Module 3 - Strategic case studies in practice

In July 2019, EDQM received information on a new N- nitrosamine N- nitrosomethylphenylamine (NMPA) – in valsartan from another API manufacturer. The levels detected for products in the EU/EEA were below the ICH M7(R1) limit calculated for NMPA at the time based on methodologies referenced in the outcome of the Article 31 review. In September 2019, at the request of the European Commission, an Article 31 review was initiated for ranitidine containing medicines (EMEA/H/A-31/1491) 2 after tests showed that some of these products contained NDMA, both in API and finished products. In a number of EU countries, national authorities initiated recalls of ranitidine medicines from pharmacies. In May 2019, the Lessons Learnt Exercise was initiated within the European network to determine what lessons can be drawn from cases of unexpected presence of N- nitrosamine impurities in sartans. A final report for this exercise has been published on 24 June 2020 3 2.2.2.1.1. Theoretically possible root-causes for N- nitrosamines in pharmaceutical products linked with water When N- nitrosamines are present in raw materials, there is a risk that they are carried over in finished products. Similarly, if nitrites are present in raw materials, they could react with amines, ubiquitous in APIs, their precursors, reagents and many solvents, to form N- nitrosamines which could also be carried over in finished products. NDMA can occur in drinking water as it is a by-product of several industrial processes and is a contaminant of certain pesticides. NDMA has recently been identified as a disinfection by-product of chloramination (by the reaction of monochloramine with dimethylamine, a ubiquitous component of waters impacted by wastewater discharges) and, to some extent, chlorination. NDMA can also be formed as a by-product of anion-exchange treatment of water. It is generally removed during water treatment by UV irradiation. The current WHO Guideline “Guidelines for drinking-water quality” (WHO/HSE/AMR/08.03/8; 4th edition, incorporating the 1st addendum) defines a limit for NDMA in drinking water of 0.1 µg/L , equivalent to 0.1 µg/kg = 0.1 ng/g = 0.1 ppb in case of ρ = 1 kg/L, du e to different sources from the environment. Maximum NDMA concentration levels were detected in different water samples from Australia and China [Krasner et al. (2013); NDMA 75 ng/L equivalent to < 75 ng/kg = 0.075 ng/g= 0.075 ppb]. The solubility of NDMA in water is high (290 g/L at 20 °C) [Alaba et al. (2017)], however considering the overall low levels at which it is found in water, it is concluded that NDMA from water highly probably does not represent a realistic source for NDMA contamination of APIs. However, disinfection procedures may lead to significant N- nitrosamine generation as by-products, in case certain active substances are present [Parr et al. (2019)]. Shen et al. (2011) have investigated the susceptibility of 20 active substances to N- nitrosamine formation after exposure to water disinfected by chloramine. Molar yields higher than 1% were observed for eight pharmaceutical substances, with ranitidine showing the strongest potential to form NDMA. Despite lower molar turnover, similar results were reported for ranitidine when treated with water disinfected by ozonation [Lv J. (2017)]. For further information on ranitidine degradation and NDMA formation please refer to the ranitidine referral under Article 31 of Directive 2001/83/EC 2 . Nitrites have been observed in various reagents, often when sodium nitrite has been used in their preparation (for example, sodium azide). This is another route by which nitrites can be inadvertently

2 https://www.ema.europa.eu/en/medicines/human/referrals/ranitidine-containing-medicinal-products 3 https://www.ema.europa.eu/en/documents/report/lessons-learnt-presence-n-nitrosamine-impurities-sartan- medicines_en.pdf

EMA/369136/2020

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