Bioequivalence and Bioavailability Forum

Dear Ohlbe,

I am not an expert in analytics, so I'm confused.

❝ Of course I agree that you can have up to 1/3 of your QCs failing. But that's not what I call exclusion. The failing results are there, and should be reported and included in the calculations,...

I've read FDA's guidance again (let's talk not about values at LLOQ): in method validation mean value ≤±15% of nominal, precision given as SD/mean ≤±15% CV (≥5 replicates).
Reading the section on routine analysis over, I couldn't find anything about precison of QCs (determined from at least duplicates) - only bias. OK, the second paragraph on page 14 states: 'Once the analytical method has been validated for routine use, its accuracy and precision should be monitored regularly to ensure that the method continues to perform satisfactorily.'
At the bottom of page 15: 'Acceptance criteria for accuracy and precision as outlined in section IV.F, "Specific Recommendation for Method Validation,” should be provided for both the intra-day and intra-run experiment.'
But on the other hand top of page 16 gives the 2/3 statement - only bias, nothing about precision.

I always thought that both bias and precison should be evaluated; now I'm not sure anymore and left confused.

Let's consider a usual method - ±15% were established in validation (bias and precision) and continue Helmut's example: QC1 bias -20% but mean (93.3%) and precision (13.5%) within limits.
Now let's decrease QC1 further down (keeping results of QC2 and QC3):
the limit of 15% CV is reached if QC1 = 77.5%,
the limit of -15% bias of the mean is reached if QC1 = 55.0%.

If limits are ±15% anyhow, why all the fuzz with the 2/3 statement? Or does it mean single QCs may be outside ±15%, if the mean and the CV is ±15%?

Regards,
Hermann