Nuclear Magnetic Resonance as a Bioprocessing QbD Application - Pharmaceutical Technology

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Nuclear Magnetic Resonance as a Bioprocessing QbD Application
The author discusses current expectations in bioprocessing and lays a framework for using NMR to enhance a QbD approach.


Pharmaceutical Technology
pp. s24-s27

Case study 2: Profiling CHO-culture media

Chinese Hamster Ovary (CHO) cells are often used for the over-expression and production of recombinant proteins. However, each newly generated CHO cell line requires a separate culture optimization process. Process scientists frequently try several different culture media and select the one providing the highest production levels. However, they may have no means of knowing whether the selected conditions are best suited for scaling or whether there is scope for significantly increasing yields.


Figure 3: The concentration of key analytes over the first eight days of a pilot culture of a new antibody-producing CHO cell line.
NMR profiling can provide full visibility of the presence and concentration of feed components, contaminants, and metabolites. Figure 3 shows the concentration of key analytes over the first eight days of a pilot culture of a new antibody-producing CHO cell line. As demonstrated, there was a fast rise in formate and lactate levels, and a rapid decrease in asparagine concentration. Decomposition of the amino acid shown is directly related to an increase in ammonia which is toxic to the cells. The NMR data enabled rapid assessment of the medium parameters which needed to be varied in order to increase cell density and protein production. In addition, comparison of the lactic acid concentration in media from a control culture and one grown under conditions designed to reduce lactate validated the efficiency of the intervention.

Conclusion

With QbD, FDA and other regulatory agencies require companies to have greater control of their bioprocesses. There is an increased need, therefore, for good methodology to monitor the concentration and identity of media components during process development and manufacturing.

In summary, NMR offers a robust, flexible analytical technique that achieves simultaneous feedback on multiple analytes. NMR is further characterized by a large dynamic range, a high specificity and reproducibility, coupled with fast throughput, making it cost efficient. The information that the industry needs for bioprocess development can be obtained with NMR, and NMR can be used across various cellular platforms, including CHO cells, NSO cells stem cells, insect cells, bacteria, yeasts, and algae.

F.C. Girard, PhD, is CEO of Spinnovation Analytical.

References

1. Spinnovation Case Studies, "Cutting-Edge Analytical Technology to Profile and Manage Optimization of Cell Culture Media" and "Stem Cell Culture: The Advantage of NMR Monitoring," available at http://www.spinnovation-biologics.com/

2. Bradley et al., JACS 132, 9531–33 (2010).

3. FDA, "Advancing Regulatory Science at FDA", p.14, available at http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/RegulatoryScience/UCM268225.pdf.


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