FDA Guidance for Industry on the AI Limits for Nitrosamine Drug Substance Related Impurities

FDA Guidance for Industry on the AI Limits for Nitrosamine Drug Substance-Related Impurities

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In Pharmaceutical Industry today’s main concern is the identification and presence of nitrosamines in drug products and drug substances. The manufacturers of active pharmaceutical ingredients (APIs) and drug products have the findings of nitrosamine impurities which may be likely human carcinogens and require the need for risk assessment strategy for potential nitrosamines and their presence.

The US Food and Drug Administration (FDA) on 4th Aug 2023 released the final guidance document on the “Recommended Acceptable Intake Limits for Nitrosamine Drug substance-Related Impurities (NDSRIs guidance)”. This guidance recommends predicting the mutagenic and carcinogenic potential of nitrosamine drug substance-related impurities (NDSRIs) that might be present in drug products and recommends (AI) acceptable limits for NDSRIs to the manufacturers and applicants of drugs including prescription and over-the-counter (OTC) drug products.

NDSRIs are the class of nitrosamine impurities that have been identified in many active pharmaceutical ingredients (APIs) and in drug products. These impurities share structural similarity to the API (having API fragment or API in the chemical structure) and hence unique to each API. Through nitrosation of APIs (or API fragments) NDSRIs form in the drug product which have secondary or tertiary amines when exposed to nitrosating agents like residual nitrites in excipients which are used to formulate drug products.

This guidance suggests a risk-based safety assessment for NDSRIs to be used by the manufacturers and applicants to identify AI limits in their APIs and drug products in alliance with recommendations given in the guidance for industry control of Nitrosamine impurities in human drugs ( Feb 2021) Nitrosamine guidance.      

The detection of nitrosamine impurities was found in some of the commonly prescribed medicines used for treating diabetes, antacids, and others. Nitrosamine impurities and their presence and investigation in some of the drug products have been carried out by the FDA since 2018 when the FDA was informed of the presence of an impurity as N-Nitrosodimethylamine (NDMA) in the angiotensin receptor blocker Valsartan.

In drug products, the initial reports of nitrosamine impurities were of small molecules of nitrosamines such as NDMA, compounds that are formed by nitrosating reactions between amines (secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts under acidic conditions) that are generally due to synthesis of API conditions that introduce nitrite, nitrous acid, and amide solvents.

FDA issued guidance to the industry in the year 2020, the Nitrosamine Guidance recommending that the manufacturers of drug products and API should take steps to detect and prevent unacceptable levels of nitrosamine impurities in drug products or to avoid their presence when feasible.

The Nitrosamine guidance introduced a three-step process that manufacturers and applicants should take to mitigate nitrosamine impurities in their drug products.

  1. Conduct risk assessments for nitrosamine impurities in their APIs and drug products.
  2. Conduct confirmatory testing if risk is identified and
  3. A reported change is implemented to reduce or prevent the presence of nitrosamine impurities in drug products and APIs in approved and pending NDAs and ANDAs.

FDA also recommends to the manufacturers and applicants whose drug products contain multiple nitrosamines: If more than one nitrosamine impurity (NDSRI(s) and /or small molecule nitrosamine(s) is identified and if the nitrosamine total level exceeds the recommended AI limit for most of the potent nitrosamine in the drug product based on the maximum daily dose the applicant or the manufacturer should contact the agency.

Recommended AI limits for NDSRIs at risk of formation in certain APIs: FDA has identified a number of APIs that have secondary or tertiary amines and so are at risk for forming NDSRIs. Hypothetically under certain conditions related to the manufacturing and formulation process for the drug product, such as residual nitrites in excipients used to formulate the drug product, these APIs could form NDSRIs.

FDA has applied the predicted carcinogenic potency categorization to these APIs. Furthermore correctly based on the scientific analysis of chemical structures they have concluded that when an API contains hypothetical nitrosated forms of secondary amine- and dimethyl tertiary amine- groups these recommended AI limits based on predicted carcinogenic potency should be applied to the NDSRIs to the extent they form in the these APIs.  

Nitroso Impurities

CAS No. Name of Impurity Catalogue No.
N/AABCRC-1 Dinitroso ImpurityVE007759
N/AABCRC-1 Nitroso Impurity-1VE007757
N/AABCRC-1 Nitroso Impurity-2VE007758
N/AAbacavir Nitroso-1VE007065
N/AAcarbose Nitroso Impurity 1VE0011237
N/AAvanafil Nitroso Impurity 1VE0014150
N/ABupropion Nitroso ImpurityVE009664
N/ACarvedilol Di-NitrosoVE0010478
N/ACilnidipine Nitroso ImpurityVE008671
N/AClevidipine Nitroso ImpurityVE0014062
7458-08-4Clomipramine EP Impurity E (Nitroso Impurity)VE009769
78213-40-8Clomipramine EP Impurity F Nitroso ImpurityVE0010055
N/ADarolutamide Nitroso ImpurityVE0010234
N/ADasatinib Nitroso ImpurityVE0011523
148950-50-9Di-Nitroso-ClonidineVE0011406
13256-12-7Diethylamine Dinitroso ImpurityVE009666
23834-30-2Diethylamine Nitroso ImpurityVE009665
55556-94-0Dinitroso-Methyl piperazine GatifloxacinVE008163
N/ADuloxetine Nitroso ImpurityVE007668
N/AElagolix Nitroso ImpurityVE009406
N/AElagolix ethyl ester nitroso impurityVE009692
N/AEletriptan Nitroso ImpurityVE0010500
N/AEthyl 1-nitroso-1H-tetrazole-5-carboxylateVE0012581
N/AEthyl 1-nitroso-4-oxo-1, 4-dihydroquinoline-3-carboxylateVE0011351
N/AEzetimibe Nitroso ImpurityVE0010294
N/AEzetimibe Nitroso Impurity 1VE0010001
N/AEzetimibe Nitroso Impurity 2VE0010003
N/AFomepizole Nitroso ImpurityVE0014755
N/AFrovatriptan Nitroso Impurity 1VE0010499
N/AFrovatriptan Nitroso Impurity 2VE0010501
N/AGranisetron Nitroso ImpurityVE0011607
1233340-45-8Imidazole Nitroso ImpurityVE007717
N/AIndacaterol Nitroso ImpurityVE0010331
N/AIrbesartan Nitroso Impurity 1VE006176
N/AIrbesartan Nitroso Impurity 2VE008461
N/AIrbesartan Nitroso Spiro ImpurityVE006185
N/AIsopropyl (2-amino-6-((4-fluorobenzyl)(nitroso)amino)pyridin-3-yl)carbamate - FlupirtineVE007901
N/AIvacaftor Nitroso ImpurityVE0010062
N/ALansoprazole Nitroso ImpurityVE007769
N/ALevomefolate Nitroso Impurity 1VE0014190
N/ALevomefolate Nitroso Impurity 2VE0014191
6972-78-7Linagliptin Nitroso Pyrimidine ImpurityVE007060
N/ALumateperone Nitroso Impurity 3VE009758
N/AMethyl (2-amino-6-((4-fluorobenzyl)(nitroso)amino)pyridin-3-yl)carbamate - FlupirtineVE007903
946126-94-9Methyl 2-fluoro-3-nitrobenzoateVE0011046
68061-82-5Methyl N-Methyl-N-NitrosoanthranilateVE0012234
N/AMetolazone Nitroso Impurity 1VE0011404
148950-49-6Mono-Nitroso Clonidine ImpurityVE0010228
N/AMononitroso Ethambutol ( S Isomer)VE009913
N/AMoxifloxacin Related Compound A Nitroso ImpurityVE0011337
N/AMoxifloxacin Related Compound B Nitroso ImpurityVE0011338
N/AMoxifloxacin Related Compound C Nitroso ImpurityVE0011339
N/AMoxifloxacin Related Compound D Nitroso ImpurityVE0011340
N/AMoxifloxacin Related Compound G Nitroso ImpurityVE0011341
N/AMoxonidine Imine Nitroso ImpurityVE009855
N/AN, N'-(5-nitroso-10, 11-dihydro-5H-dibenzo[b, f]azepine-3, 7-diyl)diacetamideVE009785
N/AN, N-DiNitroso Moxonidine ImpurityVE009854
53743-85-4N, N-Diethyl-4-nitrosoaniline HClVL6590009
N/AN, N-dimethyl-2-(1-nitroso-5-((pyrrolidin-1-ylsulfonyl)methyl)-1H-indol-3-yl)ethanamineVE0011198
13256-06-9N- Nitroso Diamyl AmineVE006109
N/AN-(1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)-N-(7H-pyrrolo[2, 3-d]pyrimidin-4-yl)nitrous amideVE009892
N/AN-(2-((2-(dimethylamino)ethyl)(nitroso)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamideVE009898
N/AN-(2-(ethyl(nitroso)amino)ethyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamideVE0010010
N/AN-(2-(ethyl(nitroso)amino)ethyl)-5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxamideVE0010011
N/AN-(2-aminopyridin-3-yl)-N-(1-nitrosopiperidin-4-yl)nitrous amideVE0010249
N/AN-(2-ethylphenyl)nitrous HydrazideVE0011263
N/AN-(3-((3-(3-chloro-10, 11-dihydro-5H-dibenzo[b, f]azepin-5-yl)propyl)(methyl)amino)propyl)-N-methylnitrous amideVE009804
N/AN-(3-(10, 11-dihydro-5H-dibenzo[b, f]azepin-5-yl)propyl)-N-methylnitrous amideVE009806
N/AN-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2-fluoro-6-methoxybenzenesulfonamideVE0011061
N/AN-(3-(3, 7-dichloro-10, 11-dihydro-5H-dibenzo[b, f]azepin-5-yl)propyl)-N-methylnitrous amideVE009808
N/AN-(3-(3-chloro-10, 11-dihydro-5H-dibenzo[b, f]azepin-5-yl)propyl)-N-(3-(dimethylamino)propyl)nitrous amideVE009805
N/AN-(3-(3-chloro-5H-dibenzo[b, f]azepin-5-yl)propyl)-N-methylnitrous amideVE009807
N/AN-(3-(dimethylamino)propyl)-N-methylnitrous amideVE009810
N/AN-(3-chloropropyl)-N-methylnitrous amideVE009809
N/AN-(4-ethyl-2-(methyl(2-(methyl(nitroso)amino)ethyl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamideVE009899
N/AN-(5-nitroso-10, 11-dihydro-5H-dibenzo[b, f]azepin-3-yl)acetamideVE009784
123704-98-3N-AcetylaminoisonitrosoacetanilideVE0014769
N/AN-Dinitroso AlmotriptanVE0011196
N/AN-Nitroso -2, 6 dichloro purineVE006125
N/AN-Nitroso 3-MPPPVE007898
N/AN-Nitroso AFBP Impurity (Flupirtine)VE007888
N/AN-Nitroso ANFP Impurity (Flupirtine)VE007887
N/AN-Nitroso AbacavirVE0011534
N/AN-Nitroso Abiraterone Acetate NitriteVE0011619
N/AN-Nitroso Abiraterone Acetate TetrafluoroborateVE0011618
N/AN-Nitroso AceclofenacVE0011687
N/AN-Nitroso AllopurinolVE0014231
N/AN-Nitroso Alogliptin Benzoate Dimer ImpurityVE0012079
N/AN-Nitroso Alogliptin Impurity 12VE0012078
N/AN-Nitroso AltizideVE008448
N/AN-Nitroso Amlodipine EP Impurity BVE0010278
N/AN-Nitroso Amlodipine EP Impurity EVE0010289
N/AN-Nitroso Amlodipine EP Impurity FVE0010288
N/AN-Nitroso Amlodipine EP Impurity GVE0010284
N/AN-Nitroso Amlodipine EP Impurity HVE0010286
N/AN-Nitroso Amlodipine Galactose Adduct ImpurityVE0010287
N/AN-Nitroso Amlodipine Impurity-1VE008552
N/AN-Nitroso Amlodipine Lactose Adduct ImpurityVE0010285
N/AN-Nitroso Amlodipine atorvastatine AdductVE0010279
N/AN-Nitroso ApremilastVE0011283
N/AN-Nitroso ArgatrobanVE0014149
N/AN-Nitroso AtazanavirVE0014358
N/AN-Nitroso Atenolol Impurity GVE0011712
N/AN-Nitroso Atenolol Impurity HVE0011713
N/AN-Nitroso Atenolol Impurity IVE0011714
N/AN-Nitroso AzithromycinVE0010108
N/AN-Nitroso Azithromycin EP Impurity IVE0010109
N/AN-Nitroso BalofloxacinVE0013088
N/AN-Nitroso BenazeprilVE0011179
N/AN-Nitroso BendamustineVE008451
N/AN-Nitroso BendroflumethazideVE008450
N/AN-Nitroso Betahistine EP Impurity CVE0010864
N/AN-Nitroso BinimetinibVE0012757
N/AN-Nitroso BrinzolamideVE0014151
2490432-02-3N-Nitroso Bumetanide ImpurityVE006127
N/AN-Nitroso Candesartan Cilexetil EP Impurity AVE0010305
N/AN-Nitroso Candesartan Cilexetil EP Impurity BVE0010308
N/AN-Nitroso Candesartan Cilexetil EP Impurity GVE0010306
N/AN-Nitroso Candesartan Cilexetil EP Impurity IVE0010307
N/AN-Nitroso Candesartan Cilexetil ImpurityVE0010328
N/AN-Nitroso CangrelorVE0014154
N/AN-Nitroso CarbidopaVE0010461
2248746-67-8N-Nitroso CarvedilolVE0010476
N/AN-Nitroso CaspofunginVE0014156
N/AN-Nitroso CeliprololVE0010031
2005-04-1N-Nitroso Cetirizine EP Impurity AVE0013096
N/AN-Nitroso ChloroquineVE0011720
N/AN-Nitroso CinacalcetVE007661
N/AN-Nitroso Citrate De BetaineVE0011305
N/AN-Nitroso Clonidine ImpurityVE0011405
156632-03-0N-Nitroso ClozapineVE0013883
N/AN-Nitroso Clozapine EP Impurity CVE0013882
N/AN-Nitroso Dabigatran Impurity 14VE0014038
N/AN-Nitroso Dabigatran Impurity 33VE0014039
N/AN-Nitroso Dabigatran Impurity 65VE0014040
N/AN-Nitroso Dabigatran Impurity 73 (TFA Salt)VE0014041
N/AN-Nitroso Dabigatran Impurity 8VE0014043
N/AN-Nitroso Dabigatran Impurity 83VE0014037
N/AN-Nitroso DaclatasvirVE0014364
N/AN-Nitroso DapsoneVE0011247
57164-17-7N-Nitroso DesipramineVE0014166
1246819-22-6N-Nitroso DesloratadineVE007389
N/AN-Nitroso Desmethyl Almotriptan ImpurityVE0011197
N/AN-Nitroso Desmethyl AzelastineVE0010362
N/AN-Nitroso Desmethyl CabergolineVE0014152
N/AN-Nitroso Desmethyl ChlorpheniramineVE0014158
55855-44-2N-Nitroso Desmethyl ChlorpromazineVE0014159
N/AN-Nitroso Desmethyl ClarithromycinVE0014163
N/AN-Nitroso Desmethyl ClomipramineVE009800
N/AN-Nitroso Desmethyl CyclobenzaprineVE0014165
N/AN-Nitroso Desmethyl Eletriptan ImpurityVE0010502
N/AN-Nitroso Desmethyl N-Nitroso Sumatriptan ImpurityVE0011262
N/AN-Nitroso Desmethyl Sumatriptan ImpurityVE0010179
N/AN-Nitroso Desmethyl TamoxifenVE0014157
N/AN-Nitroso Desmethyl TapentadolVE0014155
N/AN-Nitroso Dextromethorphan EP Impurity AVE0010481
66505-80-4N-Nitroso DiclofenacVE009623
55-18-5N-Nitroso Diethylamine (NDEA)VL3850024
55855-43-1N-Nitroso DiphenhydramineVE0011180
63819-70-5N-Nitroso DiterbutylamineVE007730
N/AN-Nitroso DolutegravirVE0014359
N/AN-Nitroso DomperidoneVE0011581
N/AN-Nitroso DorzolamideVE0010215
N/AN-Nitroso Dorzolamide-D5DVE00534
N/AN-Nitroso Doxepin EP Impurity CVE0014568
N/AN-Nitroso Edoxaban Impurity 70VE0013032
N/AN-Nitroso EltrombopagVE0010123
N/AN-Nitroso EnalaprilVE0010474
1850-61-9N-Nitroso EphedrineVE0011708
N/AN-Nitroso EpinephrineVE0014063
N/AN-Nitroso ErtapenemVE0014172
N/AN-Nitroso Escitalopram ImpurityVE006453
N/AN-Nitroso EsmololVE0014170
N/AN-Nitroso EtravirineVE0014171
N/AN-Nitroso Famotidine 1VE0011719
N/AN-Nitroso Fenoldopam ImpurityVE008184
N/AN-Nitroso Finasteride Impurity 1VE0013942
N/AN-Nitroso Finasteride Impurity 2VE0013943
N/AN-Nitroso FinerenoneVE0014374
N/AN-Nitroso FingolimodVE0011248
N/AN-Nitroso FlecainideVE0014173
150494-06-7N-Nitroso FluoxetineVE007630
N/AN-Nitroso FlupirtineVE006870
N/AN-Nitroso Flupirtine Related Compound 9VE0010473
N/AN-Nitroso Folic Acid Impurity-IIVE008186
N/AN-Nitroso Fostamatinib-1VE0014353
N/AN-Nitroso Fostamatinib-2VE0014355
N/AN-Nitroso Gentamicin 1VE007829
N/AN-Nitroso Gentamicin 2VE007831
N/AN-Nitroso Gentamicin 3VE007832
N/AN-Nitroso HydralazineVE0014352
N/AN-Nitroso HydrochlorothiazideVE009704
N/AN-Nitroso ImatinibVE0013972
N/AN-Nitroso Imidazole Ester OlmesartanVE007890
38652-29-8N-Nitroso IminostilbeneVE009768
N/AN-Nitroso Impurity A1VE0011510
N/AN-Nitroso Impurity A2VE0011511
N/AN-Nitroso Impurity A3VE0011512
N/AN-Nitroso Impurity BVE0011513
N/AN-Nitroso IsoxsuprineVE0014183
N/AN-Nitroso IsradipineVE0014184
2820170-74-7N-Nitroso LabetalolVE007835
N/AN-Nitroso LabetololVE007835
N/AN-Nitroso LercanidipineVE0011168
N/AN-Nitroso LevalbuterolVE0014185
N/AN-Nitroso Levetiracetam ImpurityVE0014273
N/AN-Nitroso LevobunololVE0014186
14340-33-1N-Nitroso Levodropropizine EP Impurity BVE0014579
2089332-99-8N-Nitroso Levodropropizine EP Impurity B-D4DVE00549
N/AN-Nitroso Lincomycin Impurity 1VE0011697
519175-80-5N-Nitroso LisinoprilVE0010130
N/AN-Nitroso Lisinopril EP Impurity EVE0011216
N/AN-Nitroso Lisinopril EP Impurity FVE0011217
2518136-84-8N-Nitroso LorcaserinVE0014162
N/AN-Nitroso LumateperoneVE009759
N/AN-Nitroso MaravirocVE0014362
N/AN-Nitroso MefloquineVE0014192
278783-22-5N-Nitroso MelatoninVE0011336
1219794-54-3N-Nitroso Melphalan EP Impurity K-D10DVE00133
N/AN-Nitroso MeropenemVE0014193
73829-38-6N-Nitroso Metamizole EP Impurity CVE0011346
N/AN-Nitroso MetforminVE0010233
7068-83-9N-Nitroso Methyl Butyl AmineVE006107
N/AN-Nitroso Midodrine ImpurityVE0014312
N/AN-Nitroso MigalastatVE0014196
N/AN-Nitroso MirabegronVE009905
N/AN-Nitroso Mitoxantrone Impurity 1VE0014197
N/AN-Nitroso Mitoxantrone Impurity 2VE0014199
1026879-47-9N-Nitroso MoexiprilVE0014201
N/AN-Nitroso MorniflumateVE0011306
N/AN-Nitroso MoxifloxacinVE008036
N/AN-Nitroso N-BOC Piperazine TeneligliptinVE007899
N/AN-Nitroso N-Desbenzyl Nicardipine ImpurityVE0010197
N/AN-Nitroso N-Desmethyl CitalopramVE0013743
N/AN-Nitroso N-Desmethyl DoxylamineVE0014167
N/AN-Nitroso N-Desmethyl MethadoneVE0014194
N/AN-Nitroso N-Desmethyl MifepristoneVE0014195
N/AN-Nitroso N-Desmethyl Olanzapine ImpurityVE0010535
N/AN-Nitroso N-desmethyl Nicardipine ImpurityVE0010196
N/AN-Nitroso N-desmethyl PheniramineVE0014203
N/AN-Nitroso Nadolol ImpurityVE0011254
2703749-87-3N-Nitroso NaphazolineVE0011181
N/AN-Nitroso Niflumic AcidVE0011307
N/AN-Nitroso NilotinibVE0011411
N/AN-Nitroso NimodipineVE009628
N/AN-Nitroso NisoldipineVE0014202
55855-42-0N-Nitroso NortriptylineVE008160
N/AN-Nitroso O-Benzyl IndacaterolVE0010554
N/AN-Nitroso OlmesartanVE0010543
N/AN-Nitroso Olmesartan Medoxomil ImpurityVE007896
N/AN-Nitroso OlodaterolVE0014204
N/AN-Nitroso Olopatadine N-Desmethyl ImpurityVE0010528
N/AN-Nitroso OmeprazoleVE0010941
N/AN-Nitroso OxomemazineVE0011308
N/AN-Nitroso Ozanimod ImpurityVE009803
N/AN-Nitroso PalbociclibVE009744
N/AN-Nitroso PantoprazoleVE0010076
N/AN-Nitroso PazopanibVE0011522
N/AN-Nitroso PemigatinibVE0010447
N/AN-Nitroso PerindoprilVE0011281
78658-64-7N-Nitroso PhenylephrineVE0011182
N/AN-Nitroso PindololVE0014205
126209-21-0N-Nitroso Pirfenidone EP Impurity AVE009705
2512237-43-1N-Nitroso Pirfenidone EP Impurity BVE009706
N/AN-Nitroso Plazomicin 1VE0014198
N/AN-Nitroso Plazomicin 2VE0014200
94511-44-1N-Nitroso Promethazine ImpurityVE0011232
84418-35-9N-Nitroso PropranololVE007279
N/AN-Nitroso ProtriptylineVE0014182
N/AN-Nitroso Pyrantel Pamoate ImpurityVE008185
N/AN-Nitroso Quinapril ImpurityVE0010651
N/AN-Nitroso Quinoline Acid ImpurityVE0010065
N/AN-Nitroso Rac N-Desmethyl TramadolVE0011408
N/AN-Nitroso RamiprilVE0010563
N/AN-Nitroso Ranitidine-1VE0014169
N/AN-Nitroso Ranolazine Impurity 1VE0010326
N/AN-Nitroso RisdiplamVE0014168
N/AN-Nitroso RitalinicVE0012694
N/AN-Nitroso RopivacaineVE0014753
2657645-00-4N-Nitroso SafinamideVE0014161
N/AN-Nitroso SalbutamolVE009145
N/AN-Nitroso SalmeterolVE0013029
N/AN-Nitroso SildenafilVE0011456
N/AN-Nitroso SilodosinVE007637
N/AN-Nitroso Sitagliptin D4DVE00101
N/AN-Nitroso Sitagliptin ImpurityVE009183
N/AN-Nitroso TMB Impurity OlmesartanVE007894
N/AN-Nitroso Tamsulosin ImpurityVE0010482
N/AN-Nitroso TeneligliptinVE0010120
N/AN-Nitroso Teneligliptin R-isomerVE007900
N/AN-Nitroso TerbutalineVE009901
N/AN-Nitroso TeriflunomideVE0011282
N/AN-Nitroso TetracaineVE0014146
N/AN-Nitroso TheophyllineVE0011721
N/AN-Nitroso TigecyclineVE008528
N/AN-Nitroso TimololVE0010214
N/AN-Nitroso TirofibanVE0014143
N/AN-Nitroso TofacitinibVE009521
N/AN-Nitroso Tofacitinib Impurity 2VE0011615
N/AN-Nitroso Torasemide EP Impurity BVE0013145
N/AN-Nitroso TrandolaprilVE0011528
N/AN-Nitroso TrientineVE0014142
N/AN-Nitroso Urapidil ImpurityVE0010871
N/AN-Nitroso Valsartan ImpurityVE008372
N/AN-Nitroso Valsartan Methyl Ester ImpurityVE008373
N/AN-Nitroso Valsartan-1VE0010124
N/AN-Nitroso Verapamil Impurity-1VE0010164
N/AN-Nitroso VilanterolVE0014141
N/AN-Nitroso VortioxetineVE009743
N/AN-Nitroso ZanubrutinibVE009880
N/AN-Nitroso ZidovudineVE0014363
N/AN-Nitroso amlodipine EP Impurity AVE0010280
N/AN-Nitroso dobutamineVE007836
N/AN-Nitroso isoproterenolVE007833
86144-35-6N-Nitroso ketamineVE0010448
N/AN-Nitroso levofloxacin diamineVE008449
N/AN-Nitroso linezolid ImpurityVE0011947
N/AN-Nitroso of Azithromycin Impurity IVE007867
N/AN-Nitroso of DSVRC-3 impurity DesvenlafaxinVE007863
2680662-11-5N-Nitroso of Desvenlafaxin Impurity-AVE007862
N/AN-Nitroso of Leve Inter (LCTRC-3) LevetiracetamVE007881
N/AN-Nitroso of N-Demethyl erythromycin A (Azithromycin)VE007865
N/AN-Nitroso of ZTA-III Impurity (Azithromycin)VE007866
2361294-43-9N-Nitroso paroxetine ImpurityVE0010300
55556-92-8N-Nitroso-1, 2, 3, 6-TetrahydropyridineVE009688
77400-46-5N-Nitroso-2, 2, 5-trimethyl-1, 3-oxazolidineVE008028
N/AN-Nitroso-3-Methyl Piperazine ImpurityVE008376
28698-93-3N-Nitroso-7-monomethylamino-6-deoxytetracyclineVE0011483
N/AN-Nitroso-AcebutololVE007667
N/AN-Nitroso-Acebutolol-D7DVE00106
N/AN-Nitroso-AmbroxolVE007666
N/AN-Nitroso-AmoxapineVE007665
N/AN-Nitroso-AtomoxetineVE007664
32635-81-7N-Nitroso-BetahistineVE007663
N/AN-Nitroso-BetaxololVE0012730
N/AN-Nitroso-BisoprololVE007662
864443-44-7N-Nitroso-CiprofloxacinVE007657
N/AN-Nitroso-Desmethyl-Minocycline-1VE0014240
N/AN-Nitroso-Desmethyl-Minocycline-2VE0014241
N/AN-Nitroso-Desmethyl-SildenafilVE0011369
N/AN-Nitroso-Desmethyl-TetracyclineVE0014242
N/AN-Nitroso-DrotaverineVE007656
2680527-91-5N-Nitroso-DuloxetineVE0010541
N/AN-Nitroso-FelodipineVE007653
30248-47-6N-Nitroso-L-azetidine-2-Carboxylic AcidVE0010032
7519-36-0N-Nitroso-L-prolineVE007000
1152314-62-9N-Nitroso-Levofloxacin Impurity-1VE0010475
N/AN-Nitroso-Lisinopril-D5DVE00515
N/AN-Nitroso-MaprotilineVE007643
62137-31-9N-Nitroso-MeglumineVE009502
N/AN-Nitroso-Moxonidine (mononitroso)VE007642
2114-63-8N-Nitroso-N-2, 3-xylylanthranilic acidVE006846
N/AN-Nitroso-N-Desmethyl DEBA ZolmitriptanVE007892
N/AN-Nitroso-N-Desmethyl ZolmitriptanVE007893
20689-96-7N-Nitroso-N-Ethyl-BenzylamineVE006349
N/AN-Nitroso-N-desmethyldoxycyclineVE0010971
4549-44-4N-Nitroso-N-ethylbutylamineVE006113
614-00-6N-Nitroso-N-methyl N- phenylamineVL3850093
61445-55-4N-Nitroso-N-methyl-4-aminobutyric Acid(NMBA)VL3850049
1184996-41-5N-Nitroso-N-methyl-4-aminobutyric Acid-D3DVE0082
1821341-18-7N-Nitroso-N-methylaniline-d5DVE00217
937-40-6N-Nitroso-N-methylbenzylamineVE006112
N/AN-Nitroso-Pramipexole-D5DVE00102
N/AN-Nitroso-PropafenoneVE007640
1850-88-0N-Nitroso-PseudoephedrineVE007671
N/AN-Nitroso-RanolazineVE0010066
2470278-90-9N-Nitroso-Rasagiline (Mixture of Diastereomer)VE007635
134720-07-3N-Nitroso-SotalolVE007638
52322-22-2N-Nitroso-Thambutol (Dinitroso)VE007654
78213-39-5N-Nitroso-Thambutol (mononitroso)VE007655
N/AN-Nitroso-Trimetazidine (2 HCl)VE007676
N/AN-Nitroso-desmethyl TrimebutineVE0011457
924-16-3N-Nitroso-di-n-butylamine(NDBA)VL3850094
1219798-82-9N-Nitroso-di-n-butylamine-d18DVE007
29291-35-8N-Nitroso-folic acidVE007631
N/AN-Nitroso-furosemideVE007632
N/AN-Nitroso-hydroxychloroquineVE007645
N/AN-Nitroso-lacidipineVE007644
N/AN-Nitroso-pramipexoleVE007641
134720-04-0N-NitrosoatenololVE007278
73785-40-7N-NitrosocimetidineVE008296
5336-53-8N-NitrosodibenzylamineVE006123
1116-54-7N-NitrosodiethanolamineVE006105
601-77-4N-Nitrosodiisopropylamine (NDIPA)VL290023
N/AN-Nitrosodimethylamine 13C-D6DVE0043
17829-05-9N-Nitrosodimethylamine-D6DVE0083
62-75-9N-Nitrosodimethylamine-¹³C₂D6DVE0099
86-30-6N-NitrosodiphenylamineVE006106
621-64-7N-Nitrosodipropylamine (NDPA)VL3850098
69278-54-2N-Nitrosoethylmethylamine-d3DVE00218
25081-31-6N-Nitrosoiminodiacetic acidVE007950
64768-29-2N-NitrosomethylamineVE0013228
26921-68-6N-NitrosomethylethanolamineVE006110
138768-62-4N-NitrosometoprololVE007073
59-89-2N-NitrosomorpholineVL3850097
N/AN-Nitrosonortriptyline-D3DVE0086
100-75-4N-NitrosopiperidineVL3850096
960049-21-2N-Nitrosopiperidine-D10DVE0081
930-55-2N-NitrosopyrrolidineVL3850099
N/AN-methyl-N-(4-methyl-1-nitrosopiperidin-3-yl)-7H-pyrrolo[2, 3-d]pyrimidin-4-amineVE009895
30533-08-5N-methyl-N-nitroso-2-PropanamineVL3850100
13256-11-6N-methyl-N-nitroso-PhenethylamineVE006384
7417-67-6N-methyl-N-nitrosoacetamideVE0011022
N/AN-nitroso (3, 4-dimethylphenyl) hydrazineVE0010337
N/AN-nitroso 3, 5-IvacaftorVE0011349
55557-03-4N-nitroso MethylphenidateVE009887
N/AN-nitroso Verapamil Impurity FVE0010324
N/AN-nitroso amlodipine BP Impurity 1VE0010277
N/AN-nitroso azithromycin EP impurity AVE0010111
N/AN-nitroso azithromycin EP impurity MVE0010110
N/AN-nitroso of GAT-IIVE008154
N/AN-nitroso of GatifloxacinVE008153
N/AN-nitroso tetrahydrofuroylpiprazineVE009556
N/AN-nitroso-N-desmethylnintedanibVE009403
N/AN-nitroso-TriazolopyrazineVE009511
62-75-9N-nitroso-dimethylamine (NDMA)VL3850010
N/AN-nitrosonintedanibVE009400
73870-33-4N-nitrosothiazolidineVE007979
26360-21-4N10-Nitroso Folic AcidVE008029
N/AN2-Nitroso ArticaineVE0013877
N/AN3-(1-nitrosopiperidin-4-yl)pyridine-2, 3-diamineVE0010248
N/ANaloxone Nitroso EP Impurity AVE0011507
N/ANicardipine Nitroso ImpurityVE009915
N/ANintedanib Nitroso Impurity 1VE009401
N/ANitroso 4-HBS ImpurityVE007746
N/ANitroso 4-Hydroxycarbazole ImpurityVE007931
N/ANitroso Abacavir ImpurityVE006520
N/ANitroso AdenineVE007649
N/ANitroso Amlodipine ImpurityVE007675
N/ANitroso Amlodipine Impurity BVE007650
885-11-0Nitroso AntipyrineVL6710004
N/ANitroso BCFI ImpurityVE007670
N/ANitroso Carvedilol EP Impurity DVE007932
N/ANitroso Carvedilol ImpurityVE007933
N/ANitroso Cyanodiol ImpurityVE007930
N/ANitroso Derivative of Prucalopride Impurity AVE0010531
N/ANitroso Dexchlorpheniramine MaleateVE0011722
N/ANitroso Escitalopram EP Impurity AVE007928
N/ANitroso Escitalopram EP Impurity CVE007929
N/ANitroso Escitalopram ESTRC-1VE007926
N/ANitroso Escitalopram ESTRC-2VE007927
N/ANitroso Fluoro PBI ImpurityVE007755
N/ANitroso HPED [Nitroso hydroxy propylethyl diamine]VE008152
6238-69-3Nitroso Isonipicotic AcidVE007756
N/ANitroso Lansoprazole Sulfide ImpurityVE007974
N/ANitroso LosartanVE006470
N/ANitroso Mercapto ImpurityVE007732
N/ANitroso Phthaloyl amlodipineVE007651
N/ANitroso Piperazine AcetamideVE007754
N/ANitroso Quinoline ester GatifloxacinVE008162
N/ANitroso Rabeprazole ImpurityVE007734
N/ANitroso Rabeprazole SulfideVE007733
N/ANitroso RifabutinVE009846
N/ANitroso VAL-II ImpurityVE007760
N/ANitroso Valsartan Benzyl EsterVE007761
N/ANitroso aryl piperazine quetiapineVE009553
67856-68-2Nitroso bis 2 chloro ethyl amineVE006103
N/ANitroso-4-Hydroxy CarbazoleVE009482
N/ANitroso-DMPC ImpurityVE007762
N/ANitroso-Epoxy propoxy CarbazoleVE009483
N/ANitroso-Linalgiptin DimerVE0011982
N/ANitroso-pyrazoloneVE0010237
674-81-7NitrosoguanidineVE007849
924-46-9NitrosomethylpropylamineVE006122
42363-85-9Nitrous HydrazideVE0011364
N/ANizatidine Nitroso Impurity 1VE0010302
N/ANizatidine Nitroso Impurity 2VE0010303
N/ANizatidine Nitroso Impurity 3VE0010304
N/AOlanzapine Nitroso Impurity 1VE0010251
N/AOlanzapine Nitroso Impurity 3VE0010536
N/AOlanzapine Nitroso Impurity 4VE0010252
N/AOsimertinib Nitroso Impurity 2VE009896
N/APantoprazole Nitroso Impurity 2VE0013066
356786-94-2Pantothenic Acid-13C3, 15N Hemicalcium SaltVE0011072
N/APhenyl nitroso(2-(phenylthio)phenyl)carbamateVE0012080
N/APlerixafor Nitroso Impurity 1VE0014187
N/APlerixafor Nitroso Impurity 2VE0014188
N/APlerixafor Nitroso Impurity 3VE0014189
N/APrimaquine Nitroso ImpurityVE0011146
N/APropyl (2-amino-6-((4-fluorobenzyl)(nitroso)amino)pyridin-3-yl)carbamate - FlupirtineVE007902
N/ARac-N-Nitroso MirabegronVE0010507
N/ARanitidine Nitroso Impurity 2VE0014181
N/ARelugolix Nitroso Impurity 1VE009886
N/ARibociclib Nitroso Impurity 1VE0011446
N/ARibociclib Nitroso Impurity 2VE0010063
N/ARibociclib Nitroso Impurity 3VE0010064
N/ARiociguat Nitroso Impurity CVE0014343
N/ARivastigmine N-Nitroso AnalogVE0012222
N/ARuxolitinib Nitroso Impurity 1VE0011162
N/AS, R, R-Thiomorpholine Derivative Nitroso ImpurityVE009979
N/AS, S, S-Thiomorpholine derivative nitroso impurityVE009978
N/AS-MAA Nitroso ImpurityVE007669
N/ASapropterin Nitroso Impurity 1VE0014160
N/ASapropterin Nitroso Impurity 3VE008522
N/ASertraline Nitroso ImpurityVE007388
N/ASumatriptan Nitroso ImpurityVE0010178
N/ATert-butyl 4-((2-(ethyl(nitroso)amino)ethyl)carbamoyl)-3, 5-dimethyl-1H-pyrrole-2-carboxylateVE0010009
N/ATert-butyl 4-((2-aminopyridin-3-yl)(nitroso)amino)piperidine-1-carboxylateVE0010246
2476859-56-8Ticagrelor -3 Nitroso ImpurityVE008628
2476859-55-7Ticagrelor Nitroso ImpurityVE008489
N/ATorasemide Nitroso Impurity 1VE009746
N/AValsartan Nitroso VAM-IIVE007988
N/AVancomycin Nitroso ImpurityVE0011293
N/AVarenicline 7, 8-Dinitro-3-nitroso-2, 3, 4, 5-tetrahydro-1H-1, 5-methanobenzo[d]azepineVE006887
N/AVarenicline Nitrosamine ImpurityVE006440
79108-51-3Vildagliptin N-Nitroso-L-ProlinamindeVE0010445
35909-01-4Vildagliptin N-Nitroso-L-Proline Methyl EsterVE0010446
N/AZanubrutinib Nitroso Impurity 1VE009879
N/AZiprasidone EP Impurity A NitrosoVE007390
N/Amethyl (Z)-3-(((4-(2-(4-methylpiperazin-1-yl)-N-nitrosoacetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylateVE009404
N/Amethyl 2-(2-chlorophenyl)-2-(nitroso(2-(thiophen-2-yl)ethyl)amino)acetateVE009421
N/Arac N-Nitroso-N-Desmethyl DapoxetineVE0011527
56859-26-81'-NitrosobiotinVE0010033
N/A1, 1'-(5-nitroso-10, 11-dihydro-5H-dibenzo[b, f]azepine-3, 7-diyl)diethanoneVE009783
N/A1, 2-dinitrosohydrazineVE0011365
13980-04-61, 3, 5-trinitrosohexahydro-1, 3, 5- triazineVE0011018
N/A1, 3-DinitrosoguanidineVE008761
N/A1, 7'-Dimethyl-3'-nitroso-2'- propyl-1H, 3'H-2, 5'- bibenzo[d]imidazoleVE0012689
N/A1-(2-((3-bromo-2, 4-dimethylphenyl)thio)phenyl)-4-nitrosopiperazineVE0010503
N/A1-(2-chloropyrimidin-4-yl)-2-(3-(2, 6-difluorophenylsulfonamido)-2-fluorophenyl)-2-oxoethyl 2, 2-dimethylpropanimidothioateVE0011062
N/A1-(2-ethoxyethyl)-2-(1-nitrosopiperidin-4-yl)-1H-benzo[d]imidazoleVE009494
N/A1-(4-((2, 4-dimethylphenyl)thio)phenyl)-4-nitrosopiperazineVE0010504
N/A1-(4-bromo-5-(1-ethyl-7-(methyl(nitroso)amino)-2-oxo-1, 2-dihydro-1, 6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylureaVE009891
N/A1-(5-Nitroso-10, 11-dihydro-5H-dibenzo[b, f]azepin-3-yl)ethan-1-oneVE009782
61379-64-41-Amino-4-cyclopentylpiperazineVE006465
61379-66-61-Cyclopentyl-4-NitrosopiperazineVE006466
29643-62-71-Ethoxy-2-ethylbenzeneVE0011025
92432-50-31-Nitroso-4-(2, 3, 4-trimethoxy-benzyl)-piperazineVE006792
7633-57-01-NitrosoindolineVE0012819
2819242-71-01-Nitrosopiperidin-3-amineVE0011771
45590-75-81-NitrosopyridiniumVE006351
N/A1-nitroso-1H-benzo[d]imidazole-2-thiolVE0011546
N/A1-nitroso-4-oxo-1, 4-dihydroquinoline-3-carboxylic acidVE0011350
N/A10-chloro-7-nitroso-2, 7-dihydrodibenzo[b, f][1, 2]oxazeto[3, 4-d]azepineVE009811
5424-21-52, 4-dichloro-6-methylpyrimidineVE0011056
28177-48-22, 6-DifluorophenolVE0011048
686258-75-32, 6-difluorobenzenesulfonic acidVE0011049
N/A2-(3, 4-dimethylphenyl)-5-methyl-1-nitroso-1H-pyrazol-3(2H)-oneVE0010235
48121-20-62-(4-nitrosopiperazin-1-yl)ethanolVE007038
N/A2-(7-ethyl-1-nitroso-1H-indol-3-yl)ethanolVE0011264
13036-57-22-Chloro-4-methylpyrimidineVE0011057
N/A2-Methyl-5-Nitro-1-Nitroso-1H-imidazoleVE006862
38361-37-42-chloro-1, 3-difluorobenzeneVE0011047
437-86-52-fluoro-1-methyl-3-nitrobenzeneVE0011045
317-46-42-fluoro-3-nitrobenzoic acidVE0011044
N/A2-methyl-1-nitroso-1H-indoleVE0012824
41075-14-33, 7-Dichloro-5-nitroso-10, 11-dihydro-5H-dibenzo[b, f]azepineVE009790
N/A3, 7-dinitro-5-nitroso-10, 11-dihydro-5H-dibenzo[b, f]azepineVE009787
N/A3-(2, 6-difluoro-3, 5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-7-nitroso-3, 4-dihydro-1H-pyrrolo[3', 2':5, 6]pyrido[4, 3-d]pyrimidin-2(7H)-oneVE009883
N/A3-(2, 6-difluorophenylsulfonamido)-2-fluorobenzoic acidVE0011060
N/A3-(4-methyl-3-(methyl(7-nitroso-7H-pyrrolo[2, 3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrileVE009894
959007-11-53-Chloro-5-nitroso-5H-dibenzo[b, f]azepineVE009799
N/A3-Methyl-1-nitrosopiperazineVE008235
N/A3-methyl-1-((4-methylquinazolin-2-yl)methyl)-7-nitroso-3, 7-dihydro-1H-purine-2, 6-dioneVE0011768
N/A3-methyl-1-nitrosoindolineVE0012823
N/A3-methyl-7-nitroso-3, 7-dihydro-1H-purine-2, 6-dioneVE0011770
N/A3-nitro-5-nitroso-10, 11-dihydro-5H-dibenzo[b, f]azepineVE009786
N/A3-nitroso-2, 3, 4, 5-tetrahydro-1H-1, 5-methanobenzo[d]azepineVE0010384
2219339-13-44-(3-Chlorophenyl)-1-nitrosopiperazineVE0011239
3438-46-84-MethylpyrimidineVE0011053
63779-86-24-Nitroso HydrochlorothiazideVE007633
N/A4-Nitroso hydrochlorothiazide-13C, 15N2, d2DVE004
N/A4-Nitrosopiperazin-1-amineVE0013670
3435-25-44-chloro-6-methylpyrimidineVE0011059
16219-99-14-nitrosomethylaminopyridineVE006116
42579-28-242579-28-2: N-Nitroso HydantoinVE0014917
N/A5-({[1, 1'-biphenyl]-4-yl}methyl)-3-methyl-1-nitrosopyrrolidin-2-oneVE0010125
N/A5-Nitro-1-Nitroso-1H-imidazoleVE006863
N/A5-Nitroso-10, 11-dihydro-5H-dibenzo[b, f]azepin-3-amineVE009788
N/A5-[3-(4-Nitrosopiperazin-1-yl)propyl]-5H-dibenzo[b, f]azepineVE0013976
N/A5-nitroso-10, 11-dihydro-5H-dibenzo[b, f]azepine-3, 7-diamineVE009789
N/A6-fluoro-3-(4-piperidinyl)-1, 2-Benzisoxazole-nitrosamineVE006599
2434-49-36-methyldihydropyrimidine-2, 4(1H, 3H)-dioneVE0011050
N/A7'-Methyl-1-nitroso-2'-propyl- 1H, 3'H-2, 5'- bibenzo(d)imidazoleVE0012691
N/A7-chloro-1-nitroso-2, 3, 4, 5-tetrahydro-1-benzazepin-5-olVE007639
N/A7-nitroso-7H-purine-6-thiolVE006867
N/A8-bromo-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-7-nitroso-3, 7-dihydro-1H-purine-2, 6-dioneVE0011767
N/A8-bromo-3-methyl-7-nitroso-3, 7-dihydro-1H-purine-2, 6-dioneVE0011769
855931-91-8855931-91-8: N-Nitroso-N-Phenyl-Glycine AnilideVE0014815
N/A((1, 5-Dimethyl-3-oxo-2-phenyl-2, 3-dihydro-1H-pyrazol-4-yl)(nitroso)amino)methanesulfonic acidVE0011347
N/A(1-(2'-(1-Nitroso-1H-tetrazol-5-yl)-[1, 1'-biphenyl]-4-yl)-2-oxohexyl)-L-valineVE009745
1038-06-8(1-nitrosopiperidin-4-yl)diphenylmethanolVE007001
N/A(2R)-2-((R)-1-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)-4-nitrosomorpholineVE009227
N/A(2R, 3S)-2-((R)-1-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)-4-nitrosomorpholineVE009228
N/A(3R, 4R)-1-Nitroso TofacitinibVE009926
N/A(4Z)-1-(3, 4-dimethylphenyl)-4-(hydroxyimino)-3-methyl-4, 5-dihydro-1H-pyrazol-5-oneVE0010236
N/A(4bS, 8aS, 9S)-3-methoxy-11-nitroso-6, 7, 8, 8a, 9, 10-hexahydro-5H-9, 4b-(epiminoethano)phenanthreneVE009881
5438-83-5(Nitrosoimino)bisacetic Acid Diethyl EsterVE009192
N/A(R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)amino)ethyl)phenyl)-N-nitrosoacetamideVE0010509
N/A(R)-2-hydroxy-N-(4-nitrophenethyl)-N-nitroso-2-phenylacetamideVE0010508
N/A(R)-7-chloro-1-nitroso-2, 3, 4, 5-tetrahydro-1H-benzo[b]azepin-5-olVE009900
N/A(R)-8-(3-aminopiperidin-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-7-nitroso-3, 7-dihydro-1H-purine-2, 6-dioneVE0011766
N/A(Z)-N-(2-(ethyl(nitroso)amino)ethyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2, 4-dimethyl-1H-pyrrole-3-carboxamideVE0010012

FAQs:

What is the FDA update for nitrosamine impurities?

The US Food and Drug Administration (FDA) released the final guidance document on the “Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)”.

What are the steps to mitigate nitrosamine impurities in drug products?

Nitrosamine guidance introduced a three-step process that manufacturers and applicants should take to mitigate nitrosamine impurities in their drug products. 1) Conduct risk assessments for nitrosamine impurities in their APIs and drug products, 2) Conduct confirmatory testing if risk is identified, 3) a report change is implemented to reduce or prevent the presence of nitrosamine impurities in drug products and APIs in approved and pending NDAs and ANDAs.

References:

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