Roche's Fuzeon Challenge

MANUFACTURING

The peptide drug Fuzeon (enfuvirtide), the first fusion inhibitor for HIV, is manufactured by Roche Colorado, a part of the Roche Group that has been in operation since 1967. The site, in Boulder, has a workforce of more than 380, three plants with a total of 70,000 sq ft, three small-scale production labs, two pilot plants with a total of 21,000 sq ft, and a technology center.

Fuzeon works by blocking the virus from entry into CD4 cells, which are human immune cells. The drug is for patients in whom other HIV medication is losing effectiveness. It was discovered by Dani Bolognesi and Tom Matthews, who were at the time researchers at Duke University’s Center for AIDS Research. They formed Trimeris in Durham, N.C., in 1993 and joined forces with Roche in 1999. Roche and Trimeris remain in collaboration for the development of second-generation fusion inhibitors.

In the late 1990s, well before Fuzeon's fast-track Food & Drug Administration approval in 2003, Roche decided that the drug should be produced in-house, expanding on the firm's peptide manufacturing experience.

The peptide presented a major challenge, however, due to its complexity and the amount required. "Back in the '70s and '80s, peptides were usually about 10 amino acids in length," says Gary Erickson, director of the technology center at Roche Colorado. Fuzeon contains 14 different amino acids in its 36-amino acid chain. It is, according to company brochures, "the most complex synthetic peptide ever produced on a large scale." Small molecules require on average eight to 12 steps for their manufacture; Fuzeon calls for 106 steps.

Production capacity for Fuzeon at the site is 3,700 kg per year, 60-300 times the annual production of synthetic peptides such as calcitonin or leuprolide. The high volume is a result of the fact that high dosages of Fuzeon are necessary for its activity. In adults, that translates to twice-daily subcutaneous injections of 90 mg.

"When you need tons of peptide therapeutic, there is the issue of raw materials-just the availability of those raw materials to produce peptides at this volume," Erikson says. Forty-four different raw materials are required from 10 different countries. Some 45,000 kg of raw materials is required to make 1,000 kg of Fuzeon. Going from start to finished product takes more than six months.

Roche and Trimeris collaborated on developing the Fuzeon manufacturing process, which was completely new territory because of the scale. "Since we had to make this peptide at a very large scale, the equipment didn't exist prior to Fuzeon," Erikson says. As scientists worked out the process chemistry, engineers had to design machinery that would run the reactions at the scale required. Development and scale-up took two years in a combination of design-and-build and learning-by-doing approaches. The company calls the technology investment "significant" but will not disclose a figure.

Fuzeon is manufactured in three fragments, a process found to deliver higher yields than when the long chain is all produced at once, company researchers found. In solid phase, the amino acids are added onto a polystyrene resin bead that supports the growing chain of amino acids. Then in solution phase, the three separate chains are hooked together. The peptide undergoes purification to remove any synthetic by-products. The active substance is then compounded into solution, sterile filtered, filled into vials, lyophilized (water is removed), inspected, tested, packaged, and labeled for use.