9/10 November 2023
The EMA/CMDh question and answer document on nitrosamine impurities for marketing authorization holders has been updated at short intervals since it was first published in August 2020. After a revision of the document on the subject of change notifications and classification of variations (see our article of February 1, 2022) in December 2021, the latest update of February 4, 2022 refers to the case where a product is contaminated by multiple nitrosamines. The revised section of the answer to question 10 ("Which limits apply for nitrosamines in medicinal products?") reads "Calculation of limit when more than one nitrosamine is identified in the same product" and details how to proceed in such a case.
There are two approaches available to marketing authorization holders for controlling multiple nitrosamine impurities in a medicinal product. The definition of the limit values is based on the specifications of the ICH M7(R1) guideline.
The total daily intake of all identified nitrosamines must not exceed the AI of the most toxic nitrosamine.
The total risk calculated from all identified nitrosamines must not exceed 1:100,000 lifetime cancer risk for a person taking the drug.
Specifications of individual nitrosamines shall be expressed in ppm or ppb. To convert the AI limit to ppm or ppb, use the maximum daily dose specifications in the drug product information.
Option 1: These specifications for all nitrosamines in the product shall be established when the total content of all nitrosamines is 10% of the AI of the most toxic nitrosamine. However, if the total content is less than 10% of this AI, specification may be omitted. Limit values for the individual nitrosamines may, but need not, be specified. However, it is necessary to specify exactly which nitrosamines were included in the calculation of the total content.
Option 2: Here, a choice can be made between two different approaches:
The Q&A document contains an example of the calculation and presentation of the results for the case of two nitrosamine impurities in one product (NDMA and NDEA).
In principle, marketing authorization holders are expected to improve the manufacturing processes of their finished drug products, even when only very low levels (< 10% of AI) of nitrosamines are detected.