The document summarizes regulatory aspects of bioavailability and bioequivalence testing for generic drug approval. It discusses single and multiple dose fasting studies, a three-way food effect study, and dissolution testing requirements. The goal is to demonstrate that a generic drug delivers the same amount of active ingredient in the same time period as the reference drug to establish bioequivalence.

1. A SEMINAR
ON
REGULATORY ASPECTS OF
BIOAVALIBILITY
AND
BIOEQUIVALANCE
PREPARED BY Guided By:
PARTH PATEL Tanvi Pandya
Roll no. 07
M. pharm (QA)sem.1
A.P.M.C.COLLEGE OF PHARMACY, HIMMATNAGAR.
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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
REFRENCES
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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.
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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.
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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.
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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.
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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.
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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).
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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.
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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%.
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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.
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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.
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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.
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