qualityassurance
☆

Jordan,
2021-10-18 07:00
(50 d 13:54 ago)

Posting: # 22631
Views: 748

## Acceptance criteria of analytical run [Regulatives / Guidelines]

Dear Forum members,

As per EMA Guideline on bioanalytical method validation Acceptance criteria of an analytical run "The accuracy values of the QC samples should be within ±15% of the nominal values. 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?

Regards,
Qualityassurance
ElMaestro
★★★

Denmark,
2021-10-18 08:35
(50 d 12:19 ago)

@ qualityassurance
Posting: # 22632
Views: 668

## Acceptance criteria of analytical run

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.

Pass or fail!
ElMaestro
dshah
★

India/United Kingdom,
2021-10-18 12:36
(50 d 08:19 ago)

(edited by dshah on 2021-10-18 19:13)
@ qualityassurance
Posting: # 22634
Views: 652

## Acceptance criteria of analytical run

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
qualityassurance
☆

Jordan,
2021-10-19 15:25
(49 d 05:30 ago)

@ dshah
Posting: # 22641
Views: 612

## Acceptance criteria of analytical run

Dear dshah, ElMaestro and Ohlbe,

Thank you for the response.

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).

May we specify in our SOP that 2/3 (67%) of the QC should be within ±15% of the nominal values? or It is advisable to reject such runs (having 66.67% passed QCs)?

Regards,
Qualityassurance
Ohlbe
★★★

France,
2021-10-19 18:54
(49 d 02:00 ago)

@ qualityassurance
Posting: # 22642
Views: 631

## Acceptance criteria of analytical run

Dear Qualityassurance,

» May we specify in our SOP that 2/3 (67%) of the QC should be within ±15% of the nominal values? or It is advisable to reject such runs (having 66.67% passed QCs)?

You can very well write in your SOP acceptance criteria of 2/3 and 50% at each level of concentration. By the way, the ICH M10 draft guideline (step 2, public consultation now ended) has dropped the awkward 67% criterion and replaced it with 2/3. We'll see what is decided in the final guideline.

I have never heard of any regulatory authority (at least in Europe or Northern America) raising a question or a deficiency because a run was validated with 8/12 QCs passing (with 50% at each level of concentration) and objecting that this is < 67%.

Regards
Ohlbe
qualityassurance
☆

Jordan,
2021-10-21 16:51
(47 d 04:03 ago)

@ Ohlbe
Posting: # 22651
Views: 509

## Acceptance criteria of analytical run

Dear Ohlbe,

» You can very well write in your SOP acceptance criteria of 2/3 and 50% at each level of concentration. By the way, the ICH M10 draft guideline (step 2, public consultation now ended) has dropped the awkward 67% criterion and replaced it with 2/3. We'll see what is decided in the final guideline.
»

Yes. Will update the SOP and then when ICH M10 will be finalized our SOP already in line with the guideline.

Regards,
Qualityassurance
Ohlbe
★★★

France,
2021-10-18 14:43
(50 d 06:11 ago)

@ qualityassurance
Posting: # 22636
Views: 666

## Acceptance criteria of analytical run

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.

Regards
Ohlbe
Helmut
★★★

Vienna, Austria,
2021-10-20 14:06
(48 d 06:48 ago)

@ Ohlbe
Posting: # 22649
Views: 564

## ’Percentage’ of few values

Hi Ohlbe & Qualityassurance,

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

Since I attended these early conference, I can confirm it… However, speaking of ‘percentages’ of <100 values is unfortunate at least and $$\small{\geq \small{^{2}/_{3}}}$$ was meant indeed. 67% is stupid and 66.7% or 66.67% hardly better.
I one insists in a percentage, it should be written as $$\small{\geq66.6666666666\ldots\%}$$ or $$\small{\geq66.\dot{6}\%}$$.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
qualityassurance
☆

Jordan,
2021-10-21 16:57
(47 d 03:58 ago)

@ Helmut
Posting: # 22652
Views: 497

## ’Percentage’ of few values

Hello Helmut,

» Since I attended these early conference, I can confirm it… However, speaking of ‘percentages’ of <100 values is unfortunate at least and $$\small{\geq \small{^{2}/_{3}}}$$ was meant indeed. 67% is stupid and 66.7% or 66.67% hardly better.
» I one insists in a percentage, it should be written as $$\small{\geq66.6666666666\ldots\%}$$ or $$\small{\geq66.\dot{6}\%}$$.

So almost all (Regulatory Assessors) agree that 2/3=66.66666667%=66.67%=67%=Accepted run.

Regards,
Qualityassurance