ABSTRACT The development and delivery of high quality therapeutic products necessitates the need for highthrough-put (HTP) process development tools. Traditionally, these works requires a combination of shake flask and small-scale stirred tank bioreactor (STR) which are labor and resource intensive and time-consuming. Here we demonstrate a strategy for rapid and robust cell culture process development by evaluating and implementing the use of a new HTP disposable micro bioreactor (MBR) called AMBRTM system (Advanced Microscale Bioreactor) that has the capabilities for automated sampling, feed addition, pH, dissolved oxygen (DO), gassing and agitation controls. In these studies the performance of two monoclonal antibody (MAb) producing cell lines (MAb1 and MAb2) was evaluated both in the AMBR system and 3-L STR. We demonstrated that cell culture performance (growth and viability, production titer and product quality) were similar in both vessel systems. Furthermore, process control and feed optimization were demonstrated in an additional cell line (MAb3) in the disposable MBR and its performance confirmed at STR scale. The results indicate that the AMBR system can be used to streamline the process development effort and facilitate a rapid and robust cell culture process development effort for MAb programs in a HTP manner.
Cite this paper
Moses, S. , Manahan, M. , Ambrogelly, A. and Ling, W. (2012) Assessment of AMBRTM as a model for high-throughput cell culture process development strategy. Advances in Bioscience and Biotechnology, 3, 918-927. doi: 10.4236/abb.2012.37113.
 ICH Guidelines (2011) ICH quality implementation working group points to consider (R2) I CH-Endorsed Guide for ICH Q8/Q9/Q10/Q11 Implementation. 6 December 2011.
 Kumar, S., Wittmann, C. and Heinzle, E. (2004) Minibio-reactors. Biotechnology Letters, 26, 1-10.
 Betts, J.I. and Baganz, F. (2006) Miniature bioreactors: Current practices and future opportunities. Microbial Cell Factories, 5, 21. doi:10.1186/1475-2859-5-21
 Schapper, D., Alam, M.N., Szita, N., Eliasson Lantz, A. and Gernaey, K.V. (2009) Application of microbioreactors in fermentation process development: A review. Analytical and Bioanaytical Chemistry, 395, 679-695.
 Bareither, R. and Pollard, D.A. (2010) A review of advanced small-scale parallel bioreactor technology for accelerated process development: Current state and future need. Biotechnology Progress, 27, 2-14.
 Girard, P., Jordan, M., Tsao, M. and Wurm, F.M. (2001) Small-scale bioreactor system for process development and optimization. Biochemical Engineering Journal, 7, 117-119.
 John, G.T., Klimant, I., Wittmann, C. and Heinzle, E. (2003) Integrated optical sensing of dissolved oxygen in microtiter plates: A novel tool for microbial cultivation. Biotechnology Bioengineering, 81, 829-836.
 Szita, N., Boccazzi, P., Zhang, Z., Boyle, P., Sinskey, A.J. and Jensen, K.F. (2005) Development of a multiplexed microbioreactor system for high-throughput bioprocessing. Lab Chip, 5, 819-826. doi:10.1039/b504243g
 Amanullah, A., Otero, J.M., Mikola, M., Hsu, A., Zhang, J., Aunins, J., Schreyer, B.H., Hope, J.A. and Russo, P.A. (2010) Novel micro-bioreactor high throughput technology for cell culture process development: Reproducibility and scalability assessment of fed-batch CHO cultures. Biotechnology Bioengineering, 106, 57-67.
 Micheletti, M. and Lye, G.J. (2006) Microscale bioprocess optimisation. Current Opinion in Biotechnology, 17, 611-618.
 Mazzei, D., Guzzardi, M.A., Giusti, S. and Ahluwalia, A. (2010) A low shear stress modular bioreactor for connected cell culture under high flow rates. Biotechnology Bioengineering, 106, 127-137.
 Wen, Y., Zang, R., Zhang, X. and Yang, S.T. (2012) A 24-microwell plate with improved mixing and scalable performance for high throughput cell cultures. Process Biochemistry, 47, 612-618.
 Harms, P., Kostov, Y., French, J.A., Soliman, M., Anjanappa, M., Ram, A. and Rao, G. (2006) Design and performance of a 24-station high throughput microbioreactor. Biotechnology Bioengineering, 93, 6-13.
 Isett, K., George, H., Herber, W. and Amanullah, A. (2007) Twenty-four-well plate miniature bioreactor high-through-put system: Assessment for microbial cultivations. Biotechnology Bioengineering, 98, 1017-1028.
 Chen, A., Chitta, R., Chang, D. and Amanullah, A. (2009) Twenty-four well plate miniature bioreactor system as a scale-down model for cell culture process development. Biotechnology Bioengineering, 102, 148-160.
 Lewis, G., Lugg, R., Lee, K. and Wales, R. (2010) Novel automated microscale bioreactor technology: A qualitative and quantitative mimic for early process development. Bioprocessing Journal, 9, 22-25.
 Hsu, W.T., Aulakh, R.P., Traul, D.L. and Yuk, I.H. (2012) Advanced microscale bioreactor system: A representative scale-down model for bench-top bioreactors. Cytotechnology, 64, 667-678. doi:10.1007/s10616-012-9446-1
 Manahan, M.S. and Ling, W.L. (2009) Profiling intracellular monoclonal antibody expression for improved cell culture characterization and process optimization. Bioprocessing Journal, 8, 22-27.