Following the recent changes in extractables and leachables (E&L) regulations, we look to discuss some of the topics that are repeatedly being debated at E&L focused webinars and conferences.1,2 Specifically, the introduction of ISO10993-18:2020, and the current challenges faced when performing testing as per the new standard.3 At the end of 2021, our E&L Waters team sponsored an event hosted by Hall Analytical and VR Analytical. This event titled: ‘The Ever-Changing World of Extractables & Leachables” saw industry and regulatory experts discussing hot topics around E&L analysis of pharmaceuticals, biopharmaceuticals, and medical devices.
Discussions were largely centered around two areas with Ted Heise, Alicja Sobantka, and Waters own presentation, looking at the current state of play in E&L analysis for both pharmaceutical and medical device applications. Covering the establishment of a consistent AET for medical device analysis, how to address E&L analysis in biological combination products, and a discussion around strategies to overcome challenges in extractable screening studies. The rest of the event looked towards the future of E&L analysis with Nick Morley, Dan Norwood, and Jason Creasy addressing many of the current challenges in the way scientists approach E&L analysis, and if or how they can be improved going forward. This raised conversations around the increasingly stringent regulations which govern the application, and possible next steps for the practicalities of E&L analysis. In an ever-changing but tightly regulated application area, the discussion really lived up to the event title; lessons learned and the future challenges.
Following the formal presentations, a lively Q&A and panel discussion took place building on the challenges raised in the talks. These were passionately debated, highlighting how critical these issues are in the current E&L climate. Both the vendor providing fit for purpose solutions and an analyst undertaking often complex studies on their materials regularly face many of these issues, whilst simultaneously having to comply with the regulations. The session was largely centered around two main themes:
1. Medical Devices versus Pharmaceutical Packaging
Often during these conversations, it was apparent that there are multiple discrepancies between how the medical device industry and producers of drug packaging, undertake E&L analysis. This topic has become a recurring theme in the E&L community, also being the first discussion point at “E&L Trends and future directions Roundtable” hosted through LCGC, highlighting how critical this topic currently is.
At this roundtable event the many differences between the testing of medical devices and pharmaceutical packaging were considered, the biggest notable difference being the material to be tested, giving rise to very different outcomes and risks, requiring an individual approach to the creation of safety frameworks.
For E&L analysis of drug products, testing the packaging extractables is just the first step to identify the potential leachables, often described as a “precursor”. The in-depth leachables testing then becomes more crucial. Whereas with medical devices, the risk involved is the result of direct contact with a patient, therefore the greater emphasis is on extractable testing, as it is not always possible to perform leachable studies. By their very design, extractable studies lead to a large number of compounds possibly migrating from a sample, compared to the number of compounds which are likely to migrate as leachables during actual use. The updated ISO 10993-18 has highlighted the importance of identifying all extractables above the Analytical Evaluation Threshold (AET) to enable the toxicological evaluation of medical devices.
One of the questions repeatedly being raised within the community is who is responsible for calculating the AET? From the panel discussions it is clear that for pharmaceutical packaging the situation is very clear cut, responsibility lies with the individuals most familiar with the drug products; in most cases the drug manafacturer. A toxicologist or a CRO would not know enough about the product or corresponding toxicological evaluation to confidently calculate an appropriate AET. For medical devices the situation is less clear, whilst the manufacturer is the main party responsible, it could also be the case that the person undertaking the toxicological risk assessment should be involved in calculating a suitable AET threshold, as they are responsible for the safety evaluation of the data.
The use of the AET was also a point of discussion and debate, again revealing different approaches depending on application area. Those working in the pharmaceutical industry use the AET as a screening threshold in the laboratory to determine leachables to be reported for assessment. Whereas in the analysis of medical devices the emphasis is on extractables, and therefore the AET is used as an absolute threshold. The panel summarized the situation well, highlighting that the concept developed for drug products (the AET) has now been applied to medical devices. This caused some confusion for everyone involved, from the manufacturer, to the analyst and the final regulatory body, in both how the data is used and how assertions are made on the safety of the final product.
2. Standardization and Qualification
In Dan Norwood’s talk entitled “What is the Future of Leachables and Extractables Assessment”, he asked the question: is it time to consider standard methods for E&L screening? This topic fed into some great conversation in the panel discussion around the qualification of screening methods and how this is achieved.
One of the toughest questions that would need to be addressed in the implementation of standards for E&L assessments is around who the key players would be. Dan Norwood suggested that it would have to come from the organizations that have statutory authority, and could potentially fall with regulatory authorities such as the USA’s Food & Drug Administration (FDA). He reflected on the authority of the USA’s Environmental protection agency (EPA), which has highly standardized regulations meaning there is no competitive advantage for companies carrying out environmental analysis to have their own analytical methods.
In contrast in the pharmaceutical industry, everyone is a competitor, therefore it becomes an advantage for each company to have their own methodologies.It seems that companies starting out in the world of E&L would typically welcome a standard method, whereas those established in the area would possibly already have analyte libraries based on their own methodolgies, adding to the difficulty of implementing standardization.
Further issues arise when looking at the complexity of this type of analysis, with different types of materials and devices leading to a wide range of chemical diversity. Furthermore, extractables screening involves untargeted methods, raising the question, how can these be standardized or qualified when looking for potential unknowns? Or more specifically, how can an initial generic extractables screening method be optimized for a standardized method? One of the dangers of standardization that was highlighted is that unknowns may be missed if everyone is using the same method. For example, a number of different methods for the analysis of nitrosamines have been used and each of these give different results, highlighting how one analytical approach may not give an analyst the full picture.
The panel discussed potentially using round robin testing to help implement standardization as it is currently underutilized in this space, but it was noted that it should be approached with caution. A round robin study to evaluate ISO 10993-12 extraction conditions was described, where results were mixed due to the study not being designed to evaluate lab to lab variability. It was also noted that using round robins and qualification approaches, may put some CROs out of business, if they cannot meet the qualification. When it comes to creating safety data and assessing risk, it should be questioned whether this is such a bad thing?
Ted Heise summarised the problems with applying standardization for E&L, commenting that the need for more flexibility, may lead towards more quality performance metrics for labs rather than standardization of the specific methods. Jason Creasey also noted that this isn’t a one-dimensional problem, that qualification approaches will need to touch on all aspects, from the methodology to the way that processing of the data needs to be done.
Lessons learned and looking forward
With different regulations, applications, and approaches to designing an E&L workflow, it is clear that there is no “one-size-fits-all” approach to E&L analysis. Also, there is a sharp contrast between the requirements of E&L testing of medical devices and pharmaceutical packaging. The complexity and variation of samples as well as of analytical methodology employed, add to the difficulty of implementing standardization. Having said that, it is apparent from the ongoing discussion that there is a lack of a streamlined and consistent approach when it comes to addressing compliance and regulatory requirements.But it shouldn’t be ignored that a lot of these materials have been analyzed many times by different labs, and this could be an opportunity for the industry to start sharing knowledge more openly.
Some of the near-term challenges faced by industry discussed at the Ever Changing World of E&L event have been summarized here but it is apparent that there could be many directions that E&L could take in the medium-long term future which will be further explored in a new blog created by Nick Morley of Hall Analytical.