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Cell cultivation in closed systems

One of today's major cell culturing challenges is to grow cells with the same properties as natural cells in a stable and repeatable production process. Cultivation using open systems has a higher risk of producing unusable cells and may result in a less efficient production process. The reasons are clear: Each time the medium must be refilled or the cells harvested, the system must be opened. This may lead to contamination and uncontrolled production conditions. 

Brian Hampson (1) of PCT Cell Therapy US explains in his article "Closed Processing for Cell Therapies" that for the production of patient-specific cell-based therapies it is necessary to revise the scale of production and the costs per batch in a way not seen so far in pharmaceuticals and biologicals. Because cells themselves are the product, sterilization during or after culturing is impossible. Aseptic processing during manufacturing is the only possibility to minimize the contamination risk.

Open vs. closed systems – a comparison

Open systems are exposed to the environment and the risk of contamination is high. To avoid cross-contamination between batches, only a single batch can be processed under the laminar flow bench. Therefore open systems cannot be used as a standardized system for the effective production of patient-specific cell-based therapies.
Closed systems (Fig. 1) are not in direct contact to the ambient environment and therefore the risk of contamination is significantly reduced. All components and reagents used with cells are pre-sterilized. Closed systems also enable a parallel cell culture from different cell lines. This approach leads to process stability, reduced labor and facility costs.
Disposable set 3HF MFig. 1: Disposable Set 3HF/M with 3 hollow fiber bioreactors and 3 gas transfer modules for diverse cell culture applications (e.g. production of monoclonal antibodies)

Closed systems for cell culture: A requirement for the future

While using closed systems (Fig. 2) for cultivation there is no significant change to process conditions when the incubator is opened. Cells can grow without interruption and without the risk of contamination. Therefore closed systems are suitable for GMP (Good Manufacturing Practice) conforming production. This is critical for future applications in the field of regenerative medicine, e.g. patient-specific cell-based therapies. Implementation ofclosed system processing requires:

  • Use of pre-sterilized components (e.g. disposables, tubes)
  • Use of closed and sterile connections
  • Supply systems with automated control of all necessary substances (e.g. CO2, O2, media, nutrients)
  • Insert of biologicals under sterile conditions
  • Integrated monitoring tools for analyzing and documentation of important process parameters (e.g. temperature, flow rate) 
  • All materials be free of hazardous and toxic substances

flow chartFigure 2: Schematic flow chart of a Cellab® Disposable Set with 1 hollow fiber bioreactor (see Fig. 1) 

Cellab® Bioreactor System: a single-use process solution at lab-scale

The closed Cellab® Bioreactor System is the first integrated lab scale system that provides for a completely closed system. It consists of a reusable docking station and a disposable set. Disposable sets are delivered sterilized and ready to use. They consist of a closed tubing system, various bioreactors and different sized medium bags. Inserting of biologicals is done through a sterile sample port. Both nutrient supply and metabolite removal is regulated automatically with a medium pump inside the closed cell cultivation system. The automated cultivation process with its individual settings is controlled and recorded by the Cellab® Control Center software package that operates the docking station (2).
With a broad range of bioreactor configurations (e.g. hollow fiber, scaffold holders) the Cellab® Bioreactor System can be optimized for particular cultivation demand.

(1) Hampson, B.: 'Closed processing for cell therapies', Genetic Engineering & Biotechnology News, Vol.34, No.9, 2014.
(2) Detailed information, see http://www.cellab.eu/en/products-services/product-portfolio/docking-station.html

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