Calculation of limit when more than one nitrosamine is identified in the same product

 - Ensured that the total risk level of the sum of all detected N-nitrosamines does not exceed 1 in 100,000 life-time risk.

- Two Options are considered acceptable in order not to exceed the acceptable risk level

Option 1 - The total daily intake of all identified N-nitrosamines not to exceed the AI of the most potent N-nitrosamine identified, or

Option 2 - Total risk level calculated for all identified N-nitrosamines not to exceed 1 in 100,000.

 For option 2 – there are 2 different approaches can be employed to achieve this risk requirement

Fixed approach: fixed AI limits (in ppm/ppb) are set for individual nitrosamines and no limit for total N-nitrosamines is needed. The limit for each N-nitrosamine should be set at a percentage of its AI limit such that the sum of the % AI limits for each specified nitrosamine does not exceed 100%.

Flexible approach: each N-nitrosamine should be specified at its AI limit in ppm/ppb and an additional limit for total N-nitrosamines is required.

 Examples as below:

 

Control of Nitrosamine Impurities in Drug Products Specification

 

•        If the nitrosamine levels are not more than 10 percent of the recommended AI limit,

•        a specification controls is not needed

•        In the life cycle, if results are found above 10 percent of the recommended AI limit, a specification should be established

•        If the nitrosamine levels exceed 10 percent of the recommended AI limit but are within the AI limit,

•        a control for nitrosamines should be established in the release and stability specifications

•        If nitrosamine levels exceed the recommended AI limit

•        changes in formulation, manufacturing process, or packaging will be required to minimize nitrosamine levels