Bioequivalence and Bioavailability Forum

Hi ElMaestro and Scopy,

❝ Blinding wrt time point would be interesting. It may be the solution to a non-existing problem, though? You mean they could use that info to create smooth profiles that more or less correspond to the expectation in terms of e.g. t half etc? I'd say that is theoretically correct, they could do that.

Even if substantial carry-over is not apparent in method validation (which would call for injecting mobile phase between samples), it exists. The EMA’s GL tells us:

If it appears that carry-over is unavoidable, study samples should not be randomised. Specific measures should be considered, tested during the validation and applied during the anal­ysis of the study samples, so that it does not affect accuracy and precision. This could include the injection of blank samples after samples with an expected high concentration, before the anal­ysis of the next study sample.

For decades the Canadian GL called for completely randomized samples but HC abandoned this requirement for good reasons. If one doesn’t want to give the scheduled time points, that’s fine. But still give an index of sample / subject / period. Then the analyst can minimize carry-over by alternating periods and increasing indices, e.g.,

Sub₁Per₁Spl₁ – Sub₁Per₂Spl₁ –
Sub₁Per₁Spl₂ – Sub₁Per₂Spl₂ –
… –
Sub₁Per₁Spl_n – Sub₁Per₂Spl_n.

Of course, this is best only for BE (where one can expect similar profiles). In BA (say EV vs. IV) inject all samples of one period followed by the other.