Can you give me the practical advice how to perform accuracy in HPLC method for rel. compunds? For FDA regulations e.g.?
We have some of them in the specification but we calculate them (at he moment without response factor)on the external st. (e.g.1%)of active component.
We have some small quantities of rel. compound but just to show them in the specificity/selectivity . Do we have to add them to the drug product in the whole range (from LOQ TO 150% specif. limits) or we have to add them to placebo? What to do if our product have some of them in real samples- subtract and calculate recovery?
Is not enough to perform accuracy just on the external st. of the acitve component because we dont' have the rel. compound in stock (cca. 5mg each)?
The secind case:
And what to do if we don't specify the rel.compund in the method( even though we know and show them in specificity)? How to perform accuracythen?

Please give me some details how are you performing this parameter and if FDA is satisfied with that?

Hi Andreja:

Whenever the impurity is not available for any adjustfied reason, I think FDA will be satisfied with using your active drug substance reference standard. Here I have another question regarding the impurity limit test:

When the impurity test is just a limit test (e.g.: < 0.5%. It is not quantitative test. Also, that limit is not actual instrument LOD (a little higher than LOD). Under this situation, If you use a standard (either active drug substance substance or impurity itself) at 0.5% level as a reference to determine if the impurity is above or below 0.5%, How do you calculate it? If it is based on peak area comparision, it becomes a quatitative test and I have to validate the accuracy and precision at this levle before I can compare the peak area to each other. Is that right? or am I missing something here? Do I have to use real instrument LOD to do Limit Test on impurity level( by doing that, it will give Yes/No answer for < 0.5%)?

Thank you fo answer
But there is still a question - add rel. compund to drug product or to placebo? Is it acceptable for FDA just to add them to placebo? Or we have to add them to drug product as in ICH?

What I think that it is necessary to add the impurities to the drug product to show the recovey.But if the recovery is to be done at LOQ level it will be difficult for the impurities present in higher amounts.So by spiking the impurities in placebo at LOQ level may solve the purpose although the recovery should be shown in the presence of the active drug component.