The Center for Drug Evaluation, NMPA (CDE) released on its website the Technical Guidelines for the Research of Nitrosamine Impurities in Chemical Drugs (Draft for Comment) on Jan. 10, 2020 with the period of opinion solicitation of one month, which has made a splash and will be of far-reaching significance to the pharmaceutical industry as it will fill in gaps in China’s regulation and technical requirements for the research of nitrosamine impurities in chemical drugs. The industry has amplified calls for the technical control guidelines for the research of nitrosamine impurities in chemical drugs in recent years. This article analyzes the pain spots and highlights in the research of nitrosamine impurities in chemical drugs in the hope of providing some reference for the said research.

I. Pain spots in the research of nitrosamine (NDMA and NDEA) impurities
What triggered people to start to pay attention to nitrosamine (NDMA and NDEA) impurities was the valsartan event of Huahai Pharmaceutical in 2018. On July 5, 2018, the EU EMA announced on its website that some medicines produced with Huahai Pharmaceutical’s API valsartan would be recalled due to the detection of an impurity: N-nitrosodimethylamine (NDMA) in valsartan by Zhejiang Huahai. Following this, various nitrosamine impurities such as NDMA and N-Nitrosodiethylamine (NDEA) were detected in other sartan APIs. Further investigations discovered that nitrosamine impurities were also detected in non-sartan drugs (ranitidine) of individual suppliers. Nitrosamine impurities belong to the "cohort of concern" mentioned in the ICH guideline M7(R1) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk, and according to the World Health Organization’s list of carcinogens, NDMA and NDEA are Group 2A carcinogens, therefore, nitrosamine (NDMA and NDEA) impurities shall be strictly controlled in pharmaceutical products. Due to the low control limits and complex matrices of genotoxic impurities, it’s necessary to develop and use the quantitative detection methods with high sensitivity and high selectivity, and the development of the analytical methods needs to be fully prepared for the volatility, thermostability, chemical reaction characteristics, matrix characteristics and interference, etc. of genotoxic impurities. The CDE has actively conducted the corresponding exploration and research of the nitrosamine impurities in pharmaceutical products and will make continuous improvement based on the research results of all sides and the risk-benefit assessment principle; it has organized the drafting of the Warning on the Risk of Nitrosamine Compound Formation in the API Processes (Draft for Comment) and Technical Guidelines for the Research of Nitrosamine Impurities in Chemical Drugs (Draft for Comment) for the reference of the pharmaceutical industry and medical equipment and supplies manufacturing of China.
Date | Milestone |
Feb. 15, 2019 | The CDE organized the drafting of the Warning on the Risk of Nitrosamine Compound Formation in the API Processes on the basis of literature research and reaction mechanism analysis, to provide technical reference for the risk of nitrosamine compound formation in the API research and production. |
Jan. 10, 2020 | The CDE released on its website the Technical Guidelines for the Research of Nitrosamine Impurities in Chemical Drugs (Draft for Comment) to fill in gaps in China’s regulation and technical requirements for the research of nitrosamine impurities in chemical dru... Read More
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