Bioequivalence and Bioavailability Forum

Hi quallityassurance,

❝ What if we have 12 QCs in run (3 replicates of each Low, Low-mid, Mid and High) and 1 replicate of each Low, Low-mid, Mid and High failed leading to pass 66.67% of QCs (8 out of 12).

❝

❝ May we accept the analytical run and considered as pass?

I think the run passed when 2/3 were ok.
I agree the wording leads to some confusion but here you should be ok. 2/3 in unrounded percent is 67.

Dear Qualityassurance!
I believe that the run shall be rejected. As per guidlence-" In case these criteria are not fulfilled the analytical run should be rejected, and the study samples re-extracted and analysed." Further the CRO's SOP is equally important as many times the SOP's are stringent compared to guideline (to keep a single SOP for many regulaotries).

❝ What if we have 12 QCs in run (3 replicates of each Low, Low-mid, Mid and High) and 1 replicate of each Low, Low-mid, Mid and High failed leading to pass 66.67% of QCs (8 out of 12).

❝

❝ May we accept the analytical run and considered as pass?

The point of interest is weather all the QC's in same sequence failed? There could be error in sampling sequence or levels failed in different sequence?
Ideally 1 more passes sample to meet the acceptance criteria may have qualified the analytical run.
Regards,
Dshah

Dear Qualityassurance,

❝ As per EMA [...] at least 67% of the QC samples and at least 50% at each concentration level should comply with this criterion.

❝

❝ What if we have 12 QCs in run (3 replicates of each Low, Low-mid, Mid and High) and 1 replicate of each Low, Low-mid, Mid and High failed leading to pass 66.67% of QCs (8 out of 12).

❝

❝ May we accept the analytical run and considered as pass?

The wording in the EMA guideline is indeed not ideal. To interpret it, let's move back in history.

The acceptance rules for QC samples were first defined officially in the 2001 FDA guidance, which itself was derived from the first two Crystal City conferences of 1990 and 2000. At that time, the common practice was to have 3 levels of QC in duplicate. The 2001 FDA guidance stated:

At least 67% (four out of six) of the QC samples should be within 15% of their respective
nominal (theoretical) values; 33% of the QC samples (not all replicates at the same concentration) can be outside the ±15% of the nominal value.

The "50% at each concentration level" criterion was added during the 3rd Crystal City meeting in 2006, to take into consideration that having more than 2 sets of QC samples was becoming frequent, and that having 3 LQC failing and only 1 passing in a run would clearly not be good, even if all MQC and HQC samples passed and the 67% global criterion was met.

The EMA guideline took the wording of the FDA guidance, but unfortunately dropped the part between brackets (four out of six) which made it clear that what was meant was two thirds, and 67% was just a rounded number.

To summarise: yes, your run is valid. This being said, remember that if you had several extraction batches within your run, you also need to look at the QC samples within each extraction batch, and one batch may actually fail.