Designing affinity chromatographic processes for the capture of antibodies. Part I: A simplified approach.

Protein A affinity chromatography is a standard technique for the purification of therapeutic antibodies. Recently, multi-column chromatographic processes have emerged to turn classical capture processes into more efficient and continuous systems. The design of such chromatographic processes, be they single-column or multi-column systems, is described in this work. A rational method to conceive, scale-up and compare processes is proposed and illustrated with different examples. All along this article, the results of the equilibrium theory, i.e. obtained with an infinitely efficient column, are used to normalize the system and propose a frame for a rigorous comparison between the different configurations considered in this work. Then, the impact of the fluid velocity, the column length, the refresh time, the sequence organization and the number of columns on the yield, productivity and fluid requirement is investigated. It is found that the optimal process, in terms of number of columns and residence time, depends in the targeted protein recovery. For instance, when considering a titer of 1g/L, 2 columns connected in series in the loading zone are necessary to reach 90% recovery, 3 columns to reach 95% and 4 columns to obtain 99% recovery.

Optimization of simulated moving bed and Varicol processes.

A new continuous chromatographic process (Varicol) has been presented recently. Its basic principle consists, in contrast to the traditional simulated moving bed (SMB) technology, of an asynchronous shift of the inlet/outlet lines in a multi-column system with a recycle loop. Due to the stronger influence of the discrete dynamics on the plant behavior, the design of a Varicol process requires the use of model-based optimization to take advantage of the very high flexibility of this process. The equilibrium theory which has been successfully applied to SMB by many practitioners fails to predict the region of complete separation accurately. In this paper, we present a rigorous model-based optimization framework, which can handle the SMB and the novel Varicol process in a systematic manner. The feasibility of the approach is demonstrated by the separation of a mixture of propranolol isomers which exhibits a highly non-linear multi-component adsorption behavior. Experimental results are presented and discussed.

Application of the "VARICOL" process to the separation of the isomers of the SB-553261 racemate.

A new continuous chromatographic process (VARICOL) has been presented recently. The basic principle of the new VARICOL process consists of an asynchronous shift of the inlet/outlet lines in a multi-column system on a recycle loop. This process has been used to perform the separation of the optical isomers of the SB-553261 racemate. In this paper, we illustrate that for this specific separation, the VARICOL process is more efficient than the well-known SMB process.

Supercritical fluid simulated moving bed chromatography II. Langmuir isotherm.

The simulated moving bed (SMB) technology offers the possibility of scaling up single column, batch chromatographic separations to continuous operation. This has proved particularly effective for the separation of enantiomers, and has been applied in the liquid and gas phase, as well as using a supercritical fluid as eluent (SF-SMB). In the last case, the main performance improvements are due to the possibility of tuning the elution strength of the mobile phase, by changing the pressure in the four sections of the SMB unit. Thus a SF-SMB can be operated in two modes, i.e. the isocratic and the pressure gradient mode. In this research, design criteria for these two operating modes have been developed, which can be applied to systems described by linear as well as nonlinear Langmuir adsorption isotherms. The role and effect of an appropriate modifier in increasing solubility and reducing retention times have been investigated. The results reported allow to identify the operating conditions, including the pressure levels and the modifier concentration, which lead to optimal separation performance in terms of productivity and desorbent requirement.

Application of the equilibrium theory to ternary moving bed configurations (4+4, 5+4, 8 and 9 zones). II. Langmuir case.

In this article, the overall methodology used to determine the working flow-rates of a true moving bed (TMB) processing langmuirian isotherms compounds is explained. Then it is applied to different ternary configurations (4+4, 5+4, 8 or 9 zones TMB) in order to characterize their performances. Finally the results obtained on all the configurations are compared on a given example. This comparison allows the choice of the more suitable configuration to be used for a given set of compounds.

Application of equilibrium theory to ternary moving bed configurations (four+four, five+four, eight and nine zones) I. Linear case.

In this article, different ternary moving bed configurations are studied by determining the working flow-rates of the equivalent true moving bed at the low solvent consumption point using equilibrium theory. This method has been applied for linear adsorption isotherms. The simulated moving bed flow-rates can then be calculated and a final comparison between the performances of each process is given based upon two different objective functions.

Design and optimisation of a simulated moving bed unit: role of deviations from equilibrium theory.

The design of a simulated moving bed involves thermodynamic, kinetic and hydrodynamic aspects and requires the optimisation of several variables: plant design variables, such as the column length and diameter, and operating variables, among them four independent flow-rates, the feed concentration and the switch time. In this work we develop an algorithm to design both the unit and its operating conditions, with an overall view on equilibrium properties, efficiency and hydrodynamics, using a simple equilibrium stage model. In this way we determine the parameters leading to the highest possible productivity for a given separation, only requiring the knowledge of the equilibrium isotherms, the Van Deemter equation and a correlation for pressure drop. The algorithm has been used to investigate the effect on the separation performance of some parameters, such as particle size and required product purity, which are not considered by equilibrium theory. The results have been compared with the predictions of equilibrium theory and the observed deviations have been put in evidence and discussed.