Enzymatic Synthesis of Ampicillin: Nonlinear Modeling, Kinetics Estimation, and Adaptive Control

Nowadays, the use of advanced control strategies in biotechnology is quite low. A main reason is the lack of quality of the data, and the fact that more sophisticated control strategies must be based on a model of the dynamics of bioprocesses. The nonlinearity of the bioprocesses and the absence of cheap and reliable instrumentation require an enhanced modeling effort and identification strategies for the kinetics. The present work approaches modeling and control strategies for the enzymatic synthesis of ampicillin that is carried out inside a fed-batch bioreactor. First, a nonlinear dynamical model of this bioprocess is obtained by using a novel modeling procedure for biotechnology: the bond graph methodology. Second, a high gain observer is designed for the estimation of the imprecisely known kinetics of the synthesis process. Third, by combining an exact linearizing control law with the on-line estimation kinetics algorithm, a nonlinear adaptive control law is designed. The case study discussed shows that a nonlinear feedback control strategy applied to the ampicillin synthesis bioprocess can cope with disturbances, noisy measurements, and parametric uncertainties. Numerical simulations performed with MATLAB environment are included in order to test the behavior and the performances of the proposed estimation and control strategies.

[1]  D. Dochain,et al.  On-Line Estimation and Adaptive Control of Bioreactors , 2013 .

[2]  R. Fernández-Lafuente,et al.  A kinetic study of synthesis of amoxicillin using penicillin G acylase immobilized on agarose. , 2000, Applied biochemistry and biotechnology.

[3]  Bernhard Maschke,et al.  Bond graph modelling for chemical reactors , 2006 .

[4]  K. Schügerl,et al.  Progress in monitoring, modeling and control of bioprocesses during the last 20 years. , 2001, Journal of biotechnology.

[5]  Eugen Bobasu,et al.  Structural identifiability of some biotechnological systems , 2007 .

[6]  Dorin Sendrescu Nonlinear Model Predictive Control of a Depollution Bioprocess , 2011, 2011 Third Pacific-Asia Conference on Circuits, Communications and System (PACCS).

[7]  J. Guisán Immobilization of Enzymes as the 21st Century Begins , 2006 .

[8]  Dorin Şendrescu,et al.  Pseudo Bond Graph modelling and on-line estimation of unknown kinetics for a wastewater biodegradation process , 2010, Simul. Model. Pract. Theory.

[9]  Carlos Heny,et al.  Pseudo-bond graph model and simulation of a continuous stirred tank reactor , 2000, J. Frankl. Inst..

[10]  L. Pastrana,et al.  Modelling the Biphasic Growth and Product Formation by Enterococcus faecium CECT 410 in Realkalized Fed-Batch Fermentations in Whey , 2010, Journal of biomedicine & biotechnology.

[11]  Monica Roman,et al.  Pseudo bond graph modeling of wastewater treatment bioprocesses , 2012, Simul..

[12]  R. Fernández-Lafuente,et al.  Influence of Substrate Structure on PGA‐Catalyzed Acylations. Evaluation of Different Approaches for the Enzymatic Synthesis of Cefonicid , 2005 .

[13]  Wolfgang Borutzky,et al.  Bond Graph Methodology , 2010 .

[14]  Roberto Fernandez-Lafuente,et al.  Improvement of enzyme activity, stability and selectivity via immobilization techniques , 2007 .

[15]  M. Farza,et al.  Simple nonlinear observers for on-line estimation of kinetic rates in bioreactors , 1998, Autom..

[16]  J. Gauthier,et al.  A simple observer for nonlinear systems applications to bioreactors , 1992 .

[17]  D. Janssen,et al.  Hybrid penicillin acylases with improved properties for synthesis of beta-lactam antibiotics , 2007 .

[18]  K. Hoo,et al.  Bond Graph Modeling of an Integrated Biological Wastewater Treatment System , 2006 .

[19]  Alan S. Perelson,et al.  System Dynamics: A Unified Approach , 1976, IEEE Transactions on Systems, Man, and Cybernetics.

[20]  J. L. Baliño Galerkin finite element method for incompressible thermofluid flows framed within the bond graph theory , 2009, Simul. Model. Pract. Theory.

[21]  Emil Petre,et al.  Sliding mode and adaptive sliding‐mode control of a class of nonlinear bioprocesses , 2007 .

[22]  Patricia V. Lawford,et al.  Systemic modelling and computational physiology: The application of Bond Graph boundary conditions for 3D cardiovascular models , 2009, Simul. Model. Pract. Theory.

[23]  Hassan K. Khalil,et al.  High-gain observers in nonlinear feedback control , 2009, 2009 IEEE International Conference on Control and Automation.

[24]  Roberto Fernandez-Lafuente,et al.  Control of protein immobilization: coupling immobilization and site-directed mutagenesis to improve biocatalyst or biosensor performance. , 2011, Enzyme and microbial technology.

[25]  Nicolas Boizot,et al.  An adaptive high-gain observer for nonlinear systems , 2010, Autom..

[26]  A. Isidori Nonlinear Control Systems , 1985 .

[27]  J. Hou,et al.  The amino acid nature of ampicillin and related penicillins. , 1969, Journal of pharmaceutical sciences.

[28]  Mohammed M'Saad,et al.  High gain observer with updated gain for a class of MIMO nonlinear systems , 2011, Int. J. Control.

[29]  Ahmed Rahmani,et al.  Proportional-integral observer for systems modelled by bond graphs , 2005, Simul. Model. Pract. Theory.

[30]  R. Rodrigues,et al.  Use of enzymes in the production of semi-synthetic penicillins and cephalosporins: drawbacks and perspectives. , 2010, Current medicinal chemistry.

[31]  Hassan K. Khalil,et al.  High-gain observers in the presence of measurement noise: A switched-gain approach , 2009, Autom..

[32]  Variational calculus (optimal control) applied to the optimization of the enzymatic synthesis of ampicillin , 2005 .

[33]  Teodoro Espinosa-Solares,et al.  Macroscopic mass and energy balance of a pilot plant anaerobic bioreactor operated under thermophilic conditions , 2006, Applied biochemistry and biotechnology.

[34]  Klaus Buchholz,et al.  Biocatalysts and Enzyme Technology , 2005 .

[35]  Alessandro Astolfi,et al.  High gain observers with updated gain and homogeneous correction terms , 2009, Autom..

[37]  Wolfgang Borutzky,et al.  Bond Graph Methodology: Development and Analysis of Multidisciplinary Dynamic System Models , 2009 .