Genotoxicity assessment in drug and device combination products connects regulatory classification, chemical characterisation and patient exposure. Prefilled syringes, transdermal patches and stents that release a medicinal substance illustrate how different product configurations can raise different questions about biological safety.
This article develops the scientific approach presented by Carla Landolfi at the Global Impurity Control Conference (2026), focusing on potential impurity assessment for genotoxicity potential originatied from device materials or API or form their interaction within the final product.
FDA and EU regulatory pathways for combination products
In the United States, combination products can include drug, device and biological constituents in the configurations defined by 21 CFR 3.2(e). The primary mode of action (PMOA) helps determine the lead FDA review centre. Assignment to a lead centre does not remove the need to address the safety of the other constituents (FDA, Combination Products FAQs).
In the European Union, the applicable pathway depends on the product configuration and the role of the medicinal substance. A device incorporating a medicinal substance with an ancillary action follows a different pathway from an integral product regulated as a medicine. Devices intended to administer medicines also require consideration of their specific configuration under Article 1(9) of the MDR. MDCG 2022-5 Rev.1 explains these distinctions.
The biological evaluation should therefore begin with a clear description of the product, its intended purpose and the applicable requirements for each constituent.
Where can device related genotoxic concerns arise?
Potential sources include residual monomers, additives, coatings, adhesives, manufacturing residues and material degradation products. Sterilisation and storage can introduce further changes. Contact with the formulation may also alter the migration of constituents or generate reaction products.
These possibilities require investigation in relation to the actual materials and manufacturing process. The presence of a potentially hazardous constituent in a material does not, by itself, establish the patient’s exposure or the resulting risk.
Extractables, leachables and patient exposure under ISO 10993
The assessment should connect the chemical profile with the conditions of use. ISO 10993-18 supports chemical characterisation, while ISO 10993-17 provides the framework for toxicological risk assessment of medical device constituents. ISO 10993-1:2025 places biological safety evaluation within a risk management process, and ISO 10993-3:2026 addresses evaluation of genotoxicity and related biological hazards.
Extractables studies can help identify potential sources of exposure. Leachables data can provide information about substances that migrate under the conditions studied. Interpreting either dataset requires attention to analytical coverage, identification confidence and the relationship between the study conditions and clinical use.
For each relevant constituent, the assessment should consider the amount potentially reaching the patient, the exposure route and the frequency and duration of administration. An analytical threshold guides the characterisation process, but does not independently establish toxicological safety.
QSAR and weight of evidence in genotoxicity assessment
Available experimental data, suitable analogue information and QSAR predictions can contribute to an expert weight of evidence assessment. Model applicability and the relevance of the endpoint must be documented. Predictions relating to bacterial mutagenicity address a particular concern and should not be presented as a complete evaluation of all genotoxic effects.
ICH M7(R2) addresses DNA reactive mutagenic impurities in pharmaceuticals. Its scientific principles can inform relevant questions, while their application to a device constituent requires justification within the applicable biological evaluation framework. TTC approaches similarly require confirmation of their applicability, including substance identity, exclusions and exposure conditions.
The current ICH Q3E guidance on extractables and leachables remains a draft, as listed by EMA at the time of preparing this article. Its proposals should be identified as draft recommendations rather than final requirements.
When is additional genotoxicity testing needed?
Additional genotoxicity testing should address a defined uncertainty remaining after review of the available evidence. The selection of assays, test article and sample preparation should reflect the relevant hazard and the chemical characteristics of the product. Potential interference with an assay also needs consideration when a medicinal substance is present in the test sample.
A defensible strategy documents what the existing evidence resolves, what remains uncertain and how further investigation will inform the safety conclusion.
How ToxHub can support your assessment
ToxHub supports medical device biological evaluation and toxicological risk assessment, interpretation of chemical characterisation data and in silico toxicology and expert QSAR review. We help manufacturers develop a scientifically justified strategy for the device constituents and their interactions with the medicinal product.
Discuss your combination product with ToxHub
Selected references
- FDA, Frequently Asked Questions About Combination Products, including 21 CFR 3.2.
- European Commission, MDCG 2022-5 Rev.1 (2024), guidance on the borderline between medical devices and medicinal products.
- ICH M7(R2), assessment and control of DNA reactive mutagenic impurities in pharmaceuticals.
- ICH Q3E, Extractables and Leachables, draft guideline, regulatory status checked on 2 October 2026.