Chromatographic processes, scale

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. 

As a matter of fact, the main advantage in comparison with HPLC is the reduction of solvent consumption, which is limited to the organic modifiers, and that will be nonexistent when no modifier is used. Usually, one of the drawbacks of HPLC applied at large scale is that the product must be recovered from dilute solution and the solvent recycled in order to make the process less expensive. In that sense, SFC can be advantageous because it requires fewer manipulations of the sample after the chromatographic process. This facilitates recovery of the products after the separation. Although SFC is usually superior to HPLC with respect to enantioselectivity, efficiency and time of analysis [136], its use is limited to compounds which are soluble in nonpolar solvents (carbon dioxide, CO,). This represents a major drawback, as many of the chemical and pharmaceutical products of interest are relatively polar. 

These policy decisions by the FDA were the driving force for chiral switches and the commercial development of chromatographic processes such as simulated moving bed (SMB) technology. Due to technological advances such as SMB and the commercial availability of CSPs in bulk quantities for process-scale purification of enantiopure drugs, the production of many single enantiomers now exists on a commercial scale. 

The purification of value-added pharmaceuticals in the past required multiple chromatographic steps for batch purification processes. The design and optimization of these processes were often cumbersome and the operations were fundamentally complex. Individual batch processes requires optimization between chromatographic efficiency and enantioselectivity, which results in major economic ramifications. An additional problem was the extremely short time for development of the purification process. Commercial constraints demand that the time interval between non-optimized laboratory bench purification and the first process-scale production for clinical trials are kept to a minimum. Therefore, rapid process design and optimization methods based on computer aided simulation of an SMB process will assist at this stage. 

Hydrophobic interaction chromatograph (HIC), while very attractive in principle, has proved difficult to scale up for processing. A recent series of articles explores some of the unique problems associated with process-scale HIC. Load sample preparation20 must be carefully examined to prevent protein aggregate formation in the presence of the relatively high salt concentrations used in this technique. Successful scale-up also requires the setting of wide specifications to accomodate routine variations in the feed.21 The effect of the salt concentration on capacity may be somewhat more... 

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 physicochemical and other properties of any newly identified drug must be extensively characterized prior to its entry into clinical trials. As the vast bulk of biopharmaceuticals are proteins, a summary overview of the approach taken to initial characterization of these biomolecules is presented. A prerequisite to such characterization is initial purification of the protein. Purification to homogeneity usually requires a combination of three or more high-resolution chromatographic steps (Chapter 6). The purification protocol is designed carefully, as it usually forms the basis of subsequent pilot- and process-scale purification systems. The purified product is then subjected to a battery of tests that aim to characterize it fully. Moreover, once these characteristics have been defined, they form the basis of many of the QC identity tests routinely performed on the product during its subsequent commercial manufacture. As these identity tests are discussed in detail in Chapter 7, only an abbreviated overview is presented here, in the form of Figure 4.5. 

As with most aspects of downstream processing, the operation of chromatographic systems is highly automated and is usually computer controlled. Whereas medium-sized process-scale chromatographic columns (e.g. 5-151 capacity) are manufactured from toughened glass or plastic, larger... 

Figure 6.8 Chromatographic columns. The glass column illustrated in (a) is manufactured by Merck. A wide variety of columns (ranging in size from 1 ml to several litres, and constructed from glass/plastic or stainless steel) are available from this and a number of other manufacturers (e.g. Bio-Rad and Pharmacia Biotech), (b) Process-scale chromatographic system. This particular system is utilized by a UK-based biotech company in the manufacture of a (protein) drug for clinical trials. The actual column is positioned to the left of picture...

Ruthven, D.M. and Ching, C.B. (1993) Modeling of chromatographic processes. Preparative and production scale chromatography. In Chromatographic Science Series, Vol. 61. Eds. Ganetos, G., Barker,... 

At present, the purification by chromatographic processes is the most powerful high-resolution bioseparation technique for many different products from the laboratory to the industrial scale. In this context, continuous simulated moving bed (SMB) systems are of increasing interest for the purification of pharmaceuticals or specialty chemicals (racemic mixtures, proteins, organic acids, etc.).This is particularly due to the typical advantages of SMB-systems, such as reduction of solvent consumption, increase in productivity and purity obtained as well as in investment costs in comparison to conventional batch elution chromatography [1]. 

Blanche et al. [45] showed that the P-CAC technology is very promising for the purification of Plasmid DNA at preparative scale especially when resins with low binding capacities for the product of interest are used. The aim of the study was to purify the Plasmid DNA out of a clear lysate of E. coli. The lysate containing RNA, nicked DNA, as well as the Plasmid DNA was loaded onto the annular column filled with Poros 20 R2 beads as the stationary phase. The chromatographic process for the purification is shown in Fig. 7. 

Nicoud, R. M. and Perrut, M. in Costa, C. A. and Cabral, 1. S. (eds.) Chromatographic andMembrane Processes in Biotechnology (Kluwer Academic Publishers, 1991) p.381. Operating modes, scale-up and optimisation of chromatographic processes. 

In this brief treatise the discussion of the scale-up of chromatographic processes can not be fully covered. I will attempt to summarize a few of the general rules that most process development chemists attempt to follow to make the transition from the bench to the pilot and production scale easier and more efficient. 

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