Cation Exchange Membrane Adsorbers
After the limitation of the Protein A wash buffer is removed, time again becomes a limiting factor. The longest processing
time at high titers in this example will become the final polishing step to remove aggregates (performed with a high flow
rate cation exchange resin). A membrane adsorber was tested to overcome this issue. Membrane adsorbers have previously been
used in MAb manufacture for the removal of impurities and viruses, so the precedent exists to use this type of technology
in established manufacturing processes.9 Because the binding capacity of adsorbers is less than that of chromatography resins, it was decided to develop the process
in flow-through mode. This had the added advantage of reducing buffer volumes.
Figure 2. The variation in process performance with changing sodium chloride concentration in the feed stream
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Capacities were high compared to chromatography, and flow rates increased by more than an order of magnitude, so the processing
time of the unit operation was greatly reduced. Step yields and aggregate clearance were comparable, if not better than those
seen with the high flow rate resin (Figure 2). The use of this technique combined with HP-TFF enabled the purification of
fermentation batches of 9.1 g/L titer with no bottlenecks.
Conclusions
Figure 3. A graphical representation of how implementing technologies and techniques have and can increase the capabilities
of downstream processes to purify fermenters with titers of over 9 g/L.
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Improvements in downstream process design have enabled significant increases in plant throughput to be achieved. Limitations
can still exist, but the implementation of existing technologies can improve the capability of the purification process still
further. It is therefore possible to purify the output of even the largest scale fermenter to beyond 5 g/L, even approaching
10 g/L (Figure 3), by the implementation of techniques without the need for radical process re-design or expensive retrofitting
of existing manufacturing facilities.
JIM DAVIES is the principal group leader in purification development at Lonza, Berkshire, UK (headquartered in Basel, Switzerland),
+44 0 1753 716634, jim.davies@lonza.com
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