Model-based design and integration of a two-step biopharmaceutical production process

This paper presents the design of a two-step process in which the first step is PEGylation of a protein, and the second step is chromatographic purification of the target mono-PEGylated protein from the unreacted and the di-PEGylated impurities. The difference between optimizing each process step separately and optimizing them simultaneously is studied. It was found that by optimizing the steps simultaneously up to a 100 % increase in productivity could be obtained without reduction in yield. Optimizing both steps at the same time makes it possible for the optimization method to take into account that the di-PEGylated protein is much easier to separate than the non-PEGylated protein. The easier separation makes it possible to get a higher yield and productivity at the same time. The effect of recycling was also studied and the yield could be increased by 30 % by recycling the unreacted protein. However, if maximum productivity is required, batch mode is preferable.

[1]  Lawrence F. Shampine,et al.  The MATLAB ODE Suite , 1997, SIAM J. Sci. Comput..

[2]  Marcus Degerman,et al.  A Model‐Based Approach to Determine the Design Space of Preparative Chromatography , 2009 .

[3]  C. Horváth,et al.  Interplay of hydrophobic and electrostatic interactions in biopolymer chromatography. Effect of salts on the retention of proteins. , 1989, Journal of chromatography.

[4]  Johan Åkesson,et al.  Model-based optimization of economical grade changes for the Borealis Borstar polyethylene plant , 2012, Comput. Chem. Eng..

[5]  Alois Jungbauer,et al.  Protein Chromatography: Process Development and Scale-Up , 2010 .

[6]  Massimo Morbidelli,et al.  Model-based prediction of monoclonal antibody retention in ion-exchange chromatography. , 2013, Journal of chromatography. A.

[7]  Marcus Degerman,et al.  Modeling and optimization of preparative reversed-phase liquid chromatography for insulin purification. , 2007, Journal of chromatography. A.

[8]  Marcus Degerman,et al.  Optimisation and robustness analysis of a hydrophobic interaction chromatography step. , 2005, Journal of chromatography. A.

[9]  Christodoulos A. Floudas,et al.  Nonlinear and Mixed-Integer Optimization , 1995 .

[10]  L. Biegler,et al.  Advances in simultaneous strategies for dynamic process optimization , 2002 .

[11]  Arne Staby,et al.  Quality by design--thermodynamic modelling of chromatographic separation of proteins. , 2008, Journal of chromatography. A.

[12]  Mark E. Davis,et al.  Numerical methods and modeling for chemical engineers , 1984 .

[13]  Ignacio E. Grossmann,et al.  Systematic Methods of Chemical Process Design , 1997 .

[14]  Mark A. Stadtherr,et al.  A simultaneous‐modular approach to process flowsheeting and optimization. Part I: Theory and implementation , 1985 .

[15]  Henner Schmidt-Traub,et al.  Preparative Chromatography: SCHMIDT-T:PREP.CHROM. 2ED O-BK , 2012 .

[16]  Niklas Jakobsson,et al.  Designing robust preparative purification processes with high performance , 2008 .

[17]  J. M. Harris,et al.  Pegylation: a novel process for modifying pharmacokinetics. , 2001, Clinical pharmacokinetics.

[18]  Massimo Morbidelli,et al.  Chromatographic separation of three monoclonal antibody variants using multicolumn countercurrent solvent gradient purification (MCSGP) , 2008, Biotechnology and Bioengineering.

[19]  Dominique Bonvin,et al.  Dynamic optimization of batch processes: I. Characterization of the nominal solution , 2003, Comput. Chem. Eng..

[20]  Karin Westerberg,et al.  Model‐Based Process Challenge of an Industrial Ion‐Exchange Chromatography Step , 2012 .

[21]  Jaime Cerdá,et al.  State-of-the-art review of optimization methods for short-term scheduling of batch processes , 2006, Comput. Chem. Eng..

[22]  Marcus Degerman,et al.  Determining Critical Process Parameters and Process Robustness in Preparative Chromatography - A Model-Based Approach , 2009 .

[23]  Anita M. Katti,et al.  Fundamentals of Preparative and Nonlinear Chromatography , 1994 .

[24]  Marcus Degerman,et al.  Model based robustness analysis of an ion-exchange chromatography step. , 2007, Journal of chromatography. A.

[25]  Lorenz T. Biegler,et al.  Integrated scheduling and dynamic optimization of batch processes using state equipment networks , 2012 .

[26]  Marcus Degerman,et al.  Pooling control in variable preparative chromatography processes , 2010, Bioprocess and biosystems engineering.

[27]  M. Morbidelli,et al.  Model simulation and experimental verification of a cation-exchange IgG capture step in batch and continuous chromatography. , 2011, Journal of chromatography. A.

[28]  Marcus Degerman,et al.  Constrained optimization of a preparative ion-exchange step for antibody purification. , 2004, Journal of chromatography. A.

[29]  Anders Axelsson,et al.  Model-based optimization of a preparative ion-exchange step for antibody purification. , 2004, Journal of chromatography. A.

[30]  M. Morbidelli,et al.  Increasing the activity of monoclonal antibody therapeutics by continuous chromatography (MCSGP) , 2010, Biotechnology and bioengineering.

[31]  Massimo Morbidelli,et al.  Simulation model for overloaded monoclonal antibody variants separations in ion-exchange chromatography. , 2012, Journal of chromatography. A.