Approach for N-Nitroso Imatinib Limits: Database vs ICH S9

Limits of Nitrosamines
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Hello All,

Please note that N-Nitroso imatinib is listed in the FDA and EDQM databases with a limit of 1500 ng/day. However, imatinib is used for advanced cancer indications, and this limit does not appear to be aligned with the approach recommended under ICH S9.

In this context, could you please advise on the most appropriate regulatory approach—should we follow the database-listed limit, or apply the principles outlined in ICH S9 for oncology products?

Regards

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Imatinib Drug Product is the tyrosine-kinase inhibitors class of drugs and it targeted anticancer drug (antineoplastic agent) used for specific cancers like CML, GIST, and Ph+ ALL, acting as a kinase inhibitor, and while used for advanced stages (like accelerated/blastic phase CML).

We can use below approach Imatinib drug product [if it is used in the advanced cancer treatment].

ICH S9 Scope: For products intended for advanced cancer, N-nitrosamine impurities should be controlled according to ICH Q3A(R2) and ICH Q3B(R2) guidelines.

ICH M7 Scope: The Threshold of Toxicological Concern (TTC) of 1.5 µg/day is generally not required for advanced cancer drugs, as higher limits are acceptable.

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Many thanks, Dr. Dinkar, for sharing the information. Imatinib is a drug product used for advanced cancer, and I am not sure why it is included in the FDA and EMA database.

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Generally speaking S9 apply for oncology products, however, I know of couple cases where the products is authorized to be used in very small doses for treatment of severe arthritis. In those cases the regulatory agency pushed back on the use of S9. Just one of the many exceptions or case by case we see in this world of nitrosamines

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Thank you Sir for input and clarity….

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I would agree with Naiffer.

To be honest, reading the therapeutic indications of Imatinib i cannot see where it is written clearly that it should be used for advanced cancer.

Neverthelss, as in its indications there are quite many which are not relative with advanced cancer, i would propose to follow the ‘‘worst case’’ scenario and proceed with the acceptance intake of 1500ng/day.

This case reminds me the case of Ribociclib, where as long as it has only one indication for advanced breast cancer there were no relative AI in the nitrosamines guideline but from the moment a second indication added for early breast cancer then its nitrosamine appears in the relevant list of AIs (see the topic

thank you!!

Christos

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