溶出试验方法验证.pdf

HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.19ANDA ANDA Development SOLIDS DOSAGE FORMS ANALYTICAL METHOD VALIDATION DISSOLUTION TEST FLUOXETINE CAPSULES 10 + 20mg Method Number SI-230-03-11061 Edition Number 01 Effective Date / / 200Y Prepared by:___________________Date:__________________ Reviewed by:____________________Date:__________________ Approved by:____________________Date:__________________ HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.20ANDA ANDA Development TABLE OF CONTENTS INTRODUCTION PRECISION System Repeatability Method Repeatability Intermediate Precision LINEARITY ACCURACY Accuracy of Standard Injections Accuracy of the Drug Product SPECIFICITY System Suitability Placebo Separation of Impurities/Degradation Products STABILITY OF STANDARD AND SAMPLE SOLUTIONS Standard Solution Sample Solutions ROBUSTNESS Factorial design CONCLUSION SI - V - 11061 FLUOXETINE CAPSULES FEBRUARY 1997 Original Containing: Fluoxetine HCl equivalent to 10mg or 20mg Fluoxetine per capsule ANALYTICAL METHOD VALIDATION DISSOLUTION TEST HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.21ANDA ANDA Development INTRODUCTION Fluoxetine Hydrochloride acts as a selective Serotonin-reuptake inhibitor and is clinically effective for the treatment of certain depression catagories. Fluoxetine Hydrochloride has been demonstrated to exhibit comparable efficacy to the tricyclic antidepressant group, but with relatively fewer anti-cholinergic side effects to the patients. C17H18F3NO?HClM.W. = 345.79CAS — 59333-67-4 Fluoxetine Capsules are available in two dosage forms Fluoxetine HCl equivalent to 10mg or 20mg Fluoxetine per capsule. The 10mg and 20mg are manufactured to the same capsule weight. This ANALYTICAL METHOD VALIDATION DISSOLUTION TEST was carried out for the method SI-230-03 which includes the Dissolution determination by HPLC. It is in-house method and currently used method for stability studies. The validation was performed on the 20mg dosage samples, from the PIVOTAL batch, Lot #001. HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.22ANDA ANDA Development PRECISION System Repeatability Ten replicate injections of the standard solution at the concentration of 0.5432mg/100mL as described in method SI-230-03 were made and the relative standard deviation of the peak areas was calculated. SAMPLEPEAK AREA I3638 II3611 III3618 IV3657 V3623 VI3618 VII3611 VIII3632 IX3659 X3617 Average3629.4 SD16.6 RSD. (%)0.5 HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.23ANDA ANDA Development PRECISION (cont.) Method Repeatability The full method as described in SI-230-03 was carried-out on the finished product Lot #001 for the 20mg dosage form, repeated six times and the relative standard deviation was calculated. SAMPLEASSAY % I89.5 II86.8 III90.3 IV89.3 V90.6 VI93.2 Average(%)89.9 SD2.1 RSD (%)2.3 HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.24ANDA ANDA Development TYPICAL CHROMATOGRAM The peak at RRT = 1.3 refers to the placebo PREPARATION Placebo Peak FLUOXETINE PEAK HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.25ANDA ANDA Development PRECISION (cont.) Intermediate Precision The full method as described in SI-230-03 was carried-out on the finished product #-001 for the 20mg dosage form. It was repeated six times by another analyst in a different day with a different HPLC. The average and the relative standard deviation were calculated. SAMPLEASSAY % I95.1 II98.7 III99.3 IV98.9 V98.8 VI98.8 Average(%)98.3 SD1.6 RSD (%)1.6 HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.26ANDA ANDA Development LINEARITY Standard solutions were prepared from 20% to 120% of the nominal concentration required by the method SI-230-03. Linear regression analysis demonstrated acceptability of the method for quantitative analysis over the concentration range required. Y-Intercept was found to be insignificant. CONC. (%) STD. CONC. (mg/mL) PEAK AREA 200.00108670468 300.001630104845 500.002716178940 1000.005432360638 1200.006584439690 Linear Regression0.99997 Slope67221605 Y - Intercept responce at 100% * 100 (%) 1.0% HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.27ANDA ANDA Development LINEARITY GRAPH CAPSULES - FLUOXETINE - [20% - 120%] HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.28ANDA ANDA Development ACCURACY Accuracy of Standard Injections Five replicate injections of the working standard solution were prepared at a concentration of 0.5432mg/100mL, as described in the assay method. The percent deviation from the true value was determined from the linear regression line. INJECTION NO. PEAK AREA % ACCURACY I363802100.6 II361774100.1 III36106199.9 IV365287101.1 V362692100.3 Average362923.2100.4% SD1673.40.5 RSD (%)0.50.5 HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.29ANDA ANDA Development ACCURACY (Cont.) Accuracy of the Drug Product Known amount of Fluoxetine HCl at THREE concentrations: 60% (Q-20), 80%(Q) and 100% was added into the dissolution vessels which contained capsules with Placebo. Duplicate samples were prepared for each concentration. The dissolution vessels were operated under the conditions described in the dissolution method. The Accuracy Test was done for the two dosage forms: 10mg and 20mg, using Placebo batches: #003 for 10mg caps and #004 for 20mg caps. Accuracy for 10mg Caps Conc. (%) Placebo Capsules Wt. (mg) Fluoxetine HCl Wt. (mg) Peak Area % Recovery Average (%) 60219.06.66170885.6 60217.26.84199297.291.4 80217.78.982780103.4 80216.49.05270899.9101.7 100217.211.393503102.7 100209.611.943659102.3102.5 HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.30ANDA ANDA Development ACCURACY (Cont.) Accuracy for 20mg Caps Conc. (%) Placebo Capsules Wt. (mg) Fluoxetine HCl Wt. (mg) Peak Area % Recovery Average (%) 60209.113.39195297.3 60207.913.652148105.1101.2 80209.017.652748104.0 80208.717.342796107.7105.9 100206.622.763418100.3 100205.422.873611105.4102.9 HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.31ANDA ANDA Development SPECIFICITY System Suitability A test for System Suitability was performed as described in the method. The resolution calculated (according to USP) between Meta-Fluoxetine peak and Fluoxetine peak should be not less than 2.0. The tailing factor for Fluoxetine peak should be not more than 2.0. Typical retention time of Fluoxetine peak is approcximately 9.5 min. TYPICAL CHROMATOGRAM Meta-Fluoxetine @ 8.6 Fluoxetine Peak @ 9.70 SYSTEM SUITABILITY SOLUTION HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.32ANDA ANDA Development SPECIFICITY (cont.) Placebo Capsules containing only non actives excipients (Placebo capsules, Lot # 003 for 10mg dosage and Lot # 004 for 20mg dosage) were prepared as in method. ?No interfering peaks were observed. ?The peak at RRT = 1.3 belong to Placebo. PLACEBO CHROMATOGRAM PLACEBO PEAK (enlarged) HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.33ANDA ANDA Development COMPARISON OF PLACEBO PEAK IN A STANDARD CHROMATOGRAM ACTIVE PEAK Placebo Peak @ 12.82 HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.34ANDA ANDA Development SPECIFICITY (cont.) Separation of Impurities / Degradation Products A mixed solution of Impurities./Degradation products (Dehydroaminoalcohol HCl, Meta-Fluoxetine HCl, Aminoalcohol Base and α,α,α-Trifluoro-p-cresol), including Fluoxetine HCl was prepared in concentration of the nominal concentration and chromatographed under the conditions of the method. It was observed, that all the Impurities/Degradation products are separated each from the other and none of them interfere with Fluoxetine peak. Dehydroaminoalcohol peak was observed in the solvent front. Aminoalcohol peak was not observed in the method conditions. TYPICAL SEPARATION CHROMATOGRAM Dehydroaminoalcohol META-FLUOXETINE PEAK α,α,α-Trifluoro-p-cresol FLUOXETINE PEAK SYSTEMS PEAK HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.35ANDA ANDA Development STABILITY OF STANDARD & SAMPLE SOLUTIONS Standard Solutions Two standard solutions were prepared, kept in the refrigerator for 1 week and compared with two new preparation of standard solutions. Standard No. 1234 Weight (mg)11.3110.6711.1110.59 Preparing Date13.08.9713.08.9720.08.9720.08.97 Response 3477327434863295 35313518 35373452 35143490 34973469 Average3511.232743483.03296 RSD (%)0.7-0.7- Comparison between standards (%) Standard234 11.180.980.25 2-2.171.43 32.17-0.73 HANDBOOK OF GENERIC DRUG DEVELOPMENTANDA DEVELOPMENT SOP # S-230-03-0600 STANDARD OPERATING PROCEDURES Pages: 21. CAPSULES VALIDATION - DISSOLUTION TEST. . Edition No: 02 Effective Date: APPROVED Ed. Status : Current June 2000 _____________ __________ ______________ _________/________ Department R &D RA QC / QA 24 VOLUME DRUG DEVELOPMENT SERIES:Sect: 15.36ANDA ANDA Development Sample Solutions The full method as described in the method was carried-out on the finished product #002 for the 20mg dosage form. The dissolution sample solutions taken from the dissolution cells were allowed to stand for 3 days at refrigerator temperatures and thereafter analyzed. Preparing DateAnalysis Date% DissolutionAverage 26.08.9726.08.9795.298.3 98.6 99.5 98.7 98.8 98.8 26.08.9729.08.9794.797.8 98