Regulatory aspect 112070804011

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Regulatory aspect 112070804011

  1. 1. A SEMINAR ON REGULATORY ASPECTS OF BIOAVALIBILITY AND BIOEQUIVALANCEPREPARED BY Guided By:PARTH PATEL Tanvi PandyaRoll no. 07M. pharm (QA)sem.1 A.P.M.C.COLLEGE OF PHARMACY, HIMMATNAGAR.1
  2. 2. CONTENTS:IntroductionREGULATORY ASPECTS : A.Single-Dose Fasting Study B. Multiple-Dose Fasting Study C. Single-Dose, Three-Way, Crossover, Limited Food Study D. Dissolution Testing REFRENCES2
  3. 3. INTRODUCTION1. BIOAVAILABILITY Bioavailability is a measure of the rate and extent of absorption of the active form or forms of a drug from its formulation as reflected by the concentration - time curve of the administered drug in systemic circulation.3
  4. 4. 2. BIOEQUIVALENCE  Two formulations of a drug are said to be bioequivalent if the rate and extent to which the drug reaches the systemic action after administration of their respective formulations are statistically comparable.3. PHARMACEUTICAL EQUIVALENTS Pharmaceutical equivalents are drug products that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients.4
  5. 5. REGULATORY ASPECTS : A.Single-Dose Fasting Study  Study 1 is conducted as a randomized, single-dose, two- way crossover design in healthy adult volunteers under fasting conditions to compare the generic formulation with the reference listed drug. A sufficient number of subjects must be used to ensure adequate statistical results. Moresubjects may be required for drugs with high intrasubject variability in the extent or rate of absorption.5
  6. 6. The following parameters are reported: area under the curve to the last quantifiable concentration (AUC0-t), area under the curve extrapolated to infinity (AUCINF), peak concentration (CMAX), and time to peak concentration (TMAX).The 90% confidence interval for the ratio between test and reference averages and should be contained within 80-125% of the reference mean.6
  7. 7. B. Multiple-Dose Fasting Study Multiple-dose, steady-state, two-way crossover design comparing the generic extended-release product with the listed drug under fasting conditions. Objective: To demonstrate bioequivalence of generic and listed products at steady state under fasting conditions.7
  8. 8. Fluctuation is calculated in two ways: 1. % fluctuation=(CMAX-CMIN)*100/CMIN. Fluctuation index (FI) = (CMAX-CMIN)/(AUC0-t /τ) The log-transformed AUC0-t and CMAX data are subject to analysis of variance (ANOVA) and their 90% CI values must meet the criteria (80-125% of the reference mean).8
  9. 9. C. Single-Dose, Three-Way, Crossover, Limited Food StudyObjective: To confirm the bioequivalence of the generic extended-release product to the listed drug, to verify the absence of dose dumping of active ingredient from the generic extended-release product and to compare the generic product under fed and fasting conditions.Study design is single-dose, three-way crossover with subjects assigned randomly to all of the six possible dosing sequences.9
  10. 10. Each subject receives the following treatment: 1. Generic extended-release product after a high fat meal 2. Designated listed reference product after a high-fat meal. 3. Generic extended-release product under fasting conditions. A comparable food effects occurs if mean values of AUC and CMAX from treatment 1 and 2 are within ±20%.10
  11. 11. D. Dissolution Testing A dissolution medium consisting of simulated gastric fluid (SGF) without enzyme for 1 h,followed by simulated intestinal fluid (SIF) without enzyme after 1 h. Dissolution testing to be performed over the entire approximate ph range of the gastrointestinal tract, employing distilled water (900 ml ) at 37*C at the following constant Ph ranges:1-1.5, 4-4.5, 6-6.5, 7-7.5.11
  12. 12. For extendedrelease capsules, USP 23 apparatus 1 (basket) is at 100 rpm.For extended release tablets, USP 23 apparatus 2 (paddle) is used at 50 or 75 rpm.If release is less than 80%, dissolution conditions shoud be changed.The range of release at each sampling time should not exceed 30%, with ranges of 20-25% preferred by DBE. 12
  13. 13. REFRENCESGuidelines for bioavailability & bioequivalence studies, Central Drugs Standard Control Organization; New Delhi; March 2005.Pharmaceutical Bioequivalence; Peter G. Welling, Francis L.S. Tse., Marcell Decker; Volume-48.Encyclopedia of Pharmaceutical Technology; edited by James Swarbrick; Vol-I; 3rd edition.13
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