Module 3 - Strategic case studies in practice

catalysts such as DMF, NMP, TEA, DIPEA, N , N- DMA, TEA.HCl and TBAB has been conducted, showing production specific impurity profiles (secondary and tertiary amines). Specifications have been established by chemical industry, covering in some cases test parameters and acceptance criteria for secondary and tertiary amines in these chemicals, suggesting the need to define adequate limits in section S.2.3 of the dossier. Solvents, reagents and catalysts such as DMF, NMP, TEA, DIPEA, N , N- dimethylaniline ( N , N- DMA), TEA HCl and TBAB have been observed to generate N- nitrosamines when combined with the nitrosating reagent NaNO 2 in the same step or sub-step of an API manufacturing processes. In line with literature data, N- nitrosamine formation is expected to be caused by hydrolytic and/or thermal degradation of solvents (DMF/NMP) and subsequent N- nitrosation of the released secondary amine and by N- nitrosative dealkylation of tertiary amines (TEA/DIPEA/ N , N- DMA) or quaternary ammonium salts (TEA HCl/TBAB). However, physico-chemical studies on the parent reaction mechanism have not been conducted by MAHs or active substance manufacturers so far, suggesting the need to initiate research on this area. In the case of valsartan, a single active substance manufacturer disclosed the (potential) presence of two valsartan specific N -nitroso compounds, i.e. derivatives of valsartan intermediates/impurities. The N-nitrosamine-carboxylic acid has been tested AMES negative. Due to the fact that the N-nitrosamine- benzyl ester cannot be considered a classical or a non-classical bio-isoster of the N-nitrosamine- carboxylic acid [Meanwell, N.A., (2011)], extrapolation of the negative AMES test result by referring simply to structural similarity was further evaluated by EDQM within a CEP procedure. It was confirmed that N-nitrosamine-benzyl ester is fully converted to N-nitrosamine-carboxylic acid (Ames negative) and this was supported by a spiking-purging study ( purge factor > 10000) and by batch data showing that N-nitrosamine-benzyl ester is consistently below 0.03 ppm in valsartan, which was considered satisfactory. However, both N- nitroso compounds are regarded recent examples of N- nitrosamines formed within a manufacturing process by nitrosation, suggesting the need for thorough nitrosatability testing of intermediates/impurities, as discussed in the aminophenazone case below.

N- nitrosamine-carboxylic acid

N- nitrosamine-benzyl ester

Figure 2.2.2.2-4 Valsartan specific N- Nitroso compounds (potentially) present in API from a single active substance manufacturer.

EMA/369136/2020

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