The role of ELSIE in evolving current thinking on extractables and leachables

THE INTERNATIONAL Council for Harmonisation (ICH) recently met in Singapore. They are convening six new working groups, including one on the ICH Q3E Guideline, titled Impurity: Assessment and Control of Extractables and Leachables (E&Ls) for Pharmaceuticals and Biologics.¹ The group will develop a concept paper and business plan.

Over the last decade, the industry group (covering pharmaceutical, biotechnology and medical device companies) that has been most influential in developing appropriate guidelines for E&Ls has been ELSIE. The group published their first guidance in 2011 outlining the benefits of their E&L database,² which enables E&L data to be shared among member companies, allowing the potential safety impact of E&Ls from drug product packaging, delivery and manufacturing systems to be ascertained. This facilitates harmonised regulatory submissions.

ELSIE then published conclusions from a controlled extraction pilot study in 2015.³ A comprehensive protocol was defined, including “a number of extraction solvents, extraction techniques, and a variety of analytical techniques”. Testing was undertaken on two common polymeric packing materials: polyethylene (PE) and polyvinyl chloride (PVC). The objective was to ascertain whether (i) a simplified extraction procedure could be used and (ii) a reduced number of extraction solvents could be used to support material selection. The data indicated that these reductions were feasible, at least for PVC.³ A further study evaluated polypropylene and a copolymer of polycarbonate and acrylonitrile butadiene styrene⁴ and concluded that “extractable testing of polymer resins is useful for material screening and, in certain situations, may replace routine component testing”.⁴ ELSIE also highlighted that container closure systems were important³ as a potential source of elemental impurities as part of any ICH Q3D risk assessment process.⁵ ELSIE, together with IPAC‐RS (International Pharmaceutical Aerosol Consortium on Regulation and Science), published a literature review on this subject in early 2015.⁶ They concluded that:

•  some elemental impurities are present in packaging materials, typically as additives or from their production process
• unless the elemental components are integral parts of the components themselves (eg, Si in glass) or intentionally added (eg, metal stearates in polymers), the amounts present are generally low
• when elemental components are present, typically only a very small percentage can be leached under conditions that are applicable to packaged drug products.⁶

However, the most significant publication from the ELSIE group was towards the end of 2016 and covered the derivation of safety‐based limits for leachables in pharmaceuticals and biologicals.⁷ Prior to that time, the E&L community had used a safety concern threshold (SCT) of 0.15μg/day, where the SCT was defined as a “threshold below which a leachable would have a dose so low as to present negligible safety concerns from carcinogenic and non‐carcinogenic toxic effects”.⁸ Unfortunately, this limit was non‐aligned with the default threshold of toxicological concern (TTC) of 1.5μg/day for mutagenic impurities⁹ and implied that all leachables should be viewed as very potent mutagens; a significant misrepresentation of the toxicity of the known majority. As such, the SCT is significantly lower than is required, wasting time, money and effort. ELSIE advocated the adoption of permitted daily exposure (PDE) or the related TTC limits for leachables, “which would still constitute a virtually safe dose (VSD), but would significantly increase productivity, and reduce time and costs, with no effect on patient safety”.¹⁰

For readers who are interested in learning more on ICH Q3E, there is a forthcoming symposium on this subject in London in May 2020.¹¹

References

1. ICH Assembly, Singapore. November 2019. Available at: https://www.ich.org/pressrelease/ich-assembly-singapore-november-2019. [Accessed 27 December 2019].
2. Nagao et al. The ELSIE Extractable and Leachable Database [Internet]. Pharm. Outsourcing. 01 November 2011. Available at: https://www.pharmoutsourcing.com/Featured-Articles/37828-The-ELSIE-Extractables-and-Leachables-Database/. [Accessed on 27 Dec 2019].
3. Teasdale et al. Controlled Extraction Studies Applied to Polyvinyl Chloride and Polyethylene Materials: Conclusions from the ELSIE Controlled Extraction Pilot Study. AAPS PharmSciTech. 16(3), 2015, 664-674.
4. Stults et al. Evaluation of extractables in processed and unprocessed polymer materials used for pharmaceutical applications. AAPS PharmSciTech. 16)1), 2015, 150-164.
5. ICH Q3D, 2014. Guideline for elemental impurities – Step 4. 16 December 2014.
6. Jenke et al. Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in Packaged Drug Products: A Literature Review. PDA Pharm. Sci. Technol. 69(1), 2015, 1-48.
7. Broschard et al. Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics – Current challenges and approaches. Toxicol. Pharmacol., 81, 2016, 201-211.
8. Norwood et al. Best practices for extractables and leachables in orally inhaled and nasal drug products: An overview of the PQRI recommendations. Res., 25(4), 2007, 727-739.
9. ICH M7. Guideline on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk – Step 4. 23 June 2014.
10. Extractables and leachables– safety-based limits. EPR, 22(4), 2017, 7.
11. Joint Pharmaceutical Analysis Group symposium entitled ICH Q3E (Extractables and Leachables): setting the scene. Thursday 7 May 2020. Available at: https://www.jpag.org/.