Ask for help with limit for Nitroso-olaparib

Limits of Nitrosamines
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Hell to all, regarding Olaparib, it was initially approved for advanced cancer therapies, then in 2022, Lynparza’s approval was extended to include the indication for early breast cancer and it is described in assessment report (Lynparza, INN-olaparib) that ‘Given the proposed extension of the patient population to an earlier line of cancer treatment (i.e. adjuvant setting), the control strategy for potential nitrosamines in the drug product has been reassessed.’ And ‘olaparib showed no mutagenic potential in the Ames bacterial mutation tests but was clastogenic in an in vitro chromosome aberration test.’, Similarly, the SmPC mentions: “Olaparib showed no mutagenic potential, but was clastogenic in mammalian cells in vitro. When dosed orally to rats, olaparib induced micronuclei in bone marrow. This clastogenicity is consistent with the known pharmacology of olaparib and indicates potential for genotoxicity in man.’

According to the EMA Q&A document on nitrosamines, ‘If the active substance itself is mutagenic or clastogenic at therapeutic concentrations, N-nitrosamine impurities should be controlled at limits for non-mutagenic impurities according to ICH M7(R2)”, which means according to ICH Q3A and B.

While, in PAR, the concentration for clastogenic study was not mentioned, I wonder if the nitroso-olaparib should be controlled as per Q3A/B limit OR calculate according to CPCA approach. Thanks very much in advance.

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Hi @lling

The guidance is not clear on what indications fall under ICHS9 and how to classify drugs which are indicated for both early and advanced cancers. However, breast cancer is not being considered as advanced cancer. There are several cases where regulators have not approved nitrosamine specs based on ICH Q3 for breast cancer. Please find link on further discussions on this topic Novartis pauses some trials of cancer drug Kisqali to fix manufacturing

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If the clastogenicity of Lynparza has not been established at the therapeutic concentrations in mammalian cells, it would be difficult to justify the limit per Q3A/B for the nitrosamine(s).

Another caveat, the USFDA does not recognize this concept of controlling nitrosamines in mutagenic/clastogenic APIs per Q3A/B limits.

So to be on the safer side, in this case it is better you control the nitrosamines according to CPCA approach or the read-across approach both of which are globally accepted by all health authorities.

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