In 2018, nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were found in several blood pressure medicinal products, known as sartans (angiotensin receptor blockers – ARBs). This led to some product recalls and a regulatory review, which set new strict manufacturing requirements for these medicinal products.<\/p>\n
Subsequently, a nitrosamine impurity was detected in batches of ranitidine, a medicinal product used to treat heartburn and stomach ulcers, and the Committee for Medicinal Products for Human Use (CHMP) in the European Medicines Agency (EMA) initiated a review.<\/p>\n
Internationally, the repercussions related to nitrosamines generated recalls and other preventive measures and, following these movements from internationally recognized agencies such as EMA and FDA, several agencies in Latin America have also published their actions related to nitrosamine impurities. Many of these publications were based entirely on international actions, but some were local actions prepared by these same authorities.<\/p>\n
The fact is that the nitrosamine issue is causing concerns for all links of the pharmaceutical supply chain.<\/p>\n
Nitrosamines are chemical compounds classified as probable human carcinogens based on animal studies.<\/p>\n
Since then, several actions have been taken by regulatory agencies around the world and it is very important that everyone be aware of publications on the subject in order to take preventive and effective actions.<\/p>\n
This publication aims to compile internationally published data on this topic. In order to facilitate the visualization, below we list the publications separated according to the agencies \/ regions responsible.<\/p>\n
<\/p>\n
Europe:<\/strong><\/span><\/p>\n EMA has been posting guidelines to marketing authorization holders (MAHs) on its website on how to avoid the presence of nitrosamine impurities in medicinal products for human use.<\/p>\n There are also step-by-step guidelines with response models for cases in which the risk is or is not identified, as well as a constantly updated questions and answers (Q&A) document. It’s worth checking it out (https:\/\/bit.ly\/336ty3L<\/a>).<\/p>\n In November 2019, an important publication was brought in a new chapter in the Q&A<\/strong> document (https:\/\/bit.ly\/3ro7yPo<\/a>), describing the causes currently identified for nitrosamine contamination. These are summarized below:<\/p>\n On December 6, 2019, EMA has confirmed that small amounts of NDMA were found in a small number of metformin-containing medicines outside the European Union (EU).<\/strong> There were no data indicating that EU medicines were affected. EMA and the European national competent authorities have been working closely to test EU medicines. EMA will provide updates as soon as possible.<\/p>\n The European agency has advised patients in EU to continue taking metformin <\/strong>as the risks of not treating diabetes far outweigh any possible effects of the low NDMA levels observed in the tests. (updated 16th December, 2019)<\/p>\n In August 2020, EMA published the update of the document Questions and Answers concerning Nitrosamines. It is important to note that the Questions and Answers refer to the Scientific Opinion Report prepared by the Committee for Medicinal Products for Human Use (CHMP) updated in June 2020. This report gathers all the available scientific knowledge about N-nitrosamines impurities in medicines humans containing chemically synthesized active pharmaceutical ingredients and their impact on the safe use of medication, and there are 90 pages of content related to nitrosamines. (updated 14th August)<\/p>\n In early February 2022, EMA issued a new version of its Q&A document (initially published in November 2019, available via the link: https:\/\/bit.ly\/3gPXCKc<\/a>). In this new revision, a new nitrosamine to be tested was included, N-nitrosodipropylamine (NDPA), with a threshold of 26.5ppm, and more clarity was given regarding the risk assessment of multiple nitrosamines in APIs. (Updated on 15th February 2022).<\/p>\n In March 2022, EMA published an update to the Q&A on the control of nitrosamines in drug products (Rev.8). Below is a summary of the updates present in the Q&A:<\/p>\n Link: https:\/\/bit.ly\/3ro7yPo<\/a>. (updated on May 9, 2022).<\/p>\n Check out some other publications related to the subject in the region below:<\/p>\n Access the updated document through the link: https:\/\/bit.ly\/3ro7yPo<\/a>.(updated on February 1st, 2023).<\/p>\n Additionally, in July 2022, EMA and CMDh have extended the deadline for submission of synthetic drug product change applications (Step 3) to include the control of nitrosamines in the quality control from September 26, 2022, to October 1, 2023, as indicated in the Q&A document. (updated on August 08, 2022). Check out the complete information on the authorities\u2019 websites:<\/p>\n In July 2023, an update to the Q&A document on nitrosamine impurities, issued by the EMA, was published. The following updates were covered in revision 16 of the document: (updated on July 19, 2023)<\/p>\n Access the new version of the Q&A document using the link: https:\/\/encurtador.com.br\/eilEN<\/a> Between July 2023 and October 2026, the EMA\/CMDh Questions and Answers (Q&A) document was revised seven times, reaching version 23. The changes made in each revision are described below:<\/p>\n \u25aa Rev. 17 \u2013 July 28, 2023:<\/strong> Update to Q&A 22: scope extended to medicinal products authorized for chronic use, with clarifications on the limits and exceptions applicable during the implementation of CAPA (corrective and preventive actions). Update to Q&As 20 and 21 to clarify that, with the introduction of the determination of the acceptable intake (AI) by the Carcinogenic Potency Categorization Approach (CPCA), the approach of a temporary universal limit (t-AI) while the formal AI is established is no longer considered necessary.<\/p>\n \u25aa Rev. 18 \u2013 October 2, 2023:<\/strong> Update to Q&A 3 to highlight the responsibilities of Marketing Authorization Holders (MAHs) to control, report and mitigate the detection of nitrosamine impurities throughout the product life cycle, using the established procedure.<\/p>\n \u25aa Rev. 19 \u2013 October 12, 2023:<\/strong> Update to Q&A 10 to allow reference to CPCA categorizations from other sources (e.g., other regulatory authorities), and to update the reference from the ICH M7(R1) guideline to ICH M7(R2). Content of Annexes 2 and 3 moved to Appendices 2 and 3.<\/p>\n \u25aa Rev. 20 \u2013 January 15, 2024:<\/strong> Update to Q&As 3 and 10 to include guidance on the handling of non-mutagenic nitrosamine impurities (NMIs). Update to Q&A 9 to clarify the sensitivity requirements for analytical methods. Update to Q&A 10 to include the timeframes for Ames test acceptability.<\/p>\n \u25aa Rev. 21 \u2013 May 28, 2024:<\/strong> Updates to Q&As 8, 9, 10, 14 and 15 to clarify expectations for risk evaluation, confirmatory testing and dossier requirements for products in which nitrosamine impurities can be controlled according to the ICH Q3A\/B limits. Update to Q&A 10 to revise the section on Ames test acceptability. Update to Q&A 16 to clarify the responsibilities of MAHs and active pharmaceutical ingredient (API) manufacturers when ASMFs and CEPs are referenced.<\/p>\n \u25aa Rev. 22 \u2013 May 19, 2025:<\/strong> Update to Q&A 10 to clarify the AI limit applicable to different routes of administration and the type of in vivo study accepted. Update to Q&A 22 to highlight the expectations for the submission of variations concerning shelf life and storage conditions needed to comply with the interim limit during CAPA implementation.<\/p>\n \u25aa Rev. 23 \u2013 October 10, 2025:<\/strong> Update to Q&A 22 to clarify the applicability period of the interim limit during CAPA implementation. The interim limit applies to products with a CAPA implementation timeline of up to 3 years from the publication date of the initial AI. The document clarifies that this 3-year period does not change for CAPAs with timelines longer than 3 years if the AI is later revised, even to a more restrictive value.<\/p>\n Appendix 1 updates (acceptable intake limits, AIs):<\/strong> Appendix 1, maintained by the Non-Clinical Working Party (NcWP) on the basis of the CPCA, has been updated periodically. On June 1, 2026, Appendix 1 was published in its Rev. 13 (EMA\/42261\/2025), with the most up-to-date list of limits for N-nitrosamines. The document can be accessed on the EMA page dedicated to nitrosamine impurities<\/a>. The nitrosamines added to Appendix 1 (n=178) are listed below by publication date:<\/p>\n October 1, 2023:<\/strong> 3 entries<\/p>\n \u25aa 3-amino-N-nitrosopiperidine (Alogliptin), N-nitroso derivative of rotigotine impurity B (Rotigotine), N-nitroso derivative of rotigotine impurity C (Rotigotine).<\/p>\n November 15, 2023:<\/strong> 11 entries<\/p>\n \u25aa 5-chloro-4-methyl-2-[(2S)-2-methyl-1-nitrosopyrrolidin-2-yl]-1H-benzimidazole (Daridorexant), Indapamide Impurity A (Indapamide), N-nitroso-calcium folinate (Calcium folinate\/ Calcium levofolinate), N-nitroso-celiprolol (Celiprolol), N-nitroso-desethyllidocaine (Lidocaine), N-nitroso-desmethyl-azelastine (Azelastine), N-nitroso-desvenlafaxine (Desvenlafaxine), N-nitroso-esmolol (Esmolol), N-nitroso-ethylenediamine-triacetic acid (Isosorbide mononitrate), N-nitroso-iminodiacetic acid (Isosorbide mononitrate), N-nitroso-leniolisib (Leniosilib), N-nitroso-tetracaine (Tetracaine), N-nitroso-ticagrelor (Ticagrelor).<\/p>\n December 15, 2023:<\/strong> 5 entries<\/p>\n \u25aa N-nitroso-cinacalcet (Cinacalcet), N-nitroso-desmethyl-citalopram\/N-nitroso-desmethyl-escitalopram (Citalopram), N-nitroso-desmethyl-nintedanib (Nintedanib), N-nitroso-imatinib (Imatinib), N-nitroso-quetiapine HEEP impurity (Quetiapine).<\/p>\n January 15, 2024:<\/strong> 16 entries<\/p>\n \u25aa 1-(2,3-dichlorophenyl)-4-nitrosopiperazine (Aripiprazole), N-nitroso-azacyclonol (Azacyclonol), N-nitroso-betaxolol (Betaxolol), N-nitroso-desmethyl-sildenafil (Sildenafil), N-nitroso-desmethyl-sumatriptan (Sumatriptan), N-nitroso-desmethyl-terbinafine (Terbinafine), N-nitroso-dorzolamide (Dorzolamide), N-nitroso-mirtazapine (Mirtazapine), N-nitroso-ranolazine impurity 1 (Ranolazine), N-nitroso-ribociclib impurity 1 (Ribociclib), N-nitroso-rivaroxaban amide (Rivaroxaban), N-nitroso-rivaroxaban open-ring acid (Rivaroxaban), N-nitroso-terbinafine degradant (Terbinafine), N-nitroso-terbinafine impurity A (Terbinafine), N-nitroso-urapidil (Urapidil).<\/p>\n February 15, 2024:<\/strong> 14 entries<\/p>\n \u25aa 2,2,5-trimethyl-3-nitroso-1,3-oxazolidine (Cyanocobalamine), N-nitroso-apixaban impurity B (Apixaban), N-nitroso-clozapine (Clozapine), N-nitroso-clozapine EP Impurity C (Clozapine), N-nitroso-desmethyl-tamoxifen (Tamoxifen), N-nitroso-diisopropanolamine, N-nitroso-flecainide (Flecainide), N-nitroso-masitinib (Masitinib), N-nitroso-meglumine (Meglumine), N-nitroso-meropenem (Meropenem), N-nitroso-ritalinic acid (Methylphenidate), N-nitroso-silodosin (Silodosin), N-nitroso-terazosin impurity C (Terazosin), N-nitroso-terazosin impurity N (Terazosin).<\/p>\n May 1, 2024:<\/strong> 16 entries<\/p>\n \u25aa 2-(4-nitrosopiperazin-1-yl)ethanol (Opipramol), 3-((ethyl(nitroso)amino)methyl)benzenesulfonate (Brilliant blue FCF), 4-nitroso-methyl piperazine-1-carboxylate (Omecamtiv mecarbil), N-(2-hydroxy-2-phenylethyl)-N-(4-nitrophenethyl)nitrous amide (Mirabegron), N-(4-aminophenethyl)-N-(2-hydroxy-2-phenylethyl)nitrous amide (Mirabegron), N-nitroso-articaine (Articaine), N-nitroso-desmethyl-edoxaban (Edoxaban), N-nitroso-fenfluramine (Fenfluramine), N-nitroso-folic acid (Folic acid), N-nitroso-furosemide (Furosemide), N-nitroso-N-ethyl-benzylamine, N-nitroso-posaconazole impurity 1 (Posaconazole), Rivaroxaban nitroso impurity 1, 2 and 5 (Rivaroxaban), N-nitroso-trientine impurity 1 (Trientine), N-nitroso-vibegron (Vibegron).<\/p>\n July 1, 2024:<\/strong> 11 entries<\/p>\n \u25aa 1-diphenylmethyl-4-nitrosopiperazine (Cinnarizine), 3-(dimethylamino)propyl 2-[benzyl(nitroso)amino]benzoate (Benzydamine), N-nitroso-bilastine impurity 2 (Bilastine), N-nitroso-caspofungin (Caspofugin), N-Nitroso-desformyl-riociguat (Riociguat), N-nitroso-desmethyl-clarithromycin (Clarithromycin), N-nitroso-desmethyl-tramadol (Tramadol), N-nitroso-desvaleryl-valsartan, N-nitroso-N-desmethyl-diphenhydramine, N-nitroso-tigecycline, N-nitroso-trandolapril (Trandolapril).<\/p>\n September 1, 2024:<\/strong> 10 entries<\/p>\n \u25aa N-nitroso-2,4-thiazole amine (Ritonavir\/Cobicistat), N-nitroso-acebutolol (Acebutolol), N-nitroso-buspirone Impurity 1 (Buspirone), N-nitroso-desmethyl-dimetindene (Dimetindene), N-nitroso-desmethyl-rivastigmine (Rivastigmine), N-nitroso-iminodibenzyl (Melipramin), N-nitroso-maprotiline (Maprotiline), N-nitroso-propafenon (Propafenon), N-nitroso-valsartan cyano-desvalerylmethylester (Valsartan), N-nitroso-vanzacaftor (Vanzacatfor), N-nitroso-vildagliptin amide impurity (Vildagliptin).<\/p>\n December 1, 2024:<\/strong> 28 entries (including the new tab Other N-nitroso-structures<\/em>)<\/p>\n \u25aa N-nitrosamines:<\/strong> anabasine (Nicotine), anatabine (Nicotine), desmethyl-chlorphenamine (Chlorfenamine), desmethyl-eletriptan (Eletriptan), desmethyl-galantamine (Galantamine), desmethyl-rizatriptan (Rizatriptan), desmethyl-zolmitriptan (Zolmitriptan), ivacaftor (Ivacaflor), nilotinib (Nilotinib), nornicotine (Nicotine), nor-oxycodone (Nalmefene).<\/p>\n \u25aa Other N-nitroso structures (new tab):<\/strong> N-nitroso-biotin (D-biotin), N-nitroso-cimetidine (Cimetidine), N-nitroso-clonidine ((Clonidine), N-nitroso-clonidine-2 (Clonidine), N-nitroso-eletriptan (Eletriptan), N-nitroso-melatonin (Melatonin), N-methyl-N’-nitro-N-nitrosoguanidine, 1-Nitroso-moxonidine Impurity 3 (Moxonidine), 1-Nitroso-moxonidine (Moxonidine), N-nitroso-naratriptan (Naratriptan), N-nitroso-rizatriptan (Rizatriptan), N-nitroso-sumatriptan (Sumatriptan), N-nitroso-tadalafil (Tadalafil), N-nitroso-tizanidine (Tizanidine<\/strong>), N-nitroso-tizanidine Impurity 3 (Tizanidine), N-nitroso-tryptophol (Tryptophol), N-nitroso-zolmitriptan (Zolmitriptan).<\/p>\n February 1, 2025:<\/strong> 11 entries<\/p>\n \u25aa 2-(N-nitrosomethylamino)-N-[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]acetamide (NNT) (Troriluzole), N-deshydroxyethyl-N-nitroso dasatinib (Dasatinib), N-nitroso-dasatinib (Dasatinib), N-nitroso-dalbavancin (Dalbavancin), N-nitroso-desmethyl-cabergoline (Cabergoline), N-nitroso-desmethyl-lercanidipine impurity D (Lercanidipine), N-nitroso-N-desmethyl-mianserin (Mianserin), N-nitroso-norfloxacin (Norfloxacin) (NMI), N-nitroso-sarcosine (Troriluzole), N-nitroso-vancomycin (Vancomycin) (NMI).<\/p>\n May 15, 2025:<\/strong> 7 entries<\/p>\n \u25aa N-nitroso-acarbose (Acarbose), N-nitroso-benzathine (Benzathine), N-nitroso-brinzolamide (Brinzolamide), N-nitroso-carvedilol (Carvedilol), N-nitroso-despropyl-ropinirole (Ropinirole), N-nitroso-frovatriptan (Frovatriptan), N-nitroso-safinamide (Safinamide).<\/p>\n August 1, 2025:<\/strong> 13 entries<\/p>\n \u25aa N-nitroso-berotralstat (Berotralstat), N-nitroso-desmethyl-doxylamine (Doxylamine), N-nitroso-doravirine dimer (Doravirine), N-nitroso-hydroxychloroquine EP impurities C and D (Hydroxychloroquine), N-nitroso-hydroxyzine impurity A (Hydroxyzine), N-nitroso-methylaminoantipyrine (Metamizole), N-nitroso-methylethanolamine (Nefopam), N-nitroso-mirdametinib (Mirdametinib), N-nitroso-nirogacestat (Nirogacestat), N-nitroso-nirogacestat impurity 1 (Nirogacestat), N-nitroso-propafenone impurity B (Propafenone), N-nitroso-venlafaxine EP impurities D and H (Venlafaxine).<\/p>\n December 1, 2025:<\/strong> 7 entries<\/p>\n \u25aa N-methyl-N-nitrosoanthranilate (Methyl N-methylanthranilate), N-nitroso-4-phenylpiperazine (Levodropropizine), N-nitroso-cytisine (Cytisine), N-nitroso-desbutyllumefantrine (Lumefantrine), N-nitroso-desmethyl-mifepristone (Mifepristone), N-nitroso- desmethyl-tapentadol (Tapentadol), N-nitroso-selumetinib (Selumetinib).<\/p>\n March 1, 2026:<\/strong> 13 entries<\/p>\n \u25aa 6-nitro-N-nitrosoadrenaline (Adrenaline), N,N’-dimethylethylenedinitrosamine (NDMEA, NNDMA), N-nitroso-adrenaline (Adrenaline), N-nitroso-brensocatib Brenzocatib), N-nitroso-dabigatran etexilate amide (Dabigatran Etexilate), N-nitroso-desbutyldronedarone (Dronedarone), N-nitroso-desmethyl-cidoxepin (Doxepin), N-nitroso-desmethyl-diltiazem (Diltiazem), N-nitroso-desmethyl-ulipristal acetate (Ulipristal acetate), N-nitroso-diazepam impurity D (Diazepam), N-nitroso-methylethylamine (Amphotericin B), N-nitroso-N-descyclopropanecarbaldehyde olaparib (Olaparib) (atualiza\u00e7\u00e3o), N-nitroso-remibrutinib (Remibritinib).<\/p>\n June 1, 2026:<\/strong> 9 entries<\/p>\n \u25aa N-nitroso-N-des(prop-2-enoyl)-remibrutinib (Remibrutinib), N-nitroso-abacavir (Abacavir), N-nitroso-alprazolam EP Impurity H (Alprazolam), N-nitroso-desmethyl-doxycycline (Doxycycline), N-nitroso-desmethyl-rifampicin (Rifampicin), N-nitroso-metamizole impurity E (Metamizole), N-nitroso-prolinamide (Vildagliptin), N-nitroso-prolinenitrile (Vildagliptin), N-nitroso-relebactam (Relebactam).<\/p>\n October 1, 2026<\/strong> \u2014 14 entradas<\/p>\n \u25aa N-nitrosamines: <\/strong>6,7-dicloro-4-nitroso-1,3,4,5-tetra-hidro-2H-benzo[e][1,4]diazepin-2-ona (Anagrelide), ethyl<\/em> N-(2,3-dicloro-6-nitrobenzil)-N-nitrosoglicinato (Anagrelide), ethyl<\/em> N-(6-amino-2,3-diclorobenzil)-N-nitrosoglicinato (Anagrelide), N,N-dinitroso-desmetil-sumatriptana (Sumatriptan), N-nitroso-desmetil-roxitromicina (Roxithromycin) \u2014 NMI, N-nitroso-desmetil-eritromicina (Erythromycin) \u2014 NMI, N-nitroso-desmetil-maralixibat (Maralixibat), N-nitroso-donepezil impurity<\/em> A (Donepezil), N-nitroso-N-metil-benzilamina, N-nitroso-fenoxibenzamina HCl impurity<\/em> A (Phenoxybenzamine HCl), N-nitroso-fenoxibenzamina HCl impurity<\/em> B (Phenoxybenzamine HCl), N-nitroso-torasemida (Torasemide), N-nitroso-\u00e1cido tranex\u00e2mico d\u00edmero (Tranexamic acid).<\/p>\n \u25aa Other N-nitroso structures: <\/strong>N-nitroso-xilometazolina (Xylometazoline).<\/p>\n Call for Review (CFR) deadlines:<\/strong> all original CFR deadlines, including steps 1, 2 and 3, for products containing chemically synthesized and biological APIs, have already expired. However, the reporting responsibilities of MAHs remain continuously in force throughout the product life cycle. MAHs that have not yet reported identified nitrosamines to the relevant competent authority should do so as a priority, including updates to previous notifications.<\/p>\n Appendix 2, published on October 12, 2023 (EMA\/451665\/2023<\/strong><\/a>),<\/strong> formalized the CPCA as the EMA’s structured method for predicting the carcinogenic potency category of N-nitrosamines from the structural features of the molecule, replacing the previous approach based exclusively on available TD50 data. The methodology assumes that the main mechanism of metabolic activation of N-nitrosamines is \u03b1-hydroxylation<\/em>, and structures the assessment into five potency categories with associated AIs of 18, 100, 400, 1500 and 1500 ng\/day, respectively. The classification process follows a sequential flowchart<\/em> that evaluates the presence of hydrogens on the \u03b1-carbons, the existence of a tertiary \u03b1-carbon and, when necessary, the calculation of a Potency Score<\/em> based on the sum of scores for deactivating and activating features of the molecule. Before Appendix 2, this rationale was scattered across sections of the main Q&A (Q&A 10), having been incorporated into the document as Annex 2 in the July 2023 revision (Rev. 16) and later removed from the Q&A and consolidated as a standalone Appendix 2 in the October 2023 revision (Rev. 19), a move that reflects the maturity of the approach and the intention to allow it to be updated independently as new scientific data emerge.<\/p>\n Appendix 3, published on March 26, 2024 (EMA\/120337\/2024<\/strong><\/a>),<\/strong> consolidated the enhanced Ames test conditions specific to N-nitrosamines in a standalone document, having originally been introduced as Annex 3 of the main Q&A in the July 2023 revision (Rev. 16) and moved to an independent appendix in the October 2023 revision (Rev. 19). The main reason for the Enhanced Ames Test<\/em> (EAT) is the reduced sensitivity of the standard assay (OECD 471) to certain N-nitrosamines, including NDMA itself, under conventional conditions, a limitation that becomes even more critical for NDSRIs (nitrosamine drug substance-related impurities<\/em>), whose toxicological profile is less well known. Compared with the standard assay, the EAT introduces four additional relevant requirements: mandatory use of the pre-incubation method (30 minutes) instead of the plate incorporation method; mandatory use of 30% post-mitochondrial S9 fraction from both rat and hamster liver, both induced with phenobarbital and \u03b2-naphthoflavone; inclusion of two positive controls of known N-nitrosamines to verify the sensitivity of the metabolic activation system; and a documented justification for the volume of organic solvent used, to demonstrate that it does not interfere with the metabolic activation of the nitrosamine tested. Appendix 3 also includes a standardized checklist<\/em> for reporting results, promoting greater traceability and comparability between studies submitted by different MAHs.<\/p>\n Report of the European Medicines Regulatory Network<\/strong><\/a> \u2013 July 2025:<\/strong> On July 8, 2025, the EMA and the Heads of Medicines Agencies (HMA) published the report ‘Nitrosamine impurities in human medicines \u2013 The response of the European Medicines Regulatory Network’ (EMA\/144509\/2025). The document consolidates the overview of regulatory actions undertaken since 2018, including: (i) 13 meetings of the NIOG (Nitrosamine Implementation Oversight Group) held to date; (ii) an estimate that approximately 40% of marketed products may be at risk of NDSRI formation based on the structural characteristics of the active substance; (iii) more than 170 AI limits published on the EMA portal; and (iv) confirmation that the addendum to the ICH M7 guideline was initiated at the ICH Assembly meeting in June 2024, with publication expected in May 2028.<\/p>\n <\/p>\n United States of America:<\/strong><\/span><\/p>\n There are ongoing updates in the Food and Drug Administration (FDA) website on recalls, as well as publications on methods to provide regulators and industry with an option to detect impurities (NDMA). Updates regarding ARBs and ranitidine hydrochloride can be found respectively at: https:\/\/bit.ly\/2ptjK5Q and https:\/\/bit.ly\/2qsdQCC.<\/p>\n In addition, on November 20, 2019, news was published about an update to the United States Pharmacopeia (USP), with a proposed update on the chapter on elastomers used in packages for injectable medicinal products. The update would also include elastomers in packages for inhalable medicinal products, and would add testing and acceptance criteria for N-nitrosamines. The inclusion of nitrosamine testing is due to the fact that nitrosamines are reaction products between specific organic precursor molecules, secondary amines, and a \u201cnitrosating agent\u201d. In the compounding of rubber, secondary amines are likely formed from vulcanization accelerators. The full proposal can be found in through the link: https:\/\/bit.ly\/2KI9rT8.<\/p>\n In early April 2020, the FDA issued a warning requesting the withdrawal from the market of all medicinal products containing ranitidine. Based on this warning, the agencies in Honduras and Panama took the same action, requesting the withdrawal of medicines containing ranitidine from their respective markets (updated 28th April)<\/p>\n Also in August 2020, the FDA published a note informing about the presence of nitrosamine impurities in two antibiotics used to treat tuberculosis. In order to avoid shortages, the FDA will maintain production authorization for some manufacturers of these drugs, even with the detection of impurities above the defined limits, until they manage to reduce or eliminate impurities, while studying, together with manufacturers, on the source of these impurities.<\/p>\n The identified impurities and their respective intake limits are:<\/p>\n In September 2020, the FDA published another guidance for industry, entitled \u201cControl of N-Nitrosamine Impurities in Human Drugs”. This guidance recommends steps manufacturers of active pharmaceutical ingredients and drug products should take to detect and prevent objectionable levels of nitrosamine impurities in pharmaceutical products. The guidance also describes conditions that may introduce nitrosamine impurities. (updated 2nd September) In February, FDA published the new version of this Guidance. This version extends the time period for preparing initial risk assessments to March 31, 2021 (i.e., within 7 months of publication of the original guidance). (updated 1st March 2021)<\/p>\n Check out some other publications related to the subject in the country below:<\/p>\n FDA informs that it is aware that some diabetes medicines containing metformin in other countries have been reported to have low levels of NDMA. Based on the available information, NDMA levels observed outside the US are within the naturally occurring range of some foods and water. While some non-US regulatory agencies may be recalling some metformin medicines, there are no metformin recalls that currently affect the US market: https:\/\/bit.ly\/34dxa4d<\/a> (updated 16th December)<\/p>\n Guidance on acceptable intake limits for NDSRIs \u2013 August 2023:<\/strong> In August 2023, the FDA published the guidance ‘Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities<\/a> (NDSRIs)’, establishing a methodology to predict the mutagenic and carcinogenic potential of NDSRIs, impurities that are structurally similar to the active substance and are, in general, unique to each API. The document formally introduced the CPCA for determining AI limits when carcinogenicity data specific to closely related compounds are not available. The CPCA assigns recommended daily exposure limits ranging from 26.5 ng\/day to 1,500 ng\/day, according to the structural category.<\/p>\n Revision 2 of the Control guidance \u2013 September 2024:<\/strong> In September 2024, the FDA published Revision 2 of the guidance ‘Control of Nitrosamine Impurities in Human Drugs’. This update represents a significant structural change from Revision 1 (February 2021). The main points are: (i) formal differentiation of two structural classes of impurities: ‘small-molecule nitrosamines’ (originating from reagents, solvents, etc.) and NDSRIs, which share structural similarity with the API and are generally unique to each API; (ii) new recommendations on potential causes of NDSRI formation, control and mitigation strategies, including reformulation as a valid strategy, with specific recommendations on stability data and bioequivalence studies to support approvals; (iii) establishment of a deadline: for approved products at risk of NDSRI formation, companies were expected to complete confirmatory testing and submit the necessary changes to the authorities by August 1, 2025.<\/p>\n Revised NDSRI deadline \u2013 June 2025:<\/strong> On June 23, 2025, the FDA granted companies additional time: instead of full implementation by August 1, 2025, they were required to submit by that date progress reports on the assessment and mitigation of the risk of nitrosamine impurities. These reports must contain the NDSRIs detected, test data and method validation, batches analyzed, confirmatory testing, mitigation measures adopted and estimated timelines for completing the study, and are included in the ‘NDSRI Update’ section of the annual report, in the ‘Log of Outstanding Regulatory Business’ field (eCTD 1.13.14). Manufacturers of products not subject to formal approval applications must prepare the progress report with a summary of activities by the end of July 2025 and keep it available for inspection.<\/p>\n Application of the less-than-lifetime (LTL) adjustment \u2013 September 24, 2026:<\/strong> In September 2026, the FDA published the guidance Application of Less-Than-Lifetime Adjustment to Nitrosamine Impurities,<\/em> which considers applying the LTL exposure adjustment to the AI limits for nitrosamine impurities, as provided in ICH M7(R2) and previously not recommended by the Agency due to uncertainties about cumulative carcinogenic risk, DNA repair capacity and simultaneous exposure to different medicines. The FDA presents four treatment duration ranges and their respective adjustment factors applied to the reference AI limit (\u22641 month: 80x; >1 month to 12 months: 13.3x; >1 year to 10 years: 6.67x; >10 years to lifetime: no adjustment). The definition of treatment duration must consider the product labeling data (if there is dosing for both short- and long-term use, the long-term duration must be used for the adjusted calculation), the total number of days of administration over a lifetime for intermittent use or recurrent symptoms, and a strategy for controlling total exposure to impurities when there is more than one nitrosamine in the product. The LTL adjustment is not recommended for provisional AI limits. The submission of a request for an adjusted AI limit must include a scientific justification for the limit, with the calculation of the adjustment factor and the target population for the medicine. For products already authorized, where the proposed AI limit is higher than the limit recommended by the FDA or higher than an AI limit whose justification has already been considered satisfactory by the FDA, the proposal will constitute a significant change requiring a submission subject to prior approval before implementation.<\/p>\n <\/p>\n ICH:<\/strong><\/p>\n The ICH M7(R2) guideline, published in April 2023, is currently in force. In addition to the incorporation of seven new compounds into Appendix 1 and textual updates relative to M7(R1), version R2 reaffirms that nitrosamines belong to the so-called ‘cohort of concern’, a class of high-potency mutagenic impurities for which the standard TTC of 1.5 \u00b5g\/day established in M7 is not applicable, and a case-by-case approach must be adopted. ICH M7(R2) does not apply to APIs and drug products intended for the treatment of advanced cancer indications, as defined in the ICH S9 guideline.<\/p>\n ICH M7 Nitrosamine Sub-Group<\/strong><\/a> \u2013 June 2024:<\/strong> at the ICH Assembly meeting in June 2024, the creation of a working subgroup (an Expert Working Group<\/em>, EWG) was agreed, dedicated to drafting an Addendum to the ICH M7 guideline focused exclusively on the safety and quality aspects of nitrosamines, to be published as ICH M7(R3). The subgroup’s Final Concept Paper<\/em> is dated May 10, 2025 and was endorsed by the Management Committee<\/em> on May 11, 2025. The main workstreams include: (i) development of monographs with compound-specific AI limits, based on carcinogenicity data accumulated by the industry; (ii) consensus on the design of in vivo<\/em> mutagenicity studies for benchmark dose<\/em> modeling; (iii) development of training materials with case examples. Quality topics may be included as scientific understanding progresses. The target date for adoption of the draft by the regulatory members (Step 2a\/2b) is the second quarter of 2028, with finalization and publication of ICH M7(R3) expected in the first quarter of 2030.<\/p>\n <\/p>\n Brazil:<\/strong><\/span><\/p>\n In Brazil, the repercussions related to nitrosamines not only generated recalls and other preventive measures but also gave rise to the publication of Resolution RDC 283\/2019, which regulates investigation, control, and elimination of potentially carcinogenic nitrosamines in ARBs<\/p>\n On November 18, 2019, ANVISA published another preventive measure in the Federal Official Gazette, due to the presence of the NDMA impurity for the active pharmaceutical ingredient (API) ranitidine hydrochloride.<\/p>\n On January 14, ANVISA issued an official letter to the regulated sector (Letter# 3\/2020\/SEI\/GIMED\/GGFIS\/DIRE4\/ANVISA) establishing the 6-month deadline for all drug registration holders containing chemically synthesized active substances to review the synthesis routes for the presence of nitrosamines <\/strong>and test their products for this risk.<\/p>\n ANVISA emphasizes that reviews should be comprehensive and consider the entire manufacturing process for Drug Substance and the Drug Product and recommends the principles outlined in Guideline ICH M7 (R1) <\/strong>for determining acceptable intake.<\/p>\n In cases where nitrosamines <\/strong>are detected in any of their medications, registration holders should notify ANVISA immediately<\/strong> in accordance with RDC 55\/2005 procedures (updated 17th January).<\/p>\n On March 12, 2020, ANVISA published the Resolution – RE N\u00b0 702 of 2020, which includes the adoption of the preventive measure for all importin\u2019s companies, distributors, fractionators of pharmacies that suspend the commercialization, distribution, or use of ranitidine hydrochloride until they are subjected to quality control on available stocks that indicate that the NDMA is at levels below 2.13 ppm.<\/p>\n Only batches that have obtained results below this limit and can be released using periodic statistics that guarantee that the raw material is kept within the acceptable limit (updated 13th March, 2020).<\/p>\n In September 2020, ANVISA launched in Brazil the Program for Monitoring Nitrosamines in Medicines. Initially, the focus of the program is on drugs that belong to the class known as \u201csartans\u201d. The nitrosamine monitoring program aims to protect public health and guarantee the quality, efficacy and safety of medicines for human use. The program will start on September 30th, 2020 which the first analysis of the program involving the active ingredient losartan is scheduled.<\/p>\n The participants involved in this project are:<\/p>\n 1. Management of Public Health Laboratories – GELAS \/ DIRE4.<\/p>\n 2. General Management of Medicines and Biological Products – GGMED \/ DIRE2.<\/p>\n 3. Management of inspection and surveillance of Medicines and Pharmaceutical Ingredients – GIMED \/ GGFIS \/ DIRE4.<\/p>\n 4. National Institute for Quality Control in Health – INCQS \/ Fiocruz.<\/p>\n The program steps are:<\/p>\n The following activities will be conducted in this program:<\/p>\n\n
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\nAccess Appendix 1 using the link: https:\/\/encurtador.com.br\/eESY0<\/a><\/p>\n\n
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