US FDA Emergency approval to treat COVID-19. The US FDA has granted Emergency approval for the use of anti-viral drug remdesivir (from Gilead Sciences – GILD US, USD79.41, not covered) to treat COVID-19. A question we have been getting from investors is why it takes so long to manufacture the drug – currently it takes around 12 months but Gilead hopes to take that down to 6-8 months.

Only 8 synthetic steps, but sequential and low yield. A 2017 paper in the Journal of Medicinal Chemistry (Siegel et al. 2017, 60, 1648-1661) described two pathways to synthesise remdesivir. The first had seven different steps but had a final yield of only 0.5 per cent, whereas the second pathway had 8 synthetic steps but a final yield of 12.7 per cent (so if you started with 100g of materials, you would get 12.7g of drug at the end). We assume that Gilead is using the second pathway to manufacture remdesivir on a commercial scale, however, while some of the reagents may be available to buy commercially, some are in limited supply and some may have to be manufactured by Gilead before remdesivir can be made. That adds to the overall manufacturing time for the drug, especially if those materials themselves are difficult to synthesise. Further each step of the chemical synthesis cannot be started until the previous step has been completely finished and the reactive catalysts removed.

Low temperatures, slow reactions and dangerous chemicals. Of the eight synthetic steps, two have to be conducted at -78°C, two at -20°C and one at zero °C. Conducting chemical reactions at low temperatures in a laboratory environment can be time consuming and onerous, but on an industrial scale, it adds further complexity. Normally chemical reactions take a longer at low temperatures, but given some of the chemicals needed to manufacture remdesivir, which are highly reactive and therefore dangerous, those reactions may occur reasonably rapidly. But it is precisely the nature of those chemicals that requires the need for special conditions. For example, in the first synthesis step, one of the reagents is TMSCl (trimethylsilyl chloride). In its PubChem entry, TMSCl is noted as being unstable in contact with water, being a highly flammable liquid and vapour, and causes severe burns and is toxic if inhaled. Another reagent in step 3 is TMSCN (trimethylsilyl cyanide) which is noted as being a highly flammable liquid and vapour and fatal if it comes into contact with skin or if swallowed or inhaled (it releases cyanide gas in contact with water). Needless to say, dealing with such chemicals and chemical reactions on an industrial scale is highly complex and not easily done. Hence, it takes 6-12 months to make the drug.

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