Skip to content
2000
Volume 20, Issue 4
  • ISSN: 1574-8863
  • E-ISSN: 2212-3911

Abstract

The presence of N-nitrosamine impurities in pharmaceutical products is well known. In 2019, it resulted in drug recall by the Food and Drug Administration (FDA). Soon, several groups identified the presence of many N-nitrosamines (NAs) in various Active Pharmaceutical Ingredients (APIs) and drug formulations worldwide. Moreover, in the last two years, another type of NAs was identified and detected in several pharmaceutical products. These are easily formed from the parent drug molecule and are known as Nitrosamine drug-related substances (NDSRIs). The amine group plays a major and unique role in the synthesis of many drug molecules, and hence, it is practically impossible to eliminate the presence of NAs and NDSRIs from drug products. The risk assessment of the health hazard to the patient was done, and the FDA has set the maximum daily acceptable intake (AI) at 18 ng/day for NAs. This limit poses a significant challenge in isolating, identifying and quantifying NAs and NDSRIs in APIs and formulations. For small, simple NAs, a lot of toxicological information and carcinogenetic data is available; however, for NDSRIs, such data is practically absent. This review article attempts to gather the toxicological data for a few NAs and NDSRIs and tries to assess the genotoxicity potential of some NDSRIs. The possible sources of NAs and NDSRIs, including synthetic methodology and processes, impurities associated with intermediates or raw materials, stability of the API, packaging materials, imprinting inks, and excipients, are also discussed. A summary of different analytical techniques used for the detection of these NAs and NDSRIs in different pharmaceutical products has also been included. Finally, various strategies employed for the minimization of these impurities along with additional control strategies to mitigate NAs and NDSRIs below acceptable limits, have also been discussed.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cds/10.2174/0115748863324951241028050225
2025-01-01
2025-09-05

  • From This Site

    /content/journals/cds/10.2174/0115748863324951241028050225
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use.2006Available from: https://database.ich.org/sites/default/files/Q3A%28R2%29%20Guideline.pdf (accessed on 8-10-2024)
  2. GolobN. PeterlinS. GrahekR. RoškarR. NDMA Formation Due to Active Ingredient Degradation and Nitrite Traces in Drug Product.J. Pharm. Sci.202311251277128610.1016/j.xphs.2023.03.007 36925105
     [Google Scholar]
  3. Q9(R1) Quality Risk Management2023Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q9r1-quality-risk-management (accessed on 8-10-2024)
  4. ReynisdóttirN. Thor IngvarssonP. María EinarsdóttirÁ. Freyr IngunnarsonA. NagyI. Excipient-free spray drying of bioactive recombinant proteins produced in plants.In: Drying Science and Technology. Intech open202410.5772/intechopen.112944
     [Google Scholar]
  5. LiY. HechtS.S. Metabolic Activation and DNA Interactions of Carcinogenic N-Nitrosamines to Which Humans Are Commonly Exposed.Int. J. Mol. Sci.2022239455910.3390/ijms23094559 35562949
     [Google Scholar]
  6. CharooN.A. DharaniS. KhanM.A. RahmanZ. Nitroso Impurities in Drug Products: An Overview of Risk Assessment, Regulatory Milieu, and Control Strategy.AAPS PharmSciTech20232426010.1208/s12249‑023‑02523‑w 36759424
     [Google Scholar]
  7. BinX. DongG. BinliangM. JunF. Determination of genotoxic impurity n-nitroso-n-methyl-4-aminobutyric acid in four sartan substances through using liquid chromatography-tandem mass spectrometry.Molecules202227217498
     [Google Scholar]
  8. ChangS.H. ChangC.C. WangL.J. A multi-analyte LC-MS/MS method for screening and quantification of nitrosamines in sartans.Yao Wu Shi Pin Fen Xi202028229230110.38212/2224‑6614.1063 35696119
     [Google Scholar]
  9. RaoS. PawarK. Development of GC-MS/MS method for simultaneous estimation of four nitrosoamine genotoxic impurities in valsartan.Trukish J Pharm Sci2022202245546110.4274/tjps.galenos.2021.17702
     [Google Scholar]
  10. NudelmanR. KocksG. MoutonB. The Nitrosamine Saga: Lessons learned from five years of Scrutiny.Org. Process Res. Dev.202327101719173510.1021/acs.oprd.3c00100
     [Google Scholar]
  11. ICH-MultidisciplinaryM7(R2) Addendum: Application of the Principles of the ICH M7 Guidance to Calculation of Compound - Specific Acceptable Intakes Guidance for Industry.2023Available from: https://www.fda.gov/media/170459/download (accessed on 8-10-2024)
     [Google Scholar]
  12. PathakM. Evaluation of various potential genotoxic nitrosamine impurities by using validated ultra - sensitive lc/ms/ms analytical method in antihypertensive drug product.J. Chem. Health Risks2024141106118
     [Google Scholar]
  13. US-FDARecommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs).Retrieved from Food and Drug Administration.2023Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/updated-information-recommended-acceptable-intake-limits-nitrosamine-drug-substance-related (accessed on 8-10-2024)
     [Google Scholar]
  14. Michelle LlamasB.C.P.A. Help for people injured by defective drugs and medical devices.Available from: www.drugwatch.com (accessed on 8-10-2024)
     [Google Scholar]
  15. Eglovitch JoanneS. USP proposes analytical methods for drug makers to detect nitrosamine impurities.2020Available from: pink.citeline.com (accessed on 8-10-2024)
     [Google Scholar]
  16. ShaikK.M. SarmahB. WadekarG.S. KumarP. Regulatory Updates and Analytical Methodologies for Nitrosamine Impurities Detection in Sartans, Ranitidine, Nizatidine, and Metformin along with Sample Preparation Techniques.Crit. Rev. Anal. Chem.2020 32691615
     [Google Scholar]
  17. ParfantT.P. SkubeT. RoskarR. A roboust analytical method for simultaneous quantification of 13 low-molecular-weight N-Nitrosamines in various pharmaceuticals based on solid phase extraction and liquid chromatography coupled to high resolution mass spectrometry.Eur. J. Pharm. Sci.2024192106633
     [Google Scholar]
  18. PatelR. PatelM. SolankiR. KhuntD. Trace level quantification of N-nitrosorasagiline in rasagiline tablets by LC-TQ-MS/MS.Ann. Pharm. Fr.202482577177910.1016/j.pharma.2024.03.006 38548223
     [Google Scholar]
  19. WichitnithadW. NantapholS. NoppakhunsomboonK. RojsitthisakP. An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals.Saudi Pharm. J.2022 36942272
     [Google Scholar]
  20. JadhavA.B. DeokateD.U. SuryavanshiR. Impurity profiling of pharmaceutical API: A review.J. Med. Chem. Drug Des.20152015235247
     [Google Scholar]
  21. Husni DariaG. FDA releases guidance on intake limits for nitrosamine drug substance-related impurities.2023Available from: www.pharmtech.com (accessed on 8-10-2024)
     [Google Scholar]
  22. Committee for medicinal products for human use (CHMP) Final agenda for the meeting on 23-26 April 2019.2019Available from: www.ema.europa.eu (accessed on 8-10-2024)
  23. YamamotoH. KagawaC. NakajimaT. Quantitation of Reactive Nitrosating Agents in Pharmaceutical Excipients for N -Nitrosamine Risk Assessments.Org. Process Res. Dev.202327101767177210.1021/acs.oprd.2c00402
     [Google Scholar]
  24. Distributed manufacturing and point-of-care manufacturing of drugs. 2022Available from: public4.pagefreezer.com (accessed on 8-10-2024)
  25. TrampužM. ŽnidaričM. GallouF. ČasarZ. Does the Red Shift in UV-Vis Spectra Really Provide a Sensing Option for Detection of N -Nitrosamines Using Metalloporphyrins?ACS Omega2023811154116710.1021/acsomega.2c06615 36643536
     [Google Scholar]
  26. SparksD. HallockS. Advances in Agronomy.Elsevier2013
     [Google Scholar]
  27. Analytical methods for the investigation of carcinogenic nitrosamines in apis and drug products.Available from: www.propharmagroup.com (accessed on 8-10-2024)
  28. DruckreyH. PreussmannR. IvankovicS. SchmahlD. Organotropic carcinogenic effects of 65 various N-nitroso- compounds on BD rats.Z. Krebsforsch.1967692103201
     [Google Scholar]
  29. LijinskyW. Chemistry and Biology of N-Nitroso Compounds.Cambridge University Press1992Vol. 46
     [Google Scholar]
  30. BogovskiP. BogovskiS. Animal Species in which N-nitroso compounds induce cancer.National Library of Medicine198147147410.1002/ijc.2910270408
     [Google Scholar]
  31. ChawlaM. Addressing nitrosamine and related impurities in pharmaceuticals.2020Available from: https://www.biospectrumindia.com (accessed on 8-10-2024)
     [Google Scholar]
  32. SeyyedsalehiM.S. MohebbiE. TourangF. SasanfarB. BoffettaP. ZendehdelK. Association of dietary nitrate, nitrite, and n-nitroso compounds intake and gastrointestinal cancers: A systematic review and meta-analysis.Toxics2023112190203
     [Google Scholar]
  33. JohnsonG. Tolerability of risk: A commentary on the nitrosamine contamination issue.Elsevier2021
     [Google Scholar]
  34. BerardiA. JaspersM. DickhoffB.H.J. Modeling the Impact of Excipients Selection on Nitrosamine Formation towards Risk Mitigation.Pharmaceutics20231582015www.mdpi.com10.3390/pharmaceutics15082015 37631229
     [Google Scholar]
  35. Guidance on nitrosamine impurities in medications Evaluating and managing the risks of N-nitrosamine impurities in human pharmaceutical, biological and radiopharmaceutical products-2024-Health CanadaAvailable from: https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/nitrosamine-impurities/medications-guidance/guidance-nitrosamine%20impurities-medications.pdf (accessed on 8-10-2024)
  36. Impurities found in certain angiotensin II receptor blocker (ARB) products, also known as sartans.2019Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/angiotensin-receptor-blocker.html (accessed on 8-10-2024)
  37. RaoG.S. RamadeviD. RaoB.M. RajanaN. BasavaiahK. Novel stability indicating LC-MS method for N-Nitroso dimethyl amine genotoxic impurity quantification in ranitidine drug substance and drug product.J. Appl. Pharm. Sci.202210611410.7324/JAPS.2022.120711
     [Google Scholar]
  38. MubarakunnisaM. A review on techniques for estimation of nitrosamine impurities in antidiabetic drugs Pioglitazones and Glifizones, Metformin.J. Pharmaceut Negat. Resul.2022202218661877
     [Google Scholar]
  39. Rojas-PabloM. Toledo-HernándezE. Rodríguez-BarreraM.A. Bacillus licheniformis M2-7 Decreases Ochratoxin A Concentrations in Coffee Beans During Storage.Curr. Microbiol.20248126210.1007/s00284‑023‑03575‑8 38216774
     [Google Scholar]
  40. DeparKLstration [Docket No. FDA-2020-D-1530] RecommKLated Impurities; Guidance for Industry public-inspection.Available from: public-inspection.federalregister.gov (accessed on 8-10-2024)
  41. M7(R1) assessment and control of dna reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk.Available from: https://www.fda.gov/media/85885/download (accessed on 8-10-2024)
  42. KruhlakN.L. SchmidtM. FroetschlR. Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA).Regul. Toxicol. Pharmacol.202415010564010.1016/j.yrtph.2024.105640 38754805
     [Google Scholar]
  43. LeeH. Acceptable exposure calculations for impurities and selected compounds from the carcinogenic potency database.In: Pharmaceutical Industry Practices on Genotoxic Impurities.CRC Press2014
     [Google Scholar]
  44. TeasdaleA. ImpuritiesM. Strategies for Identification and Control.In: Mutagenic Impurities.Wiley202110.1002/9781119551249
     [Google Scholar]
  45. GrahekR. DrevM. ZupancicB. HrenJ. OslajM. BastardaA. Stability and degradation pathways of n-nitroso-hydrochlorothiazide and the corresponding aryl diazonium ion.Org. Process Res. Dev.20232717921811
     [Google Scholar]
  46. TupeD. SuryawanshiN.R. KelkarJ. RasamP. Quantitation of 8 Nitrosamines in 12 different solvents by LC-MS/MS system.Shimadzu Application News20238045
     [Google Scholar]
  47. KhorshidianN. Yousefi AsliM. HosseiniH. ShadnoushM. MortazavianA.M. Potential Anticarcinogenic Effects of Lactic Acid Bacteria and Probiotics in Detoxification of Process-Induced Food Toxicants.Iran. J. Cancer Prev.2016In Press(In Press)10.17795/ijcp‑7920
     [Google Scholar]
  48. Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal product European Medicines Agency - EMA/409815/2020 Rev.17.2004Available from: www.mhlw.go.jp (accessed on 8-10-2024)
  49. ICH Q10 Pharmaceutical Quality System2009Available from: https://www.fda.gov/media/71553/download (accessed on 8-10-2024)
  50. PMDA's work2017Available from: www.pmda.go.jp (accessed on 8-10-2024)
  51. Control of nitrosamine impurities in human drugs.Available from: https://www.fda.gov/media/141720/download (accessed on 8-10-2024)
  52. Questions and answers on Information on nitrosamines for marketing authorisation holders.2023Available from: https://www.ema.europa.eu/en/documents/opinion-any-scientific-matter/nitrosamines-emea-h-a53-1490-questions-answers-information-nitrosamines-marketing-authorisation-holders-obsolete_en.pdf (accessed on 8-10-2024)
  53. JatharP.G. SheteN.A. DeshmukhV.K. GhawateV.K. PundA.R. A review on nitrosamine impurities present in drugs.Pharmaceut Resonance2022425
     [Google Scholar]
  54. SnodinD.J. Trejo-MartinA. PontingD.J. Mechanisms of nitrosamine mutagenicity and their relationship to rodent carcinogenic potency.Chem. Res. Toxicol.202437218119810.1021/acs.chemrestox.3c00327 38316048
     [Google Scholar]
  55. European medicines regulatory network approach for the implementation of the chmp opinion pursuant to article 5(3) of regulation (ec) no 726/2004 for nitrosamine impurities in human medicines. retrieved from european medicines agency.2021Available from: https://www.ema.europa.eu/en/documents/referral/european-medicines-regulatory-network-approach-implementation-chmp-opinion-pursuant-article-53/2004-nitrosamine-impurities-human-medicines_en.pdf (accessed on 8-10-2024)
  56. WichitnithadW. SudtanonO. SrisunakP. CheewatanakornkoolK. NantapholS. RojsitthisakP. Development of a Sensitive Headspace Gas Chromatography-Mass Spectrometry Method for the Simultaneous Determination of Nitrosamines in Losartan Active Pharmaceutical Ingredients.ACS Omega2021616110481105810.1021/acsomega.1c00982 34056258
     [Google Scholar]
  57. General chapter 1469 nitrosamine impurities.2021Available from: https://www.usp.org/sites/default/files/usp/document/stakeholder-forum/pnp/highlights-of-1469-nitrosamine-impurities.pdf (accessed on 8-10-2024)
  58. Agilent. Retrieved from Agilent2020Available from: https://www.agilent.com/cs/library/applications/Nitrosamine%20and%20Mutagenic%20Impurities%20Application%20Guide.pdf (accessed on 8-10-2024)
  59. GopireddyR.R. MaruthapillaiA. TamilselviM. Determination of potential nitrosamines NDMA, NDIPA and N-Nitroso Duloxetine in Duloxetine Hydrochloride by LC-MS/MS using APCI source.Mater. Today2022681A7A2010.1016/j.matpr.2022.11.112
     [Google Scholar]
  60. N-nitroso compounds in ‘sartan’ blood pressure medicines.2021Available from: https://www.tga.gov.au/news/notices/n-nitroso-compounds-sartan-blood-pressure-medicines (accessed on 8-10-2024)
  61. Information note nitrosamine impurities- update on nitrosamine impurities.2019Available from: https://www.who.int/news/item/20-11-2019-information-note-nitrosamine-impurities (accessed on 8-10-2024)
  62. ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.2016Available from: https://www.fda.gov/files/drugs/published/Q7-Good-Manufacturing-Practice-Guidance-for-Active-Pharmaceutical-Ingredients-Guidance-for-Industry.pdf (accessed on 8-10-2024)
  63. WHO good manufacturing practices considerations for the prevention and control of nitrosamine contamination in pharmaceutical products.Available from: www.pharmaexcipients.com (accessed on 8-10-2024)
  64. ICH Q11 Development and Manufacturing of Drug Substances2012Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q11-development-and-manufacture-drug-substances (accessed on 8-10-2024)
  65. WHO guidelines - for drinking water quality2022Available from: https://www.who.int/publications/i/item/9789241549950 (accessed on 8-10-2024)
/content/journals/cds/10.2174/0115748863324951241028050225
Loading
The Presence of Nitrosamines and Nitrosamine Drug-Related Substances in Pharmaceutical Products: An Overview of Regulatory Concerns, Analytical Methodologies, and Control Strategies
Curr Drug Saf 20, 404 (2025); https://doi.org/10.2174/0115748863324951241028050225
/content/journals/cds/10.2174/0115748863324951241028050225
/content/journals/cds/10.2174/0115748863324951241028050225
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): acceptable intake; Active pharmaceutical ingredients; dimethyl formamide; maximum daily dose; NDSRIs; Nitrosamines

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test