In the occasion that certain patients need to chronically take a higher dose of a DP due to them concomitantly receiving a strong CYP3A4 inducer, do you take this into account when setting the limit? From a biological standpoint, as these patients receive twice as much of the impurity, this would make sense, but there seems to be little explicitly stated in the guidance’s on adjusting the MDD.
Would perhaps the overall margin of safety included in a LCR of 10^-5 allow to make abstraction of this and keep the limit as is? Because for simple mathematical correction of the limit wouldn’t you want to know the possible impact (if any) of the CYP3A4 inducer on the nitrosamine metabolism as well to rationalize fully the correction?
The guidances usually don’t incorporate individual risk but are based on statistic occurrences within large groups (i.e. MDD application in M7 is based in a risk of 1:100,000), so evaluating individual CYP metabolism sounds redundant. An overall factor such as that might not be logical when you want to potentially adjust the MDD?