Limit Test for NDSRI Risk Assessment?

Risk Assessment Strategy / Tools & Technology
1

I was wondering if a “Limit Test” strategy could theoretically be used to conduct NDSRI risk assessment in drug product to demonstrate that batches do not show any identified potential NDSRIs at or above 10% of the AI limit set forth by the regulatory agency? This of course would be provided that one demonstrates specificity and an appropriate lower limit of detection as per ICH Q2 guidelines.

Essentially, I am thinking one could perform sample preparation on the drug product “as is” and a replicate sample that has been spiked with a standard of the NDSRI at the 10% of AI level. Then analyze the samples with the analytical method and determine whether the drug product “as is” has a peak area at or above that of the spiked sample. I’d expect this should also help account for recovery and matrix effects that may be encountered?

I feel as though this would be scientifically sound and would avoid some of the additional qualification needed for the analytical method, but wanted to see what others think…

2

Hi,

Yes, it is possible to use it, and it is a very good approximation. It is very useful when the nitrosamine comes from an impurity from the API and the risk assessment has identified a low/medium risk, and the analyses are performed to rule out the risk of NDSRI formation with greater certainty. I do not recommend using the limit test when the NDSRI comes from the API itself, as there is a high probability that the 10% limit will be exceeded and it will be necessary to quantify the amount of NDSRI.
To ensure that the sample is below the 10% limit, the response of the analyte in the sample must be less than half the response of the analyte in the spiked sample at the reporting threshold.