Evaluation of analytical methods:

Benicar Tablets
Natalya Stuherck RACMC
USP monographs Task Force meeting
May 27, 2014
2
Benicar analytical methods
Evaluation of the approved methods for compliance with the laboratory
practices
Benicar analytical methods that are included in DSE DMF 14884 and DST DMF
17685 are referenced in the Benicar NDA 21-286.
DMF 14884 and DMF17685 methods were evaluated against the testing laboratory
methods for compliance.
Four testing laboratories:
DSE Quality Control Laboratory (release testing)
DSE Analytical Development Laboratory (stability testing)
DST Quality Control laboratory (release and stability testing)
PPD contract laboratory (stability testing)
Four DMF methods were included in the evaluation:
identification
dissolution
assay
related substances
Analytical methods were compared among the four laboratories

Presentation Name | CONFIDENTIAL
3
Benicar - Identification
There are three ID methods: UV spectroscopy, UV spectroscopy (dissolution)
and RT (HPLC)
Derails of method evaluation are provided in the Excel file
UV spectroscopy







USP requirement:
Analytical wavelength: {if more than a single wavelength, use Wavelength range as the subsection head}
Sample solution: [ ] (g/mL in [solvent {if water, no need to state; in General Notices}]
Acceptance criteria: Absorptivities, calculated on the [dried][anhydrous] basis, do not differ by more than _.0% (normally, 1.0%).
Ratio: Ax/Ay, [ ][ ]
Is the Identification method by UV spectroscopy equivalent among laboratories?

Presentation Name | CONFIDENTIAL
Variables
DSE Test Methods

DST Test Methods

PPD Remarks
DMF/QC AD/STAB DMF QC PPD (stability)
Examination Between 200 and 360 nm
the test solution shows
absorption maxima and
minima at the same
wavelengths as the
reference solution.
Measuring range
between 200 nm and 360
nm. The presence of CS-
866 is proven if the
spectrum shows a
absorption maximum
between 255 nm and 259
nm.
Between 200 and 360
nm the test solution
shows absorption
maxima and minima at
the same wavelengths
as the reference
solution.
Measuring range
between 200 nm and
360 nm. The presence
of CS-866 is proven if
the spectrum shows a
absorption maximum
between 255 nm and
259 nm.
Spectrophotometer:
UV-2550, Shimazu
Corporation, or
equivalent
U-3300,
Hitahi Ltd.
4
Benicar Identification
UV- Spectroscopy (dissolution)
This method is used by DSE AD only (is not described in the DMF)
Retention time (HPLC)







Is the Identification method by RT (HPLC) equivalent?
USP requirement: The retention time of the major peak of the Sample solution corresponds to that of the
Standard solution, as obtained in the Assay.
Which method (UV spectroscopy, UV spectroscopy (dissolution) and/or RT
(HPLC) to be proposed for the USP monograph?

Presentation Name | CONFIDENTIAL
Variables
DSE Test Methods

DST Test Methods

PPD
DMF/QC AD/STAB DMF QC PPD (stability)
Acceptance
criteria
The retention time of the
major peak in the
chromatogram of the test
solution corresponds to that of
the reference solution
obtained as directed in the
Assay
The retention time of the
major peak in the
chromatogram of the test
solution corresponds ( 0.5
min) to that of the reference
solution obtained as directed
in the Assay
Compare to HPLC peak
of olmesartan medoxomil
in the chromatograms of
the sample solution and
standard solution.
Retention times between
sample and standard
peaks of olmesartan
medoxomil should not
exceed 0.5 minutes
Compare to HPLC peak of
olmesartan medoxomil in
the chromatograms of the
sample solution and
standard solution.
Retention times between
sample and standard
peaks of olmesartan
medoxomil should not
exceed 0.5 minutes
5
Benicar - Dissolution
One method per laboratory







Are the methods equivalent among laboratories?
The USP Performance test procedures should be considered quality control tests (demonstration of continuing quality) only
USP requirement: medium, apparatus, rpms, time, detection, sample and std. solutions, analysis, and tolerances: NLT [ ]%
(Q) of the labeled amount of [name] is dissolved.
Which method to be proposed for the USP monograph?

Presentation Name | CONFIDENTIAL
Variables
DSE Test Methods DST Test Methods PPD
DMF/QC AD/STAB DMF QC

PPD (stability)
Solvent for standard acetonitrile / water
(3:2 V/V)
ethanol acetonitrile / water (3:2
V/V)
same as DMF ethanol
10 mg dosage 10 g CS-866 / ml 5 g CS-866 / ml 10 g CS-866 / ml 10 g CS-866 / ml 5 g CS-866 / ml
20 mg dosage 20 g CS-866 / ml 10 g CS-866 / ml 20 g CS-866 / ml 20 g CS-866 / ml 10 g CS-866 / ml
40 mg dosage 40 g CS-866 / ml 20 g CS-866 / ml 40 g CS-866 / ml 40 g CS-866 / ml 20 g CS-866 / ml
UV-2550, Shimazu
Corporation, or
equivalent
Apparatus; U-3300,
Hitachi Ltd.
Wavelength 258 nm 257 nm and 358 nm 258 nm and 358 nm 258 nm and 358 nm 257 nm and 358 nm
SST Test and their
acceptance criteria
-
relative standard
deviation of the check
sample 3 % from the
theoretical amount (100
%)
-
recovery of the
quality control
samples is 97-103%.
6
Benicar - Related substances
One method per laboratory- HPLC (gradient)


Presentation Name | CONFIDENTIAL
Variables
DSE Test Methods DST Test Methods PPD
DMF/QC AD/STAB DMF QC
PPD (stability)

Mobile phase B
potassium dihydrogen
phosphate buffer solution
0.015M / Acetonitrile
(21:79 V/V)
potassium
dihydrogen
phosphate buffer
solution 0.015M /
Acetonitrile (21:79
V/V)
potassium
dihydrogen
phosphate buffer
solution 0.015M /
Acetonitrile (21:79
V/V) pH 3.5
potassium dihydrogen
phosphate buffer
solution 0.015M /
Acetonitrile (21:79 V/V)
pH 3.5
Mobile Phase B:
potassium dihydrogen
phosphate buffer
solution 0.015M /
Acetonitrile (20:80V/V)
guard column - Jasco P/N D543 50
x 4,6mm;
Polystylbenzengel
d=4.6mm, l=0.05m ? Cleanup column:
Nippon Bunko 50 x
4.6mm
polystylbenzengel
between pump A and
mixing chamber
Relative Retention time
with reference to CS-866:
RNH-6270 ~ 0.2;
RNH-6352 ~0.7;
RNH-8276 ~1.2;
RNH-6373 ~1.5
RNH-6270 ~ 0.2;
RNH-6352 ~0.7;
RNH-8276 ~1.2;
RNH-6373 ~1.5
866-7 ~3.39
RNH-6270 ~ 0.17;
RNH-6352 ~0.75;
RNH-8276 ~1.2;
RNH-6373 ~1.69
866-7 ~3.55

Retention time of the
CS-866-Peak 10 min
1
Relative Retention
time with reference to
CS-866:
RNH-6270 ~ 0.16;
RNH-6352 ~0.72;
RNH-8276 ~1.2;
RNH-6373 ~1.5; 866-
7 ~3.2
7
Benicar - Related substances (cont`d)






USP requirement for SST test:
Sample: System suitability solution or Standard solution
Resolution: NLT [ ] between ___ and ____
Column efficiency: NLT [ ] theoretical plates
Tailing factor: NMT [ ]
Relative standard deviation: NMT__.__%
Quantitative Limit Solution
Is the method equivalent among laboratories?
Which method to be proposed for the USP monograph?

Presentation Name | CONFIDENTIAL
Variables
DSE Test Methods DST Test Methods PPD
DMF/QC AD/STAB DMF QC
PPD (stability)

Resolution
minimum of 5 between
peaks due to RNH-6352
and OM

minimum of 5
between peaks due
to RNH-6352 and
OM
minimum of 5 between
peaks due to RNH-
6352 and OM
Resolution between
RNH-6352 and CS-866
5.0

w2, w1 = peak
width at the
retention time of
half of the peak
height
w2, w1 = peak width at
a half of the peak
height
Tailing factor

Tailing factor must be
2.0
8
Benicar - Assay
Two assay methods Method A (HPLC) and Method B (UPLC) exist
Method A (HPLC isocratic) is used by DSE QC, DSE AD, DST QC and PPD













Is the Assay method equivalents among laboratories?
USP SST requirements: Resolution: NLT [ ] between ___ and ____ Column efficiency: NLT [ ] theoretical plates
Tailing factor: NMT [ ] Relative standard deviation: NMT__.__% for
[{number of} replicate injections]

Presentation Name | CONFIDENTIAL
Variables DSE Test Methods DST Test Methods PPD
DMF/QC AD/STAB DMF QC PPD (stability)
Flow rate 1.1 mL/min (can be
adjusted)
1.0 mL/min (can be
adjusted)
1.1 mL/min (can be
adjusted)
1.1 mL/min (can be
adjusted)
1.1 mL/min (can be
adjusted)
resolution minimum 3.4
between the peaks
due to OM and IS
minimum 3.4
between the peaks
due to OM and IS
minimum 3.4
between the peaks
due to OM and IS
minimum 3.4
between the peaks
due to OM and IS
minimum 3.4 between
the peaks due to OM
and IS
repeatability Repeatability: max
RSD 1.0% for the
response factor due
to OM after 6
injections
max RSD 1.0% for
the response factor
due to OM after 6
injections
Reproducibility: OM
STD mg/area OM
STD/area IS is NLT
1%
(not provided)
RSD of 6 injections of
OM RS is NMT 1.0%


w2, w1 = peak width
at a half of the peak
height
w2, w1 = peak width
at a half of the peak
height

tailing factor -
- - -
NMT 2.0 for peaks of
OM and ISTD
check sample -
Check Sample:
98.5 - 101.0 % of
Standard 1
Check Sample:
98.5 - 101.0 % of
Standard 1

Standard
Comparison 98.0%
to 102.0%
9
Benicar Assay (cont`d)
Method B (UPLC gradient)
-This method is only used by DSE QC
-Column of a smaller size
-Short run time
-Gradient condition
-SST :




Which method to be proposed for the USP monograph?

Presentation Name | CONFIDENTIAL
resolution minimum 3.4
between the peaks
due to OM and IS
repeatability max RSD 1.0% for
the response factor
due to OM after 6
injections