Particle settler for use in cell culture

Details Particle settler for use in cell culture Particle settler for use in cell culture

1995-11-07

1998-10-06

Redding, David A.

Chemistry: molecular biology and microbiology

Apparatus

Including condition or time responsive control means

4352891, 4353081, 435813, 210373, 210394, 210521, 210802, C12M 300, B01D 3306, B01D 1200, B01D 2100

Patent

active

058175059

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to a particle settling device and to the use of such a device in cell culture. The invention has application in the culture of animal cells for the production of secreted substances such as polypeptides and proteins, particularly monoclonal antibodies.
2. Description of Related Art
Over recent years there has been considerable interest in the culture of animal cells for the production of a variety of useful products. Cell fusion technology (Kohler and Milstein, Nature 256 495-597 (1975)) has allowed the creation of many different hybridomas secreting murine monoclonal antibodies with a range of specificities. Monoclonal antibodies have proved useful as therapeutic and diagnostic agents, for immunopurification, and as research tools. Human monoclonal antibodies have also been produced from cell fusion processes (Thompson et al, Immunology 58 157 (1986)), further extending the range of utility. Recombinant DNA techniques have been used to alter and improve monoclonal antibodies, often still using a variety of animal cells as hosts. Recombinant DNA technology has also been used to create cell lines with foreign genes carried within capable of producing the product encoded by that gene. The animal cell has often been found to be superior to bacteria or yeast as a host for protein expression because of the animal cell's ability to glycosylate protein and to carry out post-translational modification.
Thus the technologies of animal cell fusion and recombinant DNA technology in animal cells are playing an important role in the production of useful products, in addition to their traditional role in vaccine production.
In order to make these products in sufficient quantity at an economic cost, cell culture processes have to be scaled up. Traditional batch fermentation technology has relied upon stirred tank or airlift fermenters. Several examples of large fermenters (for example, 2000 dm.sup.3 airlift fermenters) exist already. Such fermenters have to be housed in large buildings and need a supply of utilities. Downstream processing of the output, which is often relatively low, is usually required.
There has been much interest in continuous perfusion technology whereby cells are retained within the fermenter whilst cell-free supernatant containing product is continuously withdrawn and the fermenter is continuously replenished-with fresh medium for a period of weeks or months. This allows the achievement of higher cell densities within the fermenter, potentially resulting in high substrate-to-product conversion rates and better use of fermenter time; additionally, smaller fermenters can be used. In order to achieve cell retention then there must be some means of physically retaining the cell within the fermenter, ultimately separating the cell from the surrounding medium which then becomes the product stream. As animal cells have no cell wall and are sensitive, this retention means must be gentle. The device or method used for this purpose must be capable of substantially continuous sterile operation without significant breakdown or process interruption. The design should be simple, robust, sanitary and capable of economic scale up. It should also be capable of containment should hazardous organisms be required to grow within it.
A variety of devices or methods have been proposed or put into use to achieve cell retention. These include external or internal spin filters (Himmelfarb et al, Science 164 555-557 (1969)), membrane separators (Knazek et al, Science 178 65-67 (1972)), cell entrapment (Nilsson et al, Nature 302 629-630 (1983)), encapsulation (Jarvis and Grdina, Bio Techniques 1 22-27 (1983)) or gravitational settling (Kitano et al, Appl. Microbiol. Biotechnol. 24 282-286 (1986) and Batt et al, Biotechnol. Prog. 6 458-464 (1990)).
Most devices currently employed have been operated successfully at the laboratory scale and some at the industrial scale; however, they all suffer from some drawbacks. Spin filter devices are prone to clog

REFERENCES:
Bioprocess Engineering, (May 1993) vol. 9, No. 2-3, pp. 91-96, May 1993.
Biotechnology and Bioengineering, vol. 41, No. 3, pp. 361-369, Feb. 5, 1993 .

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