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Introduction:  The basic premise of this project is that without effective process control, safe, efficient and economic operation is impossible in manufacturing processes of the 21^st century; and that the stringent demands of 21st century manufacturing processes requires a fundamentally re-imagined alternative next generation regulatory controller. Over the period of this grant, we developed a novel 4-mode control scheme and an accompanying set of easy-to-apply tuning rules. We evaluated the controller’s performance first in simulation, and subsequently on a sequence of experimental systems: a laboratory scale water tank; a more complicated pilot-scale physical vapor deposition (PVD) process (prototypical of 21st century manufacturing), a bioreactor used to manufacture monoclonal antibodies. Last year’s report presented preliminary results on the bioreactor control experiments; this report focuses on additional, results confirming the achievement of effective control that has hitherto been unachievable.

Results: As discussed in last year’s report, the equipment used for this final control system evaluation 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.  The performance of our regulatory control strategy has been demonstrated specifically as follows: 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 110-hour experiment. The first 30 hours were carried out without control; during the final 80 hours, our control algorithm was used to maintain glucose nutrient concentration at desired set-point.  The results show that the controller maintained glucose concentration within 8% of the set-point, exceeding the industry standard objective of ± 10% (which are difficult enough to achieve).  Preliminary results had showed similar performance, but given the variability intrinsic to biopharmaceutical manufacturing, it was essential to demonstrate the reproducibility of these results.

This new set of results confirms the controller’s ability to exceed industry standards consistently for biopharmaceutical processes, even under stringent operating conditions.  Thus, the overall objectives of the project have been met: the theoretical results developed in the first year 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 standard PID controller, have been established.

Significance: The results from the various experimental validations, especially the final 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.

Publications resulting from this work:

1. Kapil Mukati, Michael Rasch, Babatunde A. Ogunnaike, “An Alternative Structure for Next Generation Regulatory Controllers. Part II: Stability Analysis, Tuning Rules and Experimental Validation, Journal of Process Control, 19, 272–287, (2009).

2. 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.

3. St. Amand, M. M., A.S. Robinson, and B. A. Ogunnaike “Toward Online Control of Glycosylation in MAbs” 21st European Symposium on Computer Aided Process Engineering – ESCAPE 21, E.N. Pistikopoulos, M.C. Georgiadis and A.C. Kokossis (Editors). 2011. (Archival journal version in preparation.)