Chromatographic processes, scale considerations

However, chromatographic processes stiH have a considerable appHcabiHty (106) (see Analytical methods). For instance, in small-scale operations, the greater simplicity of the chromatograph may more than compensate economically for the larger adsorbent inventory and desorbent usage. 

The principal considerations involved in design of a process-scale chromatographic purification include scalability, reproducibility, safety, and validatability. Cost factors, however, must by necessity enter into all industrial decisions. Due to the high value-added nature of most biopharmaceuticals, this cost factor is driven by throughput, rather than by capital investment cost. 

The reader will find here a complete mathematical development of the models of chromatography and other physical laws which direct the chemical engineer in the design and scale-up of chromatographic processes. For preparative chromatographic separations, our ultimate purpose is the optimization of the experimental conditions for maximum production rate, minimum solvent consumption, or minimum production cost, with or without constraints on the recovery yield. The considerable amormt of work done on this critical topic is presented in the... 

Another advantage to the incorporation of bioprocessing aids into the Step I procedure is that the clarified extract can be used directly for subsequent purification steps even without the use of a Step II system to dewater or concentrate the process stream. These factors are especidly relevant when HPLC systems arc used in Step IB for the chromatographic procedures. Nucleic acids, pigmented organics and especially cellular debris can very quickly foul an HPLC column. This is an even more important consideration for large scale protein purification schemes where the volumes of material and costs of the operation are greatly increased (3). 

Chromatography also has its own special equipment requirements that vary dependent on the type and scale of the procedure, and the efficiency level desired from the separation. This paper deals predominantly with chromatographic separations as they pertain to large-scale industrial processes and their special needs and considerations. 

Utilized in drug discovery will be the same as that used to provide commercial scale quantities. The discovery chemist may utilize a large number of synthetic steps, use a number of reagents that are expensive or not practical at scale-up, use a number of chromatographic steps for purification, and experience very low yields. For scale up, the process development chemist must factor in safety, economical, and ecological considerations while producing a robust and reproducible synthesis. Fie must consider operating limitations such as heat and mass transfer. Economic factors will dictate minimization of the synthetic steps, maximization of yield, and choice of raw materials. In addition, the process must meet environmental, occupational health, and safety requirements. 

It also needs to be emphasized that it was the development of robust and broadly applicable CSPs that has laid the foundations for economic chromatographic enantiomer separation on a preparative scale. Although indirect [57-62] and CMPA-based direct [63-65] chromatographic methodologies have seen some use in preparative enantiomer separation, the considerable efforts associated with chemical manipulation and/or recovery of the products render these approaches economically unattractive [66]. Preparative enantiomer separations employing CSPs are not subject to these limitations. With CSPs enantiomers can be processed directly (i.e. without prior derivatization) with readily volatile achiral mobile phases (devoid of SOs), simplifying product recovery to a trivial solvent evaporation step. 

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