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The nitrosamine Q&A document “Questions and answers for marketing authorization holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products” of the European Medicines Agency (EMA) contains three appendices (Appendix 1-3) in its current version (19 July 2024; Rev. 21).
On 04 September 2024, EMA released an update to Appendix 1 (EMA 393815/2024 /Rev. 6). This Appendix was prepared by the Non-clinical Working Party (NcWP) and provides an overview of nitrosamines for which acceptable intake (AI) values have been established.
New nitrosamine drug substance-related impurities (NDSRIs) linked to the manufacturing process of various active pharmaceutical ingredients (APIs) have been published (Table 1). For each of these NDSRIs, an acceptable intake is established.
NDSRI |
API |
CPCA Category |
New AI (ng/day) |
|---|---|---|---|
|
N-nitroso-2,4-thiazole amine (NNTA) |
Nirmatrelvir/Ritanovir |
1 |
18 |
|
N-Nitroso-acebutol |
Acebutol |
4 |
1500 |
|
N-Nitroso-buspirone Impurity 1 |
Buspirone |
3 |
400 |
|
N-nitroso-desmethyl-dimetindene |
Dimetindene |
1 |
18 |
|
N-nitroso-desmethyl-rivastigmine |
Rivastigmine |
2 |
100 |
|
N-nitroso-iminodibenzyl |
Melipramin |
/ |
78000* |
|
N-nitroso-maprotiline |
Maprotiline |
1 |
18 |
|
N-nitroso-propafenon |
Propafenon |
2 |
100 |
|
N-nitroso-valsartan cyano-desvalerylmethylester |
Valsartan |
2 |
100 |
|
N-nitroso-vanzacaftor |
Vanzacaftor |
4 |
1500 |
|
nitroso vildagliptin amide impurity |
Vildagliptin |
5 |
1500 |
*Limit derived using structure-activity-relationship (SAR)/read-across approach using the TD50 of N-nitroso-diphenylamine (NDPh) as point of departure
Updated AI values of existing NDSRIs are shown in Table 2.
NDSRI |
API |
CPCA Category |
New AI (ng/day) |
|---|---|---|---|
|
Ciprofloxacin |
NMI |
- |
100 |
|
N-nitroso-diclofenac |
Diclofenac |
- |
78000 |
|
N-nitroso-nortriptyline |
Amitriptyline, Nortryptyline |
1 |
18 |
|
N-nitroso-sertraline |
Sertraline |
2 |
100 |
NMI = non-mutagenic impurity
If your marketed medicine contains any of the APIs listed in Table 2, the potential presence of these new NDSRIs should be evaluated. If this evaluation has not yet been conducted, the nitrosamine risk evaluation should be promptly updated.
For APIs for which a risk was already identified (Table 3), it should be verified whether the updated AI values have an impact on the results of your confirmatory analysis.
As toxicological experts we can guide you through regulatory changes and ensure your nitrosamine risk evaluations are up-to-date and compliant. Fill in the contact form if you need help with any of the following:
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