Alan Hutchinson, principal scientist at Broughton, discusses the challenges and trends with extractables and leachables.
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543042078 medicines in blister packaging and brown glasses in backlight
Extractables and Leachables (E&L) testing aims to reduce the safety risk to end-users of products such as pharmaceutical medicines or Electronic Nicotine Delivery Systems (ENDS), from the container closure system of the product.
E&L testing in the ENDS community is a recent requirement, with new regulations introduced as part of US Premarket Tobacco Product Application (PMTA) guidance. In contrast, in the pharmaceutical industry, E&L testing has been part of the required safety evaluation of products for a while.
As pharmaceutical requirements are more developed, the materials used for these products are more consistent and understood. For the ENDS industry, the hope is that the use of grades of materials like those used in the pharmaceutical industry will become more prevalent over time.
One of the major challenges with performing leachables studies is the common requirement to meet lower detection limits, which challenges both the instrument vendors and the laboratory scientists.
Highly skilled and experienced analysts are required to develop instrument methods and sample preparation techniques to meet these low analytical evaluation thresholds, and state-of-the-art mass spectrometry instruments and software are needed to detect these low levels and process the data. The formulation of the product can contribute to this issue of sensitivity in
so-called dirty matrices such as e-liquids, as their natural flavours and biological samples can make it increasingly problematic to detect lower levels in a forest of peaks due to formulation interference.
Another challenge is a historical lack of clarity regarding the guidelines for designing and performing E&L testing. This has been a slow process and alignment of approaches would be valuable.
The greater emphasis on performing risk assessments as a first step of the E&L process is a main trend. This helps focus the studies and determine where effort is best placed to quickly and efficiently de-risk any concerns from the container closure system. To perform a valuable risk assessment, the knowledge and information, as well as the expertise of the Subject Matter Experts (SMEs) performing the risk assessment that inputs into a Failure Mode and Effects Analysis (FMEA) style process, is essential.
This helps to focus effort and can reduce testing if previous data can be used to bridge to past studies. E&L studies are expensive and time-consuming, and using previous relevant data will reduce costs and accelerate E&L projects.
The use of high-resolution accurate mass instruments for the analysis of E&L samples is becoming more widespread with E&L projects, helping to identify leachables and reduce the number of unknown compounds reported. Accurate mass instruments can help target leachables in complicated matrices, which can reduce the sensitivity burden by removing interferences from the formulation.
In the future, it would be helpful to see the further alignment of processes and methods for performing E&L projects, and this would benefit spectral libraries for identifying leachables. The development of response factor libraries for determining uncertainty factors would help in determining improved analytical evaluation thresholds for methods.
We are starting to see the use of automation for the sample preparation methods required for sample clean-up and enrichment. More use of automation can only help with the consistency of data and reduce the time taken.
The improvement of knowledge around E&L processes and materials, and the standardisation of materials used for products, will mean that E&L assessments become a more desk-based activity. For pharmaceuticals, we are already seeing this with common industry-grade materials being used; within companies, the same materials are being used across product ranges. ENDS products will likely follow this path and in the future, cleaner, better-grade plastics and rubbers will also become common across that industry.
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