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?


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?


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?


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



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%.

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Benicar - Related substances

One method per laboratory- HPLC (gradient)


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?



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]


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)




resolution 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%



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 :



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

Documents

Benicar Analytical Methods