[Ip-health] New Scientist on new, easier, unpatented method for Tamiflu production

[mpalmedo@cptech.org]

http://www.newscientist.com/article/dn9107-way-to-mass-produce-key-bird-flu=
-drug-revealed.html


Way to mass produce key bird flu drug revealed

11:52 04 May 2006
NewScientist.com news service
Debora MacKenzie

The biggest hope for saving people at the start of a bird flu pandemic,
before a vaccine is available, is the antiviral drug Tamiflu =96 but the
drug is hard to make and stocks are limited. That could soon end: a Nobel
prize-winning chemist has devised a straightforward method for making
Tamiflu, and has not patented it.

Tamiflu is now made mainly by the Swiss firm Roche, starting with a
molecule called shikimic acid, either taken from the Chinese spice star
anise, or made with genetically engineered bacteria. As demand for Tamiflu
has skyrocketed over fears of a flu pandemic, Roche has vastly increased
production capacity.

It will be able to make 400 million courses of treatment by the end of
this year. But even then it will take years to make the emergency
stockpiles countries like Britain have ordered.

Making Tamiflu is slow, partly because shikimic is hard to get, but also
because one step in the process involves a highly explosive chemical
called an azide. As a result, Tamiflu can be made only in small batches of
a few tens of litres at a time.

Novel catalyst

But Elias Corey of Harvard University =96 who won a Nobel prize in 1990 for
chemical synthesis =96 and colleagues have devised a new way to make the
drug from two cheap, plentiful petrochemicals, acrylate and butadiene.

One key is a novel catalyst developed in Corey=92s lab four years ago which
links those chemicals in the basic six-carbon-molecule backbone of
Tamiflu, with the right =93handedness=94. Many molecules exist in right and
left-handed forms (or mirror images) and in Tamiflu, only one works.

Corey=92s catalyst, made from the amino acid proline, produces the correct
form. The full production process also involves two more new processes, he
says, including =93a brand new reaction=94 using another novel catalyst,
brominated tin.

=93It can all be done at room temperature, except one step that needs
refrigeration,=94 Corey told New Scientist. And the technique produces high
yields.

Permitting production

=93Producing at lab scale is entirely different from producing at commercia=
l
scale,=94 cautions Martina Rupp of Roche. But Corey says: =93I see no reaso=
n
why this process shouldn=92t scale up quite easily.=94 Lacking an explosive
step, it might allow continuous production rather than batches. And a
similar proline-derived catalyst is already used to mass produce drugs.

The Tamiflu molecule itself is patented, regardless of how it is made, and
Roche holds the rights to the patent. But in 2005 Roche said it would not
stop other companies making Tamiflu under license, which is expressly
permitted by international law in any case.

The difficulty of making Tamiflu from shikimic acid limited the amount of
competition Roche was likely to face from such companies. That may now
have changed.

Getting regulatory approval for the new synthetic process might pose more
of a barrier than patents to prospective manufacturers. New processes must
be vetted by drugs agencies in developed countries even though the end
product is already approved.

But at least there will be no patent protection barring access to the
process itself. =93We=92re just interested in using chemistry to save human
lives,=94 says Corey.

Journal reference: Journal of the American Chemical Society (DOI:
10.1021/ja0616433)