Packaging
Common sources of extractables and leachables in pharmaceutical packaging and delivery systems
Source Rubber stoppers
Adhesives and coatings
Infusion devices Glass vials Labels and inks Material type Elastomers Polymers/resins
Thermoplastics/ elastomers
Borosilicate glass Adhesives, inks Sterilisation processes EtO, gamma irradiation Source: United States Pharmacopeia, US FDA, ISO 10993-17/-18
Extractables are chemicals that could be released from packaging materials under exaggerated conditions, such as exposure to solvents, high temperatures or extended contact times, explains consulting toxicologist Dr Greg Erexson. Leachables are compounds that migrate into the drug product under normal use and storage. Leachables might impact a drug’s stability or efficacy or even trigger adverse reactions. “Extractables testing tells us what might migrate,” Erexson explains. “Leachables studies show what actually does.” The combination of the two gives toxicologists a fuller picture and allows them to model patient exposure accurately.
E&L testing was formalised in the pharmaceutical industry in the 1990s when elastomers used in metered dose inhalers were found to leach polycyclic aromatic hydrocarbons into medicines. Over the decades since, the field has grown more sophisticated, with increasingly advanced mass spectrometry techniques helping toxicologists determine the risk of contamination. Erexson has authored thousands of toxicological risk assessments based on E&L profiles and has seen first hand how easily trace contaminants can complicate product development. It’s very rare for E&L to cause actual harm, he says. But that’s because drug developers have built multiple layers of precaution into the process, not because the risk isn’t real. Today’s drug containers may include multilayered polymers, silicone coatings, printed labels, adhesives and proprietary elastomer blends. Each component must be scrutinised for the chemicals it might release, Erexson explains.
Material issue
Certain materials are well-known sources of concern. Plastics like PVC and polycarbonate may contain additives such as DEHP and bisphenol A (BPA), both of which are associated with toxicity and hormonal disruption. “These materials can be especially
38 Potential leachables
Accelerators, antioxidants, sulphur compounds
Solvents, curing agents, monomers
Oligomers, cross-linking agents
Sodium, boron, delamination flakes
Photoinitiators, residual solvents
Residual EtO, chlorohydrin, degradation products
problematic,” Erexson explains. “Even small amounts of known hazards need to be carefully evaluated.” Inks and pigments, used in labelling, barcodes and branding present another layer of complexity, Erexson reveals. Their formulations are often poorly characterised, and variable between suppliers. Even glass, long considered the gold standard for parenteral packaging, is not without risk. In certain pH environments or under specific temperature conditions, glass can leach alkali metals or suffer delamination (where the material fractures into layers), leading to physical instability or contamination of the drug product. Some medicines have multiple components, making E&L studies particularly tricky. For instance, with a metered dose inhaler, plastic and elastomeric components are in direct contact with an organic propellant system. The two substances can interact, potentially leaching out chemicals over time that can be dosed to the patient. To evaluate the risks of E&L, scientists rely on a suite of increasingly advanced analytical techniques. Core methods such as gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry are used to detect volatile and semi- volatile organic compounds. More recently, high- resolution mass spectrometry has become a mainstay in identifying unknown or unexpected peaks in chromatographic data.
Other methods include inductively coupled plasma mass spectrometry, which is critical for identifying elemental impurities, particularly metals. Meanwhile, the rise of in silico toxicology tools such as QSAR (quantitative structure–activity relationship) models has helped scientists more efficiently evaluate the potential risks of compounds when there is no available toxicological data in the literature.
Quantification of compounds of concern is performed using relative reference standards, with toxicologists calculating the analytical evaluation threshold, above which an extractable or leachable must be reported. This can help pharmaceutical companies determine what further studies are needed to mitigate risks associated with the final product.
Many companies have also invested in internal databases of known extractables from common materials, allowing them to accelerate risk assessments and reduce the need for redundant testing. The Extractables and Leachables Safety Information Exchange (ELSIE) is a consortium of multiple pharmaceutical companies formed in 2007 to support E&L research.
Good judgement
Not all projects end in clean toxicological assessments, but when something is flagged, it doesn’t necessarily spell the end of the road for a new drug candidate. Erexson recalls one instance in which his team identified 141 extractable compounds from a polymeric
www.worldpharmaceuticals.net
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