In Corsier-sur-Vevey, Switzerland, EMD Serono uses living cells to produce biopharmaceuticals in large bioreactors
© EMD Serono
The expansion of the EMD Serono Biotech Center in the Swiss town of Corsier-sur-Vevey has made it one of the world's largest and most technologically advanced production facilities for biopharmaceuticals. What is behind all of this — and why is EMD investing in a high-wage country like Switzerland?
The figures are impressive: 120,000 liters of bioreactor capacity, 65 kilometers of new piping, 10,000 square meters of additional production and cleanroom facilities, 2,700 square meters for logistics and support, storage space for 4,500 pallets, a new wastewater treatment plant for fully biological treatment of 1,200 cubic meters of wastewater, and 2,500 square meters of 12m high retaining walls on the production site.
The recent expansion of the EMD Serono Biotech Center represents the largest single investment ever made by the EMD Group. Over the next years the Center will produce large amounts of active ingredients for biopharmaceuticals, especially for EMD’s cancer drug Erbitux® and a wide range of biosimilars, which are sufficiently similar to off-patent biopharmaceuticals. None of these products are made through chemical synthesis.
“It only takes a couple of kilograms of Rebif® to supply the entire world market.“
Head of the EMD Serono Biotech Center
Instead they are produced in animal cells and released into the surrounding culture medium, from which they are harvested and then purified. The use of living cells results in a complex production process, since any deviation from the cultivation and purification conditions can reduce both the quality and the yield of the biopharmaceutical in question.
The plant in Corsier-sur-Vevey has been producing the active ingredient for EMD Serono’s blockbuster drug Rebif® (interferon beta-1a), a second messenger used in multiple sclerosis treatment, since 1999. Because only a tiny amount is administered to each patient, production volumes are very small. "It only takes a couple of kilograms of Rebif® to supply the entire world market," says Jens Regelin, Head of the EMD Serono Biotech Center since 2011. "That's the great strength of hormones and second messengers."
By contrast, therapeutic antibodies for targeted cancer therapies such as Erbitux® are produced by the ton or hundreds of kilograms, since dosages can be much as 18,000 times higher than for Rebif®. That also applies to biosimilars. The site's original bioreactor capacity would not have sufficed to produce such volumes, hence the massive expansion undertaken by EMD.
The U.S. Food and Drug Administration (FDA), Swissmedic as well as various health authorities from all around the world (including recently China, Brazil andSouth Korea for example) inspect the new facility regularly. "We already received European Medicines Agency clearancein October 2012 for our large scale expansion in record time," says Regelin.
Active ingredients for biopharmaceuticals are produced in one of two ways. With perfusion technology, the cells in the bioreactor are continuously supplied with fresh culture medium. At the same time, culture harvests that already contain the therapeutic protein are drawn off and purified. This process is only suitable for producing small amounts, as in the case of Rebif®.
The fed-batch method is used for larger amounts. Here the cells are successively cultivated in larger and larger bioreactors, beginning with 120 liters and finishing with 15,000 liters. As soon as the cells have multiplied sufficiently, they are transferred to the next-largest bioreactor including successive medium feeds. At the end of the process, the entire content of the final bioreactor is harvested and the valuable therapeutic protein is purified. Following the recent expansion, the site now has eight bioreactors with a capacity of 15,000 liters each.
Production of biopharmaceuticals in glass reactors
© EMD Serono
At the expanded EMD Serono Biotech Center, process development and production are neatly dovetailed. "Close proximity and rapid communication mean that we can react very flexibly," Regelin explains. Process development begins in the Cell Sciences Department. It is here that the gene with the blueprint for producing the biopharmaceutical is introduced into the animal cells.
The next task is to select cell lines that produce the therapeutic protein in high yields and outstanding quality. These cell lines are then handed to Process Development, which determines the optimal conditions for cultivation and purification. "We investigate every parameter imaginable: the makeup of the culture medium, the temperature, pH value, ventilation, and a whole lot besides," says Matthieu Stettler.