Exciting developments have taken place during the past decade, revolutionizing mammalian cell culture and production of monoclonal
antibodies (mAbs). Product titers have increased from levels that would have been economically unacceptable—if there had been
a workable alternative—to levels considered quite satisfactory. Today's early commercial antibody production processes can
deliver 3–5 g/L of bioreactor volume compared with the meager 300–500 mg/L of years ago. Even greater capacities are promised.
This growth would remain impressive even if those who claim the improvement to be 1000-fold got it wrong by a factor of 100.
The production processes of the 1990s used purification resins at a capacity of 15–18 g/L column volume. Today, we have capacity
that is 3-fold higher, better flow properties, and longer lifetimes. Overall, industry has seen a 10- to 20-fold increase
in productivity, which is quite similar to recent cell-culture improvements. In addition, this new capacity can help reduce
variable costs to as low as 10–30% of first-generation levels for downstream processes alone. Although the latest resin generation
has not been implemented into very large production processes for antibodies yet, it is entering new processes everywhere.
Industry may assume, therefore, that current technology will cope for some time to come.
Most experts agree that the designers of manufacturing facilities did not anticipate the recent developments in cell culture
that dramatically increased product yields. As a consequence, downstream processing equipment and associated tankage capacity—and
to a lesser extent, downstream technology—will constitute a processing bottleneck if product titers continue to increase.
But will they? Should they?
The cost-reduction curve flattens out at capacities of 3–5g/L, and there are no signifcant gains above capacities of 6–7 g/L.
On the contrary, new problems are created further downstream: Manufacturers will need to increase expensive filter areas and
change purification processes to new resins. Alternatively, they could scale up, which brings significant capital cost and
space constraints. Some manufacturers claim a paradigm shift away from current downstream technology is just under the radar
screen. I disagree and here's why.
Because increased product titers, alongside new facility constructions have effectively increased manufacturing capacity,
many mAb manufacturers are reporting significant overcapacity. This overcapacity is likely to affect the fixed-cost burden
on manufacturing costs. A normal percentage in a new facility would be 60–70% of total cost of goods sold (COGS). Fixes to
the downstream process and its variable cost will at best yield cost reductions in the low single-digit percentage range or
will require significant capital for facility refurbishing.
Risks for failure of such an undertaking are not negligible. There are few technical alternatives capable of keeping batch
failures low and helping to ensure product and patient safety while also offering a true shift in economy. Existing alternatives
are likely to be found by competitors first, and thus available only at high licensing costs.
Such de-bottlenecking hardly deserves the name "paradigm shift," even if achieved with new technical alternatives. The cost
problem simply cannot be addressed at the right level. Some may argue that the plasma industry, with its low-priced protein
therapeutics intravenous immunoglobulin (i.v.-IgG) and human serum albumin (hSA), has successfully used alternative separation
technology for decades to make multiton-scale production possible at low cost. But since the 1980s, the plasma industry has
added chromatography steps to its processes to improve previously insufficient yield, purity, and safety. The leader in this
industry today, Australian-based CSL, was the first to install a plasma fractionation plant that was based entirely on chromatography.
In addition, the production of insulin, another ton-scale protein drug, has undergone a complete processing renovation from
low-yield purification processes that involve 15–20 steps and use chemical reaction and precipitation to a 4–5 step chromatography
with great economical improvement. No logical person in the biopharmaceutical industry would want to return to those "good
At present, I can see two possible scenarios, very similar in nature, in which the cost of making mAbs becomes out of reach.
For most other situations, cost is not a driver for technology change (1).