Information for Marketing Authorization Holders (MAH)
In June 2018, authorities (FDA, EMA, etc.) became aware of the presence of a nitrosamine, N-nitrosodimethylamine (NDMA), in a product for the treatment of high blood pressure 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. The FDA has since also detected nitrosamines in a product that inhibits stomach acid production, another for the treatment of type 2 diabetes and most recently in two tuberculosis drugs.
Following a review of risk, a general advice letter summarizes 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.
EMA finalized a review under Article 5(3) of Regulation (EC) No 726/2004 in June 2020 to provide guidance to marketing authorization holders on how to avoid the presence of nitrosamine impurities in human medicines.
The outcome of the risk evaluation for all products should be reported complete at the latest by 31 March 2021 for chemical medicines and 1 July 2021 for biological medicines.
If needed, Marketing authorization holders should complete the confirmatory testing and submit their variation applications by 26 September 2022 for chemical medicines and 1 July 2023 for biological medicines.
The United States Food and Drug Administration (US FDA) Center for Drug Evaluation and Research (CDER) has issued a Guidance for Industry for immediate implementation (Docket Number: FDA-2020-D-1530, dated 01 September 2020). This guidance outlines what the FDA expects from all manufacturers to prevent or reduce the presence of nitrosamines in active pharmaceutical ingredients (APIs) and drug products. The risk assessment for all currently approved or marketed drug products (including their respective APIs) conclude within 6 months of guidance publication (i.e. by end of February 2021), and confirmatory testing and submission of required changes conclude within 3 years (i.e. by September 2023). Pending applications’ risk assessments and confirmatory testing should be performed expeditiously.
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 Authorization 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 specialized 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
- Selection and approval of contract laboratories
- Instrument qualification and method validation requirements
- 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. The 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 https://go.pharmalex.com/l/484291/2020-03-16/2cj33p
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