Aventis Recombinant Insulin Plant, Frankfurt, Germany

Early in 2003, Aventis Pharma Germany completed their third insulin plant in Frankfurt, Germany. The new plant produces the established insulin treatment, insulin glargine (Lantus). The plant may also be involved in the production of a new inhalable insulin product Exubera. Exubera is currently in Phase III clinical trials, which are being conducted by Nektar on behalf of Aventis.

The construction of the new bioengineering insulin production facility was started in April 2003. The investment for the new plant totalled €150 million. The construction continues a long history of insulin production in Frankfurt.

Aventis predecessor company, Hoechst, has produced insulin in Frankfurt since 1923. Aventis is a major supplier of insulin products worldwide and this new plant is in response to market demands. Forecasters predict a large increase in the numbers of Type I and Type II diabetics worldwide over the next five years. Insulin glargine is a long-acting single dose insulin injection that will last over a 24 hour period (24-hour basal insulin).

CONTRACTORS AND CONSTRUCTION

The contractor, Linde-KCA-Dresden, was appointed for the engineering, design, construction and procurement of the new plant. The company was involved in detailed designing and the majority of the engineering for this new biotech fermentation plant. The company was also involved in the fitting out the plant with fermentation vessels, bulk media vessels, storage tanks, refolding suites and downstream processing facilities including filtration suites as well as process scale chromatography.

The chromatographic supports, a unique polydivinylbenzene resin, was provided by Bio-Rad. Bio-Rad provide much of the chromatographic support resin involved in insulin production for Aventis and other companies involved in producing insulin. Linde has also installed several class 100,000 clean room suites for the fill and finishing of the insulin products.

AVENTIS AND LANTUS

Aventis supplies insulin products throughout the world. Its drug Lantus is only available in Western Europe. It was launched in Germany in 2000 and the United Kingdom in mid-2002 and in France in September 2003. The new insulin production plant is set to support the launch of Lantus onto the US market. The same site also has three other insulin production plants run jointly by Aventis and Pfizer as a collaborative company called Diabel.

PROCESS AND PRODUCTION

The insulin production is started by the inoculation of a vessel of culture medium with a genetically modified E. coli bacterium. The E. coli have had a human gene spliced into their DNA compelling them to produce human insulin. The insulin is harvested by lysing the dead bacteria and then separating out the pre-insulin from the rest by centrifugation and filtration. The pre-insulin has then to be 'refolded' into its active tertiary structure by treatment in a refolding vessel with buffers of various concentrations.

After enzymatic cleavage of this product and chromatographic separation the insulin product is crystallised, deep frozen (under clean room conditions) and is then ready for fill and finish either by Aventis in Frankfurt or Pfizer and Inhale Therapeutic Systems in the US.

The new inhalable insulin product requires the insulin to be put through a process called micronisation, where very small particles are produced suitable for blister capsules to be used in a normal inhaler. Aventis has a goal in 2003 to be able to offer the widest range of insulin products from any pharmaceutical company worldwide.