validating method with clumsy unstable impurities

[michael.k raj]

Dear friends,
How to go about a validation of a chromatographic method for related substances(r.s), if the impurities resolved in the method are
1.Not isolable
2.with handling difficulties
3.degrading after isolation.

As it is a normal practice that in validating the r.s method,the characterised impurities are injected at the specification level and their linearity ,.....to responsefactors to be arrived at.
What if the analyte involves such impurities.
Hope to see more.
Any sites or links reg.this will also be of great help.
Thanks in advance.
-M.K.Raj

[Heinz Sarter]

hello
i would propose the following strategy,
carry out the validation characteristic "selectivity" and verify that the impurities are well separated,
specify them on the basis of relative retention times and (if possible) uv-spectra (DAD),
if your method is involved in a stability study, evaluate these impurities using the response factor of the active ingredient as far as they are less than the specification limit (and hope they remain),
carry out linearity, detection limit and quantitation limit with the active ingredient,
good luck
heinz

[ravi]

Can you determine what causes the degradation? A better control of that may help you.

[michael.k raj]

thanks heinz,
But here the case is that the method resolves the impurity but..., for determinig the responsefactor,,linearity,(LOD.LOQ detmin too),spiking the same for recovery calculation ..etcthe impurity has to be stable and easy to be handled no?(even if it is characterised and we know what it is)
Any guideline regarding this?
thanks
-aj

[Heinz Sarter]

you can use ICH-guidelines,
but i think, for the first step you needn't perform all required validation steps. Verify the selectivity and the fact that the method is stability indicating.
Then determine detection- and quantitation limit with the active ingredient (not the impurities) and specify and monitor the impurities, determined with the response factor of the active ingredient. This strategy is suitable as long as the impurities are less than the specification limit.
Heinz

[michael.k raj]

Dear Heinz,
Thanks for the response.
Is that essential to find the LOD and LOQ of the API in rel.subs method?Even if that is found for determining the response factor of the impurity ,we need that to be stable ,is that not?Can we assume the resp.fac of the problematic impurity to be 1?Where as the other impurities are stable for conventional procedure
regards,
M.K raj