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Introduction:  Meeting the stringent demands of 21st century manufacturing processes requires a fundamentally re-imagined alternative next generation regulatory controller. In previous reports, we have discussed the development of a new 4-mode control scheme; the development of easy-to-apply tuning rules; an evaluation of the controller’s performance on a laboratory scale water tank; and an evaluation on the more complicated pilot-scale physical vapor deposition (PVD) process that is prototypical of 21st century manufacturing. The focus of this report is on a novel application to another 21^st century manufacturing process: a bioreactor used to manufacture monoclonal antibodies. Until recently, biopharmaceutical manufacturers could remain profitable in spite of significant inefficiencies in their manufacturing processes.  However, with rapidly expanding product portfolios, the emergence of generics, and tighter regulatory requirements, to remain competitive, biopharmaceutical manufacturers will need to develop and implement novel methods for assuring product quality consistently and efficiently. In this regard, the biopharmaceutical industry, with its offline and post-production quality assurance methods, clearly lags behind other industries in the development and implementation of innovative strategies to ensure product quality.  This state-of-affairs in biopharmaceutical manufacturing is usually attributed to the fact that bioprocessing, in general, involves highly complex processes with many production and purification steps.  The application of our control strategy is designed to provide effective options for this industry. 

 Results: The equipment used for this case study involves a parallel bioreactor system (DasGip, Julich Germany) with capability for temperature, pH, DO, feed rate and agitation control.  The bioreactor is integrated through an OPC interface with a bioanalyzer (Nova Bioprofile 100+) that provides measurements of the metabolites.  To demonstrate the performance of our regulatory controller, Chinese hamster ovary (CHO) K1 cells were cultured in serum free suspension culture with 30% DO and pH 7.3 and glucose and glutamine media concentrations measured at 3-hour intervals over the course of a single 80 hour experiment. Our control algorithm was used to maintain media nutrient concentrations at desired set-points one at a time.  Based on the Nova Bioprofile readings of media concentration, the controller either adjusted the feed rate of a 50g/L stock solution of glucose or a 29.3g/L solution of glutamine. The results show that the controller maintained glucose within 8% of the set-point compared to the ±25% of the set-point that is common with standard control.

With this final set of results, we can state conclusively that we have met the objectives of the project: the theoretical results have been validated; the tuning rules have been shown to be effective, and the ease of tuning and superior performance of this controller, compared to that of the PID controller, have been established. The bioreactor process results show that achieving manufacturing objectives for biopharmaceutical processes is possible with our regulatory controller.

 Significance: The results from the various experimental validations, especially the set of results presented in this report, indicate that the new regulatory controller indeed makes possible the high degree of performance required of 21^st century processes—performances that are not possible with classical PID controllers. The entire collection of results also confirms that the controller is applicable to a wide variety of processes, but especially for complicated processes with stringent operating requirements.

 Publication resulting from this work:

M. St. Amand, P. Millili, M. McCabe, B. A. Ogunnaike. “A Strategic Vision for Integrated PAT and Advanced Control in Biologics Manufacturing;” Chapter 3 in Process Analytical Technology Applied in Biopharmaceutical Process Development and Manufacturing: Enabling Tool for Quality-by-Design. Eds. C. Undey, D. Low, M. Monteiro, and M. Koch, CRC Press, Boca Raton, FL, 2010.