(480e) Automated Monitoring of Mammalian Cell Cultures Via An Auto-Sampler and An Integrated Multi-Functional off-Line Analyzer

Authors: 
Derfus, G. E., Genentech Inc.
Abramzon, D., Genentech, Inc.
Amaah, A., Genentech Inc.
Tung, M., Genentech, Inc.
Kiss, R., Genentech, Inc.


Mammalian cell-based bioprocesses are used extensively for production of therapeutic proteins. Some bioprocess control parameters, such as temperature, dissolved oxygen and pH, can be monitored on-line using in situ sensors. Other key parameters, however, are still typically monitored via manual sampling and several off-line analyzers. Off-line monitoring is labor-intensive, and introduces operator-dependent error into the process. The BioProfile FLEX, manufactured by Nova Biomedical, combines the functionality of three off-line analyzers (cell counter, osmometer, gas/electrolyte/nutrient/metabolite bio-profile analyzer) into one device. An auto-sampler has also been developed to support up to ten reactors with output to the FLEX. In combination, the FLEX and auto-sampler offer the potential for more robust, operator-independent processes, resulting in increased efficiency and process reproducibility. Furthermore, the ability to sample more frequently with less operator effort could lead to improved understanding of bioprocesses.

This work demonstrated the function of the FLEX and auto-sampler for on-line monitoring of mammalian cell cultures, with data output to a DeltaV bioreactor control system via OPC. FLEX measurements were generally equivalent to those obtained using instruments it would replace (Beckman Coulter Vi-Cell, Advanced Instruments Osmometer 3900, Nova BioProfile 400). FLEX measurements correlated particularly well with those of the other instruments for key process decision parameters including glucose concentration, pH, and cell counts. Inter-instrument variability, assessed using three FLEX analyzers, was minimal for most parameters. Measurements of samples provided to the FLEX by the auto-sampler prototype correlated well with those from manual samples, indicating that the auto-sampler did not alter the samples. In addition, bioreactors connected to the auto-sampler remained contamination-free during fifty days of frequent automated sampling. This work suggests that the FLEX and auto-sampler, along with OPC-based communication between the FLEX and a bioreactor control system, have the potential to dramatically reduce the manual labor involved in maintaining mammalian cell bioprocesses.