Journal Article

Nitrosamines crisis in pharmaceuticals − Insights on toxicological implications, root causes and risk assessment: A systematic review

Jat, Sandeep, Gurupadayya, Bannimath, Vikram, Hemanth P.R., Bannimath, Namitha, Kumar, Tegginamath Pramod, Kumar, Gunjan, Beeraka, Narasimha M., Kumar, Pramod, Deka, Rajashree, Padmanabhan, Gayatiri, Suhail, Sheik Mohammed, Chandan, Ravandur S.

2024

Overview

The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates their toxicity in active pharmaceutical ingredients (APIs), drug products, and pharmaceutical excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, and regulatory guidelines for nitrosamines. This review emphasizes the molecular toxicity of N-nitroso compounds, focusing on genotoxic, mutagenic, carcinogenic, and other physiological effects. Additionally, it addresses the ongoing nitrosamine crisis, the development of nitrosamine-free products, and the importance of sensitive detection methods and precise risk evaluation. This comprehensive overview will aid molecular biologists, analytical scientists, formulation scientists in research and development sector, and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products. [Display omitted] •The nitrosamines crisis in pharmaceuticals is discussed.•We delve into the toxicological implications and toxicity profiles of N-nitroso compounds.•We discussed root cause analysis, risk assessment, and mitigation strategies for nitrosamine impurities.•We highlighted GC and LC methods for detection and quantification of N-nitroso compounds in pharmaceuticals.•The emphasis is on developing nitrosamine-free pharmaceutical products to ensure regulatory compliance.

• Publisher: Elsevier B.V,Xi'an Jiaotong University, Journal of Pharmaceutical Analysis,Department of Pharmacology,Raghavendra Institute of Pharmaceutical Education and Research(RIPER),Ananthapuramu,515721,India,Xenone Healthcare Pvt.Ltd.,New Delhi,110076,India%Department of Pharmaceutics,JSS College of Pharmacy Mysuru,JSS Academy of Higher Education and Research(JSSAHER),Mysuru,570015,India%Xenone Healthcare Pvt.Ltd.,New Delhi,110076,India%Department of Human Anatomy,I.M.Sechenov First Moscow State Medical University(Sechenov University),Moscow,119991,Russian Federation,Herman B.Wells Center for Pediatric Research,Department of Pediatrics,Indiana University School of Medicine,Indianapolis,IN,46202,USA%Animal Physiology and Biochemistry Laboratory,Department of Zoology,Gauhati University,Guwahati,781014,India%Department of Pharmacology,JSS College of Pharmacy Mysuru,JSS Academy of Higher Education and Research(JSSAHER),Mysuru,570015,India%Department of Pharmaceutical Analysis,National Institute of Pharmaceutical Education and Research(NIPER)-Guwahati,Changsari,781101,India%Department of Pharmacology,University of Galway,Galway,H91 TK33,Ireland%Department of Pharmaceutical Chemistry,JSS College of Pharmacy Mysuru,JSS Academy of Higher Education and Research(JSSAHER),Mysuru,570015,India,Department of Pharmaceutical Chemistry,JSS College of Pharmacy Mysuru,JSS Academy of Higher Education and Research(JSSAHER),Mysuru,570015,India,Elsevier
• Subject: Carcinogenicity / Carcinogens / Case reports / Drugs / Epidemiology / Genotoxicity / Molecular toxicity / Mutagenicity / N-Nitroso compounds / Nitrosamine drug substance-related impurities / Nitrosamine impurities / Nitrosamines / Pharmaceutical industry / Physiology / R&D / Research & development / Reviews / Risk assessment / Sensitivity analysis / Systematic review / Toxicity