In mid-2018, nitrosamine content (specifically N-nitrosodimethylamine, or NDMA) was found to exceed the guidelines on daily intake limits in a widely used hypertension medicine, with potentially carcinogenic effects for patients. What followed was a detailed risk assessment of all relevant drug products, leading to more than 1,400 product lots being recalled from the market by September 2020.
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In mid-2021, the picture worsened when a range of medicines were recalled due to the presence of various other nitrosamine drug-substance-related impurities (NDSRIs). And according to a 2023 paper, “industry and regulators are now in the challenging situation that NDSRIs may be present in hundreds if not thousands of medicinal products, some of them affecting whole essential drug classes such as β-blockers.”
First identified 40 years ago, nitrosamines are ubiquitous carcinogens that are commonly present in food and water. As highlighted by the events of the past six years, nitrosamines can also form in drug products through chemical reactions that take place during manufacturing. The European Medicines Agency (EMA) later published a long list of causes for nitrosamine formation in pharmaceutical products. These included the use of contaminated raw materials in API manufacturing, the use of recovered materials, and cross-contamination on manufacturing lines.
Packaging materials as a source of E&L
Due to their prolonged contact with the drug product, packaging components have always been a potential source of contamination, with impurities migrating from primary packaging materials into the product as extractables and leachables (E&L).
In the case of nitrosamines, contaminants can originate from reactions of residual amine impurities with nitrosating sources in the excipients of packaging materials, or from reactions of nitrosating sources in the drug formulation with residual amines in the packaging. Nitrocellulose blister packs are of key concern, but there is also a well-known link between nitrosamines and rubber – an important material used in the container closure systems of injectable (parenteral) products.
However, according to Dr Tine Hardeman, Material Development Manager at Datwyler, a parenteral packaging provider, it’s not all bad news, since the typical link made between rubber and nitrosamines is no longer valid for most rubbers used in parenteral packaging today.
Due to a history of chemistry advancements that have reduced the industry’s reliance on antioxidants and additives in rubber formulations, combined with major improvements to the crosslinking systems and the introduction of coating technologies, today’s pharmaceutical rubber is often classed as having ‘ultra-low’ extractable and leachables content.
“Over the years, a lot of progress has been made in the industry,” says Dr Hardeman. “It’s difficult or almost impossible to fully limit the amount of extractables, but it has been greatly reduced when you compare the older formulations with modern ones.”
The evolution of pharmaceutical rubber
In a recent webinar, Dr Hardeman describes the full evolution of pharmaceutical elastomers – from natural rubber compounds to synthetic ones like BIMs.
Despite offering excellent elastic properties, natural rubber is often remembered for its ability to cause anaphylaxis in individuals with a latex allergy. Even after the industry removed latex allergens by switching to synthetic polyisoprene, drug manufacturers were still dealing with the elastomer’s poor gas barrier properties and unclean crosslinking system. Crosslinking processes are fundamental for achieving desirable mechanical properties, but the system used for polyisoprene typically involved a very slow reaction between sulfur and zinc, which required accelerators like Thiuram. These accelerators are no longer seen as safe for patients and should be avoided at all costs.
“Pretty quickly a shift was made towards butyl rubber, which has a much lower gas permeability,” Dr Hardeman says. “It is still quite difficult to crosslink, which leads to not-so-clean rubber. This is why halobutyl rubber was introduced.”
Like its predecessor, halobutyl came with a naturally low gas permeability. The key improvement was in the cleaner crosslinking system that the compound enabled on account of its halogenation with bromine or chlorine, which speeds up the process considerably.
“With this, the material becomes more reactive in itself, meaning that you have to add less harsh chemicals to get the crosslinking reaction going,” explains Dr Hardeman. It is this avoidance of accelerators which has protected modern container closure systems from nitrosamine formation, she adds. Accelerators generate secondary amines, which are potential nitrosamine precursors. Being able to eliminate accelerators in the formulation recipe therefore eliminates the related nitrosamine risk.
Halobutyl has a range of other advantages, including better resistance to ageing and reduced need for antioxidants. Antioxidants should always be limited as much as possible, says Dr Hardeman. When absolutely necessary, she recommends using larger, bulkier molecules which will have a much harder time extracting from the material into the drug product.
The latest generation of pharmaceutical rubber
While halobutyl addressed many of the problems drug manufacturers had been experiencing for decades, there was still room for improvement, especially when it came to packaging large molecule drugs which are particularly sensitive to interactions with E&L. Fortunately, these improvements came with the development of an even cleaner elastomeric formulation known as brominated polymers (BIMS). Moreover, the introduction of coatings applied as a thin layer on top of the BIMS material provides an additional barrier for E&L.
“The BIMS material has all of the advantages of halobutyl rubber but with even better resistance to ageing and no rubber oligomers,” notes Dr Hardeman. “These rubber oligomers are quite important extractables from the typical halobutyl rubber; they are present in quite large amounts compared to other typical extractables that you have. Being able to avoid those makes BIMS ideal for the development of rubber with extra low extractables.”
Pharmaceutical rubber formulations have clearly come a long way over the decades, but scientists are continually seeking out further improvements. While the industry’s recent nitrosamine crisis cannot be tied back to modern pharmaceutical rubber, it still serves as a reminder of the necessity of advancing materials to strive for ever higher levels of cleanliness and quality.
Datwyler is an industry-leading provider of system-critical elastomer components. Its FM457 formulation is based on the BIMS technology, representing a best-in-class solution for customers looking to achieve very low levels of E&L. The option to apply fluoropolymer coatings, either spray or film, takes this one step further, forming a strong barrier with superior chemical compatibility and the lowest possible levels of E&L.
To learn more about nitrosamines and parenteral packaging, please download the whitepaper below.
