Module 3 - Strategic case studies in practice

depletion of residual quantities of azide reagents. In some cases, inconsistencies were identified in the dossiers, regarding the regulatory status of sodium nitrite (included in eCTD Module S.2.3 but omitted from the reaction scheme and the process description in S.2.2). It is reminded that all materials used in the manufacturing process should be included in the documentation, irrespective of their intended use. In sartan CEPs suspended by the EDQM, a few API manufacturing processes were changed over the time by adding NaNO 2 into the processes as part of scale up activities. In some cases, these changes of processes were introduced by variation procedures on already granted CEP dossiers, in order to ensure process safety for large-scale production by azide quenching, to minimize genotoxic azide impurities, to treat waste streams and/or to optimize economic efficiency and reduce costs, suggesting the need to improve control, review and assessment of manufacturing processes as they are scaled up. According to the CHMP Assessment Report for the sartans referral, N- nitrosamines such as NDMA, NDEA, DIPNA, EIPNA and NMBA were also identified as impurities in tetrazole-containing sartans. These impurities were generated in the same step or sub-step of manufacturing processes, considering that the most relevant way of N- nitrosamine formation is related to the simultaneous presence of amines and nitrosating agents as outlined below. However, carry-over of amine and NOx sources from previous into subsequent steps can also lead to N- nitrosamine formation as documented in the Pioglitazone case (see below). The use of solvents/reagents/catalysts sourced as “fresh” and “recovered” from third party suppliers was identified as another root cause of N- nitrosamine contamination (see above). In addition, GMP non-compliance such as cross-contamination in multi- purpose facilities and operator-related issues such as inadequate phase separations also led to N- nitrosamine contamination of APIs (see above). Subsequent to the sartans Referral, N- nitrosodibutylamine (NDBA) and N- nitrosomethylphenylamine (NMPA) were shown to be additional (potential) N- nitrosamine impurities. The phase transfer catalyst tetrabutylammonium bromide (TBAB) and the solvent/reagent N , N- dimethylaniline ( N , N- DMA) are expected to be potential sources for secondary and tertiary amines such as dibutylamine, tributylamine, dimethylamine and N- methylaniline. Based on the identified routes of formation discussed above, and the fact that quaternary alkylammonium salts and tertiary amines have also been found to be directly susceptible to nitrosative de-alkylation [Fiddler et al. (1972)]. NDBA, NMPA and NDMA would likely be formed in combination with nitrosating agents such as NaNO 2 . In the sartans Referral API manufacturers identified deliberately added NaNO 2 as the common source of NOx in tetrazole containing sartans. In contrast, different sources were stated to be responsible for the concomitant presence of secondary and tertiary amines in the processes. Solvents such as DMF and NMP were reported to be sources for secondary amines such as N , N- dimethylamine (DMA) and for 4-methylaminobutyric acid (MBA). Reagents such as the tertiary amines TEA and DIPEA were identified to be the origin of the secondary amines N , N- diethylamine (DEA), diisopropylamine and ethylisopropylamine respectively. The phase transfer catalyst TEA HCl was identified as the source of the tertiary amine TEA and the secondary amine DEA. According to the CHMP Assessment Report of the sartans referral, N- nitrosamine formation was caused by the reaction of NaNO 2 as the common NOx with different sources of secondary and tertiary amines as illustrated below. Two different routes of N- nitrosamine generation were identified which can be classified into two main reaction types: 1. Hydrolytic and/or thermal degradation of the solvents DMF and NMP to give the secondary amines DMA and MBA respectively, followed by subsequent N- nitrosation, finally yielding NDMA and NMBA

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