Framework for sensitization assessment of extractables and leachables in pharmaceuticals

Abstract

During the toxicological assessment of extractables and leachables in drug products, localized hazards such as irritation or sensitization may be identified. Typically, because of the low concentration at which leachables occur in pharmaceuticals, irritation is of minimal concern; therefore, this manuscript focuses on sensitization potential. The primary objective of performing a leachable sensitization assessment is protection against Type IV induction of sensitization, rather than prevention of an elicitation response, as it is not possible to account for the immunological state of every individual. Sensitizers have a wide range of potencies and those which induce sensitization upon exposure at a low concentration (i.e. strong, or extreme sensitizers) pose the highest risk to patients and should be the focus of the risk assessment. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium has reviewed the status of dermal, respiratory, and systemic risk assessment in cosmetic and pharmaceutical industries, and proposes a framework to evaluate the safety of known or potential dermal sensitizers in pharmaceuticals. Due to the lack of specific regulatory guidance on this topic, the science-driven risk-based approach proposed by ELSIE encourages consistency in the toxicological assessment of extractables and leachables to maintain high product quality and ensure patient safety.

Keywords:

• Extractables
• leachables
• sensitization
• risk assessment

Acknowledgements

The manuscript was sent to all members of the Safety Information Working Group and the Board of Directors of the ELSIE Consortium for review, and no objections were received. The authors would like to thank the immunotoxicology subject matter experts Curtis Maier (GlaxoSmithKline) and Catherine Betts (AstraZeneca) who kindly educated on and discussed sensitization, risk assessment and particularly systemic sensitization in relation to parenteral drug products. We would also like to acknowledge the excellent support and advice received from Gavin Maxwell, Cameron Mackay, Nicky Gilmour, Stella Cochrane and Maria Baltazar from Unilever who hosted a visit and provided an excellent insight into skin sensitization risk assessment in the consumer/cosmetics industry, as well as discussing the development of the DST. And finally, many thanks to Martyn Chilton (Lhasa Limited) for providing the Derek Nexus applicability domain analysis for E&Ls in the ELSIE database.

Declaration of interest

The authors have no conflict of interest to disclose. The content of the manuscript was developed solely by the authors, and their affiliations are indicated above. Maureen Cruz and Lee Nagao are members of the ELSIE Consortium Secretariat, which is funded by the Consortium members. All other author’s employers are members of the ELSIE Consortium, a nonprofit association that provides a forum for industry experts to share safety information on extractables and leachables. Statements in this manuscript are those of the authors and not of their employers. All experts that provided substantive input or advice are listed as authors or included in the acknowledgments. In the last five years, none of the authors have participated in any legal, regulatory, or advocacy activities related to the contents of the paper.