Nitrosamine impurities are a distinct group of chemical contaminants classified as probable human carcinogens based on animal studies. Their detection in sartans in 2018 led to a specific assessment, testing, and mitigation process for medicinal products within the European Union.
Risks of Formation in the Manufacturing Process
Nitrosamines can form when suitable precursors and nitrosating conditions coincide within a manufacturing or degradation pathway. Risk assessment therefore tracks not only the active substance process, but also solvents, reagents, recovered materials, excipients, water, packaging, and potential interactions within the finished medicinal product. It must comprehensibly reflect the specific chemistry and actual operating conditions.
A process route without intentionally used nitrosamines is not automatically risk-free. Reused solvents, impurities in starting materials, or unexpected reactions during storage can open relevant pathways. The assessment examines which substances are used in what order, whether nitrite sources are present, and at which points a product or intermediate might be sensitive.
Assessment, Confirmation, and Risk Mitigation
The first step is a documented risk assessment of the individual medicinal product. If it indicates a plausible formation pathway or a source of contamination, a targeted confirmatory test follows using a suitable, sufficiently sensitive method. The analytical strategy must capture the nitrosamines in question and must not be limited to a non-specific total parameter.
If a risk is confirmed, the focus is on eliminating or controlling the cause. This may involve a change in reagents, suppliers, process conditions, purification, or packaging. For Marketing Authorisation Holders, measures include updating the marketing authorisation if a quality-relevant process change or specification adjustment becomes necessary.
The EMA distinguishes between the initial risk identification, targeted confirmation through analysis, and subsequent regulatory and technical measures. This sequence is important: a negative result for a single substance does not answer the question of whether other nitrosamines, plausible from the same process chemistry, were overlooked. The analytical selection must align with the description of potential formation pathways.
In biological medicinal products, the relevant sources may differ from those of a small-molecule active substance. EMA guidance covers both types of products; therefore, the assessment can focus on processes, raw materials, and materials that do not originate from classical organic synthesis. The risk analysis remains product-related rather than based on a previous finding pattern.
Risk mitigation is evaluated based on its actual effectiveness. A mere change of supplier is not sufficient if the new starting material does not demonstrate robust control of the nitrite source. Likewise, a changed process condition must show that it prevents the reaction or reliably reduces the impurity in question to an acceptable level.
Distinction from Elemental Impurities
Nitrosamine impurities are not a subcategory of elemental impurities. Elemental impurities concern individual metals or other elements and are assessed via element- and route-of-administration-specific permitted daily exposures. Nitrosamines are organic chemical compounds whose risk assessment is based on their specific structure, carcinogenicity, and potential formation pathways.
The regulatory pathway is also independent. For nitrosamines, the EMA refers to the scientific review under Article 5(3) of Regulation (EC) No 726/2004 and the resulting guidance for Marketing Authorisation Holders. The risk assessment is monitored throughout the entire product lifecycle, rather than being treated as a one-time incoming goods inspection.
The documentation brings together the assessed starting materials, conceivable reaction pathways, analytical results, and derived measures. This ensures it remains clear why a risk was excluded, confirmed, or mitigated through a specific process control.
The assessment is updated in the event of relevant changes, such as a new synthesis route, a different reagent manufacturer, or a modified solvent recovery process. It thus remains tied to actual process development.
Significance for Clinical Trials
The development of an investigational medicinal product may introduce new synthesis routes, batch sizes, suppliers, or packaging materials that alter the nitrosamine pathway. Therefore, even before later marketing, it must be checked whether the intended active substance and medicinal product process contains a plausible risk. This is particularly relevant when a clinical program relies on material from multiple manufacturing campaigns or from a modified route.
Full-service CROs like Mediconomics support the coordination of CMC risk assessment, investigational medicinal product documentation, and change information between the sponsor and manufacturing partners. If targeted analyses or process adjustments become necessary, they can track their impact on clinical delivery dates, batch status, and regulatory communication.
Frequently Asked Questions (FAQ)
Are nitrosamines only relevant in sartans?
No. The discovery in sartans was the trigger for regulatory work, but the EMA guidance applies to chemical and biological medicinal products where a corresponding risk may exist.
Is a single general laboratory test for nitrosamines sufficient?
Confirmatory testing must be targeted at the nitrosamines plausible in the specific product and must be sufficiently sensitive. The selection follows the previously documented risk analysis.
Who bears the responsibility for the assessment?
Marketing Authorisation Holders are responsible for the quality, safety, and efficacy of their medicinal product. This includes monitoring and mitigating nitrosamine risk throughout the product lifecycle.
Regulatory References
- Regulation (EC) No 726/2004, Article 5(3) — Basis of the scientific EMA review on nitrosamines.
- EMA “Nitrosamine impurities” — describes the background, risk, and the European regulatory response.
- EMA “Nitrosamine impurities: guidance for marketing authorisation holders” — explains risk assessment, confirmatory testing, and mitigation measures.