Human health risk assessment of unknown contamination

Client

A pharmaceutical consulting firm.

Background

The client reported that small “brown spots” had been observed on the inside surface of a batch of aluminium tubes that contain a topical drug product. The source and chemical composition of the brown spots was unknown.

Project goals

To assess whether a product recall might be required, bibra was asked to evaluate the human health risks posed to patients being treated with the contaminated drug product.

Approach and outcome

To begin with, the worst-case exposure to the spot contaminant was estimated based on details provided by the client regarding the drug product use, as well as information regarding the size and number of spots per contaminated tube. 

Given that the chemical composition of the brown spots was not known, health-precautionary assumptions were made that the spots were (a) entirely organic, (b) entirely inorganic, and (c) a mixture of organic and inorganic constituents. Health risk assessments were conducted for each scenario.

In the case that the spots were entirely organic, taking a health-precautionary approach, bibra assumed that the spot chemicals could be potent systematic toxins, possess mutagenic potential, and be skin sensitisers. To add further conservatism, it was also assumed that the constituents were structurally related, sharing a common toxicological Mode-of-Action (MoA), thus acting in an additive manner. The Threshold of Toxicological Concern (TTC) concept was applied, and the Less-Than-Lifetime (LTL) TTC of 120 µg/day established in ICH M7 was determined to be an appropriate safety benchmark for the assessment of (cancer and non-cancer) systemic toxicity. Comparing the LTL TTC with the calculated worst-case exposure to the contaminants, a reassuring Margin of Safety (MoS) was estimated. With regards to possible sensitisation risk, the suggested applied amount of contaminant was compared with “human threshold” values reported by Expert Groups, and No Expected Sensitisation-Induction Levels (NESILs) quoted, for known sensitisers. Given the much lower proposed exposure to the contaminants, it was deemed highly unlikely that sensitisation would be induced. It was concluded that the anticipated exposure, should the brown spots be organic in nature, was not anticipated to pose any significant threat to patient health.

In the case that the spots were entirely inorganic, the exposure was assumed essentially to be to iron, based on analysis provided to bibra by the client. Comparison of the worst-case estimated exposure (assumed to be to iron) with a Permitted Daily Exposure (PDE) value for iron previously established by the European Medicines Agency (EMA) demonstrated a negligible health risk. It was therefore concluded that, should the brown spots be inorganic in nature, no significant threat to patient health would be anticipated.

In a scenario where organic and inorganic substances contribute to the total exposure, the levels of each type of substance, along with any potential health risks, would be even lower. Since neither previously proposed scenario posed a significant health risk, the same could be said for a mixed exposure scenario.

The result

Overall, the brown spots were not anticipated to pose any significant health risks to patients, and the client therefore was not obliged to recall the product.

Why bibra?

• An extensive in-house database TRACE enables comprehensive literature searching 
• All of our senior team are UK and European Toxicologists 
• Bibra has been providing expert, industry-leading toxicology consulting for the pharmaceutical industry for decades, and we have established ourselves as authorities in this area 

Learn more about our work in pharmaceutical toxicology

We have many years of experience in preparing toxicological assessments required in the pharmaceutical sector. We regularly provide our clients with assessments of novel or unexpected impurities, excipients and other intentionally-added substances, and extractables and leachables. Get in touch if we can help you!