Nitrosamine Impurities in Pharmaceuticals & Foods

Data integrity and its Compliance
Data integrity and its Compliance
August 26, 2020
Qualification of Pharmaceutical Working Standard
Qualification of Pharmaceutical Working Standards
August 28, 2020
Nitrosamine impurities in phrmaceuticals and foods
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Overview

Nitrosamines are general organic complexes and found often in foods, vegetables, rubber products, pharmaceutical products, and even in water in trace levels. Nitrites found in fertilizers which results in a nitrosamine in agriculture products e.g. Cereals, rice, potatoes, and fruits. One and all are susceptible to some extent of nitrosamines.

Nitrosamines contain nitro functional group (–NO) which forms when nitrates or nitrites in reaction with secondary or tertiary amines. The nitro group is related to mutagenicity and genotoxicity, which may be possible human carcinogens, based on the studies. As per the pre-clinical test study finding it is confirmed the evidence of their carcinogenicity. Due to this reason nitrosamines content is not acceptable by the regulatory agencies.

So far FDA has declared about a number of nitrosamines described as per below:

Chemical NameAbbreviationAllowable Daily Intake
N-Nitroso dimethyl amineNDMA96.0 ng/day
N-Nitroso diethyl amineNDEA26.5 ng/day
N-Nitroso di-isopropyl amineNDIPA26.5 ng/day
N-Nitroso-ethyl iso-propylamineNEIPA26.5 ng/day
N-Nitroso-N-methyl-4-aminobutyric acidNMBA96.0 ng/day

Table-1: Provisional allowable daily intake limits for nitrosamine impurities

Possible reasons for nitrosamine impurity formation:

  1. Contamination from starting materials such as chemicals, solvents, catalyst and other raw materials.
  2. Packaging materials is one of the reason of nitrosamines in finished products. Imprinting inks based on nitrocellulose is the potential source of nitrites and azo pigments are another source of aromatic amines.
  3. Nitrates are used as a preservative in foods. Amines are certainly derived from food stuffs like meat products including cured meat, bacon, fish etc.
  4. Nitroso di-methyl amine formed in foods as an effect of the direct-fire drying process. 
  5. Nitrosamine impurities formed during manufacturing processing of drug substance with some specific starting materials, raw materials, and intermediates.
  6. Secondary or tertiary amines are generated by degradation reactions due to the use of sodium nitrite (NaNO2), or other nitrating agents, in combination with chemicals, reagents, solvents and catalysts.
  7. Nitrosamine impurity formed due to incomplete reduction of sodium nitrite (NaNO2), or other nitrating agents in presence of secondary, tertiary amines or quaternary ammonium salts within the same or different step of synthesis.
  8. Degradation of drug substance or drug product happened during the reaction with unreacted sodium nitrite or may be due to finished product formulation or storage.
  9. Use of contaminated raw materials such as recycled solvents, reagents and catalysts which may carriage a risk of presence of amines during recycling,
  10. The use of contaminated materials from vendors using processes that lead to the formation of nitrosamines or different manufacturing process on similar line.

List of Drug Products Presence of Nitrosamine Impurities:

Following are the drug products were recalled worldwide due to the presence of nitrosamine impurities:

  1. Valsartan, Candesartan, Irbesartan, Losartan and Olmesartan,
  2. Pioglitazone,
  3. Ranitidine,
  4. Nizatidine,
  5. Metformin.

Analytical Challenge:

Analysis of nitrosamines can be challenging because of its ultra-low levels in pharmaceuticals and food products. It may require the sophisticated and most sensitive equipment to meet these limits, including, LC-MS-MS and GC-MS-MS systems. It needs highly selective and sensitive method for quantification of nitrosamines. The methods need to be validated to conform its intended use.

Conclusion:

Detection of nitrosamine in various pharmaceutical products raised concern about the safety of its intended use. Hence manufacturer ensure take proper precautions with appropriate synthesis procedure to develop the drug product with assigned acceptable limits. Analytical method must be capable to detect the nitrosamine limit levels as per FDA recommendation with LOD and LOQ levels.

Reference:

  1. ICH Harmonised Guideline Assessment and Control Of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7(R1),
  2. Crews, C. (2019). The determination of N-nitrosamines in food. Quality Assurance and Safety of Crops & Foods,
  3. www.who.int/medicines/publications/drugalerts/InformationNote_Nitrosamine-impurities/en.
  4. www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine.
  5. www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-information-nitrosamines-marketing-authorisation-holders_en.pdf.
  6. P. Song, L. Wu and W. Guan, “Dietary Nitrates, Nitrites, and Nitrosamines Intake and the Risk of Gastric Cancer: A Meta-Analysis,” Nutrients 7(12), 9872–9895 (2015).

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