Continuous progress

US pharmaceuticals company Genzyme is best known as one of the major biotechnology players. Its largest investment to date, however, has been in a plant based on conventional chemistry - a large-scale manufacturing facility in Haverhill, Sussex.

The plant was built to handle production of sevelamer hydrochloride, the active ingredient for Genzyme's renal disease drug, Renagel. One of the few polymers to be approved as a pharmaceutical, Renagel is taken by dialysis patients to control the levels of phosphorus in their bloodstreams - a task which would normally be performed by the kidneys, and which dialysis machines cannot handle.

Unlike most drugs, it does not itself pass into the bloodstream - the polymer molecules are not broken down in the stomach and are too large to pass through the intestinal wall. This is the key to its function - the main source of phosphorus is food, so phosphorus binding sites on the undigested sevelamer molecules grab the molecules as they pass through the digestive system and carry them out of the body.

The drug was developed by Genzyme subsidiary GelTex, which specialises in polymer-based drugs. The company combines chemical recognition techniques with monomer and polymer science to create compounds which contain a high density of binding sites for their target molecules, which keeps dosage levels low. Another of its products, colesevelam hydrochloride, has also been approved by the FDA - it uses similar techniques to remove LDL cholesterol from the bloodstream.

Demand for Renagel grew extremely quickly once it was launched, and is still climbing. Genzyme expects demand for Renagel to reach the billion-dollar per year scale, so needed to ensure that it could produce large volumes of the drug.

The new facilities, begun in 2000 and opened in August of this year, increase Genzyme's production capacity for Renagel tenfold. The Haverhill plant, once a light bulk fine chemicals operation, was chosen as the main manufacturing site because of the workforce's expertise in polymer science and manufacturing.

Unusually for a pharmaceutical, the drug is produced by a continuous, rather than batch, process at Haverhill - another facility is currently manufacturing the substance under contract, using a batch process. The Haverhill facility houses two plants, both of which operate the same process, although they differ in capacity - one can produce 210tonnes per year, the other 350tonnes per year. The larger plant was begun half-way through the building of the first, as demand grew faster than the company was expecting. Genzyme's total investment in the project was over £55million.

The process to make Renagel uses standard concepts, says Genzyme vice-president at Haverhill, Simon Cousins. The first stage is the cross-linking of the polymer to give the crude drug substance, which is then put through an extensive washing and filtration stage. This is followed by drying, before the product is cured, milled and sieved. The resulting solid white substance is then packed. All of the stages are carried out under hygienic conditions, with the final packing in a clean-room. The product is then sent to a tableting plant in Northern Ireland. 'It's simple in outline, although very complex in detail,' he comments.

Construction of the plant was handled by the EPC contractor, CE International. Using the 'partnering' concepts of the ECI-ACTIVE initiative, CEL formed a team including suppliers such as Sinclair Stainless and CRS for glass-lined and steel process vessels, and Netherlands-based Panavis for filtering, to put the project on the fast track process. The first plant took a year to build, the second eleven months, a record for CEL, which won the company ECI-ACTIVE's project of the year award.

'The project was run to a demanding timetable which was beaten, to a cost plan which was met and a scope that continued to develop as the project progressed - and everyone enjoyed the task,' comments Genzyme's director of engineering, Ian Thorne.

The unusual nature of the process meant that several pieces of equipment were adapted for purposes outside their standard scope. For example, Krauss Maffei Process Technology supplied several atmospheric plate dryers to the plant, where they are used as part of the curing process. The dryers are continuous contact machines normally used to remove all the moisture from a product, but at Haverhill they are instead used to hold the purified product for a specific period of time at a set temperature and humidity.

The wet sevelamer hydrochloride is fed onto the heated top plate of the dryer, where a series of ploughs, attached to rotating transport arms, push it in a spiral pattern across the warm surface. The ploughs also turn the layer of product over frequently, preventing it from being damaged by the heat. At the same time, a series of blowers circulate humidified vapour through the dryer, maintaining a constant level of moisture around the product.

The drying operations themselves also had special requirements. Rietschle's Twister VSA800 dry screw vacuum pumps, which supply vacuum to the horizontal belt dryers used in the process, were chosen strictly because of their technical capabilities, Thorne says. 'They use a dry-running vacuum system that handles entrained spray and is corrosion resistant,' he says. 'It gave us a complete solution on a single skid, which was designed and built exactly to our specifications.'

This is not the end for Genzyme's investment in Renagel. A new tableting plant is currently under construction in Waterford, Ireland, and qualifying runs will begin here in the coming months. Genzyme's growth projections for the drug will also necessitate a further new plant in the coming years, says Cousins, although no decision has yet been taken on its location. Meanwhile, back at Haverhill, Thorne expects that commercial production is 'just days away.'