Quick question regarding the LoQ of 0.03 ppm for nitrosamines. Should this limit be reported in relation to the declared amount of API in the drug product or in relation to the sample amount (taking into consideration excipients + API) ?
Method for Losartan tablet:
Sample preparation of Losartan tablet:
500 mg of grinded powder (equivalent to 150mg of Losartan API) / 5ml diluent
concentration: DP = 0.1 g/mL; API = 0.03g/mL
LoQ analytical concentration should be: 0.003 ug/mL of nitrosamine or 0.0009 ug/mL to achieve 0.03 ppm?
I have seen several methods taking into account the amount of drug product to calculate this limit, which is easier to achieve thinking in terms of detection. But I wonder if it is correct. I don´t know if I am missing something, but EMA and FDA guidelines mention to calculate in relation to API concentration…
The acceptable intake (AI) are referred to the nitrosamine so the acceptable limit (AL) should be calculated in function of the maximum daily dosage of the product you are considering. If you are dealing with drug products the maximum daily dosage of the finished product should be taken into account for analytical purposes.
You must take care about the measure unit you use since 0,66 mg/kg (expressed on API) or 0,074mg/kg (expressed on the drug product) are equivalent in the given example.
Nevertheless the experimental LOQ is always verified on the tested product so if you are analyzing finished products the analytical LOQ must be compared with the acceptable limit expressed on the drug product.
Indeed, if you consider different strengths the analytical LOQ requested (expressed on the tested product) could change significantly even if the API MDD and the LOQ expressed on the API is the same.
For example (in case of nitrosamine with AI=26,5ng/day):
Case 1 (MDD = 1 tablet 40mg API, 360mg finished product): acceptable limit is 0,66mg/kg (expressed on API) or 0,074mg/kg (expressed on drug product)
Case 2 (MDD = 2 tablets 20mg API, 360x2=720mg finished product): acceptable limit is 0,66mg/kg (expressed on API) or 0,037mg/kg (expressed on drug product)
So the analytical LOQ must be 50% lower in Case #2.
LOQ is the lowest concentration for quantification, which is mainly determined by the nature of the analytical method and instrument.
When the analytical method and instrument are selected, the LOQ is fixed.
Therefore, it is necessary to evaluate the LOQ (ng/mL) first, and then calculate the concentration (mg/mL) of the sample preparation. The concentration of the LOQ minus the sample needs to be greater than 0.03ppm, so as to meet the relevant requirements.
It can not prepare the concentration of the sample before evaluating the LOQ concentration, because the LOQ of your analytical instrument may not necessarily reach the LOQ of the test sample.