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Hi,we have a Bioanalytical Method which is validated for all
parameters as per FDA guidelines with the Calibration Curve(CC) range
of 10-750 ng/ml.when we started the analysis of bioequivalence study
with the above method, around 20% of the subject samples (for first 10
subjects of a total 55 subject study) are going beyond CC,hence we
have decided to stop the analysis and extend the calibration curve
range from 10-750 ng/ml to 10-1500 ng/ml by performing three Precision
and Accuracy(P&A) for the extended range.
at this stage, shall we continue the study sample analysis with the
new CC range, or we need to do full validation for the new CC range.
as some people suggest that for extending the CC range, three
Precision & Accuracy(P&A) batches and a Recovery experiment is
sufficient.
please provide opinion/comments to handle the situation with the
regulatory compliance.
Regards,Debbie.
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The following message was posted to: PharmPK
Debbie,
Instead of extending the calibration curve, why not dilute your samples
with appropriate matrix so that they are within your original 10-750
ng/mL calibration range.
Purvi
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The following message was posted to: PharmPK
Hi Debbie.
Good Morning.
There is no need to go for full validation. If your sample
concentration goes beyond the CC range you perform 3 P&A batch and
recovery experiment with proper justification.
Hopefully it work for you.
Regards
laxman
09892602178
LifeSan Clinical Research
Mumbai,India
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Dear Debbie
As you are altering your CC range your QC range will also be altered.
For example initially if your HQC was 650 ng/ml now it would be 1200
ng/ml, so that they cover the Cmax points. If your QC range changes
then i presume stability exercises will come in the picture, therefore
i think this point should also be noted while doing a partial
validation.
Regards
Bharat
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Dear Debbie, I think you can continue with the remaining subjects and
perform the dilution integrity/ Partial volume for the initial samples
showing conc. above the CC range. Make sure you have performed
dilution integrity/ Partial volume experiment during validation and
has met the acceptance criteria. Also the extent of validation
performed for new CC range seems enough.
Dr. Mandar MoteSr. Manager Bio-analyticalBio-equivalence
DivisionMacleods Pharmaceuticals Ltd.Mumbai.
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Dear Debbie
I think you can do one more validation parameter with same CC rane
as dilution integrity. Same you can follow for analysing the subject
sample.
Hope this will help you some extend.
NIL
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The following message was posted to: PharmPK
Debbie: One simple way to proceed is to validate that you can dilute
the sample into the range with reasonable accuracy and precision.
You should obtain an estimate of c max in the highest dose group, then
double it to give yourself a reasonable margin. Prepare 3 sets of
samples at this level, then dilute each into the range of the assay
with your matrix to target the upper, middle and lower range of the
curve. Each should back calculate to the nominal value within the
tolerance of the assay. You are done. You can include a dilutional
QC for anything above the range of dilution you tested. With your PK
scientist you can estimate the concentration in samples and then
dilute appropriately with screened negative matrix.
Does PK forecast support 1500 as the ULOQ or will you need to go higher?
1. Extending the range of the curve still assumes some risk that you
will encounter samples above the range.
2. Since your new ULOQ is 1500 your original HQC will be at <50% and
you will need to redo your HQC and test in stability challenges, not
just P&A.
3. There is also some risk that your current LLOQ may fail and if it
does you will need to reset the LLOQ and LQC, and associated stability.
4. If you do not wish to run the dilutional linearity portion, and
you are restting the ULOQ it may be cleaner to restart the entire
validation using the extended range
--
Ed O'Connor, Ph.D.
Laboratory Director
Matrix BioAnalytical Laboratories
25 Science Park at Yale
New Haven, CT 06511
Web: www.matrixbioanalytical.com
Email: eoconnor.-a-.matrixbioanalytical.com
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Dear debbie,
along with P&A AND RECOVERY in such cases you need to go for Dilition
integrity experiment also as your ULOQ is higher so, again you have to
prepare DQC = 3*ULOQ and also have to prove stability at modified HQC
level
injection carry over is also required
--
Dear debbie
i have gone through replies for post query
most of the friends arerecommanding for dilution of study sample ,
BUT a have gone through a FDA warning letter where such case was
there , analyst have diluted study sample and continue study and FDA
given 483 for not modifing CC range so better to go for PMV with
required experiment
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