In detail
Background and legal basis
In mid-2018, N-nitrosodimethylamine (NDMA) was detected in sartan blood pressure medicines. In September 2019, the European authorities set up a dedicated framework, the so-called call for review, initially for medicines containing chemically synthesised active substances. Following the CHMP review under Article 5(3) of Regulation (EC) No 726/2004, it was extended to biological medicines. The recommendations apply to all human medicines irrespective of marketing status, including generics and OTC products.
The three steps
- Step 1: risk evaluation of whether the active substance or finished product could contain nitrosamines. The deadline was 31 March 2021 for chemical and 1 July 2021 for biological active substances.
- Step 2: confirmatory testing where a risk has been identified.
- Step 3: effective risk mitigation measures, submitted as a variation to the marketing authorisation.
The evaluation is not a one-off exercise. Where new risk factors emerge, EMA expects marketing authorisation holders to revisit their evaluation.
Causes and limits
Nitrosamines form when amines meet nitrosating agents such as nitrites. EMA lists, among other things, contaminated or recovered solvents, traces of nitrite in excipients and blister lidding foils containing nitrocellulose. Particular attention is paid to active substances with a nitrosatable amine group, from which N-nitroso impurities of the active substance itself can form. ICH M7(R2) places nitrosamines in the cohort of concern. The limit is therefore a substance-specific acceptable intake (AI), corresponding to a theoretical excess cancer risk of less than 1 in 100,000 over a lifetime of exposure. Where data are lacking, the AI is derived using the Carcinogenic Potency Categorisation Approach (CPCA).
Analytical requirements
Methods must reliably capture trace levels. For routine control, the limit of quantification should be at or below the limit; to justify skip testing, at or below 30 per cent of it; and to justify omitting a specification, at or below 10 per cent. EMA requires mass-selective techniques such as MS/MS or high-resolution mass spectrometry to avoid false results from co-eluting substances. If a nitrosamine is detected, the competent authority must be informed without delay, irrespective of the amount.
In practice at A&O Pharma
Our GMP-certified laboratory in Itzehoe offers trace analysis by triple quadrupole LC-MS/MS, the kind of mass-selective technique EMA requires for nitrosamine testing. We handle the validation of analytical methods as part of our GxP consulting. Before testing starts, we agree with you whether a method is suitable for your product and the required limit.
Analytical ServicesFrequently asked questions
Does the nitrosamine assessment also apply to generics and OTC medicines?
Yes. According to EMA's Q&A document, marketing authorisation holders of all human medicines must ensure that nitrosamines are controlled and kept as low as possible, irrespective of marketing status or product type.
What has to be done if a nitrosamine is detected?
The competent authority must be informed without delay, irrespective of the amount found. If the limit is exceeded, EMA also expects an investigation report with the root cause, a risk mitigation plan and a benefit-risk assessment.
How sensitive does the test method need to be?
That depends on its purpose. For routine control, the limit of quantification must be at or below the limit; to omit a specification, at or below 10 per cent of it.
