Study pushes conventional envelope on bioprocessing

By Katrina Megget

- Last updated on GMT

Related tags: Cell culture

The first study comparing traditional and optical sensors in cell
culture has been published and the authors are heralding it as a
potential paradigm shift in the realm of bioprocessing.

The report, published in the journal Biotechnology and Bioengineering​, compares the monitoring of pH and dissolved oxygen (DO) between traditional electrochemical probes and optical sensors during mammalian cell culture. The findings of the study, by researchers from the University of Maryland Baltimore County's (UMBC) Centre for Advanced Sensor Technology in collaboration with and the US Food and Drug Administration (FDA), showed there was a "good agreement"​ between the two instruments. The report stated: "The accuracy as compared to electrochemical probes is sufficient to prohibit any significant impact on growth, production kinetics, and protein product quality. Agreement between these two technologies is necessary to ensure consistent productivity when transferring technology from development into larger scales, as the standard probes are much more expensive and can't be used in small scale cell culture platforms." ​ Speaking to, UMBC Centre for Advanced Sensor technology director and study author Govind Rao said the study was important for the biopharmaceutical industry because it highlighted the advances in technology which could be applied to make the process more efficient. "This is an extremely conservative industry with regard to adopting new technologies, no matter how much more convenient they are, given the hurdles of FDA regulation. Therefore, comparability to an existing technology is vital and showing equivalency and that it does not affect the process in any way is critical." ​ The findings indicated the monitoring of DO and pH was possible from small scale to manufacturing in large reactors, Rao said. "Currently, only larger scale systems are instrumented. This technology is paradigm shifting and allows process monitoring and control using the same sensor technology at all scales." ​ This was important considering the FDA was pushing Process Analytical Technologies and urging the industry to use better defined processes, he said. Traditional electrochemical probes were commonly used for monitoring but had setbacks as they were unable to be used in small-scale bioprocess development, which caused problems downstream when trying to upscale because of the limited information. "Without the ability to monitor these important parameters, accurately controlling them is impossible,"​ the report noted. "If pH and DO concentration are left to vary freely, the value of cell culture models is suspect given no relationship can be established between the other critical development variables and product quality attributes,"​ the authors added. The report said the FDA identified that problems associated with scale-up and mass production as a result of the limited information, led to slow product development and additional costs. "An example of undesirable results that can happen if inconsistency occurs during technology transfer happened at a cGMP pilot plant. In this case, a poorly executed transfer from a development lab to the pilot plant resulted in, a seemingly minor 0.2pH unit discrepancy between the two cell culture systems; this discrepancy led to a 30 per cent reduction in volumetric productivity,"​ the report said. The optical probes, on the other hand, were able to be used in small-scale bioprocessing, thereby eliminating the problems of being unable to monitor the parameters, and the more common practice where manufacturers resorted to more expensive mid-scale culturing platforms to generate the monitoring information required for up-scaling, the report said. The optical sensors involved in the study were derived from fluorescence-based sensing technologies, which have been used for some time. The fluorophores used in the sensors, which are disposable, were immobilized in a patch that gets affixed to the inside of the reactor vessel, thereby making the sensor non-invasive. The DO sensor used a fluorescent dye whose emission was quenched by oxygen at a rate dependent upon oxygen concentration, while the pH sensor used a fluorescent dye whose absorbance spectrum changed with respect to pH, the article said. For the comparison of the sensors, a model mammalian culture of murine hybridoma cells expressing anti-MCPS immunoglobulin G3 monoclonal antibodies was used. Overall, there was a 98.7 per cent Pearson Correlation between the two DO probes, and a 99.7 per cent Pearson Correlation between the two pH probes, the study found. The same lab has previously shown that the non-invasive optical sensors used in this work do not affect cells or the antibodies produced. Optical sensors are currently commercially available from Fluorometrix and Ocean Optics.

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