Module 3 - Strategic case studies in practice

2.5. Methodology for defining limits for N-nitrosamines

The methodology guiding decision making on immediate market actions in case of nitrosamine contaminations has so far followed the ICH M7(R1) approach. The generally accepted approach recommended for compound specific limits in ICH M7(R1) is to use the TD 50 as the point of departure for the calculation of excess cancer risk and to calculate the AI / the dose associated with a theoretical excess cancer risk of 1:100,000 to define the limit. A well acknowledged and accepted source for TD 50 values from cancer studies is the CPDB. The extrapolation to the excess risk level for cancer is performed by linear back extrapolation to the dose theoretically causing a 1:100,000 risk by dividing the TD 50 by 50,000 (50% or 0.5 x 100,000). For a person with a bodyweight of 50 kg, the AI level is then calculated as AI = 50 x (TD 50 /50,000). This approach has been extensively discussed for NDMA and NDEA already in the CHMP Art 31 referral on sartans. In cases where robust TD 50 values as point of departure for excess cancer risk calculations are not available, the SWP recommends using a class specific threshold of theoretical concern (TTC) of 18 ng/d as default option with the possibility to justify a higher limit based on the structure-activity-relationship (SAR) approach described in the ICH M7(R1). Of note, the class specific AI of 18 ng/d for nitrosamines recommended by SWP as outlined below was determined using a novel methodology not widely used at this stage. The SAR approach has already been used for setting limits for NDBA, NMBA, DIPNA and EIPNA following the sartan referral. When using the SAR approach, the TD 50 of the structurally closest related N- nitrosamine for which robust data are available to calculate a reliable TD 50 should be applied to the nitrosamine in question, and as the methodology is established, the use of SAR can be considered an alternative approach to the TTC above. 2.5.1. Limits for individual nitrosamines, for multiple N -nitrosamines and less than lifetime (LTL) approach The N- nitrosamines listed in table 2.4.3.1 with a TD 50 below 1.5 mg/kg/day belong to the cohort of concern as defined in ICH M7(R1) and are: NMPEA, NDEA, NDMA, NMEA, NNK, NNN, NMOR, NMA, NDPA, NDBA, NPYR, MNNG, NMBA, NPIP. It is recommended that the primary attention with respect to risk for patients should be on these highly carcinogenic N- nitrosamines and closely related molecules for which no sufficient data are available. Limits for individual N-nitrosamines should be set using the compound-specific ICH M7(R1) approach considering a lifetime daily exposure. For individual nitrosamines with sufficient animal carcinogenicity data, limits can be calculated using the risk-based approach and methodology described in ICH M7(R1) with TD 50 as the PoD. This approach is already described in section 2.4.5. Using the risk-based approach described in ICH M7(R1), it may be possible to accept the presence of multiple, highly carcinogenic N- nitrosamines within one medicinal product as long as the excess lifetime risk of the total nitrosamine content is kept below a risk of 1:100,000. As discussed above, the environmental background exposure levels to N- nitrosamines are difficult to estimate. Amounts of NDMA, NDEA, NPIP, and NPYR in medicinal products at their AIs would, in a ‘worst case’ assumption, theoretically result in a patient exposure of up to 2.351 µg/day (96 ng +26 ng + 799 ng +

EMA/369136/2020

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