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A team of scientists led by Dr Moira Bode, has developed an economically-competitive route for the production of generic antiretrovirals (ARVs) – technology which could empower African governments to afford wider roll-out of ARV treatment programmes. On December 1 as the world commemorates international aids day under the theme “Leadership” with the slogan “Stop Aids. Keep the promise”, she reveals the science behind a project that could also lead to the establishment of an industry for local manufacture of active pharmaceutical ingredients.
At times the most important people are not necessarily those at the forefront of a campaign but often those who can make a difference while working behind the scenes. This is what Dr Moira Bode and other scientists at the CSIR demonstrated recently. Bode, a synthetic organic chemist in the discovery chemistry research group in the biosciences unit, was project leader of an investigation into mechanisms of reducing the manufacturing costs of generic antiretrovirals.
The focus was on minimising the cost of producing the active pharmaceutical ingredient (API) which is the part of the drug responsible for the therapeutic effect. On a global scale the market for the most cost-effective production of APIs is dominated by India and other overseas players. South Africa’s pharmaceutical industry is not robust enough to make a genuine impact meaning that APIs are usually imported.
“There are currently no ARV active pharmaceutical ingredients (APIs) produced in South Africa,” she adds. “The fact that they are not produced locally means that we’re always at the mercy of other countries if we don’t have our own supply.”
In 2007, UNAIDS found South Africa to be “the country with the largest number of HIV infections in the world. A 2008 report by the same organisation found the prevalence of HIV/Aids to be stabilising in the country. However, the number of South Africans requiring ARVs still calls for cost-effective treatment to allow government to extend its free ARV programme to many more infected citizens.
The CSIR project, initiated in 2004, focused on reducing the cost of preparing nucleoside reverse transcriptase inhibitor (NRTI) drugs by relying on a biocatalytic step for the preparation of thymidine - one of the important intermediates in the manufacturing of drugs such as stavudine and AZT. NRTIs act against the viral enzyme reverse transcriptase preventing replication of the virus. Biocatalysis involves the use of enzymes, in this case two enzymes, to catalyse a reaction.
Research partners from the University of Cape Town were initially involved in some of the small-scale chemistry but the bulk of the science was conducted at the CSIR. Research focused on converting an inexpensive relatively abundant nucleoside into a high-value nucleoside. Bode and her team comprising of biochemists, molecular biologists, chemists and process chemists were essentially upgrading 5-methyluridine to high-value thymidine which is a valued ingredient in the manufacturing of many antiretrovirals.
“We were looking at a process that works based on enzymes isolated from a bug not used before in this type of application, in conjunction with another enzyme. Our aim was to do the process as cheaply as possible,” she explains.
The overall project involved initial screening work to identify useful enzymes, the fermentations to produce enzymes and the process development for the biocatalytic reaction. CSIR Biosciences also looked at developing the chemistry. Once the chemistry work was complete, the process was scaled to produce thymidine at kilogram scale to prove that the concept is feasible.
The only setback encountered in the early stages were low yields obtained in the biocatalysis reaction, for enzyme production, as well as in the chemistry. “Much development work was undertaken to make this into a viable process. The belief the team had in the process and its potential was largely responsible for their determination to make it work,” she says.
While Bode would not be drawn into discussion on the actual cost of producing an antiretroviral API using the CSIR technology, she did add that costs were significantly lower than current market rates. The final technology package produced for the client Arvir Technologies (Pty) Ltd, a new start-up biotech company, included an approximate techno-economic model which forecast the cost of making the raw material and the costs of establishing a manufacturing plant. Arvir will investigate commercialisation including sub-licensing the CSIR technology for which a patent has been filed. It is hoped that this initiative will stimulate an active pharmaceutical ingredient manufacturing industry for South Africa.
Bode believes that this can become a reality should government allow for incentives such astax breaks, assistance in setting up and initial co-investment. “It would be such a boost for scientists to know that there is a viable pharmaceutical industry and it would stimulate SA research in that area,” she says.
CSIR Communication:
Asha Speckman, email: Asha Speckman
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