Dear Sir or Madam,
We would like to request a scientific clarification regarding the analytical approach for nitrosamine determination in an oral suspension drug product containing quetiapine.
The maximum daily dose of the drug product is 800 mg/day and the product concentration is 20 mg/mL, corresponding to a maximum daily intake of 40 mL of the suspension.
Based on the acceptable intake for NDAQ (400 ng/day), the calculated product-specific limit corresponds to approximately 3.96 ng/mL in the finished product.
Due to the very low concentration level, achieving the required limit of quantification directly in the sample matrix by LC–MS/MS presents significant analytical challenges. Therefore, we are considering the application of a sample preparation procedure including a pre-concentration step resulting in an overall sample concentration factor of approximately 40.
Under this approach, the analytical result obtained from the instrument would be corrected by the concentration factor (i.e., divided by 40) to determine the actual concentration in the original drug product.
We would like to kindly ask whether this approach, where a validated analytical method incorporates a defined sample concentration factor and results are back-calculated to the original product concentration, would be considered scientifically acceptable for nitrosamine control in the finished product.
We would greatly appreciate your guidance on this matter.
Hello Ergun. I believe the method you mentioned is acceptable. Additionally, I would like to ask you about the calculation of the limit. Based on your description, I think the limit should be 400/40 = 10 ng/mL. I was wondering how the value of 3.96 ng/mL was calculated. Secondly, considering that your sample dosage form is a suspension, the sample pretreatment might be somewhat troublesome. I suggest performing a spiked recovery test during the sample concentration process to verify the stability of impurities during concentration. At the same time, when preparing the solution, adding a deuterated internal standard could help eliminate systematic instrument errors.
当然是可以的。不过必须确保浓缩过程中亚硝胺杂质的稳定性。
Concentration is possible and has worked for us in the past.
From a scientific standpoint, there is generally nothing that speaks against including a concentration step.
However, since concentrating the sample also increases the matrix load, you must verify whether this affects your recovery. Unfortunately, in most cases it will. This makes it somewhat challenging to find the optimal balance between the concentration factor and the resulting loss in recovery. Ultimately, only experimental testing will reveal where that balance lies.
I would recommend using a gentle evaporation technique, such as moderately heated tubes combined with a gentle nitrogen stream.
Another option is the use of SPE. For example, you could load 40 mL of sample solution onto the cartridge and elute the analyte with only 1 mL of solvent. This approach not only concentrates the analyte but also reduces the matrix load on your system compared with evaporation alone.