Sequential/parallel production of potential Malaria vaccines – A direct way from single batch to quasi-continuous integrated production

Luttmann, R.; Borchert, Sven-Oliver; Mueller, Christian; Loegering, Kai; Aupert, Florian; Weyand, Stephan; Kober, Christian; Faber, Bart W.; Cornelissen, Gesine

doi:10.1016/j.jbiotec.2015.02.022

Cited by 23 publications

(8 citation statements)

References 24 publications

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“…This strategy usually lacks process control opportunities and large numbers of failed batches are generated. The in-line measurement of important media components, and parameters for the online evaluation of process reproducibility and stability, thus remain among the unsolved problems of industrial biotechnology [81,82].…”

Section: Process Controlmentioning

confidence: 99%

Concepts for the Production of Viruses and Viral Vectors in Cell Cultures

Grein¹,

Weidner²,

Czermak³

2017

New Insights Into Cell Culture Technology

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The industrial-scale manufacturing of viruses or virus-like particles in cell culture is necessary for gene therapy and the treatment of cancer with oncolytic viruses. Complex multistep processes are required in both cases, but the low virus titers in batch cultures and the temperature sensitivity of the virus particles limit the production scale. To meet commercial and regulatory requirements, each process must be scalable and reproducible and must yield high virus titers. These requirements are met by establishing a cell culture process that matches the properties of the virus/host-cell system and by using serum-free cell culture medium. This chapter focuses on two case studies to consider the different aspects of process design, such as the reactor configuration and operational mode: the continuous production of retroviral pseudotype vectors in a retroviral packaging cell line and the production of oncolytic measles virus vectors for cancer therapy.

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Section: Process Controlmentioning

confidence: 99%

Concepts for the Production of Viruses and Viral Vectors in Cell Cultures

Grein¹,

Weidner²,

Czermak³

2017

New Insights Into Cell Culture Technology

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“…However, only a limited number of successful implementations of bench‐scale end‐to‐end integrated processes has been demonstrated for the production of biologics (Arnold et al, 2019; Godawat, Konstantinov, Rohani, & Warikoo, 2015; Luttmann et al, 2015; Steinebach et al, 2017). Possible explanations are the increased product and system complexity, lack of real‐time process information as well as difficulties to handle disturbances and drifts due to changes in raw materials or biological systems when dealing with a continuously operating sequence of units.…”

Section: Introductionmentioning

confidence: 99%

“…To enable the interaction among different process units, analyzers, and actuators, a digital platform or supervisory control and data acquisition (SCADA) system is required, which implements a centralized database as well as computational tools for monitoring, control, and optimization (Luttmann et al, 2015; Markl et al, 2013). Although there are solutions on the market, thorough customization of existing software is necessary to respond to the specific requirements of an end‐to‐end integrated biopharmaceutical process (Chopda et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Process‐wide control and automation of an integrated continuous manufacturing platform for antibodies

Feidl

Vogg

Wolf

et al. 2020

Biotech & Bioengineering

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Integrated continuous manufacturing is entering the biopharmaceutical industry. The main drivers range from improved economics, manufacturing flexibility, and more consistent product quality. However, studies on fully integrated production platforms have been limited due to the higher degree of system complexity, limited process information, disturbance, and drift sensitivity, as well as difficulties in digital process integration. In this study, we present an automated end‐to‐end integrated process consisting of a perfusion bioreactor, CaptureSMB, virus inactivation (VI), and two polishing steps to produce an antibody from an instable cell line. A supervisory control and data acquisition (SCADA) system was developed, which digitally integrates unit operations and analyzers, collects and centrally stores all process data, and allows process‐wide monitoring and control. The integrated system consisting of bioreactor and capture step was operated initially for 4 days, after which the full end‐to‐end integrated run with no interruption lasted for 10 days. In response to decreasing cell‐specific productivity, the supervisory control adjusted the loading duration of the capture step to obtain high capacity utilization without yield loss and constant antibody quantity for subsequent operations. Moreover, the SCADA system coordinated VI neutralization and discharge to enable constant loading conditions on the polishing unit. Lastly, the polishing was sufficiently robust to cope with significantly increased aggregate levels induced on purpose during virus inactivation. It is demonstrated that despite significant process disturbances and drifts, a robust process design and the supervisory control enabled constant (optimum) process performance and consistent product quality.

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“…In the last decade, several trends could be observed in biopharmaceutical process development: a shift from yield maximization to quality optimization, the utilization of miniaturized and parallelized high throughput techniques, single‐use technologies, continuous bioprocessing, and continuous data acquisition as well as the utilization of data‐ and knowledge‐driven tools for process analysis, forecasting, monitoring, and control . Many of these trends are already well‐established in the “older” industries such as automotive.…”

Section: Introductionmentioning

confidence: 99%

Sequential Multivariate Cell Culture Modeling at Multiple Scales Supports Systematic Shaping of a Monoclonal Antibody Toward a Quality Target

Sokolov

Morbidelli

Butté

et al. 2018

Biotechnology Journal

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The development of cell culture processes is highly complex and requires a large number of experiments on various scales to define the design space of the final process and fulfil the regulatory requirements. This work follows an almost complete process development cycle for a biosimilar monoclonal antibody, from high throughput screening and optimization to scale-up and process validation. The key goal of this analysis is to apply tailored multivariate tools to support decision-making at every stage of process development. A toolset mainly based on Principal Component Analysis, Decision Trees, and Partial Least Square Regression combined with a Genetic Algorithm is presented. It enables to visualize the sequential improvement of the high-dimensional quality profile towards the target, provides a solid basis for the selection of effective process variables and allows to dynamically predict the complete set of product quality attributes. Additionally, this work shows the deep level of process knowledge which can be deduced from small scale experiments through such multivariate tools. The presented methodologies are generally applicable across various processes and substantially reduce the complexity, experimental effort as well as the costs and time of process development.

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Sequential/parallel production of potential Malaria vaccines – A direct way from single batch to quasi-continuous integrated production

Cited by 23 publications

References 24 publications

Concepts for the Production of Viruses and Viral Vectors in Cell Cultures

Concepts for the Production of Viruses and Viral Vectors in Cell Cultures

Process‐wide control and automation of an integrated continuous manufacturing platform for antibodies

Sequential Multivariate Cell Culture Modeling at Multiple Scales Supports Systematic Shaping of a Monoclonal Antibody Toward a Quality Target

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