Skipping risk assessment

Dear Team,

I just want to know if i can skip performing the risk assessment step and go directly to confirmatory testing for the specific impurity (NDSRIs) . the APIs are having secondary and tertiary amines , excipients (almost) are having nitrite impurity , i will consider the risk is high and move to confirmatory testing without performing the risk assessment. is it accepted ?

Dear @sbasaleh.

While internally you can proceed to carrying out the confirmatory testing you will still need to carry out the risk assessment alongside this. There are numerous reasons for this, including:
Regulatory authorities expect there to be a risk assessment available, even if you already know that there is a possibility/probability of nitrosamines being formed - for existing marketed products then these risk assessments should have already been created/submitted for most markets, and for an application for a new license there is a requirement generally to submit the risk assessment as part of the application process.
Carrying out a thorough risk assessment, with all of the increased knowledge that the nitrosamines community has now, compared to when we first started doing risk assessments, means that you could be able to identify much more: not only the potential nitrosamines that may be formed in your finished product, but where the most likely source of that formation is (different stages on the manufacturing process, or long term stability etc.), which may help you in the long term if you need to reduce the levels of nitrosamine in your product.
Audits by regulatory authorities. Others may be able to advise on this more, but from experience I would expect to start to see auditors asking for these risk assessments during the audit process, in a similar way to what happened when ICH Q3d Elemental Impurities was launched. Auditors would ask to see either a risk assessment, or real data as to the elemental impurity risk or composition of a product. Developing a suitable method for your nitrosamines, and validating it, can be a timely process, believe me, and so having your risk assessment in place during this, in case of audits, is recommended personally.

Others may be able to add many more reasons, but I would say to get the risk assessment done as soon as possible.


dear @MarkS

thank you very much for the clarification.

Dear @sbasaleh,

I agree with @MarkS. Risk assessment should take precedence over confirmatory testing.

EMA Q&A Q8 says if the source of risk has been identified and is well understood (e.g. by spike and purge studies) such that impurity levels are expected to be consistent from batch to batch, testing should be conducted on 10% of annual batches, or 3 per year, whichever is highest. The source of risk has not been identified and well understood without risk assessment. Therefore, further batch analyses may be required.


thank you for clarification.