Module 3 - Strategic case studies in practice

More extensive and carefully designed experiments are considered to be useful on API and finished products and additional considerations for such experiments were made by the experts in general as well as specifically for ranitidine and metformin. The experts highlighted the importance of manufacturing process development and manufacturing processes designed to avoid generation or presence of nitrosamines. When avoidance is not possible, risk mitigating actions should be adopted. It was suggested that certain raw materials (e.g. DMF) should be avoided unless there is no alternative. If, the presence of nitrosamines cannot be avoided (e.g. in case of no alternative synthetic step or if use of certain excipients or solvents cannot be avoided), it is expected that a suitable control strategy to reduce nitrosamine impurities (e.g. purification steps) is implemented. This should include adequate control of materials, process controls and suitable analytical controls based on regulatory guidance already in place. Furthermore, appropriate risk mitigation measures should be adopted. In addition, the information to be submitted in an application file should be more detailed taking account this new aspect. So, for instance the description of a manufacturing process of an API should also describe more comprehensively, including a risk management about potential side reactions, steps which do not necessarily relate directly to the synthesis of the API itself but for instance description of workups, purifications and steps to deplete certain reagents (e.g. use of sodium nitrite to deplete excess of NaN 3 used in the tetrazole formation). Furthermore, experts recommend that theoretical purge calculations should be confirmed with analytical data for nitrosamines. Feasibility in routine and at industrial scale of purging steps should be evaluated and adequately validated. In addition, experts recommended conducting steps at risk of generating nitrosamines early in the manufacturing process to have sufficient opportunities for purge downstream. In contrast, telescoped reaction sequences with minimal isolations reduce purge capability and increase risk of carry-over. Analytical methods Sample preparation is considered the main difficulty in establishing analytical procedures for nitrosamines. The experts considered that due to the presence of multiple excipients in different combinations in different products, the development of methods for finished products is more challenging than for APIs. However, it is regarded possible to develop analytical procedures to measure the most commonly encountered volatile nitrosamines (NDMA, NDEA, NDBA, NEiPA (=EIPNA), NDiPA (=DIPNA), NDPA), even in a single method. Methods currently used by the OMCL network are GC or LC coupled with mass spectrometers of sufficient sensitivity. Due to its non-volatility and chromatographic properties, NMBA requires a separate LC-MS determination. Due to the trace analytical level (e.g. 30 ppb), special care should be taken to avoid interference, matrix effects or artefacts generated during work up and measurement and conducting control experiments to identify any artefacts, for example, running orthogonal methods or carrying out confirmatory testing using a second method is deemed essential. For pharmacopoeial purposes, analytical procedures should be developed based on commonly available instruments but ensuring sufficient sensitivity and specificity. Overall, experts support this approach for standardisation purposes. The experts also noted that analytical methods have been published in Pharmeuropa 32.2, recently: 2.4.36. N-Nitrosamines in active substances

EMA/369136/2020

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