The regulatory deadlines for nitrosamine impurities have passed, but the obligation has not. What began in 2018 as an urgent response to contaminated sartans has hardened into a permanent expectation: every marketing authorisation holder must be able to show, at any time, that its products are free of nitrosamines above the acceptable limit. For companies supplying the Greek and wider EU market, nitrosamine control is now a standing feature of the product lifecycle rather than a one-off exercise.
From crisis to standing obligation
The detection of N-nitrosodimethylamine (NDMA) in valsartan-containing medicines triggered a European referral procedure and, ultimately, an Article 5(3) opinion from EMA’s Committee for Medicinal Products for Human Use (CHMP). That opinion set out how manufacturers should evaluate, test for and prevent nitrosamines across their portfolios. The formal reporting deadlines have now elapsed, and in July 2025 EMA and the CMDh published a joint report on the regulatory network’s overall response. The message from regulators is unambiguous: any holder that has not completed its assessment, or that has new information to report, should act as a matter of priority.
The three-step approach — which never truly closes
The framework asks holders to work through three stages for every product:
- Risk evaluation — a structured review of active substances, excipients, manufacturing processes, packaging and storage to identify any route by which a nitrosamine could form or be introduced.
- Confirmatory testing — where a risk is identified, validated analytical methods are used to determine whether nitrosamines are actually present, and at what level.
- Changes to the marketing authorisation — where necessary, submitting variations to tighten specifications, change suppliers or reformulate.
Because supply chains, suppliers and processes change over time, these steps are not a project with an end date. A new source of active substance, a reformulation or a fresh scientific finding can reopen the assessment at any point.
NDSRIs and the potency-based limits
The more recent challenge concerns nitrosamine drug-substance-related impurities (NDSRIs) — nitrosamines derived from the active substance’s own molecular structure rather than from a contaminated reagent. To help set limits proportionately, EMA adopted a Carcinogenic Potency Categorisation Approach (CPCA), which groups impurities into categories with corresponding acceptable-intake limits based on structural features. Where a compound-specific limit is needed, an enhanced Ames test or robust toxicological data may support a case. The regulatory science here continues to evolve, and published limits are updated periodically — so relying on an out-of-date list is itself a risk.
What good control looks like
A defensible nitrosamine control strategy typically includes:
- A documented, product-by-product risk evaluation that is reviewed and kept current;
- Validated, sensitive analytical methods and a clear rationale for the limits applied;
- Active engagement with active-substance and finished-product manufacturers, backed by robust technical agreements;
- A change-control process that automatically re-triggers assessment when suppliers or processes change.
How PQRA helps
PQRA supports pharmaceutical companies and healthcare innovators across the full nitrosamine workflow — from risk evaluations and gap analyses to method and specification review, variation submissions and inspection readiness. We combine regulatory affairs and quality assurance expertise to keep your dossiers current with evolving EMA and EOF expectations, and to make sure a nitrosamine question never becomes a supply interruption in the Greek or EU market.
To review your nitrosamine risk position or prepare an upcoming submission, get in touch with the PQRA team.
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