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Asia: Japan’s PMDA provides update on managing nitrosamine contamination risks

2023/08/31  PMDA

**1. Introduction **
In recent years, nitrosamines, such as N-nitrosodimethylamine (NDMA), which may have carcinogenic risks, have been detected in sartan drugs, ranitidine, nizatidine, metformin, etc. in Japan and overseas, and some products have been voluntarily recalled. Based on these cases, the MHLW is promoting efforts to reduce and control the contamination with nitrosamines in drugs. This article introduces the latest information.

**2. Response to contamination with nitrosamines **
In July 2018, NDMA was detected in the drug substance manufactured by Zhejiang Huahai Pharmaceutical Co., Ltd., and it was announced that the drug product using the drug substance in question would be recalled throughout Europe. Thereafter, contamination with nitrosamines for the following drugs has also been reported in Japan: Sartan drugs, ranitidine, nizatidine, and metformin. Since it is important to reduce the risk of contamination with nitrosamines as much as possible, on October 8, 2021, the MHLW notified prefectural governments in Japan to instruct the marketing authorization holders (MAHs) under jurisdiction to perform self-inspection on the risk of contamination with nitrosamines. Mainly, the following three measures are to be taken in selfinspection of drugs already on the market.

(1) The risk of contamination with nitrosamines shall be evaluated by April 30, 2023, in consideration of the manufacturing method, etc. with reference to the known causes of contamination with nitrosamines.
(2) For products that have a risk of contamination with nitrosamines, the amount of nitrosamines that may be contained in the drugs concerned shall be measured using an appropriate number of lots.
(3) As a result of (2) above, products that are found to be contaminated with nitrosamines exceeding the acceptable limit shall be promptly reported to the MHLW, and risk mitigation measures such as setting specifications and changing the manufacturing method to reduce the amount of nitrosamines shall be implemented by October 31, 2024. (If an application for approval of partial change or a notification of minor change is required, such an application or notification shall be made by October 31, 2024.)

In the presence of secondary or tertiary amines, nitrosamines may be formed by the reaction with compounds with nitrosation potential such as sodium nitrite (NaNO2). Contamination with nitrosamines is known to be caused by various reasons, such as generation in the manufacturing process, contamination from raw materials, etc., and generation during storage. However, the cause of the contamination may not be identified immediately at the time of detecting the contamination, and a certain period of time is required before establishing risk mitigation measures by setting specifications or changing manufacturing methods.

**3. Risk assessment of contamination with nitrosamines **
Assessment of impurities with a carcinogenic risk in drugs is generally based on whether it exceeds the carcinogenic risk (“approximately 1 additional cancer per 100 000 persons” over a lifetime of exposure), which is considered to be acceptable in international guidelines (“Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” (ICH-M7 Guidelines)).

For this risk assessment, data, etc. from toxicity studies in which carcinogenicity was investigated by administering the impurity to animals are used. However, contamination with nitrosamines for which toxicity study data are not available has recently been reported. In this case, while the carcinogenicity of the nitrosamines concerned in animals is unknown, a provisional risk assessment has been performed using the toxicity data of compounds with a similar chemical structure, etc. To elucidate the carcinogenicity of these nitrosamines, it is generally confirmed whether they have carcinogenicity caused by genotoxicity in studies to detect mutation using bacteria and gene mutation studies in transgenic animals. If carcinogenicity is not ruled out, carcinogenicity studies in animals will be considered to clarify the strength of carcinogenicity. This carcinogenicity study requires a period of several years.

If the risk assessment based on the toxicity study data or provisional risk assessment reveals the presence of nitrosamines exceeding the acceptable limit in terms of the carcinogenic risk, the MAHs, etc. are required to inform healthcare professionals of the fact. In recent cases, contamination with N-nitrosonortriptyline, a compound classified as a nitrosamine, has been found in nortriptyline products. On the supposition that N-nitrosonortriptyline is carcinogenic, the level of increase in the risk of developing cancer was found to be greater than the risk of “approximately 1 additional cancer per 100 000 persons.”1 Since nortriptyline is a tricyclic antidepressant, patients may experience withdrawal symptoms, etc. by rapid dose reduction or discontinuation of the drug. Therefore, patients need to be informed that they should not stop taking the drug without consulting a physician. In addition, physicians or pharmacists are requested to explain other treatment options as well as the level of the risks to patients currently taking the drug.

**4. Conclusion **
For nitrosamines that may have carcinogenic risk, reducing the risk of contamination as much as possible is a very important issue. The MHLW cooperates with foreign regulatory authorities, etc. to continuously implement and review necessary measures to deal with the contamination with nitrosamines, etc. Even if contamination of nitrosamines exceeding the risk of “approximately 1 additional cancer per 100 000 persons” is detected, we consider that it is generally important that patients do not stop taking the drug without consulting a physician, and healthcare professionals are encouraged to communicate with patients for proper use of drugs based on the information provided for each drug.

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