Back to the Top
The following message was posted to: PharmPK
Hello,
I have a question to pose regarding acceptance of parts of
bio-analytical runs. I am up against a group of colleagues who
believe it is OK to accept parts of runs, here is the scenario:
LC/MS
12 total QC samples are analyzed, 4 replicates at Low, Mid and High
ranges.
Calibration curve looks fine. (9 point curve)
All replicates at the HQC pass, 3 replicates at the Mid pass but all 4
reps at the Low fail.
The thinking is that they will accept the analytical run for any
sample that had a calculated concentration higher then the mid QC and
reject any sample lower.
I disagree because the guidance clearly states that the you cannot
have multiple failures at the same level. any suggestions on how I
can change their minds? Their rationale is that the mid and high QC's
prove that the calibration curve and assay was working fine at the
higher levels.
thanks,
Steve
Back to the Top
The following message was posted to: PharmPK
Dear Stephan,
The situation which you are explaining is clearly shows that you should
not accept the batch.
The guidance will not allow you to play on these things.
Hope this will help.
Nagesh
Back to the Top
Dear Steve,
Regarding the question of accepting parts of runs when multiple QCs
fail at a given concentration, I agree with you. You should have
SOPs that define how to accept or reject runs, and they should be
based on the guidance you cite. (If you don't have an SOP about
using QC data to accept or reject runs, you need it; it should
settlethe argument.)
You could possibly write an SOP to describe a process for accepting
part of a run, but if you do you better be prepared to explain and
justify the process (repeatedly) to regulatory authorities and to
your QA unit. You could also possibly reanalyze a portion of the
"acceptable" samples to confirm that the initial value was valid, but
such a process would also need to be documented in an SOP or in the
method. Unless your SOPs or the specific method describe how a
partial run can be accepted, then on what objective basis can you say
that an apparently failed run was actually OK for certain samples but
not for others? I don't know the details of the sample, standard,
and QC sequence in the run, but it could be that concentrations below
a certain value are unreliable, or samples run during a certain time
period are unreliable, or some other grouping makes them unreliable.
I know that the FDA does issue 483 citations for accepting data that
the guidelines say should not be accepted, and the data or possibly
the study risks regulatory rejection.
You could also ask your QA unit for their opinion, as they must to
assure that your process was compliant with regulations.
Tom
Thomas L. Tarnowski, Ph. D.
Bioanalytical Development
Elan Pharmaceuticals
800 Gateway Blvd.
South San Francisco, CA 94080
thomas.tarnowski.at.elan.com
Back to the Top
The following message was posted to: PharmPK
Dear Steve:
You are on the right side of the fence, if all the replicates of low QC
fails you can not do batch acceptance based on two set of QCs (you are
opening yourself for tough inquiries during dreaded inspections), smart
way is to continue your analysis is as follows
1. Reanalyze the entire batch in a fresh analytical run.
2. During subsequent analytical runs add additional QCs (LLQC, LQC, MQC,
MMQC..... HQC) that will allow truncating the calibration standard low
or high ends, during the recent Third Crystal city meeting the following
key points were discussed (along with some of the points I entirely
don't subscribe for) a) you can add additional QC in the middle of
sample analysis if you feel they truly represent the spreading of QC
over the entire range of observed concentrations, you have to have at
least two set of QC that are within the range of measure concentrations
in subject samples (not calibration curve) 2) you have to have a SOP in
place prior to the analysis start for truncated analysis, adding
additional QCs.
3. By adding QC than more than the needed LQC, MQC, and HQC you are
giving room for dropping one entire set of QC still be able to accept
the truncated analysis.
In the particular case you are describing you are out of luck as you
have only two set of QCs; )--- I wonder what your smarties think if the
only LQC and HQC passes and entire QC set of MQC fails....
Happy thanks giving,
Prasad Tata, Ph.D.
Saint Louis, MO
Back to the Top
The following message was posted to: PharmPK
Dear Steve,
FDA guideline they are mentioned that, in each set of QCs at least
50% must be pass. In overall QCs 66.6% is the acceptance criteria.
You can tell him to that refers FDA guidelines.
Regards
Suresh
Back to the Top
Dear Sir,
The guidelines clearly state that -
'The results of the QC samples provide the basis of accepting or
rejecting the run....'and '...that not all replicates at the same
concentration can be outside the +/-15% of the nominal value'.
In this case you cannot accept the results of the run, if any one of
the QC levels (all replicates) are outside the acceptance criteria.
What if the QC level failed would have been MQC or HQC instead?
So the FDA guidance can serve as the rationale for explaining the group.
Hope this helps.
Thanks and Regards,
Rupali Morye.
QA-Wockhardt
Back to the Top
Hello everyone,
We had a similar issues a few years ago and this is what came out of
the FDA audit.
Presently, we follow the FDA validation guidelines where your low Qc
levels should be 2-3 the LOQ.
In addition, we add an additional QC in the low end so that if the
lowest acceptable standard is rejected, this additional QC becomes
2-3 times the level of the new LOQ and this way you still fulfill the
FDA requirement and only have to repeat samples which are below the
new LOQ.
Of course, all this procedure should be described in an SOP detailing
exactly what do to in the event that either your low end or high end
of the curve is rejected.
Comments/remarks are more than welcome
Best regards,
Sylvain Mandeville, Ph.D.
Lab Research
www.labresearch.com
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)