Bioequivalence and Bioavailability Forum

Hi Comp,

❝ Don't it possible for FDA to give some light about the LLOQ requires for method in OGD recommendation.

I am not exactly sure what you mean but in my opinion the LLOQ in itself is not always king. Often it is, and often companies strive to get it as low as possible but other factors weigh heavily in when it comes to judging if an assay is good enough.
1. As a rule of thumb Cmax should be at least 20x the LLOQ. If it isn't then the problem may not be the assay but something else, such as the subject or the clinic; or there might not be a problem at all anyway.
2. Subjects can be dosed 2, 3, 4... tablets per period if need be. In certain types of BE studies the dose should reflect a high tolerable dose anyway in which cases the LLOQ might be a relatively pointless parameter to improve.
3. An LLOQ may depend on the matrix. Forcing a specific LLOQ onto a lab could imply less freedom in the choice between e.g. plasma or serum. Traditionally both are generally acceptable, as far as I can tell.
4. A high LLOQ in combo with good general GLP compliance is in all likelihood preferable to a low LLOQ with bad general GLP compliance. These things are however never crystal clear. For example, old chromatographic columns often give much more baseline noise than new columns. So one might say that in evaluating signal-to-noise and making the choice about LLOQ one should be conservative and use old columns. Or go even further into the extreme and say it is a potential GLP violation to use only new columns when evaluating S/N and LLOQ and such. But this is solely an interpretation since there is no specific GLP clause that dictates anything about the LLOQ.
(I am sure there are at least 50 other things to mention here).

So all in all I would say the LLOQ, while often a very important indicator of assay performance, is on its own not a good single indicator to base decisions on and pt. 1 vs. pt. 4 illustrates how the LLOQ can be both a very objective performace indicator as well as one that involves subjectivity. This is just my humble and unqualified opinion and I'd love to hear input from others here.