In January 2007 Novozymes created a new business area known as Biopharmaceutical Ingredients to provide recombinant ingredients to the biopharmaceutical industry. It was created by combining the existing business, know-how and expertise in this area of Novozymes GroPep Ltd, Novozymes Delta Ltd, Novozymes Biopharma AB and Novozymes. About 260 employees in Australia, the UK, Sweden and Denmark work in the new area.

“Why should Novozymes only be active in industrial biotechnology when we have a lot of leading-edge know-how in the design and manufacturing of recombinant proteins that can create value in other areas?” says Peter Rosholm, explaining the thinking behind the new business area. He is the newly-appointed Vice President of Biopharmaceutical Ingredients. “With the expertise and capability in this new business area, we can make a significant impact on our customers’ options for achieving consistent, low-risk biomanufacturing.”

What makes biopharmaceutical proteins particularly interesting for Novozymes is the trend away from ingredients extracted from animal tissue or human blood.

The acquisition of GroPep in December 2006 is the latest of three acquisitions by Novozymes to build a new business area within recombinant ingredients for the biopharmaceutical industry.

“We can provide advanced recombinant proteins not from animals, but from microbes,” says Peter Rosholm. “Novozymes is building up a very interesting product portfolio in animal-free ingredients for cell culture media and other areas in biopharmaceutical production. We have the products and the know-how to help biopharmaceutical companies eliminate animal-derived ingredients.”

The advantage of microbially produced ingredients is that they come from an identified controlled source and can be made consistently to recognised quality standards. All raw materials from an animal or human source must be assessed for the presence of viral or other potentially pathogenic organisms. The risk of contamination or infection can be avoided by using recombinant proteins produced microbially by fermentation. Large volumes can be produced with a uniform quality and high purity, whereas the supply of ingredients extracted from animals and humans is limited by the availability of a potentially unsuitable range of raw materials that can vary in quality.

The needs of cells
Today, more than 500 biopharmaceutical products are in the development pipeline at different companies. A large number of these will be produced by animal cell culture techniques. For example, monoclonal antibody products such as Remicade® and Herceptin® are produced in CHO (Chinese hamster ovary) cells and generate several billion dollars in sales annually.

Most animal cell lines have relatively complex nutritional requirements. The culture media for growing these cells typically contain a carbohydrate source, vitamins, mineral salts and amino acids. Serum may also be added as a source of essential nutrients. Bovine calf serum has traditionally been used. Another source of serum is human blood from donors. Serum albumin is produced by the liver and found in human blood plasma. Often a mixture of bovine serum albumin, insulin and transferrin is used as a supplement for cell culture media. The most important of these medium supplements can now be provided from microbial sources, thus avoiding the risks associated with animal-derived materials.

rHSA
Novozymes has applied its recombinant technology developed for enzyme production to human serum albumin (HSA) production. As a result, recombinant human serum albumin (rHSA) is being produced from the fungus Aspergillus on lab scale, and samples are available to potential customers for testing.

In 2006 Novozymes increased its presence in the cell culture market with the acquisition of Delta Biotechnology Ltd. The company is based in Nottingham in the UK with around 100 employees and was renamed Novozymes Delta Ltd on July 6, 2006. It produces and sells recombinant human albumin called Recombumin®. This is the only commercially available rHSA approved by the FDA (Food and Drug Administration) and the EMEA (European Medicines Agency) for use in the manufacture of human therapeutics. Apart from being used as an ingredient in cell culture media, Recombumin is used as a stabiliser in vaccines and other biopharmaceutical products.

Novozymes Delta is also developing a recombinant human transferrin called DeltaFerrin™. This animal-free transferrin for cell culture will offer advantages over current alternatives derived from plasma.

Recombumin® is the only commercially available rHSA approved by the FDA and the EMEA for use in the manufacture of human therapeutics.

In addition, Novozymes Delta has patented scientific knowledge of baker’s yeast, Saccharomyces cerevisiae, which is widely used in the expression of biopharmaceutical compounds. Novozymes Delta has also extended this technology to produce biopharmaceuticals linked to albumin to achieve longer half-life in the body; this means that proteins ‘fused’ to recombinant human albumin are injected less frequently (once a week instead of daily) and cause fewer side effects.

Insulin-like growth factors (IGFs)
In December 2006 Novozymes made another acquisition - the Australian company GroPep, now called Novozymes GroPep. Their strong position in IGFs with a product called Long-R3® will fill a gap for Novozymes in the cell culture product portfolio. This product complements Novozymes’ other ingredients of non-animal origin for cell culture.
The sound knowledge of mammalian cell culture underlying GroPep’s technology was also a good strategic match for Novozymes.

cGMP-grade production facilities
The origins of the new Biopharmaceutical Ingredients business area date back to 2002, when Novozymes acquired a cGMP (current Good Manufacturing Practice) plant in Lund, Sweden, now called Novozymes Biopharma. This gave Novozymes the ability to manufacture to pharmaceutical quality standards. Novozymes Biopharma provides fermentation and purification services to the Novozymes group as well as to its corporate partners. It also undertakes contract manufacturing of active pharmaceutical ingredients for pharmaceutical and biotech companies. The main product sold is Protein A, which helps to recover drugs, especially monoclonal antibodies, from the fermentation liquid.

Longer time to market
A new drug takes 10-15 years from the early development phase to the marketing phase. With this in mind, it will typically take five years or more for the ingredients being sampled today by pharmaceutical companies to have the potential to be sold in larger volumes for full-scale biomanufacturing.

“This is a new and exciting area for Novozymes. It is totally different from enzymes, where the time to market is much shorter,” comments Peter Rosholm. “Customers have specific conditions and environments, so it is very

difficult to make a standard solution. Therefore we provide customers with expertise on how to use our products efficiently.”

Total sales from Biopharmaceutical Ingredients at Novozymes reached just over DKK 130 million in 2006 and are expected to more than double in 2007, mainly due to the full-year effect of the acquisitions, but also due to organic growth.

The creation of the new Biopharmaceutical Ingredients business area is an important step towards Novozymes’ achieving its goal of applying leading-edge protein know-how and technologies to areas other than enzymes. If the current trend persists, microorganisms will provide future supplements for growing cell culture rather than animal tissues or human blood.