Bioequivalence and drug product assessment PDF/ PPT

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Submitted by: Gaurav, M.Pharma 1st sem

(Department of pharmaceutics)

Jamia hamdard



 Introduction
 Objectives
 Definition
 Need of bioequivalence
 Type of equivalence
 Need of in vivo studies
 Statistical evaluation of bioequivalence data
 Design and evaluation of bioequivalence
 Types of evidence to establish bioequivalence
 Evaluation of data
 Biowaivers


 Bioavailability and bioequivalence studies

provides important information in overall
set of data that ensure availability of safe
and effective medicines.

 The concept of bioavailability and
bioequivalence have gained during the last
three decades.

 Now it is very important for approval of
brand name and generic drug worldwide


 The most important objective is to

measure and compare the formulation
performance between two or more
pharmaceutically equivalent drug


By United State Food And Drug Administration(FDA): the absence

of a significant difference in the rate and extent to which the
active ingredient or active moiety in pharmaceutical equivalents
or pharmaceutical alternatives becomes available at the site of
drug action when administered at the same molar dose under
similar conditions in an appropriately designed study.

By World Health Organization (WHO):
Two pharmaceutical products are bioequivalent if they are
pharmaceutically equivalent or pharmaceutical alternatives, and
their bioavailabilities, in terms of rate (Cmax and tmax) and
extent of absorption (area under the curve), after administration
of the same molar dose under the same conditions, are similar
to such a degree that their effects can be expected to be
essentially the same


Need of bioequivalence

 The need of bioequivalence studies is increasing
due to the large growth of the production and
consumption of generic product

 Bioequivalence studies are conducted if there is :

 A risk of bio inequivalence or

 A risk of pharmacotherapeutic failure

 No clinical studies have been performed in patient
with the generic product to support its efficacy and


Types of equivalence
1. Chemical equivalence

Two or more drug product contain same labelled chemical in a same

2. Pharmaceutical equivalence
Two or more drug are identical in strength, quality, purity, content

uniformity, disintegration and dissolution
3. Therapeutic equivalence

Indicate that two or more drug product that contain the same
therapeutically active ingrediant elicit identical pharmacological effect
and control the disease to the same extent

4. Bioequivalence
It is a relative term which denotes that the drug substance in two or more

identical dosage form, reches the systemic circulation at the same
relative rate and relative extent


Need of in vivo studies
 Oral immediate release product with

systemic action

Narrow therapeutic margin

 Modified release product with systemic

 Non oral immediate release product


Statistical evaluation of
bioequivalence data
 Statistical evaluation studies is based on analysis

of drug blood or plasma concentration.

 Area under the plasma conc. v/s time curve (AUC)
is used as an index of extent of drug absorption.

 In the early 1970s, approval was based on mean
data. Mean AUC and Cmax values for the generic
product had to be within 20% of those of the
brand- name product.


Design and evaluation of
bioequivalence studies
Study designs

Food intervention Multiple dose
Fasting study

study study

• Use for • Co-administration • Multiple dose,
immediate of food with an randomized,
release and oral drug product crossover study
modified release may affect the • Three
oral dosage form bioavailability of consecutive

• Overnight fast drug trough
and 4 hour after concentration on
dosing three consecutive



Type of design

1. Complete randomized design
All treatment are randomly allocated among all

experimental subject
example: if there is 20 subjects, number them from 1 to

20. Random select non repeating number

1. Easy design
2. Can accommodate any number of treatment and



 Disadvantages
All subject must be homogenous

2. Randomized block designs
Subjects are sorted into homogenous group called

Subjects having similar background characteristics are

formed as blocks


 Different treatment not need equal

sample size
 Can accommodate any number of

 Statistical analysis is relatively simple
 degree of freedom is less


3.Repeated measured, cross
over, carry over design
 Randomised block design
 Administration of two or more treatment one after the other is

specified or random order to the same group of patient is called
crossover design or change over design

1. Good precision for comparing treatments

2. Economic on subjects
1. Order effect which is connected with the position in the

treatment order
2. Carry over effect


Crossover parallel design
• A Parallel design is completely randomized

design in which each subject receive one
and only one formulation of the drug in a
random fashion.

• The simplest parallel design is two group
Parallel design , which compares two
formulation of the drug

• Each group contain equal number of


Crossover studies

Randomized complete block design of
two subjects receiving four

Subjects Period 1 Period 2

1 T S

2 S T


 Randomized complete block design of
six subjects receiving four

Subject Period 1 Period 2 Period 3 Period 4

1 B C A D

2 D C A B

3 B C D A

4 D C B A

5 C D A B

6 D C B A


Replicated cross over design

Use for determination of individual


Latin square design



Types of evidence to establish
bioequivalence in descending order of accuracy,

sensitivity, and reproducibility
 In vivo measurement of active moiety or

moieties in biologic fluid;
 In vivo pharmacodynamic comparison;
 In vivo limited clinical comparison;
 In vitro comparison;
 Any other approach deemed appropriate by



Evaluation of data
 Analytical data

Analytical method for measurement of drug
must be validated for accuracy, precision,
sensitivity and specificity.
More then one method during
bioequivalence study may not be valid
because different methods may yield
different values.


Dosage Drug in
Gut wall

Form solution

Therapeutic Site of
effect activity Blood

Pharmacokinetic measurements


o The term Biowaiver is applied to a drug regulatory approval

process when a dossier (application) is approved based on the
evidence of Bioequivalence.

o The biowaiver means that the in vivo bioavailability and
bioequivalence studies may be waived (i.e not necessary for the
product approval)

o In 1995 , US department of Health and Human Services , and
US-FDA started the Biopharmaceutical Classification System ,
with the aim of granting so called Biowaivers for SUPAC.

o Applicant can request biowaiver for immediate release product
based on an approach termed the biopharmaceutics
classification system BCS (32).


 The BCS is a framework for classifying drug substances based on
solubility and intestinal permeability.

 The BCS classifes drug substances as:


 Biopharmaceutics and pharmacokinetics by D.M.



 Shargel.L, Kanfer.I, Generic drug product
development (solid dosage form), Scale up, post-
approval changes and post-marketing surveillance
page no.227