-
Journal of Pharmaceutical Sciences May 2023The potential presence of N-nitrosamines in medicinal products has become a matter of concern for health authorities and pharmaceutical companies. However, very little...
The potential presence of N-nitrosamines in medicinal products has become a matter of concern for health authorities and pharmaceutical companies. However, very little information is available in published literature on N-nitrosamine formation within pharmaceutical drug products. In response, experiments were undertaken to test if secondary and tertiary amines present in solid drug products could undergo nitrosation due to the presence of nitrite in the excipients used in the manufacture of the drug product. This work focused on solid dosage forms exploring several model amines of varying chemical structure, solubility and pKa which were formulated using common excipients with and without added nitrite. Monitoring the formation of the N-nitrosamines after processing and upon stressed stability conditions showed that N-nitrosamine formation can occur in solid drug product formulations. The results show that the rate and extent of N-nitrosamine formation depend upon the solubility of the amine, level of nitrite, expected local acidity in water layers within the drug product and mode of processing. Our findings agree with the rank order of dosage form risk from the published EFPIA workflows for quality risk management of N-nitrosamine risks in medicines (EFPIA, 2022): amorphous > wet granulation > direct compression > dry blends. In all cases the level of N-nitrosamine formation in solid dosage forms plateaued at a level that was significantly lower than the maximum theoretical yield based on the level of nitrite present. Trace secondary amine impurities were shown to be a significantly lower risk relative to cases containing a secondary amine present at drug substance levels. A comparison of secondary and simple tertiary alkylamine reactivity showed the tertiary amine to be significantly less reactive with nitrite.
Topics: Nitrosamines; Nitrites; Excipients; Amines; Water
PubMed: 36736774
DOI: 10.1016/j.xphs.2023.01.027 -
Arhiv Za Higijenu Rada I Toksikologiju Mar 2021In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received... (Review)
Review
In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: -nitrosodimethylamine (NDMA) and -nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives.
Topics: Carcinogens; Diethylnitrosamine; Dimethylnitrosamine; Drug Contamination; Humans; Nitrosamines
PubMed: 33787187
DOI: 10.2478/aiht-2021-72-3491 -
Bioanalysis Aug 2022-nitrosamines (nitrosamines) are attracting increased attention because of their high toxicity and wide distribution. They have been strictly restricted by regulations... (Review)
Review
-nitrosamines (nitrosamines) are attracting increased attention because of their high toxicity and wide distribution. They have been strictly restricted by regulations in many fields. Researchers around the world have conducted substantial work on nitrosamine detection. This paper reviews the progress of research on nitrosamine detection methods with emphasis on biological-matrix samples. After introducing the category, toxicity, regulatory limit and source of nitrosamines, the paper discusses the most commonly used sample-preparation techniques and instrumental-detection techniques for nitrosamine detection, including some typical application cases.
Topics: Nitrosamines
PubMed: 36125029
DOI: 10.4155/bio-2022-0091 -
Journal of Pharmaceutical Sciences Jul 2023N-nitrosamines are likely human carcinogens. After N-nitrosamine contaminants were detected in pharmaceutical products in 2018, regulatory authorities set a framework... (Review)
Review
N-nitrosamines are likely human carcinogens. After N-nitrosamine contaminants were detected in pharmaceutical products in 2018, regulatory authorities set a framework for the risk assessment, testing and mitigation of N-nitrosamines in drug products. One strategy to inhibit the formation of N-nitrosamines during the manufacture and storage of drug products involves the incorporation of nitrite scavengers in the formulation. Diverse molecules have been tested in screening studies including the antioxidant vitamins ascorbic acid and α-tocopherol, amino acids, and other antioxidants used in foods or drugs, for inclusion into drug products to mitigate N-nitrosamine formation. This review article outlines key considerations for the inclusion of nitrite scavengers in oral drug product formulations.
Topics: Humans; Nitrosamines; Nitrites; Antioxidants; Ascorbic Acid; Pharmaceutical Preparations
PubMed: 37023856
DOI: 10.1016/j.xphs.2023.03.022 -
Drug and Therapeutics Bulletin Mar 2021Topics for DTB review articles are selected by DTB's editorial board to provide concise overviews of medicines and other treatments to help patients get the best care.... (Review)
Review
Topics for DTB review articles are selected by DTB's editorial board to provide concise overviews of medicines and other treatments to help patients get the best care. Articles include a summary of key points and a brief overview for patients. Articles may also have a series of multiple choice CME questions.
Topics: Animals; Drug Contamination; Drug Industry; Government Agencies; Humans; Nitrosamines; No-Observed-Adverse-Effect Level; Risk
PubMed: 33627351
DOI: 10.1136/dtb.2020.000036 -
Journal of Pharmaceutical Sciences Sep 2023Most N-Nitrosamine compounds are found to be genotoxic in several animal species. Some are classified as probable or possible human carcinogens and very low acceptable... (Review)
Review
Most N-Nitrosamine compounds are found to be genotoxic in several animal species. Some are classified as probable or possible human carcinogens and very low acceptable daily intake has been established such as 96 ng/day for N-nitrosodimethylamine (NDMA) and 26.5 ng/N-nitrosodiethylamine (NDEA). The pharmaceutical industry has considered all processing areas for potential formation or contamination of N-nitrosamine. One risk is the potential contamination of nitrosamine during drug product blister packaging using lidding foils containing nitrocellulose, and different approaches have been used by pharmaceutical companies to evaluate and mitigate this risk. Herein we share a perspective from IQ Consortium N-nitrosamine Working Group on some of the approaches and corresponding results. From these assessments, it was concluded that the risk of nitrosamine contamination during blister packaging is negligible. The approaches shared in this perspective can be incorporated into risk assessment for nitrosamine contamination during drug product packaging at other pharmaceutical companies.
Topics: Animals; Humans; Nitrosamines; Blister; Dimethylnitrosamine; Drug Contamination; Product Packaging; Pharmaceutical Preparations
PubMed: 37478970
DOI: 10.1016/j.xphs.2023.07.014 -
Current Topics in Medicinal Chemistry 2024Since their discovery in valsartan-containing drugs, nitrosamine impurities have emerged as a significant safety problem in pharmaceutical products, prompting extensive... (Review)
Review
Since their discovery in valsartan-containing drugs, nitrosamine impurities have emerged as a significant safety problem in pharmaceutical products, prompting extensive recalls and suspensions. Valsartan, candesartan, irbesartan, olmesartan, and other sartans have been discovered to have additional nitrosamine impurities, such as N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso-Di-isopropyl amine (NDIPA), N-nitroso-Ethyl-Isopropyl amine (NEIPA), and N-nitroso-Diethyl amine (NDEA). Concerns about drug safety have grown in response to reports of nitrosamine contamination in pharmaceuticals, such as pioglitazone, rifampin, rifapentine, and varenicline. This review investigates the occurrence and impact of nitrosamine impurities in sartans and pharmaceutical goods, as well as their underlying causes. The discussion emphasizes the significance of comprehensive risk assessment and mitigation approaches at various phases of medication development and manufacturing. The link between amines and nitrosamine impurities is also investigated, with an emphasis on pH levels and the behaviour of primary, secondary, tertiary, and quaternary amines. Regulations defining standards for nitrosamine assessment and management, such as ICH Q3A-Q3E and ICH M7, are critical in resolving impurity issues. Furthermore, the Global Substance Registration System (GSRS) is underlined as being critical for information sharing and product safety in the pharmaceutical industry. The review specifically focuses on the relationship between ranitidine and N-nitroso dimethyl amine (NDMA) in the context of the implications of nitrosamine contamination on patient safety and medicine supply. The importance of regulatory authorities in discovering and correcting nitrosamine impurities is highlighted in order to improve patient safety, product quality, and life expectancy. Furthermore, the significance of ongoing study and attention to nitrosamine-related repercussions for increasing pharmaceutical safety and overall public health is emphasized.
Topics: Nitrosamines; Drug Contamination; Humans; Pharmaceutical Preparations
PubMed: 38321910
DOI: 10.2174/0115680266278636240125113509 -
Cardiology in Review 2020Nitrosamines are known carcinogens which have been recently discovered in several angiotensin receptor blockers (ARBs). This led to the recall of valsartan in the United...
Nitrosamines are known carcinogens which have been recently discovered in several angiotensin receptor blockers (ARBs). This led to the recall of valsartan in the United States in 2018, and afterward, the recall of other ARBs as well as unrelated medications (e.g., ranitidine). The presence of nitrosamine in ARBs was likely a result of changes in the manufacturing process, although nitrosamine contamination is believed to occur by different mechanisms with other medications. The United States Food and Drug Administration has since taken steps to identify products affected by nitrosamine contamination and mitigate this concern going forward. Despite the contamination of some drug products, studies estimate that the overall risk to patients is low enough to not necessitate changes in prescribing patterns at this time.
Topics: Angiotensin Receptor Antagonists; Antacids; Carcinogens; Drug Compounding; Drug Contamination; Drug Recalls; Humans; Nitrosamines; Pharmacovigilance; Ranitidine; Safety-Based Drug Withdrawals; United States; United States Food and Drug Administration
PubMed: 32467427
DOI: 10.1097/CRD.0000000000000323 -
Bioanalysis Jan 2022
Topics: Nitrosamines; Pharmaceutical Preparations
PubMed: 34743592
DOI: 10.4155/bio-2021-0238 -
The Proceedings of the Nutrition Society Feb 1985
Review
Topics: Amides; Amines; Animals; Diet; Food Preservatives; Gastric Mucosa; Humans; Neoplasms; Nitrites; Nitrogen Oxides; Nitrosamines; Nitroso Compounds; Nutritional Physiological Phenomena; Oxidation-Reduction; Saliva; Urea
PubMed: 3885233
DOI: 10.1079/pns19850015