22/23 February 2024
The latest version of the "REPORT ON THE RISK OF POTENTIAL PRESENCE OF NITROSAMINE IMPURITIES" has been available on the APIC website since April 2021. The questionnaire is to be seen as a summary report and can be used to document the results of risk assessments with regard to contamination by nitrosamines in APIs. It needs to be completed for one API at a time and complies with the applicable requirements for risk assessment in the field of nitrosamines as specified by the regulatory authorities.
As early as February 2020, the Active Pharmaceutical Ingredients Committee (APIC) published the first version of the report together with the guideline "Additional guidance on the risk assessment for presence of N-nitrosamines in APIs." While the first version of the guideline remained unchanged, the second version of the questionnaire shows some essential updates and changes.
In section 1 "Introduction" it is now clear that the questionnaire has not only been prepared in line with the requirements of the EMA, but is also based on the requirements of the US FDA and other regulatory authorities such as Health Canada.
In the next section, the number of subtopics has been extended from 8 to 11. Here, it is specified which points should be evaluated in the course of risk assessment and which sources of potential nitrosamine contamination can occur. It is also clearly stated here that this consideration is based on the European specifications, and reference is made to further, explanatory documents from the respective global authorities.
Sections 3 and 4 remained unchanged in the latest version of the report.
Whereas in section 5, the summary of the points considered in the course of risk assessment, some updates and additions have been made. Both the introductory statement and the subtopics are much more detailed and explain even more specifically how to complete the questionnaire. A justification must now be added to each subtopic in addition to the answer, whether applicable or not. Also here, the number of subtopics has been extended from 8 to 11. In addition to raw materials such as solvents, reagents and catalysts, the subtopic 5.3 now also explicitly includes water. "Recycled material" has been added under 5.4. The topics of cross-contamination and carry-over effects during production are now presented in more detail and listed in three subsections. The subsection 5.11 "Presence of nitrosatable nitrogen functionality in APIs or their impurities" is completely new.
Minimal to no updates and additions were made to sections 7 and 8. Likewise, section 6 merely indicates an adjustment to the table listing the nitrosamine impurities in question and clarification of the results' presentation. There is now an additional field in the table that includes the request for analytical test results and their presentation.
The currently valid versions of the report and guidance "Additional guidance on the risk assessment for presence of N-nitrosamines in APIs" can be found on the APIC website.