Method Development And Validation Protocol

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Method Development for Dissolution Test of Delayed Release Aspirin Tablet 300mg :

Method Development for Dissolution Test of Delayed Release Aspirin Tablet 300mg QAA303 Group 2, QA06-4

Aspirin:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Aspirin Aspirin is an odourless, colourless, white crystalline powder

Delayed Release Aspirin Tablet 300mg :

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Delayed Release Aspirin Tablet 300mg Generic name: Aspirin (ASA) Brand name: Bayer aspirin, Ecotrin Chemical name: Acetyl salicylic acid Systematic name: 2-acetoxybenzoic acid Dosage form: tablet Coating preparation: enteric-coated Release type: delayed–release

Delayed Release Aspirin Tablet 300mg:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Delayed Release Aspirin Tablet 300mg Molecular formula: CH 3 COOC 6 H 4 COOH Molecular weight : 180.16 Chemical structure:

3D Still Image and Flash:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT 3D Still Image and Flash

Physical and Chemical Properties:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Physical and Chemical Properties Density: 1.40 g/cm³ Melting point: 136 °C Boiling point: 140 °C (decomposes) Solubility in water: 1 mg/ml (20 °C) Specific gravity: 1.35 pKa: 3.48

Pharmacokinetic Properties:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Pharmacokinetic Properties Bioavailability : rapid and complete Protein binding: 99.6% Toxicity: Oral rat LD50: 200 mg/kg Derivation: 2-Hydroxy-Benzoic Acid i.e.Salicylic acid (SA) {Aspirin is rapidly hydrolyzed to salicylic acid}

Salicylic Acid(Degradation Product) :

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Salicylic Acid(Degradation Product) Chemical name: 2-Hydroxybenzoic acid Molecular formula: HOC 6 H 4 COOH Molecular mass: 138.123 g/mol Chemical structure:

Salicylic Acid(Degradation Product):

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Salicylic Acid(Degradation Product) SA structural image is as follows: Melting point: 159 °C Boiling point: 211 °C (2666 Pa) Density: 1.44 g/cm³ (at 20 °C) pKa: 2.97

Strategy in Method Development :

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Strategy in Method Development collect background info.on Aspirin study design of dissolution test method and apparatus choice Specifications to be set up assay method pre-validation consideration of media parameters test on different agitation speeds test on sampling time points determination of the isosbestic points linearity/range verification Precision verification deaeration temperature volume pH value start runs of dissolution test

Assay Method Prevalidation :

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Assay Method Prevalidation Determination of the isosbestic points Linearity/range verification Precision verification Instrumental calibration Repeatability Ruggedness

Determination of Isosbestic Points:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Determination of Isosbestic Points In spectroscopy, an isosbestic point is a specific wavelength at which two (or more) chemical species have the same absorptivity An isosbestic point may be attained by drawing an isosbestic plot at which the absorption spectra of two species cross each other when two print-outs of isosbestic plot s are put together and overridden

Determination of Isosbestic Points:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Determination of Isosbestic Points According to USP 29,Aspirin RS.Salicylic Acid RS, the isosbestic point of ASA and SA is about 280nm in the acid stage,and about 265nm in the buffer stage Verification needs to be made if the isosbestic point falls within 280 + 3nm in the acid stage,and within 265 + 3nm in the buffer stage If not,the validation has to be done

Linearity/Range Verification:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Linearity/Range Verification Linearity is the ability of the method to elicit test results that are directly proportional to analyte concentration within a given range Range is the interval between the upper and lower levels of analyte concentration (inclusive) over which the method shows acceptable linearity, accuracy and precision

Linearity/Range Verification :

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Linearity/Range Verification Range: from 0% to 120% The working concentrations of Aspirin at both acid stage and buffer stage are pre-set as: 1. 40ppm at the acid stage (300mg 10%÷750ml) 2. 300ppm at the buffer stage (300mg ÷1000ml) Calibration Curves of Aspirin RS in 0.1 N HCl solution and the premixed buffer solution to be drawn after the following tests:

Calibration Curve of Aspirin RS in 0.1 N HCl Solution:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Calibration Curve of Aspirin RS in 0.1 N HCl Solution Abs(_nm) sequence Unspiked Aspirin RS solution Reading 1 Reading 2 Reading 3 mean blank 20ppm 25ppm 30ppm 35ppm 40ppm 45ppm 50ppm

Calibration Curve at the Acid Stage :

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Calibration Curve at the Acid Stage Make a series of dilutions of the Aspirin RS stock solution into 20ppm, 25ppm, 30ppm, 35ppm, 40ppm, 45ppm and 50ppm Measure absorbances with a UV/Visible spectrophotometer at the confirmed wavelength of the isosbestic point of ASA and SA Do statistical analysis with linear regression and plot the asymptote of calibration curve Calculate R 2 to verify the linearity/range

Calibration Curve of Aspirin RS in the Premixed Buffer:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Calibration Curve of Aspirin RS in the Premixed Buffer Abs(_nm) sequence Unspiked Aspirin RS solution Reading 1 Reading 2 Reading 3 mean blank 60ppm 110ppm 160ppm 210ppm 260ppm 310ppm 360ppm

Calibration Curve at the Buffer Stage:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Calibration Curve at the Buffer Stage Make a series of dilutions of the Aspirin RS stock solution into 60ppm, 110ppm, 160ppm, 210ppm, 260ppm, 310ppm and 360ppm Measure absorbances with a UV/Visible spectrophotometer at the confirmed wavelength of the isosbestic point of ASA and SA Do statistical analysis with linear regression and plot the asymptote of calibration curve Calculate R 2 to verify the linearity/range

Acceptance Criteria of the Calibration Curves:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Acceptance Criteria of the Calibration Curves The Coefficient of Determination is greater than 0.999 (i.e. R 2  0.999 ) The slope is significantly different from zero (i.e. S  0 ) The intercept is not significantly different from zero (i.e. k close to 0 )

Precision Verification:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Precision Verification System Precision The UV/Vis spectrophotometer used in this project (e.g.Pharmacia Biotech ® Ultraspec 3000 or 2000) needs to be calibrated before daily measurement Repeatability ( inter-assay precision) Ruggedness ( intermediate precision)

Inter-assay Precision at Acid Stage:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Inter-assay Precision at Acid Stage Abs(_nm) sequence Spiked Aspirin RS in 0.1 N HCl Reading 1 Reading 2 Reading 3 Mean % Recovery blank 40ppm 40ppm 40ppm 40ppm 40ppm 40ppm

Repeatability at Acid Stage:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Repeatability at Acid Stage Make 6 replicates of 40ppm Aspirin artificial mixture in 0.1 N HCl solution Measure the absorbances at the plotted wavelength of the isosbestic point Do statistical analysis to verify the inter-assay precision at acid stage

Inter-assay Precision at Buffer Stage:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Inter-assay Precision at Buffer Stage Abs(_nm) sequence Spiked ASA in the premixed buffer Reading 1 Reading 2 Reading 3 Mean % Recovery blank 300ppm 300ppm 300ppm 300ppm 300ppm 300ppm

Repeatability at buffer stage :

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Repeatability at buffer stage Make 6 replicates of 300ppm Aspirin artificial mixture in the premixed buffer Measure the absorbances at the plotted wavelength of the isosbestic point Do statistical analysis to verify the inter-assay precision at buffer stage

Acceptance Criteria of the Inter-assay Precisions:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Acceptance Criteria of the Inter-assay Precisions RSD should be varied within 2%, after statistical calculation and analysis

Ruggedness:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Ruggedness Intermediate precision (Ruggedness) is the ability of the method to withstand changes external to the method It expresses within laboratory variations: different analysts, different equipments, different days, etc.

Samples used in Ruggedness:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Samples used in Ruggedness Acid stage: 40ppm spiked Aspirin RS solution triplicates (Rep.1, Rep.2, Rep.3) Buffer stage: 300ppm spiked Aspirin RS solution triplicates (Rep.1, Rep.2, Rep.3)

Intermediate Precision at Acid Stage:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Intermediate Precision at Acid Stage Abs(_nm) sequence Ultrapec2000 Ultrapec3000 Readings Mean Readings Mean 1 2 3 1 2 3 Blank Analyst 1 Rep.1 Rep.2 Rep.3 Analyst 2 Rep.1 Rep.2 Rep.3

Intermediate Precision at Buffer Stage:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Intermediate Precision at Buffer Stage Abs(_nm) sequence Ultrapec2000 Ultrapec3000 Readings Mean Readings Mean 1 2 3 1 2 3 Blank Analyst 1 Rep.1 Rep.2 Rep.3 Analyst 2 Rep.1 Rep.2 Rep.3

Acceptance Criteria of the Intermediate Precisions:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Acceptance Criteria of the Intermediate Precisions Acid stage : hypothesis tests with two-factor ANOVA would be used to justify if there are significant differences between Analyst 1 and Analyst 2, And between Pharmacia Biotech ® Ultraspec3000 and Ultraspec2000 Buffer stage : hypothesis tests with two-factor ANOVA would be used to justify if there are significant differences between Analyst 1 and Analyst 2, And between Pharmacia Biotech ® Ultraspec3000 and Ultraspec2000

Dissolution Method Development :

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Dissolution Method Development Method and apparatus selection Suitability of dissolution testers Tests on deaerated and non-deaerated media Tests on different agitation speeds Study design on sampling time points Design on the dissolution tests

Method and Apparatus Selection:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Method and Apparatus Selection Apparatus choice (paddle/basket) Method A of USP chapter <724> Volumes of media in Method A 750ml of 0.1N hydrochloric acid is poured into each vessel at acid stage 250ml of 0.2M tribasic sodium phosphate is replenished into every vessel at buffer stage

Test on Degassed and Gassed Media:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Test on Degassed and Gassed Media medium items of observations vessel # deaeration non-deaeration acid stage buffer stage acid stage buffer stage 1 2 1 2 3 4 3 4 An even distribution of tablet particles Tablet clings to the side of the vessel Adhesion of particles to the paddle Coning/mounding of tablet directly under the apparatus Dosage unit settled at the bottom of vessel Air bubbles inside of the vessel or sticky to the apparatus/dosage unit Tablet floats at the surface of medium Dancing/spinning of the dosage unit, or the unit being hit by the paddle

Test on Different Agitation Speeds:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Test on Different Agitation Speeds agitation speed (RPM) observations vessel# 50 123 75 1 2 3 100 123 125 1 23 Even distribution of tablet particles quickly Tablet waving inside the vessel unstably Coning/mounding of tablet under apparatus Dosage unit settled at the bottom of vessel Tablet floats at the surface of medium Dosage unit hit by the paddle

Study Design on Time Points:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Study Design on Time Points Sampling time point(hr’min”) Vessel # 1 Vessel # 2 Vessel # 3 Vessel # 4 Vessel # 5 Vessel # 6 Acid Stage 1’30” 10ml 10ml 10ml 10ml 10ml 10ml 1’40” 10ml 10ml 10ml 10ml 10ml 10ml 1’50” 10ml 10ml 10ml 10ml 10ml 10ml 2’00” 10ml 10ml 10ml 10ml 10ml 10ml Buffer Stage 2’05” 10ml 10ml 10ml 10ml 10ml 10ml 2’10” 10ml 10ml 10ml 10ml 10ml 10ml 2’15” 10ml 10ml 10ml 10ml 10ml 10ml …… 2’45” 10ml 10ml 10ml 10ml 10ml 10ml 2’50” 10ml 10ml 10ml 10ml 10ml 10ml

Acceptance Criteria at Acid Stage :

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Acceptance Criteria at Acid Stage Level # tested Criteria A 1 6 No individual value exceeds 10% dissolved. A 2 6 Average of the 12 units (A 1 + A 2 ) is not more than 10% dissolved, and no individual unit is greater than 25% dissolved. A 3 12 Average of the 24 units (A 1 + A 2 +A 3 ) is not more than 10% dissolved, and no individual unit is greater than 25% dissolved.

Acceptance Criteria at Buffer Stage:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Acceptance Criteria at Buffer Stage Level # tested Criteria B 1 6 Each unit is not less than Q + 5%. B 2 6 Average of 12 units (B 1 +B 2 ) is equal to or greater than Q, and no unit is less than Q – 15%. B 3 12 Average of the 24 units (B 1 +B 2 +B 3 ) is equal to or greater than Q, not more than 2 units are less than Q – 15%, and no unit is less than Q – 25%.

Specifications to Be Set up:

clemfeng yahoo.ca Clement Feng : QA06-4 @TIPT Specifications to Be Set up Testing parameters Acceptance criteria Tolerance Method choice Method A Isosbestic point acid stage buffer stage Apparatus type Apparatus 2 Medium volume acid stage 750 ml buffer stage 1000 ml Agitation speed %Release acid stage <10% in __minutes buffer stage ≥80% in _minutes Apparatus 2: ____ rpm Q≥75% in ____ minutes

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