- 7 октября 2019
- 4-(methyl)(nitroso)amino)butanoic acid, acceptable intake, active substance, AI, analysis, API, ASMF, authorities, cancer, candesartan, carcinogen, CEP, change, chemically synthesized, CHMP, competent, confirmatory, contamination, cross-contamination, detection, DIPNA, drug product, EIPNA, EMA, evaluation, finished product, formation, generics, GMP, HCl, human, hydrochloride, ICH M7, impurity, interim, irbesartan, limit, losartan, MA, MAH, manufacturer, manufacturing, manufacturing authorisation, marketing authorisation holder, medicinal product, medicines, method, MIA, mitigate, N-nitrosodiethylamine, N-nitrosodiisopropylamine, N-nitrosodimethylamine, N-nitrosoethylisopropylamine, NDEA, NDMA, nitrosamine, NMBA, non-sartans, olmesartan, OTC, pioglitazone, process, public health, ranitidine, referral procedure, review, risk, sartans, specific ring structure, temporary, test, testing, tetrazole, valsartan, variation,
EMA’s human medicines committee (CHMP) is requesting as a matter of precaution that marketing authorisation holders (MAHs) for human medicines containing chemically synthesised active substances review their medicines for the possible presence of nitrosamines and test all products at risk. If nitrosamines are detected in any of their medicines, marketing authorisation holders must inform authorities promptly so that appropriate regulatory actions can be taken.
Nitrosamines are classified as probable human carcinogens, which means that long-term exposure above certain levels may increase the risk of cancer. They are present in some foods and drinking water supplies and where they have been found in medicines the risk of developing cancer has been low.
It should be reminded here that the findings of the review of sartans with a tetrazole ring indicate that there is a potential for nitrosamines to be present in APIs for other medicines (i.e. non-sartans APIs), depending on the API and the finished product manufacturing processes.
It should be also noted that traces of N-nitrosodimethylamine (NDMA) have been found in pioglitazone hydrochloride from one API manufacturer. As the nitrosamine levels in this case were within the interim limits established in the sartans review (please refer to the table below), no market action was deemed necessary. As a precaution, companies using certain reagents to manufacture pioglitazone have been requested to test their products and check their processes to rule out the presence of nitrosamine impurities. More recently nitrosamine impurities have been identified in batches of ranitidine and consequently an EU-wide review has been initiated.
Temporary limits for NDMA, NDEA as well as for NMBA, DIPNA and EIPNA impurities have been set in line with current ICH M7(R1) guidelines and are given in the table below.
NDEA, DIPNA, EIPNA
Acceptable Intake [ng/day]
Acceptable Intake [ng/day]
NDMA – N-nitrosodimethylamine
NDEA – N-nitrosodiethylamine,
NMBA – 4-(methyl)(nitroso)amino)butanoic acid
DIPNA – N-nitrosodiisopropylamine
EIPNA – N-nitrosoethylisopropylamine
Nitrosamines are not expected to be formed during the manufacture of the vast majority of APIs outside the class of sartans with a tetrazole ring. However, it is now known that these impurities can form during production under certain conditions and when certain solvents, reagents and other raw materials are used. In addition, impurities can be carried over during the manufacturing process when using already-contaminated equipment or reagents. Furthermore, in cases where nitrosamines can form or are carried over during production, the impurities should normally be controlled and removed during the manufacturing process. Therefore, despite the low risk of nitrosamines being present, Marketing Authorisation Holders (MAHs) are asked to take precautionary measures to mitigate the risk of nitrosamine formation or presence during the manufacture of all medicinal products containing chemically synthesised APIs, i.e. MAHs should review their manufacturing processes to identify and, if found, to mitigate risk of presence of nitrosamine impurities in all human medicinal products containing chemically synthesised active pharmaceutical ingredients.
MAHs should work with manufacturers of API and finished products in order to review the API and finished product manufacturing processes with respect to the arrangements for preventing nitrosamine formation as well as contamination or cross-contamination, taking into account their knowledge of the manufacturing processes as well as the potential sources of nitrosamine impurities.
MAHs are responsible for ensuring that their medicinal products are manufactured in accordance with the requirements laid down in Directive 2001/83/EC. MAHs are responsible for the quality, safety and efficacy of their products, including the quality of the APIs, excipients and raw materials used in the manufacture of finished products. MAHs should therefore ensure (via quality agreements) that they and the holder of the manufacturing authorisation have access to relevant information from the API manufacturers concerning potential formation of nitrosamine impurities and the potential for cross-contamination. The holder of the manufacturing authorisation is also reminded of their responsibility to ensure the use of APIs that have been manufactured in accordance with good manufacturing practice (GMP) for active substances.
The information necessary for risk evaluation should be made available to the MAHs by the manufacturers. Even for products with active substance master files (ASMFs) and certification of suitability to the monographs of the European Pharmacopoeia (CEPs) containing information that is not available to MAHs, MAHs remain responsible for ensuring that robust risk evaluations have been appropriately carried out by the ASMF or CEP holder to enable the MAH to take responsibility for the quality of the active substance and the medicinal product.
For medicinal products containing APIs other than sartans with a tetrazole ring,
the following steps should be taken:
Step 3: changes to the marketing authorisation
MAHs should perform risk evaluation of their medicinal products containing chemically synthesised API (i.e. all authorised human medicinal products including generics and over-the counter (OTC) products) using quality risk management principles and evaluate possibility of nitrosamines being present in every concerned medicine at the latest within 6 months of the publication of the notification (26 September 2019);
MAHs should prioritise products in order to establish the sequence in which their products are to be evaluated, starting with medicines more likely to be at risk of containing nitrosamines;
for the purposes of this prioritisation, MAHs may consider factors such as the maximum daily dose taken, duration of treatment, therapeutic indication and number of patients treated; for example, medicinal products with higher daily dose and those for chronic use may take priority;
MAHs should take into account findings from CHMP’s review of sartans;
MAHs should inform the concerned Competent Authorities of outcome of risk evaluations;
in the event that a risk of presence of nitrosamines is identified as a result of the risk evaluation, confirmatory testing should be carried out using appropriately validated and sensitive methods in accordance with the prioritisation deriving from the risk evaluation;
Acceptable Intakes (AIs) on which temporary limits should be based for NDMA, NDEA, NMBA, DIPNA and EIPNA are presented in the table above;
products identified as high priority should be tested as soon as possible;
confirmatory testing of all medicinal products identified to be at risk of presence of nitrosamines and submission of required changes in the manufacturing authorisations should be concluded at the latest within 3 years of the publication of the notification (26 September 2019) or at an earlier time if otherwise justified;
MAHs should inform the competent authorities immediately if tests confirm the presence of an nitrosamine impurity irrespective of the amount detected;
MAHs should apply for a variation in a timely manner to introduce any required changes, such as amendment of the manufacturing process or changes to product specifications;
At all steps, timelines should be shortened and authorities immediately informed if findings indicate
an immediate risk to public health.