Modeling of Transient Flow Through a Viscoelastic Preparative Chromatography Packing Dariusch Hekmat, Michael Kuhn, Verena Meinhardt, and Dirk Weuster-Botz Inst. of Biochemical Engineering, Technische Universit€ at M€ unchen, 85748 Garching, Germany DOI 10.1002/btpr.1768 Published online June 25, 2013 in Wiley Online Library (wileyonlinelibrary.com) The common method for purification of macromolecular bioproducts is preparative packed-bed chromatography using polymer-based, compressible, viscoelastic resins. Because of a downstream processing bottleneck, the chromatography equipment is often operated at its hydrodynamic limit. In this case, the resins may exhibit a complex behavior which results in compression–relaxation hystereses. Up to now, no modeling approach of transient flow through a chromatography packing has been made considering the viscoelasticity of the res- ins. The aim of the present work was to develop a novel model and compare model calcula- tions with experimental data of two agarose-based resins. Fluid flow and bed permeability were modeled by Darcy’s law and the Kozeny–Carman equation, respectively. Fluid flow was coupled to solid matrix stress via an axial force balance and a continuity equation of a deformable packing. Viscoelasticity was considered according to a Kelvin–Voigt material. The coupled equations were solved with a finite difference scheme using a deformable mesh. The model boundary conditions were preset transient pressure drop functions which resem- ble simulated load/elution/equilibration cycles. Calculations using a homogeneous model (assuming constant variables along the column height) gave a fair agreement with experi- mental data with regard to predicted flow rate, bed height, and compression–relaxation hys- teresis for symmetric as well as asymmetric pressure drop functions. Calculations using an inhomogeneous model gave profiles of the bed porosity as a function of the bed height. In addition, the influence of medium wall support and intraparticle porosity was illustrated. The inhomogeneous model provides insights that so far are not easily experimentally acces- sible. V C 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:958–967, 2013 Keywords: preparative chromatography, viscoelastic resins, modeling, transient flow Introduction The most common method for large-scale purification of macromolecular pharmaceutical bioproducts is preparative chromatography. 1 Since conventional packed-bed chromatog- raphy often represents a downstream processing bottleneck because of limited volumetric flow rates, other approaches like membrane chromatography have been under investiga- tion for more than 20 years. 2,3 Membrane chromatography can be a viable alternative, especially for flow-through appli- cations as a polishing step as flow limitations are reduced compared to packed-bed chromatography, 4,5 However, when overall advantages and disadvantages are compared, the inclination of the pharmaceutical industry to apply mem- brane chromatography is rather limited. Therefore, the majority of preparative chromatography is still performed using conventional packed beds. Because of the mentioned bottleneck, equipment and chromatography media have to be utilized in an optimized manner. Hence, the media have to be used for a maximum number of cycles while maintaining the column performance at a high level during this time period. 6 However, it is well known that the operation of the columns at high flow rates near the hydrodynamic design limit may lead to column integrity breaches. 7 These integrity breaches typically comprise medium wall detachment, devel- opment of cracks and flow channels near the column wall and/or inside the bed, partial subsidence of the top of the packing, and even bed collapse. 8 Up to now, the detailed causes of these phenomena are largely unknown. However, some evidence was reported by Ladisch and Tsao as early as 1978 that the compressibility behavior of the commonly used polymer-based resins may be the origin of the prob- lem. 9 In fact, the majority of the polymer-based resins is rep- resented by compressible, viscoelastic, porous media and exhibit a complex, dynamic compression behavior that has to be considered properly. Therefore, a necessity exists for mathematical models, which describe the resins as a visco- elastic material. J€ onsson and J€ onsson reported the occurrence of compression–relaxation hysteresis behavior for the first time. In their work, steady-state flow through a chromatogra- phy column was modeled considering both compressibility and permeability of the media. 10 Dynamic modeling yielded the time dependency of the extra-particle porosity as a func- tion of bed height at different mechanical and/or hydraulic loads. 11 However, these calculations were not validated Correspondence concerning this article should be addressed to D. Hekmat at hekmat@lrz.tum.de. 958 V C 2013 American Institute of Chemical Engineers