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1. What
technologies do QPS currently use?
QPS currently has 36 triple quadrupoles and 1 linear ion trap
mass spectrometers dedicated to drug concentration determination
and metabolite identification.
QPS-US has
33 mass spectrometers (25 API 4000s, 3 Quattro Ultimas, 2 Quattro
LCs, 2 Quattro IIs, 1 ProteomeX LTQ). 24 triple quadrupoles are
dedicated to GLP drug concentration determination studies while
8 triple quadrupoles and the linear ion trap are assigned to discovery
and non-GLP ADME studies.
Although the
standard LC/MS/MS platform for drug concentration determination
is API 4000 coupled to Shimadzu VP-series LCs and LEAP injectors,
Cohesive Technologies ARIA Systems are available for special cases.
QPS-US also has Agilent LCs and Shimadzu VP-series LC with Agilent
UV, Agilent fluorescence, and Waters fluorescence detectors for
LC/UV and/or LC/fluorescence analysis.
QPS-Taiwan
is in the growth phase, and currently has 4 API 4000s dedicated
to GLP drug concentration determination.
2. What
ionization techniques do you currently use?
QPS uses both ESI and APcI ionization.
3. Do you
work on multiple-analytes assays?
Since our inception in 1996, most of our assays are developed
for the parent drug and metabolites. Usually these are "2-in-1"
or "3-in-1" or "4-in-1" assays, however we
have developed "6-in-1" and "7-in-1" assays.
4. Do you
work on isomeric assays?
We regularly work with positional cis-trans isomers and single-chiral
center enantiomers. We have also developed two-chiral centers
enantiomers assays.
Our goal for
chiral assay is to develop methods with run-time of less than
10 minutes, if at all possible. Although this implies substantial
investment on method development, we found that it is more time
and cost effective when it comes to sample analysis, particularly
for the dose-escalation studies.
5. Do you
work on peptides, polypeptides, oligonucleotides, and other large
molecules?
The complexity of the assays depends on the molecules of interest.
Generally, we found that an integrated approach with the appropriate
multiple sample clean-up and extraction methods with good chromatography,
and stable ionization is needed.
We have also
used immuno-affinity (antibody) columns couple with LC/MS/MS for
polypeptides quantitation. This methodology brings with it a whole
unique set of issues, such as column stability, batch-to-batch
variability. Nevertheless, immuno-affinity columns are viable
approaches as compare to the traditional sample clean-up and concentration
procedure.
We have used
both LC/MS/MS and LC/UV for oligonucleotide drug concentration
determination. Contrary to common beliefs, we have found that
LC/UV is a viable alternative to CE/UV or hybridization-ELISA
for certain oligonucleotides drugs.
6. How
many GLP LC/MS/MS methods do you develop and validate in a year?
What is ratio of method development vs. method transfer?
Between 2005 and 2007, QPS-US developed and fully validated 300
methods, and performed about 250 cross-species and/or cross-matrix
partial validations. The ratio of method development to method
transfer is approximately 5:1.
7. What
sample clean-up procedure do you use?
We try a variety of methods, such as protein precipitation, SPE,
LLE, solid support LLE, and column switching as part of the method
development procedure. The exact procedure depends on the analyte(s),
the internal standard(s) and the matrix. We tend not to use protein
precipitation for clinical studies.
8. Do you
explore sample stability as part of method development?
Compound stability from the collection point to sample work-up
is a very important part of method development., and is part of
the guidance. We usually
9. What
is the scope of your LC/MS/MS method development for GLP studies?
QPS will examine the following parameters as part of method feasibility/method
development to optimize for linearity, precision, accuracy, sensitivity,
selectivity, extraction recovery, reproducibility, matrix effect,
potential cross-talk, and interference peaks. If required additional
studies, such as whole-blood stability, hemolysis effect, endogenous
species, interference from co-administered drugs, and enzymatic
reaction to check for Phase II metabolites will be conducted.
The method
will have to demonstrate the following before going into validation:
►Linearity of the calibration
curve (1-day calibration curves with minimum 6 concentration levels
in duplicate)
►Precision and accuracy
(1-day quality controls with minimum 4 concentration levels, including
LLOQ; n = 3)
►Batch size evaluation
►Absolute recovery (low
and high concentrations, n = 3)
►Selectivity test (LLOQ
level; n = 6)
►Matrix effect test (low
and high concentrations; n = 3)
►Carry-over test (extracted
blank after a high standard)
►Room temperature stability
(minimum 4-hour; 2 concentration levels; n = 3)
10. What
is your validation criteria for LC/MS/MS assay?
The scope of the full or partial validation which follows the
latest Crystal City Bioanalytical Validation guideline, and the
AAPS Journal 2007; 9 (1), E30-E42 article "Workshop/Conference
Report - Quantitative Bioanalytical Methods Validation and Implementation:
Best Practices for Chromatographic and Ligand Binding Assays"
is defined below. A validation report will be issued which will
be suitable for regulatory filing.
The full validation
will demonstrate:
►Linearity of the calibration
curve (3-day calibration curves with minimum 6 concentration levels
in duplicate)
►Precision and accuracy
(3-day quality controls with minimum 4 concentration levels, including
LLOQ)
►Absolute recovery (low,
middle, and high concentrations; n = 5)
►Dilution test (1 concentration
level, one dilution factor; n = 5)
►Selectivity test (LLOQ
level; six individual lots)
►Matrix effect test (low,
middle, and high concentrations; n = 5)
►Carry-over test (extracted
blank after a high standard)
►Stock solution stability
(minimum 6-hour cycle; 1 concentration level @ RT for a minimum
of 6 hour and -20oC or below to cover sample storage time; n =
5)
►Sample stability:
►Long term frozen stability
(at about one month, minimum of 2 concentration levels @ -20oC
or below; n = 5). The concentrations will lie within the validation
assay range.
►Room temperature stability
(minimum 4-hour cycle; 2 concentration levels; n = 5)
►Freeze/thaw stability
(one 24-hour cycle, and two 12-hour cycle; 2 concentration levels;
n = 5)
►Post preparative re-injection
reproducibility (minimum of 3 concentration levels in reconstitution
solvent in duplicates at room temperature)
The one intraday
partial validation will demonstrate:
►Linearity of the calibration
curve (1-day calibration curves with minimum 6 concentration levels
in duplicate)
►Precision and accuracy
(1-day quality controls with minimum 4 concentration levels, including
LLOQ; n = 6)
►Absolute recovery (low,
middle, and high concentrations; n = 5)
►Dilution test (1 concentration
level, one dilution factor; n = 5)
►Selectivity test (LLOQ
level; n = 6)
►Matrix effect test (low,
middle, and high concentrations; n = 5)
►Carry-over test (extracted
blank after a high standard)
►Sample stability:
►Long term frozen stability
(at about one month, minimum of 2 concentration levels @ -20oC
or below; n = 5). The concentrations will lie within the validation
assay range.
►Room temperature stability
(minimum 4-hour cycle; 2 concentration levels; n = 5)
►Freeze/thaw stability
(one 24-hour cycle, and two 12-hour cycle; 2 concentration levels;
n = 5)
►Post preparative re-injection
reproducibility (minimum of 3 concentration levels in reconstitution
solvent in duplicates at room temperature)
11. Do
you run your standard curves and QC with matrix samples?
Yes, this is part of the Bioanalytical Method Validation guidance.
Nevertheless, if the matrices are hard to come by, we will look
for a scientifically valid alternative matrix with the sponsor's
approval.
QPS also offers
"validation test" in patient matrix, if the matrix is
available.
12. What
are some of the matrices you have worked on?
Probably 90% of QPS-US GLP studies are plasma and urine. However,
we have been seeing a higher portion of whole-blood assay in the
past few years. We have validated LC/MS/MS methods in peripheral
blood mononuclear cells (PBMC) for biomarker assays; and liver,
kidney, spleen, lung, myocardium, arteries, intestine, brain,
CSF, ovaries, testis, prostate tissues for target organ penetration
studies.
100% of QPS-Taiwan
studies are plasma, whole-blood, serum, and urine samples.
13. How
many protocols and samples do you run in a year? What is the ratio
of clinical to preclinical/nonclinical samples?
Between 2005 and 2007, QPS-US GLP LC/MS/MS group worked on approximately
1400 protocol-driven studies, which equates to approximately 350,000
samples. The ratio of clinical to preclinical/nonclinical samples
averages about 60/40 over the years. The exact ratio depends on
the development cycle of our sponsors.
Between 2005
and 2007, QPS-Taiwan worked on approximately 132 protocol-driven
studies, which equates to approximately 85,000 samples. As QPS-Taiwan
is currently mostly geared towards generic compounds and non-proprietary
assays, the ratio of clinical to preclinical/nonclinical samples
averages about 9:1 over the years.
14. Do
you have the capability to run assays with radioactive samples?
QPS-US can run radioactive samples from mass balance/excretion
and metabolism studies. QPS-Taiwan does not have a radioactive
license.
15. Do
you have a GLP compliant version of software for data management
and report writing?
Both QPS-US and QPS-Taiwan use Watson LIMS v6.4 for all validation
and sample analysis projects.
16. How
many scientists work in your LC/MS/MS group?
The QPS-US GLP LC/MS/MS group has 40 direct head count, and 15
support staff, including project managers, sample management team,
report writers, and metrologists. The ratio of PhD/MS-level scientist
to BS-level scientist is usually at 1:2.
The QPS-US
discovery LC/MS/MS group has 6 direct head count, and 4 support
staff, including sample management team, report writer, and metrologists.
The ratio of PhD/MS-level scientist to BS-level scientist is usually
at 1:1.
Both QPS-US
LC/MS/MS groups are always in the growth mode and have 20 open
positions for laboratory personnel.
The QPS-Taiwan
LC/MS/MS group has 11 direct head count, 1 support staff, and
1 open position. The ratio of PhD/MS-level scientist to BS-level
scientist is usually at 2:1.
17. Do
QPS-US and QPS-Taiwan shares the same operation principles?
Both QPS-US and QPS-Taiwan operate under the same regulatory guidance
(FDA, OECD, and MHLW), shares the same SOPs, and the same laboratory
procedures. This ensures that our sponsors can use both laboratories
for compounds under development as well as non-proprietary compounds.
18. What
quality criteria can be used ensure QPS-US and QPS-Taiwan have
similar quality?
Some sponsors have sent blinded-QC samples to cross-validate between
the two QPS facilities, and their own bioanalysis organization.
19. What
regulatory agencies have audited QPS?
In 2000 EPA audited a series of FIFRA studies performed in 1997-2000
by QPS-US. A 483-equilvant was issued with "No Finding".
In 2007 FDA audited a BE study performed in 2002-2004 by QPS-US.
Three of the four points on the 483 were focused on chromatography.
At that time, QPS-US, like the rest of the industry did not have
a chromatography SOP. QPS had a draft version of that SOP before
the FDA audit. FDA recognizes that although QPS did not have an
effective SOP in place, the PI was consistently using the same
integration parameters. The final point of the 483 was about documentation,
which was addressed before the audit, as the documentation procedure
during the 2002-2004 period was different than the current effective
procedure.
FDA has not
audited QPS-Taiwan. Taiwan DOH (Taiwan FDA) audited QPS-Taiwan
in 2007, so far seven (7) BA/BE studies have been approved by
Taiwan DOH.
20. Do
QPS-US and QPS-Taiwan share the same bioanalysis report format?
Before initiation of the bioanalysis QPS-US and QPS-Taiwan will
confirm with the clients to ensure QPS meets all the needs and
special requirements with respect to client reporting templates.
Most of the time, this will mean the same report format for both
QPS laboratories.
21. Are
there any cross-training and specific interactions between the
technical and operational staff of QPS-US and QPS-Taiwan?
The QPS-Taiwan operations were set-up by QPS-US technical operations
staff. Furthermore, QPS-Taiwan QA auditors, and technical staffs
have training time in QPS-US laboratory. QPS-US QA auditors IT
personnel have also been to QPS-Taiwan laboratory for internal
inspection and audits.
22. How
can US/European companies gain more comfort and experience with
the QPS-Taiwan?
Some of our US sponsors have been using QPS-Taiwan to support
the bioanalysis of some non-critical Drug-Drug Interaction and/or
concomitant drug studies, plus discovery dog PK studies. This
way the client can test the Quality, Timeline, Project Management,
and Cost Saving of the QPS-Taiwan.
23. What
direct contact would US or European clients have with QPS-Taiwan
to manage or get updates on projects?
This depends on the clients. If the clients are comfortable working
with QPS-Taiwan directly, then all communication can go directly
through to Asia. If the clients prefer to work through QPS-US,
then the projects can be managed through US.
24. Can
non-Human Primate samples be shipped to Taiwan?
Yes, with the appropriate import permit.
25. Can
samples be shipped from Mainland China?
No. Biological samples containing extractable nucleic acid material
cannot be shipped out of Mainland China.
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