Biopharmaceutical manufacturing involves a balancing act between the capacity of cell culture and downstream purification. Balancing the two has always been difficult because construction decisions are taken 3–5 years before production is started. Hence, by definition, plants coming online today are designed on the technology and yield assumptions from 3–5 years ago.
In fact, over the past 20 years, it would appear that the productivity improvements from increasing titres in upstream have created a challenge in downstream purification. But when one looks into the math it becomes obvious that downstream technology was significantly more capable than upstream technology until just a few years ago, and recent developments prove it is just as capable today, despite the popular downstream bottleneck misconception. The real issues are flexibility in manufacturing and uncertainty about future demands.
As an example, at the turn of the century, if you were to plan to produce 500 kg per year of a particular protein, your manufacturing suite would contain 9 or 10 of the largest commercially available bioreactors but only need three downstream process trains. This is based on the following formula, one 10,000-L bioreactor could produce roughly 60 kg per year (15 batches/year x 10,000-L bioreactor x 500 mg/L titre x 80% yield/1,000,000 mg/kg). And, on the downstream side, one process train could purify roughly 240 kg per year (65 runs/year x 300-L column x 15 g/L capacity x 80% yield/1,000 g/kg).
To check this example, one may study the Enbrel™ (Amgen) case. Following first approval in November 1998, demand for this new drug soon exceeded expectations, and production capacity started lagging. Even though the estimated scale was still below 1,000 kg per annum, several production sites, each with multiple large-scale bioreactors each, had to begin production of this protein.
Why then is there a public debate about downstream bottlenecks? Because of the following: plant equipment is fixed, bioreactors are generating more product at increasing product titre, and the downstream capacity, designed previously for low upstream productivity, needs to be increased to match the new upstream productivity.
Upstream improvements in the last 20 years have led to a dramatic development from our example of 500 mg/L product titre it has now increased to 2–3 g/L in production, and we see 5 g/L in clinical manufacturing projects.
The same bioreactor in an existing facility can now potentially make fivefold more per batch with little change to the installations. Separation technology can handle these quantities, with more process trains or at larger column volume or membrane area. But it wouldn’t be necessary to increase fivefold, because during the same time period the productivity of chromatography resins used in capture steps has increased at the same rate through both higher capacity and processing speed.
So downstream technology can handle the purification scale, but the industry underestimated the capacity required. While one 20,000-L bioreactor will soon be capable of producing nearly 1,000 kg per year, one downstream line is already capable of doing this today.
Run at its best capability (modern resin, largest column size, highest column height), one downstream line can process product from six bioreactors of up to 15,000 L, each operating at the still-to-be realized product titre of 5 g/L.