Get Ready to Scale Up


Biotech is getting bigger. And the next challenge facing the industry is learning how to scale up its therapeutic protein manufacturing facilities. Today's plants just don't supply current demand, and that demand is set to rise sky high. In a traditionally high-risk sector, the potential rewards for R&D scientists with the skills to help it meet its growing need are equally high.

Therapeutic proteins and monoclonal antibodies belong to the new, and growing, class of biotechnology drugs known as biologics. Products that occur naturally in the human body, industry produces them using recombinant DNA technology. Although the bulk of the commercial manufacturing uses cultures of bacteria, such as Escherichia coli or Chinese hamster ovary cells, a few biotech companies are trying to produce therapeutic proteins in the milk of transgenic mammals (such as GTC Biotherapeutics, which is using goats; PPL Therapeutics, which is using sheep; and BioProtein Technologies, which is working with rabbits), transgenic chicken eggs (such as Avigenics or Vivalis), or even in transgenic crops (such as ProdiGene or Meristem Therapeutics); but it is early days for these 'pharming' methods.

There are currently 300 therapeutic proteins in the biopharmaceutical industry's development pipeline, while those already on the market will soon be out of patent and ripe for exploitation as generics. Not only is the number of proteins increasing, but the amount of these substances being administered to patients is rising too. For example, Swiss biotechnology company Serono typically produces just 400 grams per year of its recombinant multiple sclerosis drug, Rebif. But Serono needs to produce several kilograms per year of its next-generation therapeutic proteins. Moreover, companies are moving into the use of new types of therapeutic proteins such as antibodies, which are only effective at high doses. Instead of micrograms, each patient will need doses on the order of grams. Consequently, production has to be scaled up by a factor of 1000.

That scaling up is already under way. At Serono, bioreactors currently produce between 75 and 300 litres of cell culture per year. And the company is gearing up to produce between 2500 litres and 3000 litres. All the other players in the field are doing the same thing. Pharmaceutical company Wyeth is currently building Europe's largest biomanufacturing facility in Dublin, Ireland--12 bioreactors of 15,000 litres each. At the same time, Genzyme, is building what will be the second biggest biologics production plant in Europe in Geel, Belgium, with six bioreactors that will hold 10,000 litres each; Geel will start hiring at the end of 2004. Meanwhile, Biogen is building a new plant in Denmark.

The problem for the industry is that producing biologics requires a lot more know-how than the production of traditional drugs such as aspirin, which are based on chemistry. Biotech urgently needs MSc and PhD graduates to carry out R&D to improve the production process for biologics and thus accelerate the scale up. For example, almost one-quarter of the 220 people working for Serono at its Vevey production site have a doctorate--a proportion that is not unusual in the industry.

The challenge associated with scaling up is to "define and control processes which produce similar products as those obtained at small scale," when producing the proteins needed for clinical trials, says Wim Croonen, human resources director of Genzyme for the Flanders region of Belgium.

As the field matures there will be a shift in the skills profile required towards industrial engineers who can implement high-tech production processes. But highly trained life scientists will still be needed for such tasks as late-stage development (ensuring smooth implementation of final phase (III and IV) clinical trials) as well as compliance with regulatory demands (so-called commissioning and validation specialists), according to Croonen.

So what is so attractive about this field? "Scaling up is totally unique," says Croonen. "It is a sector in full expansion, very dynamic and high tech which is also totally international," agrees Jean-Pierre Bascoul, human resources director for Serono in Vevey, Switzerland. The sector offers a lot of future prospects, full of challenging opportunities and the possibility to grow, according to Christian Jensen, associate director of human resources at Biogen in Denmark. "People who are gaining experience in the biotech sector are in good shape for the rest of their careers," concludes Croonen.

In addition, "what attracts people to biotech rather than pharma is that decision lines are much shorter; there is an easy access to everyone in the company," comments Nicolas Hollanders, a recruitment consultant specialising in biotechnology at Egon Zehnder International in Brussels. "And people feel more responsible and see that they can make a difference as individuals," he adds.

Scale Up: The Recruitment Sites

Some of the Europe-based companies involved in the manufacture of biologics are listed here. If you want advice on networking your way to a job in biotech, see this month's Industry Insider Resources page.

There is a consensus among recruitment specialists that there is likely to be shortage of qualified people. Already, supply "is far from meeting the demand," agrees Hollanders. This means that experienced people are in a good position to negotiate their salaries.

No surprise there, since large-scale biomanufacturing is new in Europe. Many people have experience of producing proteins in the small quantities required for clinical trials, but there are very few out there with experience of producing the high volumes required for commercial exploitation. Genzyme gets around the problem by sending its new recruits for training in their Boston office and bringing in experienced people from the United States, where the industry is more mature (see the profile of Kristina Van Houdt). Wyeth had to look abroad, mainly in the UK and in the US, to staff its Irish plant. As a result, "there is a mobility problem which is not easy to solve," points out Hollanders.

Nonetheless, facilities are being sited to try to ameliorate the skill shortage. Wyeth chose Ireland for the above average rate of life science graduates among its population--200 graduate with BScs and MScs in biotechnology each year. Similarly, Biogen choose to build its plant near Copenhagen for the quality of graduates trained in Denmark and in the neighbouring region of southern Sweden. What's more, having the Danish giant Novo Nordisk, a specialist in insulin and growth hormone products, and Novozyme, known for its enzyme technology, as neighbours, certainly helps. Both Novo companies work closely with local universities to ensure that graduates have the skills they need.

But even though examples of industry collaborating with universities exist, the shortage of skilled people comes in part from the way higher education trains graduates. "Universities train students in fashionable topics such as molecular biology, genomics, and genetic engineering," complains Bascoul. "But we have problems finding PhDs with expertise in the [manufacturing] processes of cell culture, fermentation, and purification," he adds. Such disciplines are fairly recent and universities have not always integrated such topics into their curricula.

Which is why many of biotech's new hires may come from other industry sectors. "People with experience in fermentation and purification could be coming from the brewery industry and from the food processing industry," says Biogen's Jensen. Such employees would bring not just expertise with industrial enzymes, requiring know-how in culture, fermentation, and purification techniques, but an understanding of good hygiene too.M

Others could come from the pharmaceutical industry, bringing experience of complying with regulatory authorities. Pharma, like biotech, has to comply with high-quality standards such as Good Manufacturing Practice (GMP) in production. "GMP is not in the curriculum, it is something you learn from experience," points out Croonen. People working in biomanufacturing need to be prepared for inspections by the US Food and Drug Administration and the European Medical Evaluation Agency designed to ensure that mass-produced proteins are of the same quality as those used in clinical trials.

To acquire relevant experience, Croonen advises students "to take advantage of the links between universities and industry." In particular, when choosing a PhD topic, it is important to have a supervisor well connected to industry. Secondly, he advises, take advantage of the fact that a lot of biotech companies are still small, open, and informal. Make contact with them and learn as much as possible about opportunities. They might even be able to sponsor PhDs.

Even if the industry offers a bright future, the downsides of working in biotech comes from "the volatility of the industry, which makes it high risk," points out Jensen. But in return, the pay is attractively correlated to the high level of skills and risk.

Another potential downside is linked to public opinion. In the same way as public opinion on genetically modified organisms affected the agbiotech business, public opinion could turn against biologics. But, because such products tend to bring solutions to rare and debilitating diseases, the risk of this is rather low, estimates Croonen.

What's more, the biotech industry is still not mature. "Biotech companies are small," meaning that opportunities to move "from one specialisation to another, like you could in the pharma industry" are limited, points out Barcoul. And the number of companies you can work for is also limited--although it is growing in Europe. Sicor, for example, has recently acquired a plant in Vilnius, Lithuania, and Genentech a cell culture manufacturing facility in Porriño, Spain. Lonza Group has a contract manufacturing production plant in Slough, UK. Smaller biotech company GeneMedix has a plant in Ireland. Meanwhile bigger, well-established pharmaceutical companies such as Novartis in France, Roche and Boehringer Ingelheim in Germany, and Akzo Nobel through its biotech branch Diosynth in the Netherlands--to name only a few--are also developing their own production facilities for biotech products.

In the end, candidates seeking to join biotech manufacturing scale up should have more than academic skills. "The ideal candidate profile is the combination between expert and manager," says Hollanders (see the profile of Frederic). His advice: "Work on your technology while acquiring organisational and management skills by learning from a different type of environment where such expertise is already present, such as the pharmaceutical industry."

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