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November 5, 2005
Is Bird Flu Drug Really So Vexing? Debating the Difficulty of Tamiflu
By ANDREW POLLACK
If a bird flu pandemic breaks out, the world's ability to fight back may come down to an ancient Chinese cooking spice - or the perseverance of people like Professor Frost.
The Chinese spice, star anise, provides the starting material for the manufacture of the anti-influenza drug Tamiflu, which is expected to be the first line of defense in a pandemic.
But there is probably not enough star anise in China or anywhere else to meet the rapidly growing global demand for Tamiflu. That could mean that Tamiflu production cannot be ramped up, even if the maker, Roche, bows to pressure to allow other companies to manufacture the drug.
The professor is John W. Frost, a chemist at Michigan State University who developed a technique for making the starting material, shikimic acid, without the coveted star anise. Roche has used Professor Frost's method in recent years, in fact, but he says he heard the company had cut back. Undeterred, Professor Frost is starting a company that he says could produce huge quantities of the material.
"I'm just completely astonished about the gnashing of teeth and the wringing of hands about the shikimic acid," Professor Frost said. "The bottleneck should not be shikimic acid availability."
Professor Frost is one of many entrepreneurs seeking to help ramp up production of Tamiflu, perhaps the most sought-after drug in the world right now. Roche says it has received licensing inquiries from more than 100 companies. And some countries and companies say they might produce Tamiflu, also known as oseltamivir, even without Roche's permission.
But a debate is raging on how easy that would be to do.
Roche has said the manufacturing process requires 10 steps that take six to eight months once the raw materials are in hand. It also says that some steps in production are potentially hazardous because they involve the use of sodium azide, the chemical that makes automobile air bags inflate in an explosive rush. The company says it would take a newcomer two to three years to be able to start production.
Roche has never said how much Tamiflu it can make, only that by next year it will be making 8 to 10 times the amount it did in 2003. Roche would not discuss its manufacturing for this article, saying it would do so at a presentation Wednesday at its headquarters in Basel, Switzerland.
But others insist that the manufacturing process, while more challenging than for some drugs, is not extremely difficult.
"I don't think the chemistry is such a big issue," said Yusuf K. Hamied, chairman of Cipla, a generic drug company in India that has announced it will produce oseltamivir, the generic name for Tamiflu. He said Cipla already uses sodium azide, the air bag chemical, to produce the AIDS drug AZT and an anti-epilepsy drug.
Part of the disagreement about the difficulty might stem from the difference between making small quantities in the laboratory, which can be done quite easily, and producing large amounts commercially. Ernie Prisbe, vice president for chemical development at Gilead Sciences, which invented Tamiflu and licensed it to Roche, said an industry rule of thumb is that each step, even if well defined, takes one month to six weeks to put into practice. Tamiflu manufacturing, by his count, involves 12 steps.
The National Health Research Institutes of Taiwan took only 18 days to produce a small quantity of Tamiflu, with guidance from published papers and patents. But producing large quantities is "another story" said K. S. Shia, who headed the project. Officials in Taiwan would not say how long it would take to achieve larger production.
Even if companies can make the drug, they might not have enough shikimic acid. That ingredient is extracted from the fruit of star anise trees, which grow in Southern China. Most of the star anise is now used for Roche's production, but it is also an Asian cooking spice and is used in herbal medicines and in the production of the liqueur pastis.
Since demand for Tamiflu started growing recently, the price of shikimic acid from China has soared to more than $400 a kilogram, from $40.
"We managed to corner a few tons but it won't go very far," said Mr. Hamied of Cipla. The company hopes by March to have produced enough oseltamivir to treat 100,000 to 200,000 people, he said.
Last week, the Taiwan government said it had signed an agreement with an unidentified supplier for three metric tons of shikimic acid, which could conceivably provide enough drug to treat 2.3 million people.
According to a presentation at a conference last year by a Roche chemist, it takes 13 grams of star anise to make 1.3 grams of shikimic acid, which in turn can be made into 10 Tamiflu capsules - enough to treat one person. By that reckoning, one ton of shikimic acid would be enough for 770,000 people.
But Mr. Hamied, a chemist, disputed that, saying one ton of shikimic acid would yield enough for only 300,000 people at most. And newcomers are not likely to have the same production efficiency as Roche, he said.
The alternative method of producing shikimic acid developed by Professor Frost involves fermentation using vats of genetically engineered bacteria. He said people he knew at Roche told him the company has curtailed the fermentation of shikimic acid to devote fermenting equipment to more valuable products. If so, that would increase the pressure on star anise supplies.
In the fiscal year that ended in June, Michigan State received $113,000 in royalties from Roche, according to Paul Hunt, the university's associate vice president for research and graduate studies. Roche pays $1.85 for each kilogram of shikimic acid it makes using the process, indicating it made about 60 metric tons in that year.
Roche has given conflicting statements about its use of fermentation. In an e-mail message, Daniel Piller, a spokesman for Roche, said the company got about a third of its shikimic acid from fermentation and planned to increase that over time.
In a conference call with securities analysts two weeks ago, William M. Burns, the head of Roche's pharmaceutical business, said fermentation was part of the company's plan for the medium term. But for now, he said, the use of star anise was the only process approved by regulators.
Professor Frost, some industry consultants and Gilead, though, said that government manufacturing regulations did not cover the production of shikimic acid.
In any case, Roche is apparently looking to farm out fermentation to others, according to Professor Frost. He is starting a company, Draths Industries, in hopes of supplying it to Roche and other companies.
Professor Frost, working with MBI International, a fermentation company in Lansing, Mich., near the university, said he hoped to raise $1 million and had lined up a big fermentation company in Asia that would be able to produce 100 tons of shikimic acid a year.
Gilead initially chose quinic acid over shikimic acid as a starting material. Quinic acid, from the bark of the tropical cinchona tree, was available in much greater supply and at lower prices, even though using it required more steps than using shikimic acid, Mr. Prisbe said.
But political upheaval in Zaire, the source of its material, raised doubts about future supplies, forcing Gilead to scramble. "Roche was saying if you guys don't come up with a starting material you don't have a deal with us," Mr. Prisbe said.
Gilead began looking at extracting shikimic acid from gingko trees and even found a scientific paper discussing the extraction from needles of giant sequoias. A gingko products company in Beijing offered to supply the material but suggested star anise would be a better source.
Still, quinic acid could be a potential alternative starting material and there might be other sources of shikimic acid besides star anise. Virtually all plants produce some shikimic acid, which they use in making certain amino acids. The herbicide Roundup, in fact, works by interfering with this process.
To make Tamiflu, shikimic acid is turned into an intermediate called an epoxide through a series of about five steps that are not considered out of the ordinary. But then the ring-shaped epoxide molecule must be opened up and some atoms substituted for other atoms.
That is where the air bag chemical, sodium azide, comes in. Chemists say it is used because it can produce a sharp, clean reaction that leaves few impurities. Although the reaction used to produce Tamiflu does not involve explosions, the azides, as a class, can be explosive. But sodium azide is not dangerously so, some experts say, or it would not be used inside cars.
"It's a wimpy explosive," said Thomas Archibald, a chemical consultant in the Virgin Islands. He and some others say that drug companies have a needless aversion to azide chemistry - a fear that K. Barry Sharpless, a Nobel Prize-winning chemist at the Scripps Research Institute, has referred to as "azidophobia."
Many drug companies, including Roche, farm out azide processing steps to companies that specialize in what the industry calls "energetic" chemistry. Such contractors, presumably, would be available to companies besides Roche that want to make Tamiflu.
Many of the companies started doing work on explosives for the military or other uses. Aerojet Fine Chemicals, which did the initial azide processing for Gilead, is part of a company that builds rocket motors outside of Sacramento.
"This is our version of turning swords into plowshares," said Joseph Carleone, Aerojet's president. "We took our ability to handle explosives and propellants and applied it to pharmaceuticals."
Mr. Carleone would not say whether his company was doing Tamiflu work for Roche, citing customer confidentiality. Roche has recently said that it has set up manufacturing in the United States at the behest of the federal government, which was worried about reliance on foreign supplies of a vital drug.
Among those looking at Tamiflu manufacturing is Gilead, which wants to regain control of the drug from Roche. It accuses Roche of not doing an adequate job in manufacturing and marketing. Roche denies that, and the dispute is in arbitration.
Whether for Gilead or for others, when it comes to making Tamiflu "on a scale of 1 to 10 in difficulty, this is maybe a 7 or so,"' Mr. Prisbe said, "There's nothing that overwhelming in this kind of synthesis, or that formidable, that someone couldn't do it."
Keith Bradsher contributed reporting for this article.
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