In October 2019, the EDQM requested companies holding CEPs to perform a risk assessment of their chemically synthesised APIs with regards a potential nitrosamines formation, using quality risk management principles. It was highlighted that the factors to be taken into account were outlined in the dedicated Questions and Answers documents available on the EMA and CMDh websites.

The deadline given to CEP holders to perform step 1 of the risk evaluation and to inform the EDQM of any identified risk was initially 26 March 2020 and was later on postponed to 31 July 2020 due to the COVID-19 pandemic.

In June 2020, the EMA finalised a review under Article 5(3) of EU Regulation (EC) No 726/2004 to provide guidance to Marketing Authorisation Holders (MAHs) on how to avoid the presence of nitrosamines in human medicinal products. As part of the outcome of this review, the European medicines regulatory network agreed new deadlines to implement the Article 5(3) opinion. However, the EDQM has decided not to change the deadline for CEP holders, which remains therefore 31 July 2020. The reason is that risk assessments for the presence of nitrosamines in active substances should be available early enough to allow MAHs to collect the relevant data for their medicinal products. In addition, most CEP holders have already completed this step. Any CEP holders encountering difficulties in performing this risk assessment should inform the EDQM as soon as possible and propose a justifiable timeline.

Moreover, in line with the Questions and Answers documents mentioned above, from 1 October 2020, applicants and CEP holders should systematically include a risk assessment regarding the potential formation of nitrosamines in any new CEP application, sister file or renewal application, as well as in any revision where a risk of nitrosamine formation may be introduced (i.e. changes to the manufacturing process, change of suppliers of starting materials or intermediates, etc.).

The risk evaluation should not only address risks related to the manufacturing process but also those deriving from the introduction of materials used in the manufacturing process and other potential sources of contamination (e.g. starting materials, reagents, solvents, recovery of materials, equipment, degradation, etc.). The risk assessment should be included in the CEP submission, whether a risk is identified or not.

See also:

• The EDQM’s response to nitrosamine contamination
• CEP background & legal framework