Module 3 - Strategic case studies in practice

• Root causes for presence of N -nitrosamines and proposed measures to mitigate it.

• Consideration for analytical method development to identify and quantify N -nitrosamines in drug substances and medicinal products. Satety • Considerations for calculating risk for exposed patients in case of in case of detection of N - nitrosamines in medicinal product(s).

• Methodology for defining limits for N-nitrosamines in medicinal products.

• Consideration on epidemiological studies. 2.2.1. Root causes for presence of N -nitrosamines in medicinal products and measures to mitigate them

Presence, formation and regulation of N-nitrosamines in different areas

Environment N -nitrosamines occur and are formed in the environment. In the air they form mainly by combustion processes and in water by biological processes in trace amounts. Control strategies are according to the as low as reasonably achievable (ALARA) or as low as reasonably practicable (ALARP) principles. Concentrations are considered to be higher in areas with less control and high air and water pollution. Food In food products formation of N -nitrosamines mainly occurs by reaction of nitrite and nitrosatable amines in meat, fish and other products at higher temperature. The formation and occurrence have raised major concerns in the seventies to nineties of the last century and measures had been undertaken to minimize formation by reducing the use of nitrate and nitrite in food production. This has been reviewed by the European Food Safety Authority (EFSA) which refers to various surveys concluding that the exposure to volatile N -nitrosamines (NDMA plus NDEA) via processed meat as a main source of overall external exposure is 0.2 ng/kg/day in infants to 3.5 ng/kg/d in toddlers (see also section 2.4). Unpublished data on actual levels of nitrosamines in cooked/processed food analysed N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), NDIPA, NDPA but only found NDMA (and NPIP) at levels of 0.7-0.9 ppb or 14-17 ng/day consumption (Ad-hoc Expert Group Minutes). Regulations to minimize formation of N -nitrosamines in food, beverages and beer aim to minimize exposure and are based on the ALARA principles (EFSA, 2017). Drinking Water In Germany, control limits for NDMA in drinking water are 10 ng/l and considered as health-based according to the German Umweltbundesamt (UBA) for lifetime and less than lifetime exposure. California has set a public health goal of 3 ng/l for drinking water and New Jersey 0.7 ng/l for NDMA and 5 ng/l for NDPA in groundwater. The Environmental protection Agency (EPA) set health reference levels for NMBA (30 ng/l), NDEA (0.4 ng/l), NDMA (0.6 ng/l), NDPA (7ng/l), NMEA (3 ng/l), and NPYR (2 ng/l) (EPA, 2016). Products from technical processes (e.g. pesticides, rubber, beer, cosmetics) Pesticides, Rubber, Beer, Cosmetics (products from technical processes) The level of N -nitrosamines is minimized according to the ALARA principles in these areas. According to Directive 2009/48/EC on the safety of toys, levels of N- nitrosamines are limited to ≤10 µg/kg and

EMA/369136/2020

Page 8/90