Benicar Analytical Methods
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Transcript of Benicar Analytical Methods
Evaluation of analytical methods: Benicar Tablets
Natalya Stuherck – RACMCUSP monographs Task Force meetingMay 27, 2014
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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: identificationdissolutionassayrelated substances
Analytical methods were compared among the four laboratories
Presentation Name | CONFIDENTIAL
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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
VariablesDSE Test Methods
DST Test Methods
PPD Remarks
DMF/QC AD/STAB DMF QC PPD (stability)
Examination Between 200 and 360 nm the test solution showsabsorption 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.
Benicar analytical methods
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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
VariablesDSE 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
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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 µg CS-866 / ml 5 µg CS-866 / ml 10 µg CS-866 / ml 10 µg CS-866 / ml 5 µg CS-866 / ml
20 mg dosage 20 µg CS-866 / ml 10 µg CS-866 / ml 20 µg CS-866 / ml 20 µg CS-866 / ml 10 µg CS-866 / ml
40 mg dosage 40 µg CS-866 / ml 20 µg CS-866 / ml 40 µg CS-866 / ml 40 µg CS-866 / ml 20 µg 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
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relative standard deviation of the check sample ± 3 % from the theoretical amount (100 %)
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recovery of the quality control samples is 97-103%.
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Benicar - Related substances
One method per laboratory- HPLC (gradient)
Presentation Name | CONFIDENTIAL
VariablesDSE Test Methods DST Test Methods PPD
DMF/QC AD/STAB DMF QCPPD (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 ±1Relative 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
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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
VariablesDSE Test Methods DST Test Methods PPD
DMF/QC AD/STAB DMF QCPPD (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
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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%
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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