Following our last article on February 20th regarding the impending deadline for nitrosamine, the EMA has now extended the deadline to complete the nitrosamines risk evaluation for commercial drugs to October 1st, 2020 due to reports on the challenges encountered by several companies to meet the original deadline and restrictions in place to combat the COVID-19 pandemic. An updated Q&A was published on the 27th March.
Information regarding the requirements for Marketing Authorization Holders (MAH) remains the same. The EMA publication instructing MAH to take precautionary measures to mitigate the risk of nitrosamine formation or presences during manufacture of all medicines containing chemically synthesized active substances can be found here>>
The publication also serves as a reminder of the responsibilities of the MAH as laid down in Directive 2001/83/EC. While the MAH can delegate activities such as API manufacturing, they cannot delegate responsibility for ensuring the quality, safety and efficacy of the finished product for the patient.
The MAH together with API and finished product manufacturers should perform a risk evaluation using Quality Risk Management Principles that are set out in ICH Q9 of their medicinal products containing chemically synthesized API. The risk assessment should consist of the identification of hazards and the analysis and evaluation of risks associated with the arrangements for preventing nitrosamine formation as well as contamination or cross contamination. The following products are under scope:
- Approved products (reference listed drugs, generics and OTCs)
- On-going procedures
- Investigational Medicinal Products (IMPs)
Key questions to consider during the risk assessment are:
- Is there a risk of nitrosamines forming in the API synthetic process taking into consideration the combination of reagents, solvents, catalysts and starting materials used, intermediates formed, impurities and degradants?
- Is there a potential risk of nitrosamine contamination (e.g. from recovered materials such as solvents, reagents and catalysts, equipment, degradation, starting materials or intermediates)?
- Is there any potential of nitrosamine formation during the manufacture of the finished product and/or during storage throughout its shelf life?
Should the risk evaluation lead to the identification of nitrosamines confirmatory testing should be performed using appropriately validated and sensitive testing methods. Following that, updates to the MAH may be required.
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. Contact us at firstname.lastname@example.org