Confidence Beyond Compliance

In June 2018, authorities (FDA, EMA, etc.) became aware of the presence of a nitrosamine, N-nitrosodimethylamine (NDMA), in valsartan substance from one active pharmaceutical ingredients (APIs) manufacturer. Subsequently another nitrosamine, N-nitrosodiethylamine (NDEA), was detected and other ‘sartans’ from more API manufacturers were later implicated. NDMA and NDEA are classified as probable human carcinogens and their presence in ‘sartans’ was, at the time, unexpected.

On the 13th September, 2019, the FDA announced that preliminary tests found low levels of NDMA in Ranitidine (original brand name Zantac®). Subsequently to this announcement, Sanofi voluntarily recalled over-the-counter (OTC) ranitidine due to possible NDMA contamination. Moreover, pharmaceutical companies such as Novartis and Apotex announced that they are recalling all their generic ranitidine products sold in the US and other territories too.

Following a review of ‘sartans’ risk, a general advice letter summarises FDA and EMA findings to date and provides recommended actions to be taken to ensure that the drug product, drug substance / API, and raw materials are absent of these impurities or below recommended limit.

The EMA has come up with a notification (EMA/189634/2019, dated 19th September 2019) specifying its expectation on the risk assessment of nitrosamines in the medicinal products. The advice states that all authorised human medicinal products containing chemically synthesised APIs are to be reviewed, including generics and OTC products. However, in view of the large number of authorised products, MAHs should use a risk-based approach and prioritise their evaluations and confirmatory testing. This risk evaluation for all products should be submitted before 26th March, 2020.

If you would like help in understanding and acting on the guidance, please contact us to see how we might be able to support you –


As leading experts in regulatory affairs, PharmaLex have written a detailed whitepaper on the background and recommended steps required to ensure your medicinal products comply with the latest guidance for nitrosamines.

To download our Whitepaper, click here>>

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Q&A Nitrosamines

Q & A on Nitrosamines

In this Q&A session with Thurloch O’Criodain, we address some of the question industry has in relation to the regulation around Nitrosamines. With the deadline for compliance fast approaching we look to offer practical advice to support compliance.

Pharmalex has available a risk assessment tool and the associated expertise to draw conclusions from the obtained information. This tool can assist Marketing Authorisation Holders and manufacturers to identify the causative factors that could lead to nitrosamines being present in the drug product, and the level of risk. Pharmalex can also provide a review service in relation to risk assessments already carried out in order to provide confidence that those assessments are valid.

The tests require specialised equipment: GC-MS, LC-MS, and LC-MS/MS. The qualification of the equipment has special requirements. The establishment of limits and the test method validation are dependent on the API in question. Pharmalex has available the expertise to help manufacturers develop a test strategy, including

  1. Selection and approval of contract laboratories
  2. Instrument qualification and method validation requirements
  3. QA controls associated with the testing

Swissmedic, the South Korean authorities and Health Canada each require risk assessments to be carried out and testing to be done based on the conclusions of the risk assessment. FDA has not asked for risk assessments but are themselves reviewing all filings based on their understanding of the risk factors involved. FDA are also pursuing any companies and products where they see a risk. Pharmalex has available the expertise to assist companies in addressing the concerns of these authorities in relation to nitrosamines.

All new MA applications should include the risk assessment, and dependent on the conclusions of that assessment, it may be appropriate to build it into the process validation, especially for the API manufacturing process. As with the risk assessments for existing products as mentioned above, Pharmalex can provide expertise and assistance in that regard.

PharmaLex can support companies in making sure that they understand the regulatory requirements in relation to nitrosamines, that their risk assessment is valid, that they are carrying out appropriate testing, and that they are interpreting the information correctly.

There is also an opportunity to gather further information by viewing your recent webinar

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