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.
（已压缩）Nitrosamine Research.pdf (2.2 MB)Hello Ergun,
I am from Milestone Pharma. Our company provides a one-stop service platform covering the entire life cycle of nitrosamine research. We also have the NDAQ impurity you are studying in stock and can support your nitrosamine-related research.
If you have any needs, feel free to contact our Senior Director Ms. Dongmei Xiong at: Dongmei.xiong@mstonepharma.com.
For any questions regarding nitrosamine research, you may also follow my topic on the forum. I look forward to your reply.
Thank you!