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Development of biologicals via high-speed workflow Posted 15/05/2019

Abstract
In order to accelerate the development process of biologicals, UGA Biopharma GmbH established a high-speed cell line development workflow using an optimized high yield expression vector and bioprocess development in bioreactors.

Keywords: cell line, CHO, purification

The manufacturing of biologicals based on genetically modified living cells in bioreactors is extremely demanding. For example, the behaviour of the clones depends on many factors such as temperature during fermentation, pH, dissolved oxygen concentration and nutrient supply. Unlike their chemically produced counterparts, biopharmaceuticals are highly complex molecules and react extremely sensitive to fluctuations of process parameters or the composition of the culture medium during manufacturing. Therefore, a careful selection process of the cell clone and the development of a robust manufacturing process are essential as well as thorough checks in order to ensure straightforward production later on. However, this is very time-consuming, costly and a deep understanding is necessary, considering that the product quality could be affected or that the isolated monoclonal cell lines (clones) could be unstable, see Figure 1. 

Figure 1: Cultivation of clones in 96-well plates during cell line development

In order to prevent this, UGA Biopharma GmbH pays particularly close attention to the productivity, stability and quality of the clones when developing new cell lines. This is done in accordance with the requirements of the European Medicines Agency (EMA). But thanks to many years of experience and the implemented advanced processes using an optimized expression vector, the company requires only seven months for the entire development, covering cell line development, bioprocess and purification process development, in addition to the provision of all necessary analytical data.

‘In recent years, we have optimized the expression vector and cell line generation work flow to such an extent that we are able to create highly productive and stable production cell lines within a very short period of time, achieving product concentrations of up to 7 g/L’, says Dr Lars Kober, Managing Director of UGA Biopharma GmbH. A Chinese hamster ovary (CHO) cell has proven particularly well suited for this. During the actual cell line development workflow, the expression vector is introduced into this CHO cell, creating a mixture of cells with different characteristics. Using single-cell cloning, highly productive monoclonal cell lines can then be isolated, cultivated and used to create cell banks for long-term storage at 196°C. However, in order to guarantee the scalability of the cell lines, the laboratory staff carry out a process transfer into bioreactors and derive a suitable bioprocess therefrom, see Figure 2.

Figure 2: Testing highly productive cell lines in bioreactors

‘But even the “best” cell line is of no use to pharmaceutical companies if the manufactured biological drug has not the expected quality or cannot be purified’, Dr Kober says. Therefore, the company also develops a suitable downstream purification process while the potency of the purified biologicals is being tested via various binding assays and in different cell culture model, see Figure 3. Also the company conducts glycan analyses in order to obtain useful information about the selection of promising clones early on.

Figure 3: Developing purification processes for biologicals

It only takes seven months in total until the developed bioprocess can be transferred to the manufacturing facility: four months are required for cell line development and three for the bioprocess, downstream process development and analytics. ‘Since patent protection for pharmaceuticals generally expires after 20 years, such short development times are essential in the pharmaceutical industry’, says Dr Kober.

For further information, visit: www.ugabiopharma.com

UGA Biopharma GmbH was founded in Hennigsdorf near Berlin in 2009. The company’s core area of business is the contract development of biologicals and biosimilars. This involves all the necessary steps from cell line development and bioprocess development to the development of purification processes and analytics. Furthermore, high-performance cell culture media and feeds are supplied under the trade name First CHOice in order to optimize the quality and product concentration of biologicals and biosimilars. If necessary, the company can support its customers in transferring the manufacturing process to their production facility. UGA Biopharma’s unique selling feature is also that it offers its customers what are known as ready-to-use biosimilar cell lines. The company supplies its customers in Germany and abroad from its headquarters in Hennigsdorf and already has several users with UGA products in clinical trials or who have already received a market approval.

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