Mutagenic Impurities. Группа авторов

support the assessment (see Barber et al. [19]). Purge assessments are conservative due to the limitation in purge value that can be assigned at each step, whereas in practice the true purge may be far greater. If this can be demonstrated, then the application of an Option 4 approach remains valid. To this effect, nitrite testing during Stage 6 found it was not present above 100 ppm (limit of detection [LoD]), thereby confirming the conservatism within the Stage 5 assessment.

Figure 3.13 Purge calculation summary for NaNO2.

The use of purge calculations therefore, in conjunction with analytical testing, established the formation of NDEA or NDMA cannot occur to a level of concern within the synthesis of candesartan, as there are sufficient levels of control of the component parts (amines and NaNO₂) to ensure that they are never present within the same stage at a concentration of concern, something that can be easily conveyed through a simple schematic (Figure 3.14).

Figure 3.14 Schematic of candesartan process highlighting the purge‐based risk assessment for nitrosamine formation and clearance.

      The de‐risking process described for candesartan was further validated through trace analytical testing for NDMA and NDEA. While no risk of nitrosamine formation was identified within the candesartan synthesis, had the potential for formation been established, the purge principles could have been further exploited to determine the risk of carryover of the nitrosamines themselves into the final API, as any nitrosamine formed would still have the opportunity to be purged and controlled in subsequent stages. In the case of candesartan, a purge assessment of NDMA and NDEA from Stage 5 onward indicates theoretical purge factors of ~10 000 and ~1000, respectively.

      In addition, analytical testing of over 100 batches of candesartan have confirmed the absence of NDMA or NDEA above 5 ppb (LoD), thereby validating the expert theoretical assessment that they could not be formed to a level of concern.

References

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      Notes

      1 1 The maximum observed PMI level can be designated by several means. These include: (i) by the amount of PMI introduced to the process, (ii) by the amount of PMI measured at a specific stage in the process, (iii) the amount in the process or by a level allowed by an acceptance criterion such as an assay value in an intermediate, or (iv) a hypothetical