cell culture engineering, the production process consists of a multiscale seed train from lab scale to large scale. The oxygen demand of the cells has to be satisfied in all scales. Computational fluid dynamics (CFD) s...

Medicinal plants are sustainable bio-factories for valuable active pharmaceutical ingredients (API). They are commonly grown in the field and their extracts have a given combination of constituents. There is some variation due to climate fluctuations and plant diseases (microbial infections), genotypic changes, soil differences, etc. Additionally,...

One of the most sensitive process characteristics in the cultivation of filamentous biological systems is their complex morphology. In submerged cultures, the observed macroscopic morphology of filamentous microorganisms varies from freely dispersed mycelium to dense spherical pellets consisting of a more or less dense, branched and partially inter...

For the commercially established process of paclitaxel production with Taxus chinensis plant cell culture, the size of plant cell aggregates and phenotypic changes in coloration during cultivation have long been acknowledged as intangible parameters. So far, the variability of aggregates and coloration of cells are challenging parameters for any vi...

In suspended culture, most relevant for biotechnological application, plant cells form aggregates. This phenomenon is of importance as it is related to productivity, leads to local heterogeneities, and might be a reason for the considerable shear sensitivity of these cultures. The valid measurement of plant cell aggregates, however, is not trivial,...

The filamentous fungus Aspergillus niger is a widely used host in industrial processes from food, chemical to pharmaceutical industry. The most prominent feature of this filamentous microorganism in submerged cultivation is its complex morphology which comprises dense spherical pellets as well as viscous elongated filaments. Depending on culture co...

One of the most frequently used microorganisms in industrial bioprocesses is the filamentous fungus Aspergillus niger with not easily controllable morphology, ranging from dense spherical pellets to viscous mycelia depending on culture conditions. The main parameter which in fluences the morphology is the mechanical stress induced by either stirrin...

Filamentous fungi have been widely applied in industrial biotechnology for many decades. In submerged culture processes, they typically exhibit a complex morphological life cycle that is related to production performance - a link that is of high interest for process optimization. The fungal forms can vary from dense spherical pellets to viscous myc...

The filamentous fungus A. niger is a widely used strain in a broad range of industrial processes from food to pharmaceutical industry. One of the most intriguing and often uncontrollable characteristics of this filamentous organism is its complex morphology. It ranges from dense spherical pellets to viscous mycelia (Figure 1). Various process param...

The present study describes the design of bio-pellet morphologies of the industrial working horse Aspergillus niger strains in submerged culture. The novel approach recruits the intended addition of titanate microparticles (TiSiO(4), 8 µm) to the growth medium. As tested for two recombinant strains producing fructofuranosidase and glucoamylase, the...

The filamentous fungus Aspergillus niger is a widely used strain in a broad range of industrial processes from food to pharmaceutical industry. One of the most intriguing and often uncontrollable characteristics of this filamentous organism is its complex morphology, ranging from dense spherical pellets to viscous mycelia depending on culture condi...

Because of their metabolic diversity, high production capacity, secretion efficiency, and capability of carrying out posttranslational modifications, filamentous fungi are widely exploited as efficient cell factories in the production of metabolites, bioactive substances, and native or heterologous proteins, respectively. There is, however, a compl...

Functional expression of heterologous Pseudozymaantarctica lipase B (PalB) in the periplasm of Escherichiacoli was explored using four fusion tags, i.e. DsbC, DsbA, maltose-binding protein (MBP), and FLAG in the sequence of increasing expression efficacy. Amongst these fusion tags, FLAG and MBP appear to be the most effective ones in terms of boost...