Tamiflu Production Deficiency
Oseltamivir Production Deficiency Due to Lack Of Shikimic Acid
By 2006, Roche was putting out close to 400 million full treatments of oseltamivir annually. This number far exceeded the number of actual orders Roche had received for the drug and they stated there was no longer a shortage. Government orders of tamiflu in the 2 years between 2005 and ’07 totaled approximately 200 million full course doses. This is about the time Roche announced it would be slowing production if orders did not increase. At this time, any increased production of oseltamivir could be attributed to the fifteen licensed suppliers in nine different countries that Roche had on board.
Presently the requirements are be satisfied for antiviral drugs used for seasonal flu therapies and warehousing, the uncertainty comes from what happens in the case of a pandemic? Some doctors are currently trying generic tamiflu in double doses beyond the standard treatment amounts with fingers crossed that the H5N1 avian virus mortality rate will decrease. Obviously if this double dose worked, it would cut the supply even more at a potentially crucial time.
Word out of Roche is that the holdup in the manufacture of Oseltamivir is because of a lack of shikimic acid, a main ingredient that currently cannot be made cost effectively and the compound can only be had from the Chinese spice “star anise”; which is used in traditional Chinese medicine as well. Though shikimic acid is located in many different organisms, it is found in low quantities and is difficult to harvest. The fact that star anise is so difficult to produce in large enough quantities; the result is a global dearth of oseltamivir.
Star anise is grown in China and Vietnam and the harvest is limited to between March and May. The extraction process for shikimic acid is a lengthy ten step process that produces 1.3 gm of shikimic acid for every thirteen grams of star anise resulting in one – ten pill course of the drug. As of now, ninety percent of the harvest is already going to make shikimic acid and oseltamivir by Roche and their subsidiaries.
There is disagreement amongst certain experts regarding the problem with manufacturing shikimic acid using other methods than the mining from star anise. Alternatively, a method is available for the acid production by a fermentation procedure of genetically tailored bacteria. Lately biosynthetic pathways in Escherichia coli have been improved so this organism can collect sufficient shikimic acid for commercial use.
A pharmaceutical company out of Canada is trying to change oseltamivir so it will be able to integrate a synthetic substitute for the shikimic acid. Shikimic acid has also been found as a production resource in vegetation such as sweetgum and ginkgo trees. Another option could be quinic acid found in bark from cinchona trees to meet the ingredient deficiency of oseltamivir development. Aminoshikimic acid biosynthesized by fermenting genetically changed bacteria has displayed some promise as a potential substitute for manufacturing oseltamivir.
All this to say that there is a shortage of a vital compound for oseltamivir but more than that, the production process and steps required to manufacture this drug are extensive and time consuming. There would be a demand for new facilities for production for a rise in volumes of oseltamivir and even then, the slow process of production and ingredient yields would make it difficult to say the least. The entire procedure takes many months to finish and there are hazards in the process. Some steps in synthesizing necessitate a vigilant hand since the conditions can be chemically reactive and even explosive. Research by Roche and others is ongoing to find ways to speed up the production phase. Various alternatives are being tested for everything from different ingredients to streamlining synthesizing, and chemical processes. It is inevitable that successful breakthroughs will occur making oseltamivir production less time consuming and more economical, concerns are based on the timing versus nature.