The European Medicines Agency (EMEA) recommended the suspension late last week, which would prevent Roche's drug being produced or prescribed with immediate effect. The World Health Organization has also suspended the drug from its list of prequalified products. The moves follow concerns from the EMEA regarding the genotoxic substance found to be contaminating the HIV drug Viracept (nelfinavir) earlier this month. A meeting of toxicology experts at the EMEA concluded that insufficient information was known regarding the contaminant, ethyl mesylate, and its effects on the human body. As such, the EMEA has asked the European Commission (EC) to suspend Roche's marketing authorisation and requested that the company carry out animal studies to try and establish what levels of ethyl mesylate are toxic to humans. The agency believes preliminary results from the research may be available by the end of the year, but Roche will be unable to market Viracept anywhere in Europe until at least that time if the EC backs the proposals. In addition to this, the company also has to assure the regulatory authorities that manufacturing issues at the Swiss plant responsible for the contamination have been adequately resolved before production at the site can restart. No other products were affected by the contamination at the plant. Although ethyl mesylate is a known genotoxic substance (harmful to DNA), it is unknown at precisely what levels the compound is harmful to humans. Until more accurate figures have been calculated, the Committee for Medicinal Products for Human Use in the UK (CHMP) has proposed an interim limit in line with scientific consensus on genotoxic impurities and available data on the compound. The level has been set at 0.6 parts per million, the equivalent of a maximum daily intake of around one and a half micrograms of ethyl mesylate for an adult patient taking the recommended daily dose of Viracept. However, danger-levels for genotoxic substances can be difficult to pin down, according to Dr Andrew Smith of the toxicology unit at the UK's Medical Research Council (MRC). "With other chemicals there can be a distinct threshold," he explained to in-PharmaTechnologist.com. "But the problem with genotoxic chemicals is that it's much more difficult as there might not be an actual threshold as such. A genotoxic risk analysis is difficult." The contamination in Roche's Viracept spiked as a result of human errors in cleaning processes used at the manufacturing site in Switzerland, and has affected batches released on the market from March this year. However, after further examination, Roche discovered that earlier batches of the drug were also contaminated, albeit to a lesser extent. As a result, the company is reviewing its manufacturing processes and has also established a number of patient registries to monitor all Viracept patients who may be at risk as a result of the tainted drugs. A spokesperson for Roche recently told in-PharmaTechnologist.com that the firm was well aware that there had always been a low background level of ethyl mesylate in Viracept products, due to residual ethanol from the cleaning processes reacting with the drug's active ingredient. When asked why the company had not carried out research into how harmful this known genotoxic substance could be to patients prescribed the drug, a spokesperson for the company simply said that it had adequately "followed regulatory processes". Despite the potential consequences for patients who may have taken contaminated Viracept, Roche is insisting that patient registries and its intention to keep track of patients for several years is a "very precautionary measure" and that the firm will be manufacturing Viracept again once the investigations are complete and any marketing authorisation suspension has been lifted. When this might actually be, however, is still an unknown. Implications As the the genotoxic impurity under investigation is known to have been present at a low background level in the drug through the company's standard manufacturing processes, there are wider implications of the drug's suspension that could ripple through pockets of the pharma industry. Pfizer, for example, is responsible for manufacturing and distributing Viracept across the US, Canada and Puerto Rico. Pfizer's product hasn't been approved in the EU and as such cannot be provided as a substitute to Roche's Viracept patients, but the EMEA decision could have consequences for Pfizer's production of the drug. The US Food and Drug Administration (FDA) was unable to answer questions regarding how or whether ethyl mesylate is currently regulated in the US. Pfizer, however, appears to have thought ahead. According to Joel Morris, a spokesperson for the company, Pfizer has provisions in place to prevent a situation similar to Roche's current predicament. "Ethyl mesylate is a potential byproduct of the synthetic process," said Morris, speaking of Pfizer's Viracept manufacturing procedure. "However, Pfizer has controls in place to prevent its formation during manufacture." It would appear, therefore, that Pfizer should be spared the rigmarole taking place on the other side of the Atlantic. To further emphasise the significance of the Roche episode, the loss of the marketing authorisation would also mean the loss of the originator product, which could have implications for the approval of any generic versions of the drug. This could prove a particularly thorny issue if generics manufacturers produce the drug in low-cost regions where manufacturing standards can be below those required in the West, and the possibility of contamination as experienced by Roche consequently somewhat higher. Although the original contamination incident was triggered by complaints from just a handful of patients, the case could trigger a domino effect impacting several manufacturers as well as regulatory guidelines regarding genotoxic impurities. As for the impact on Roche's bank balance, the company is currently confidently asserting that that the debacle will have no effect on its financial guidance. However, as it will no doubt take some time before any adverse effects in patients become apparent, Roche can only hope that any damage is fairly limited and that Viracept won't emerge as the new Vioxx.