Linearity of Related Substances as per ICH

[jayroseville58]

As per ICH guidelines, Linearity should start from reporting level (LOQ) up to 120% of test concentration (100%) of your impurity. As per USP <1225>, linearity can be made from 50% to 120% of (100% of impurity concentration).

Normally on our validation, what we usually did was the latter but some query from us requiring the former guideline. Questions:

Given to follow the ICH guideline, what is the best way in order for us to meet the requirement given that we are always dealing with product and method not knowing the LOQ yet?

Can we just still justify our side providing that instead of following ICH guideline, we did what was written as per USP? From this method, that is the only time we are able to calculate the LOQ using standard deviation method.

[krickos]

Hi

That part of ICH applies if:
- if assay and purity are performed together as one test and only a 100% standard is used, linearity should cover the range from the reporting level of the impurities1 to 120% of the assay specification.

So if you use the 100% assay standard also for calculation of impurities yes ICH requires a greater range/linearity.

Even if you have another procedure/quantification for impurities or diluted standard for impurities the ICH approach is still generally stricter as soon the limit exceeds 0,10%
- for the determination of an impurity: from the reporting level of an impurity to 120% of the specification;


So my advice is to apply ICH recommendations as they are stricter in general in that regard. USP/NF is also about to apply ICH Q3A+B so it is likely that <1225> may be impacted in the near future with regard to reporting levels based on daily dose.

[jayroseville58]

Hi

That part of ICH applies if:
- if assay and purity are performed together as one test and only a 100% standard is used, linearity should cover the range from the reporting level of the impurities1 to 120% of the assay specification.

So if you use the 100% assay standard also for calculation of impurities yes ICH requires a greater range/linearity.

Even if you have another procedure/quantification for impurities or diluted standard for impurities the ICH approach is still generally stricter as soon the limit exceeds 0,10%
- for the determination of an impurity: from the reporting level of an impurity to 120% of the specification;


So my advice is to apply ICH recommendations as they are stricter in general in that regard. USP/NF is also about to apply ICH Q3A+B so it is likely that <1225> may be impacted in the near future with regard to reporting levels based on daily dose.

Thanks for your reply. Normally, what we are doing is that, we derive the LOQ based from the linearity curve via standard deviation method. Does it mean that we have to perform again linearity by including the LOQ calculated? Or would it be better, that we should just always start our linearity from 0% up to 120% to cover the LOQ already. Thanks.