Multicolumn continuous chromatography defies most of the conventional wisdom about commercial-scale chromatographic separation.
Conventional wisdom says process chromatography is expensive. It is necessary for biomolecular separations, but should be
avoided in small-molecule manufacturing. It is inherently a batch process, usually requiring multiple injections to process
a single reactor-load of product, and it consumes vast amounts of solvent and packing material.
Everything conventional wisdom says about process-scale chromatographic separations is wrong—or at least requires a lengthy
footnote to explain the exceptions. And high on the list of exceptions is multicolumn continuous chromatography, the category
that includes simulated moving bed (SMB) chromatography and its descendants.
The largest multicolumn continuous chromatography unit in service in North America: the 5 x 1000-mm Novasep Process system
which went into service in March 2006 at Ampac Fine Chemicals' Rancho Cordova, California facility.
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From its origins in the 1950s as a technique for chiral separations of commodity chemicals, continuous chromatography has
come into its own in the pharmaceutical world over the past four or five years, as single-enantiomer active pharmaceutical
ingredients (APIs) have come to dominate the roster of top-selling drugs. Of 2005's seven top-selling formulations, six are
single-enantiomer products (1).
Tortoises and hares
Continuous chromatography links multiple columns—typically five to eight of them—in a loop, outlet to inlet, with additional
inlets for raw product feed and two outlets, one for target product (extract) and the other for discarded product (raffinate).
To make the process continuous, the feed, extract, and raffinate ports cycle from column to column, lagging behind the solvent
flow. The effect is as though the stationary phase were moving backward relative to the feed port, while the solvent is moving
forward. If the stationary phase, mobile phase, and flow rate are chosen properly, the viewer straddling the feed port sees
the product stream divide into two continuous streams, with one component flowing continuously downstream and the other flowing
continuously upstream (Figure 1).
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Figure 1: Operating principles of a four-column continuous chromatography system. Trying to follow the inlet and outlet ports
as they cycle around the system (facing page) can be confusing. By focusing on the view from the feed port (right), it becomes
apparent that one fraction moves upstream from the feed to the extract port, and the other moves downstream. In this view,
switching the feed and outlet ports around the loop makes it appear that the columns "Shift left" as noted.
