Bioequivalence and Bioavailability Forum

Dear Ladi,

❝ My first question is whether this statement is considered acceptance criteria of each analytical run?

Clearly not:

• this is not mentioned in section 5.2 (Acceptance criteria of an analytical run) but in section 5.3 (Calibration range);
  
• section 5.3 states that It is not necessary to reanalyse samples analysed before optimising the standard curve range or QC concentrations.

❝ Supposedly, we validated a calibration curve range of 10-100 ng/mL, and LQC is 30, MQC is 50 and HQC is 80 ng/mL. Now please let me set up two scenarios as following.

With just a 10-fold difference between the LLOQ and the ULOQ you're in trouble...

❝ 2) Would you continue with the study or what would you do next?

I would stop and lower the LLOQ to be able to measure concentrations down to 5 % of Cmax... SCNR. I understand that you took this as a theoretical example.

To answer your questions:

• Each run is acceptable. As mentioned above, this should not be considered as an acceptance criterion for each run.
  
• Problems may not be seen right from the very fist run, but only in the 2nd or 3rd.
  
• It can happen that some subjects will have a Cmax lower than the MQC sample - even after changing the MQC concentration or adding an extra QC level. No big deal. At least you can show that you did look at your data and that you did make the effort to adjust. If you make your MQC concentration too low in order to be sure it remains below the lowest Cmax, some regulators may say it is too low compared to the highest Cmax...

The idea is that the concentrations of the QC samples should not be totally disconnected from the concentations in the study samples. But the guideline leaves some flexibility.