Occurrence of N-Nitrosamines as Harmful Impurities in Pharmaceuticals

Mengru Cao; Zhiwei Ye; Jun Wang; Xiaojin Zhang; Pengfei Lin; Chao Chen

doi:10.7536/PC230328

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Prog Chem ›› 2023, Vol. 35 ›› Issue (12) : 1881-1894. DOI: 10.7536/PC230328

Review

Occurrence of N-Nitrosamines as Harmful Impurities in Pharmaceuticals

Mengru Cao ¹^,³ ,
Zhiwei Ye ² ,
Jun Wang ²^,³ ,
Xiaojin Zhang ³ ,
Pengfei Lin ³ ,
Chao Chen ²^,³^,^*

Author information +

History +

Abstract

Since the “valsartan event” in 2018, the occurrence of N-nitrosamine as genotoxic impurities in pharmaceuticals has become a hot topic for academia, industry, and the public. N-nitrosamines are a class of strong carcinogens, and more than ten nitrosamines have been included in the International Agency for Research on Cancer (IARC) carcinogen list, with N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) listed as Class 2A carcinogens. In this article, the toxicological characteristics, carcinogenic mechanism, and detection methods of N-nitrosamines are summarized. The causes of nitrosamine impurities in drugs such as valsartan, ranitidine, and metformin are reviewed as well as the regulatory requirements and measures for nitrosamine impurities in drugs in the European Union, the United States, and China. The carcinogenic risk caused by nitrosamine impurities in the above mentioned drugs is estimated. Valsartan has the highest concentration of nitrosamine impurities (NDMA content: not detected~20.19 μg/tablet; NDEA content: not detected~1.31 μg/tablet), resulting in the highest extra cancer risk (CR): the median CR value is 4.69 × 10^-6 while the 75^th percentile CR value is as high as 5.61 × 10^-4 which means at least 25% of tablets can bring high cancer risk. Ranitidine and metformin have much lower nitrosamine impurities, and their cancer risk is close to or below the 10^-6 safety level. The carcinogenic risk caused by unqualified pharmaceuticals with nitrosamines impurities is much higher than that caused by nitrosamines in food and drinking water, and even slightly higher than that caused by tobacco nitrosamines. Therefore, the health effect due to unqualified pharmaceuticals needs to be regarded seriously. Since 2020, there is no problem of excessive nitrosamine impurities in raw materials and finished drugs thanks to enhanced administration. This article provides references for professionals from the relevant institutions in the fields of pharmaceutical production, health evaluation, research, and regulation.

Contents

1 Introduction

2 Detection of nitrosamine impurities in pharmaceuticals

3 Toxicological properties of nitrosamines

3.1 Basic characteristics

3.2 Carcinogenic mechanism

3.3 Carcinogenic effect factor

3.4 Carcinogenic risk assessment of pharmaceutical nitrosamines

4 Epidemiological investigation

5 Sources of nitrosamine impurities in pharmaceuticals

6 Endogenous production of nitrosamines after administration

7 Comparison with other exogenous exposure pathways

8 Pharmaceutical regulatory measur

Key words

N-nitrosamine / pharmaceutical / carcinogenicity / impurity / risk analysis

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Mengru Cao , Zhiwei Ye , Jun Wang , et al . Occurrence of N-Nitrosamines as Harmful Impurities in Pharmaceuticals[J]. Progress in Chemistry. 2023, 35(12): 1881-1894 https://doi.org/10.7536/PC230328

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