Up to 25,000 patients affected by Viracept contaminant, reapproval on the cards

By Anna Lewcock

- Last updated on GMT

Related tags: Roche, Pfizer, European commission

European regulators have recommended that Roche's marketing
authorisation for HIV drug Viracept (nelfinavir) be reinstated,
following serious good manufacturing practice (GMP) deviations that
caused toxic contamination of drug batches distributed to up
to 25,000 patients.

According to a statement made by the European Medicines Agency (EMEA), the regulator is now satisfied that Roche has adequately addressed manufacturing issues at its Basel plant that resulted in massive amounts of the genotoxic compound ethyl mesylate (EMS) being found in the final drug product. The "critical GMP deficiencies​" found by inspectors at the production plant following the EU-wide recall of Viracept led to contamination of the drug at levels of up to around 920ppm in the final tablets, and 2,300ppm in the active ingredient - magnitudes higher than the Threshold of Toxicological Concern (TTC) of 0.6ppm. At the end of August, Roche briefed non-governmental organisations regarding the contamination case, and estimated that around 45,000 patients were taking Viracept at the time of the June recall. According to Roche's figures, 20,000 - 25,000 of these patients are from countries that received batches of Viracept manufactured from active ingredient containing over 1,000ppm of the toxic contaminant. In Europe, the countries with the greatest number of patients taking Roche's Viracept were Italy (around 2,000 patients), Spain (1,700 patients) and France (1,500 patients). Mexico has around 2,600 patients currently on the medication. Several other countries have large patient populations; Brazil, for example, accounts for 30 per cent of Viracept sales, though may not have been affected by the highly contaminated batches. However, patients all over the world may have been victim to elevated levels of EMS in Viracept since it first hit the market 10 years ago. Roche has been aware of the presence of EMS in its drug product since production began. A by-product of the synthetic process used to manufacture the drug, the known genotoxic compound has been lurking in the medication at steadily increasing levels unbeknown to patients merrily taking their meds. According to Roche, quick to point out that EMS measurement was not required by health authorities, the majority of its batches contain less than 1ppm of EMS. However, over the period 1999 - 2003, records show EMS levels in the active ingredient up to 25ppm, and by 2004 - March 2007 this had risen to a peak of 132ppm. Although significantly less than the 2,300ppm found in the highly contaminated batches in June, these levels are again significantly higher than those recommended in agency guidelines. Apparently, Roche has now addressed the issues in its manufacturing processes and convinced the EMEA that the 'corrective and preventative' measures put in place will stop such gross contamination and maintain appropriate quality standards in its drug products. The key culprit in the production process, it appears, was a holding tank used to manufacture the drug. Cleaned with ethanol but not dried out properly, methane sulphonic acid (MSA) held in the tank during the manufacture of Viracept reacted with residual ethanol causing the spike in EMS. Roche has now removed this holding tank from the manufacturing process altogether, opting instead to use a disposable container. The company has also adapted the production process so that the tank is charged with the MSA more slowly, which reduces the risk of EMS occurring as the nelfinavir mesylate that makes up Viracept forms more quickly than the toxic compound. Roche looked at eight different areas of its manufacturing process, a spokesperson for the company said, identifying danger areas where EMS formation could be triggered. Two of those areas were given the all-clear, with the remainder the target of modifications to help minimise the risk of EMS. As well as throwing out the holding tank, Roche has also introduced checks to ensure that any EMS can be detected as early as possible during manufacture, making use of gas chromatography mass spectrometry (GCMS). Strict acceptable limits for EMS will also be set for the active substance and final drug product, and while these still appear to be under discussion, a Roche representative seemed to suggest they would follow the EMEA 0.6ppm guideline. The changes to the production process and the enforced manufacturing suspension mean that even if the European Commission (EC) backs the EMEA's recommendation and reinstates Roche's marketing authorisation, Viracept is still unlikely to be available to patients before the beginning of 2008. Around the same time the drug will start making its way back to patients' medicine cabinets, the results of toxicity tests Roche was instructed to carry out should also become available. The original evaluation carried out by toxicologists following the Roche recall in June concluded that there was insufficient data to quantify the risk posed by exposure to EMS, and as such the company was instructed to carry out studies to help establish this potential danger. Roche instigated two studies in mid August looking at gene mutations and chromosomal damage caused by EMS, with an update due in November before the final results expected in January 2008. The European Commission will have the final say on whether Roche will regain marketing authorisation for its HIV drug, with a final decision anticipated in the next month or so. Roche is confident that it acted "responsibly, quickly and always in the best interests of patients,"​ and presumably will be hoping that those patients will return the favour and come back to Viracept next year. What proportion of the 25,000 patients who may have taken contaminated Viracept will return to the drug, however, remains to be seen.

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