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In Corsier-sur-Vevey, Switzerland, EMD Serono uses living cells to produce biopharmaceuticals in large bioreactorsStage Image

In Corsier-sur-Vevey, Switzerland, EMD Serono uses living cells to produce biopharmaceuticals in large bioreactors

© EMD Serono

Biopharmaceuticals

Where cells produce active ingredients

2013/4/16

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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?

  • Jens Regelin, Head of the EMD Serono Biotech Center
  • Jens Regelin, Head of the EMD Serono Biotech Center
    © EMD Serono

    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.“

    Jens Regelin
    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.

    Large and small amounts for the world market


    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."

    The EMD Serono Biotech Center

     
     

     

  • The expansion of the EMD Serono Biotech Center is the largest single investment ever made by the EMD GroupEnlarge
  • Gorian Nourdin, a technical production assistent, alongside a 4,000 liter tank in EMD Serono's facility in VeveyEnlarge
  • In Corsier-sur-Vevey EMD Serono produces biopharmaceuticals, among other uses for the cancer drug Erbitux® and for Rebif®, which is used for the treatment of multiple sclerosisEnlarge
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    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.

    But what wasbehind the decision to create a biotech facility on this scale in Switzerland? "In the case of biopharmaceuticals, the production process in itself is part of the product," Regelin explains. "That's why the production conditions are so important. This applies not only to the cell culture but also to the purification of the therapeutic protein, combined with state-of-the-art utilities systems, cleanrooms as well as fully compliant Quality Systems. 

    We therefore need highly skilled and trained employees, the right know-how, and the very best raw materials. Even the stainless steel of the bioreactors and the silicon for the tubes need to be of the very best quality. Moreover, in Switzerland we have good access to the important regulatory bodies, proximity to the most prestigious academics and universities, a reliable political environment, and good access to the sales markets and distribution channels. All of these factors speak for Corsier-sur-Vevey."
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  • Perfusion or fed-batch


    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®.



  • Enlarge

  • 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

    Production of biopharmaceuticals in glass reactors

    © EMD Serono

    Development and production under one roof


    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.

  • The top four biopharmaceuticals from EMD by salesEnlarge
  • The top four biopharmaceuticals from EMD by sales
    Source: EMD Annual Report 2012

    2013/4/16

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    All of this is part of the development of a fully commercial production process. Since 2011, Stettler and his colleagues have been using robots to simultaneously test as many parameters in parallel as possible using a minimal amount of cells. 

    As a result, the number of cultures tested last year rose sixfold compared to the total of 1,000 in 2008. Similarly, plant-engineering software and automation ensure that all of the production processes are closely monitored and controlled. The concept is known as “E-plant” including electronic batch records. Despite such high standards, Regelin and his team are always on the lookout for further ways of improving the operation. "There's always potential for improving any process," he says. "In the three years from 2010 to 2012, we increased our Rebif® production yield by 50 percent."
     
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