From Valsartan to Ranitidine: Nitrosamine Impurities and the Measures taken by the EMA and the EDQM

The carcinogenic contaminant N-nitrosodimethylamine (NDMA) was discovered in medicinal products containing Sartan (for the treatment of high blood pressure) for the first time in June 2018. The API originated from the production site of the Chinese manufacturer Zhejiang Huahai. It was detected as an impurity in the end product following a change in the synthesis process (see our News "Valsartan: what caused the contamination?"). Since that time, reports of new cases have kept coming in. NMDA and N-nitrosodiethylamine (NDEA) were found in several preparations, most recently also in pioglitazone (for the treatment of type 2 diabetes mellitus) and ranitidine (to control gastric acid production in heartburn).

Reactions and measures of the EMA

Shortly after the discovery of the incident, the EMA launched a review of drugs containing Sartan. The result of it was that in the vast majority of cases, no or only very low concentrations of nitroso impurities were detectable. Following this review, the EMA recommended that all companies manufacturing medicinal products containing Sartans review their manufacturing processes. The press release entitled "Sartan medicines: companies to review manufacturing processes to avoid presence of nitrosamine impurities EMA/44960/2019" of February 1, 2019, also describes the assessment of the highest possible cancer risk - derived from animal studies - due to these impurities: Out of 100,000 patients who would be treated with a maximum dose of Huahai's Valsartan for 6 years (the highest concentrations of nitroso impurities were measured in this preparation), a rate of 22 additional cases of cancer could be expected in relation to NDMA. Regarding NDEA, there would be 8 cancer cases with a treatment time of 4 years. The 6 and 4 years respectively are based on the assumption that NDMA and NDEA were present in Zhejiang Huahai's valsartan during these periods.

The EMA granted the companies affected by the recommended review of their manufacturing processes a two-year transition period during which they must make any necessary changes and introduce appropriate testing procedures to detect the lowest concentrations of these contaminants. Moreover, the EMA defined transition limits for impurities  due to NDMA and NDEA for 5 different Sartan preparations. After expiration of the transition period in April 2021, the strict limit values of < 0.03 ppm will apply to concentrations of NDEA or NDMA.

In another document entitled "Update on nitrosamine impurities: EMA continues to work to prevent impurities in medicines" EMA/241020/2019 dated April 26, 2019, the EMA reiterates its request to manufacturers of pioglitazone preparations to review their manufacturing processes. This was preceded by the discovery of traces of NDMA in some pioglitazone batches of the Indian manufacturer Hetero Labs, which, however, are below the transitional limits for Sartan described in the above-mentioned document.

Five months later, on September 20, 2019, the EMA issued a report entitled "EMA to review ranitidine medicines following detection of NDMA". The reason for this was the discovery that ranitidine preparations contain significant concentrations of NDMA. In this communication, the EMA announced a review of ranitidine preparations, similar to that already performed for Sartan preparations, and a corresponding risk assessment for patients treated with this medicinal product. The EMA also stresses that its cooperation with the national authorities and the EDQM is aimed at taking effective measures against the occurrence of nitroso contamination.

In a further press release dated September 13, 2019, the EMA finally announced that the Executive Director had commissioned the Human Medicines Committee (CHMP) to prepare a guidance document on the prevention of nitrosamine contamination in chemically synthesized APIs.

An extensive list of the EMA's documents on measures relating to nitrosamine impurities in Sartan preparations can be found on the EMA website under the sections "News and Events - What's new" by searching for "sartan medicines" and clicking on "Categories" "Human" and "Type of content" "Documents".

Reactions and measures of the EDQM

Soon after the nitrosamine impurities in Sartan drugs became known, the EDQM reacted on July 27, 2019, with a press release on a package of measures consisting of 5 actions (including the withdrawal of the CEP for the API manufactured by Zhejiang Huahai).
In the meantime, further announcements followed with information on the continuous monitoring of this problem under the leadership of the EDQM:

• Complete review of all CEPs and CEP applications for Sartan-containing preparations (August 28, 2018)
• Cooperation with Official Medical Control Laboratories (OMCLs) on appropriate analytical methods for the detection of nitrosamine contaminants (14 September 2018)
• Publication of three analytical methods for nitrosamine detection (21 September 2018)
• Publication of an analytical method for the simultaneous determination of NDMA and NDEA in Sartans (October 11, 2018)
• Current information on the review of CEP applications for Sartan and the currently available detection methods for nitrosamines in Sartans (17 October 2018)
• Current Information on the review of CEP applications for Sartan and CEP suspensions on November 19, 2018, January 18, 2019 and February 4, 2019
• Communication on the revision of the pharmacopoeia monographs of 5 Sartan preparations (Valsartan, Candesartan, Irbesartan, Losartan and Olmesartan) (13 June 2019). The monographs were updated within the two-year transitional period in accordance with the European Commission's decision on the limit values for these Sartans.
• Further up-to-date information on the status of the review and withdrawal of CEPs for Sartan (June 18, 2019)

This was finally followed on 16 September 2019 by the communication on nitrosamine impurities in ranitidine and the announcement by the EDQM to work closely with the EMA on this issue.

These concerted actions by the authorities, which also include inspections of the relevant API sites by European GMP inspectors (see our news "Valsartan: New Inspection reveals significant GMP Violations"), are contributing to the elimination of nitrosamine contaminants from the market. It is to be hoped that recent incidents have been the last of their kind.