Toxic truth about leachables – the battle against contamination

30 September 2015

In 2010, scientists at the University of Toronto discovered something dark at the heart of American popcorn. While testing the properties of a particular brand's packaging, they found that its greaseproof inner lining was shedding polyfluoroalkyl phosphate esters, or PAPs. The prospect of many thousands of Americans unwittingly ingesting these chemicals was a disturbing one. Previous tests on lab rats concluded that long-term exposure to PAPs resulted in hormone disruption and higher chances of tumour growth.

PAPs are just one example of a leachable - a chemical shed by packaging that serves to contaminate foodstuffs or drugs. Sometimes their presence alone is enough to trigger unanticipated side effects in the patient, although often leachables react with other chemicals in the container product to produce an omnium gatherum of different symptoms. Matters are further complicated for manufacturers by the relatively late stage in the supply chain at which contamination is discovered, sometimes resulting in mass recalls and a public relations disaster.

The same chemical principles apply as much to pre-packaged medical products as they do to the food industry.

"A leachable that migrates into the drug product can potentially react with elements in the formulation and thereby change its quality," explains Carsten Worsøe, the principle scientist for extractables and leachables at pharmaceutical company Novo Nordisk. "There are also examples of leachables that have actually reacted with the active pharmaceutical ingredient and thereby changed the mechanism of the drug product, which of course can be quite critical."

The dangers posed by the manufacturing process in this respect are considerable. The typical biological drug product has to undergo a process of filtration, purification, formulation, filing, packaging and eventually storage. These are all points in which the drug could be exposed to contamination. Caution also needs to be observed in other medical products. In 2010, health authorities in Canada declared bisphenol A, a chemical leached from polycarbonate bottles, a "toxic substance" after studies on rodents linked exposure to neurological difficulties. Another example involved the presence of polysorbate 80 inside EPREX pre-packaged syringe kits. The chemical leached vulcanising agents from uncoated rubber components, leading to a rise in cases among users of antibody-mediated pure red blood aplasia.

Usually, the method of identifying how and when leachables are being produced lies in subjecting the production equipment or drug-product packaging to extractable testing. They are placed in conditions more extreme than those expected in a normal use and storage environment. This accelerates the chemical processes that enable leaching, allowing scientists to quickly pinpoint how and why the process is occurring.

Valuable tool for quality control

"Simulating a worst-case leachable situation furthermore facilitates the identification of the low-concentration leachables, since during the extraction we will extract a much higher concentration compared with their normal storage environment," says Worsøe. In this respect, the test remains a valuable tool for quality control. "If you can control your extractables - meaning the compounds that are encountered in the container closure system - then you also can control your leachables profile over time," he says.

Whether or not you get a sizeable reaction during testing is entirely dependent on what type of product you're dealing with. "If you have a protein drug product, you have a large molecule," Worsøe explains.

"The larger the molecules, the more potential sites for reaction you will have. In a chemical entity, the molecule is much smaller and there you should expect a lower risk for reaction chemistry, simply based on the number of reactive sites on the active component."

These testing conditions work well with many drug product forms. However, complications arise when soluble drugs with complex formulations are subjected to the extractables testing.

"The challenge for soluble products, like many parenteral drug products, is that extractable testing is a very difficult tool to predict actual leachables due to the difference in polarity, surface tension and pH between an extraction solvent and the drug product formulation," says Worsøe. "The extraction solvent could be an aqueous or an organic solvent, for example ethanol or isopropanol. These are very bad predictors of a typical parenteral drug product, which would have a different polarity. There, you can have a protein in the drug product, a number of formulation components, including preservatives, stabilisation, surfactants, buffer and isotonic agents, that will change the polarity, surface tension and pH of that drug product far from an extraction solvent."

It is for these reasons that Worsøe recommends a simulated study. As the name suggests, the test replicates rather than acts out the conditions upon which leachables might react with the drug product. This overcomes the difficulties presented in the chemistry of a typical extractable study and allows the product to be used for the test.

"Simulated studies are becoming more and more common," Worsøe says. "When I chaired a conference on extractables and leachables in Vienna in 2011, I remember then it was all very much about the advantages of extractables testing. We discussed the simulated study quite a lot and the more we discussed it, the more people realised that it was probably the best prediction tool for leachables in soluble drug products with complex drug-product formulations."

Container closure systems

While testing regimens are certainly improving, Worsøe remains sceptical that all cases of leachable contamination are being accurately recorded.

"I think many companies have actually observed this, but it's not something that is described in detail," he says. "I think it's because it's very difficult to observe and document, but it's also something that pharmaceutical companies potentially would keep to themselves. Of course, they will do a full evaluation and it will come out as 'not critical,' but they will not go out and publish the data. Furthermore, much of the extractables and leachables work is performed by contract research organisations that do not own the data they obtain."

One lingering area of concern for Worsøe has been the proliferation of medical products that include combinations of drug products and a device.

"It's something that health authorities have shown little interest in and in which the hazards involved could potentially be critical because there are a number of contact materials within both the container closure system and the device system," he explains. It is a situation that is exacerbated by the relative lack of regulatory crossover between medical devices and drug products. "The fact is that drug products are reviewed by one set of regulations and devices by another. I should say I feel that there is little harmonisation between the two."

Nevertheless, useful reforms are beginning to be made to limit the potentiality of contamination within the supply chain. A recent innovation has been the addition of coated stoppers for vial products, which serve to slow leaching from the rubber materials used in the tool. Manufacturers of pre-filled syringes have also taken steps to minimise their leachable properties by optimising and regularly replacing the tungsten pins used to make the needle channel in glass prefilled syringes.

This is all the more important when considering the increasing complexity of the supply chain that pharmaceutical companies rely upon to get their drugs to market. "A pharmaceutical company would typically deal with the supplier of a component for a container closure system, but that supplier has of course a number of under-suppliers," Worsøe says. All links in the supply chain have to be monitored. The scenario if this was not the case hardly bears thinking about. "Eventually there could be a critical leachables potential that could affect the safety and the quality of the drug product," Worsøe says.

Worsøe and his colleagues at Novo Nordisk find the current research encouraging, especially as they witness growing interest in the simulated study. However, as they see it, technological achievements can only be effective if they complement healthy personal relationships between pharmaceutical companies and their manufacturers. "This collaboration remains essential and it's something that consumer companies need to invest in," concludes Worsøe. If they don't, it's safe to say that quality control staff scientists will have to second-guess more than just the average packet of American popcorn.



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