A US-based medical devices manufacturer.
The company had commissioned leachables studies on a syringe medical device intended for flushing of intravenous catheters/tubing with saline. The leachables profile was examined at two time points (day 0 and about 2 months) and numerous substances were detected at low concentrations.
Bibra was asked to conduct a toxicological risk assessment (TRA) in compliance with ISO 10993-17 as part of the biological safety evaluation of the device. The client advised on the syringe use rate (number/day) and the length of treatment.
Approach & Project Outcome
Bibra conduced a screening assessment as a preliminary phase, aimed at identifying a smaller number of leachables that were health critical (high priority) for evaluation in the TRA, the underlying logic being that if a favourable conclusion is reached in the TRA for the highest concern chemicals, then the same would be true for the lower concern chemicals. The screening exercise involved a combination of information sources, including (quantitative) structure-activity relationship ((Q)SAR) analysis and consideration of human health classification data, as well as the toxicologists’ expert knowledge regarding critical toxicological endpoints (e.g., genotoxicity) and a consideration of the estimated patient exposure levels.
The subset of high priority leachables were subjected to a full TRA in compliance with ISO 10993-17 guidance. Bibra’s in-house TRACE database was used as an efficient means of identifying the critical toxicological literature on each leachable, and supplementary searches of key external data sources (e.g., PubMed) were also conducted. In each case, the critical toxicological data on the relevant biological endpoints (e.g., repeated-dose toxicity) were summarised and an appropriate Point of Departure (PoD) was identified for each leachable, where possible. Tolerable Intake (TI), Tolerable Exposure (TE) and Margin of Safety (MoS) values were calculated for each of the priority substances and relevant patient subpopulations, following application of appropriate Uncertainty Factors (UFs) to the PoD (e.g., for extrapolation from data derived in a species other than humans, or to account for potential differences in bioavailability between the exposure route of the critical study (commonly oral) and the intravenous (systemic) exposure that would be experienced by patients). In the absence of substance-specific data, bibra made use of read-across insights on structurally similar substances and/or application of the Threshold of Toxicological Concern (TTC).
For most leachables, the calculated MoS figures were reassuringly higher than 1 for each patient subgroup, indicating toxicological acceptability. Where the MoS was below (or closely approaching) 1, further discussion of the exposure scenario and the assumptions employed in the health risk assessment provided reassurance over patient health risks in practice.