Just over a week after Roche was forced to initiate a Europe-wide recall of HIV drug Viracept (nelfinavir), in-PharmaTechnologist.com considers the contamination case and the pharmaceutical processes blamed for the incident.
The recall was prompted following reports from patients that their medication had a strange odour; six patients from three different countries made the complaint within a single week, with two experiencing nausea after taking their medication.
Following investigations by Viracept's manufacturer Roche, samples of the tablets were found to contain abnormally high levels of ethyl mesylate, a harmful genotoxic substance. On discovering the contamination, the company initiated a recall of all Viracept products manufactured by Roche across the whole of Europe.
The contamination was tracked down to a manufacturing plant in Basel, Switzerland, where a reaction between the drug's active ingredient, nelfinavir, and chemicals used as part of cleaning processes at the site were blamed for the toxic substance found in the tainted drugs.
Ethanol present in the cleaning products is thought to have reacted with the active pharmaceutical ingredient (API) to form the harmful molecule, according to Roche's investigations.
"The contaminant is actually usually present at very low levels in the drug, the upper threshold in the manufacturing process is around three parts per million," Dr Herath, associate head of medical affairs in virology and transplants at Roche UK explained to in-PharmaTechnologist.com.
"However, as part of the maintenance programme at the site there may have been a cleaning error which resulted in more ethanol being present, and therefore higher levels of the molecule."
According to Herath, the contamination is believed to have occurred at the Basel facility towards the end of December 2006, with the batch release occurring in Spain. No other products were affected by the mistake and the contamination error has now been rectified, he said.
However, the recall has left patients without their drugs and Roche out of stock.
Although the company foresees supplies restarting within the next month, the World Health Organization is recommending that patients find a suitable alternative therapy, such as lopinavir/ritonavir, indinavir/ritonavir or saquinavir/ritonavir among others.
According to Martina Rupp, speaking from Roche's Swiss headquarters, the company is trying to source the drug from other countries unaffected by the contamination to try and make up for the shortfall, but this can only offer limited options. Although Viracept is also manufactured and distributed by Pfizer in the US, this version has a different formulation which is not registered in Europe, and can therefore not be used to replace the quarantined EU stocks.
As a second line therapy Viracept is not as widely prescribed as other HIV drugs on the market. Precise numbers, however, are difficult to come by. Roche was unable to put a figure on just how many patients are currently taking its drug across Europe, though it estimates the global figure at around 45,000.
According to the Medicines and Healthcare products Regulatory Agency (MHRA), around 550 people in the UK are prescribed the drug, but Herath noted that it is more widely used in other European countries such as France (where media reports have estimated 1,400-1,500 patients), Portugal and Spain.
Despite the comparatively small patient population, the quarantining of the potentially affected drugs was of course critical, and the company quickly informed the appropriate regulatory authorities. However, Roche's claims that a cleaning error was the cause of the entire episode truly emphasises the danger of underestimating the importance of the cleaning process in pharmaceutical manufacturing.
Although many companies outsource cleaning of the manufacturing environment, cleaning of the process equipment itself is usually carried out in-house, as the manufacturer is likely to have a greater understanding and appreciation of the cleaning requirements appropriate to its particular drugs and processes.
Rebecca Brewer, director of consultancy at the Dober Group which supplies customised cleaning solutions to the pharmaceutical industry, stresses the importance of a thorough understanding of the cleaning process in order to avoid unfortunate incidents like that experienced by Roche.
"Knowledge of chemistry and potential interactions is priceless," she told in-PharmaTechnologist.com.
"It is important to remember that cleaning always affects the next product to be produced, not the prior product. You have to understand the compatibility of cleaning products with both."
Brewer commented that ethanol-based cleaning products are not widely used, particularly in the US where there are taxes associated with ethanol use. More companies, she said, opt for products using isopropyl alcohol which is a better sanitant and doesn't have the same tax burden as ethanol-based products.
According to Brewer, one of the most frequently asked questions in terms of the use of alcohols in cleaning processes is whether it is important to assay for the existence of alcohol as part of the cleaning validation process.
"The traditional answer is that if the equipment is in an open space where the alcohol can evaporate and not accumulate, then don't bother. If the alcohol is passing through a contained space (such as piping) there is more of a risk of fumes or slow evaporation," she said.
"What the Roche case highlights is the need to really understand your process equipment, and the consequences it has for your cleaning processes."
Validation of cleaning processes is of key importance in the pharmaceutical industry, with chemical or bacterial contamination of drug products potentially leading to severe public health risks. As such, regulatory bodies such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) strongly advocate validation of cleaning processes and will act on evidence of firms cutting corners in their cleaning activities.
Philip Payne of RSSL Pharma, a UK firm offering analysis, testing and consultancy services to the pharma industry, notes that while contamination of drug products due to insufficient or incorrect validation of cleaning processes (or any other source) is of course undesirable for any company, it is important to have an action plan outlined just in case.
"Training and quality awareness is the key to prevention of quality issues such as recalls which are highly detrimental to both patients and the industry," he said.
"Even though prevention is the best kind of cure it is always important to have a plan in place to deal with this eventuality. Obviously this plan should be based on trying to identify the contaminant, and to resolve the problem as quickly as possible."
It was with this in mind that RSSL launched its Emergency Response Service to offer companies a 24/7 service to help deal with unforeseen contamination incidents, from manufacturing problems to product tampering. The firm also offers a number of training courses covering the cleaning validation process and counterfeit drugs.
With Roche's recall following hot on the heels of a spate of counterfeit drugs reaching the patient level (fake versions of Zyprexa (olanzapine), Plavix (clopidogrel) and Casodex (bicalutamide) were all discovered within a period of a week earlier this month), unease among consumers could easily be forgiven.
The last thing the industry needs right now, with the trade in counterfeit goods hitting an all-time high, is for its own legitimately manufactured drugs to be the subject of distrust. It's therefore clear that as well as doing all they can to protect themselves against the illegal activities of drug counterfeiters, pharma firms should not lose sight of their own internal processes, ensuring that controls are in place to maintain the quality of their own drug products, and escape Roche's unfortunate predicament.