Nitrosamines – deadline approaching!

By Diego Martinez, Senior Manager, Regulatory CMC at PharmaLex

Diego Martinez, Senior Manager, Regulatory CMC at PharmaLex, experts in specialized end-to-end pharmaceutical regulatory consultin

Diego Martinez, Senior Manager, Regulatory CMC at PharmaLex, experts in specialized end-to-end pharmaceutical regulatory consulting, outlines the steps that ‘sartan’ marketing authorization holders (MAHs) must take by 26 March.
In June 2018, regulatory authorities 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 were recalling generic ranitidine products sold in the US and other territories too.
Following a review of ‘sartans’ risk, a general advice letter summarized the FDA and EMA findings to date and provided 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 limits.
On 26 September, 2019, the EMA published a document titled “EMA advises companies on steps to take to avoid nitrosamines in human medicines (EMA/511347/2019)”. It requests that all MAHs conduct a risk evaluation regarding potential nitrosamine contamination. All authorised human medicinal products containing chemically synthesized APIs are to be reviewed, including generics and over-the counter (OTC) products. However, in view of the large number of authorised products, MAHs should use a risk-based approach and prioritize their evaluations and confirmatory testing. This risk evaluation for all products should be submitted before 26th March 2020.
The necessary information for risk evaluation should be made available to the MAHs by the manufacturers. Even for products with active substance master files (DMF, ASMFs) and certification of suitability to the monographs of the European Pharmacopoeia (CEPs), containing information which is not available to MAHs, MAHs remain responsible for ensuring that robust risk evaluations have been appropriately carried out by the DMF, ASMF or CEP holder, to enable the MAH to take responsibility for the quality of the active substance and the medicinal product.
There are a number of key steps companies should take.
1. Risk evaluation
  • Evaluate possibility of nitrosamines being present in every concerned medicine within 6 months: MAHs should perform risk evaluation of their medicinal products containing chemically synthesized APIs. MAHs together with API and finished product manufacturers are required to perform risk evaluations using quality risk management principles, as outlined in ICH Q9 guideline. The principles described in ICH M7 guideline in relation to toxicology assessment, control strategy and changes to the manufacturing processes for active substances should be applied. In order to undertake the analysis of the identified medicinal products at risk, MAHs can also use tools such as Failure Mode Effects Analysis (FMEA) and Failure Mode, and Effects and Criticality Analysis (FMECA), as outlined in the ICH Q9 guideline on quality risk management.
  • Prioritize evaluations, starting with medicines more likely to be at risk of containing nitrosamines: MAHs should prioritise products in order to establish the sequence in which their products are to be evaluated. The factors that can be considered may be: the maximum daily dose taken, duration of treatment, therapeutic indication and number of patients treated. For example, medicinal products with higher daily dose and/or those for chronic diseases treatments may take priority. For products identified as high priority, the risk evaluation should be done immediately.
  • Take into account findings from the review of sartans
  • Notify authorities of outcome of risk evaluations
  • The risk evaluation of all products should be concluded within 6 months of the publication of the notification at the latest. MAHs should inform the concerned Competent Authorities when the risk evaluation is concluded. Risk evaluation documents do not need to be submitted but should be made available upon request.
2. Confirmatory testing
  • Test products at risk of containing any nitrosamines
  • 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 prioritization derived from the conducted risk evaluation. Products identified as high priority should be tested as soon as possible. Confirmatory testing of all medicinal products identified to be at risk of nitrosamines presence and submission of required changes in the manufacturing authorizations should be concluded at the latest within 3 years of the publication of this notification or at an earlier time if otherwise justified.
  • Immediately report detection of nitrosamines to authorities
3. Changes to the marketing authorization
  • Apply for necessary changes to marketing authorizations to address nitrosamine risk
  • 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.
Diego Martinez, Senior Manager, Regulatory CMC at PharmaLex GmbH, Bahnstraße 42-46, Friedrichsdorf, Hessen 61381, Germany