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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 (15 January 2024; Rev. 20).
On 04 July 2024, EMA released an update to Appendix 1 (EMA/154403/2024 /Rev. 5). 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.
In the updated Appendix 1, acceptable intake (AI) values of some solvent-related nitrosamines impurities (i.e. NDIPA, NEIPA and NMBA) have been re-evaluated according to carcinogenic potency categorisation approach (CPCA) described in Appendix 2 (Table 1).
Nitrosamine |
Previous AI (ng/day) |
CPCA Category |
New AI (ng/day) |
|---|---|---|---|
|
N-nitroso-diisopropylamine (NDIPA) |
26.5 |
5 |
1500
|
|
N-nitroso-ethylisopropylamine (NEIPA) |
26.5 |
3 |
400 |
|
N-nitroso-N-methyl-4-aminobutyric acid (NMBA) |
96 |
4 |
1500 |
Furthermore, new nitrosamine drug substance-related impurities (NDSRIs) linked to the manufacturing process of various active pharmaceutical ingredients (APIs) have been published (Table 2). For each of these NDSRIs, an acceptable intake has been established.
NDSRI |
API |
CPCA Category |
New AI (ng/day) |
|---|---|---|---|
|
1-diphenylmethyl-4-nitrosopiperazine |
Cinnarizine |
3 |
400 |
|
3-(dimethylamino)propyl 2-[benzyl(nitroso)amino]benzoate (3-DPN) |
Benzydamine |
3 |
400 |
|
N-Nitroso-bilastine impurity 2 |
Bilastine |
3 |
400 |
|
N-nitroso-caspofungin |
Caspofungin |
4 |
1500 |
|
N-Nitroso-desformyl-riociguat |
Riociguat |
2 |
100 |
|
N-nitroso-desmethyl-clarithromycin |
Clarithromycin |
NMI |
- |
|
N-nitroso-desmethyl-tramadol |
Tramadol |
1 |
18 |
|
N-nitroso-desvaleryl-valsartan |
Valsartan |
NMI |
-
|
|
N-nitroso-N-desmethyl-diphenhydramine |
Dimenhydrinate/ Diphenhydramine |
1 |
18 |
|
N-nitroso-tigecycline |
Tigecycline |
NMI |
- |
|
N-nitroso-trandolapril |
Trandolapril |
5 |
1500 |
NMI = non-mutagenic impurity
Updated AI values of existing NDSRIs are shown in Table 3.
NDSRI |
API |
CPCA Category |
New AI (ng/day) |
|---|---|---|---|
|
Nitroso-STG-19 (NTTP) |
Sitagliptin |
2 |
100 |
|
N-nitroso-desmethyl-citalopram |
Citalopram |
- |
100 |
The increased acceptable intakes of solvent-related nitrosamines impurities (Table 1) can positively impact your nitrosamine risk evaluation, shifting from a ‘risk’ to a ‘no risk’ conclusion. Furthermore, detecting the impurity is less challenging due to the higher specification limit.
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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