The criteria for evaluating leachables and extractables are well-defined in ICH guidelines for pharmaceutical products, and in ISO standards for biomedical devices. However, these papers primarily focus on systemic effects such as acute, subacute, subchronic, and chronic toxicity, reproductive and developmental toxicity, genotoxicity, and carcinogenicity, without providing clear guidance on assessing sensitizers.
Currently, there is no universally accepted risk level for sensitization reactions, as the immune system’s activation is a threshold-based effect that varies among allergenic compounds. Despite this, the Product Quality Research Institute (PQRI) has suggested an acceptable threshold limit of 5 micrograms per day for sensitizers found as extractables in pharmaceutical products. However, this lacks defining criteria, and sensitizers can vary significantly in potency.
To address this gap, various authors have proposed approaches for the toxicological risk evaluation of sensitizers. Notably, two recent publications by Liu & Hutchinson (2023) and Parris et al. (2025) offer distinct methods.
Liu & Hutchinson focus on extractables from parenteral pharmaceutical products, suggesting the calculation of an “acceptable exposure level” (AEL) for local sensitization. This AEL is derived from the EC3 parameter, which can be obtained from a Local Lymph Node Assay (LLNA) study or estimated using in silico methods. The AEL represents the exposure level to a sensitizer considered sufficiently safe.
Parris et al. (2025) build upon previous work by utilizing the ELSIE framework, which assesses the sensitization potential of extractables and leachables in the pharmaceutical and medical device industries. The ELSIE consortium involves expert toxicologists from various industries to derive Threshold of Toxicological Concern (TTC) values for organic, non-mutagenic substances administered parenterally, by analyzing databases, expert reviews, and case studies. It aims to protect against T-cell mediated hypersensitivity reactions and assesses sensitizer potency, with strong or extreme sensitizers posing the highest risk.
Parris et al. (2025) indicate that about 5% of extractables have the potential to be strong or extreme skin sensitizers (ECETOC definition). As a safety concern threshold, the authors propose existing safety threshold values like the Acceptable Intake from ICH M7 or modified TTC values proposed by ELSIE. These TTC-based values are adjusted for treatment duration, as illustrated by Masuda-Herrera et al. (2022), with thresholds of 35, 110, and 180 μg/day for human exposures exceeding 10 years, between 1–10 years, and less than or equal to one year, respectively.
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