9/6/23, 6:15 PM Difference between Bioavailability and Bioequivalence

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Difference between Bioavailability and

Bioequivalence
March 24, 2023

Bioavailability and bioequivalence studies are essential in the regulatory submission of

a new drug product or a generic drug product. Innovator drug product vs Generic drug
product. Studies on bioavailability and bioequivalence are necessary to verify
therapeutic equivalency. Frequently bioavailability and bioequivalence rely on
pharmacokinetics measures such as Area under the Curve (AUC) to assess the extent
of systemic exposure and Cmax and Tmax to assess the rate of systemic absorption. You
may read: Generic name of drugs, Brand name of Drugs, Generic drug/ medicine,
Brand name drug/medicine

Table of Contents

Definition of Bioavailability vs Bioequivalence

According to USFDA, Bioavailability is the rate and extent to which the active ingredient
or active moiety is absorbed from a drug product and becomes available at the site of
action [1].

According to EMA, The rate and extent to which a substance or its active moiety is
delivered from a pharmaceutical form and becomes available in the general circulation
(taking into consideration that the substance in the general circulation is in exchange
with the substance at the site of action).

Also, according to WHO, The rate and extent to which the active moiety is absorbed
from a pharmaceutical dosage form and becomes available at the site(s) of action.
Dose, Dosage, Dosage Form, and Dosage Regimen.

Whereas, according to USFDA, Bioequivalence means 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

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9/6/23, 6:15 PM Difference between Bioavailability and Bioequivalence

site of drug action when administered at the same molar dose under similar conditions
in an appropriately designed study [1].

A short expression of Bioavailability vs Bioequivalence

BA or F is a short expression of bioavailability. BE is a short expression of

bioequivalence.

Which application type requires a BA or BE?

Bioavailability (BA) information of a drug product is essential for Investigational New

Drug Application (IND), New Drug Application (NDA), and NDA supplements [2].

On the other hand, a bioequivalence study with pharmacokinetic endpoints of a drug

product is essential for Abbreviated New Drug Application (ANDA [3].

The Main focus of Bioavailability vs Bioequivalence

Studies on bioavailability concentrate on figuring out how and when a drug substance
escapes from the oral dosage form and reaches the site of action.

On the other hand, bioequivalence studies focus on the performance of the drug
product and usually involve comparisons of two drug products: T and R. Here T is the
test product. In the United States, R is termed the RLD. In the WHO document, R is
termed the “comparator pharmaceutical product” (CPP) [5].

Reference product for Bioavailability vs Bioequivalence

Generally, for the bioavailability study of a new drug product, the reference product
should be a solution, suspension, or intravenous (IV) dosage form of the new drug.
Conducting a BA study with an intravenous (IV) reference product enables assessment
of the impact of the route of administration on BA and defines the absolute BA of the
drug released from the drug product. Conducting a BA study comparing one
formulation to another enables an assessment of relative BA.

Whereas, for the bioequivalence study of a generic drug product, the reference product
should be the innovator drug product or reference listed drug. BE study is to measure
and compare formulation performance between two or more drug products. However,

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in the case of bioequivalence studies of a new formulation of an innovator drug

product, the reference product should receive approval. For regulatory approval of a
generic drug product (test product, T) must be bioequivalent to the Reference listed
drug product R.

What are the objectives of Bioavailability vs Bioequivalence?

Objectives of Bioavailability [2, 6]

1. Bioavailability data provide an estimation of the fraction of the drug absorption,

distribution, metabolism, excretion, and the effects of food on the absorption of
the drug, dose proportionality, or linearity in the pharmacokinetics of the active
moieties and when appropriate inactive moieties.
2. BA provides useful information to establish dosage regimens and to support
drug labeling, such as distribution and elimination characteristics of the drug.
3. Bioavailability of drug products aids in the FDA’s evaluation of the safety and
effectiveness of a product in IND, NDA, or NDA supplements.

Objectives of Bioequivalence [3, 6]

1. To measure and compare formulation performance between two or more drug

products.
2. Bioequivalence provides a link between pivotal and early clinical trial
formulation.
3. To determine the therapeutic equivalence between the pharmaceutical
equivalence generic drug product and a corresponding reference listed drug.
4. For an innovator drug product, bioequivalence studies establish the performance
of the new formulation product intended for marketing with an already approved
innovator drug product to evaluate the safety/efficacy of the new formulation
drug product. Efficacy vs Potency.
5. To provide information on product quality and performance when there are
changes in components, composition, and method of manufacture after approval
of the drug product.

Measurement of Bioavailability vs Bioequivalence

Measurement of Bioavailability

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9/6/23, 6:15 PM Difference between Bioavailability and Bioequivalence

Bioavailability is an indirect or surrogate measure of the rate and extent to which the
drug substance or active moiety is absorbed from a drug product and becomes
available at its target sites of action. Bioavailability is measured by using three main
pharmacokinetic variables:

The area under the blood drug concentration versus time curve (AUC)
The maximum blood concentration (Cmax)
The time to reach maximum concentration (Tmax)

Measurement of Bioequivalence

On the other hand, Bioequivalence (BE) is a surrogate measure of in vivo drug product
performance, and dissolution profile comparisons as a measure of in vitro drug product
performance. BE has been established via bioavailability testing. Bioequivalence is
measured based on the relative bioavailability of the innovator drug product versus the
generic drug product.

It is important to note that bioequivalence studies are also performed for innovator drug
products in some situations such as: between early and late clinical trial formulations;
between formulations used in clinical trials and stability studies, if different; or between
clinical trial formulations and to-be-marketed drug products, if different; or between
equivalence of product strengths; between marketed innovator product and a new
formulation of marketed innovator product (change in one or more excipients).

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Bioequivalence is based on a comparison of ratios where the ratio of generic to

innovator for each pharmacokinetic variable does not differ by more than 8:10, this is
how the range for the confidence intervals is defined: 8/10 = 0.80 gives the lower limit
and 10/8 = 1.25 gives the upper limit. The 90% confidence intervals for the ratios of
[4]
both Cmax and AUC should be contained within the limits of 0.80–1.25 . The FDA
considers two products bioequivalent if the 90% confidence intervals (CI) of the relative
mean Cmax, AUC (0–t), and AUC (0–∞) of the test (e.g. generic drug product) to RLD
(e.g. innovator drug product) should be within 80% to 125% in the fasting state. [1].

Nature of Study

Bioavailability studies are expletory. Whereas, bioequivalence studies are a

confirmatory or statutory term that requires ANDA applicants to demonstrate, among
other things, that the proposed generic product is bioequivalent to its reference listed
drug.

The interrelation between bioavailability and bioequivalence

Bioavailability is not been assessed via bioequivalence testing. Bioavailability is

assessed using three main pharmacokinetic variables

The area under the blood drug concentration versus time curve (AUC)
The maximum blood concentration (Cmax)
The time to reach maximum concentration (Tmax)

On the other hand, bioequivalence is assessed via bioavailability testing.

Example of Bioavailability vs bioequivalence

Examples of Bioavailability: after oral administration of 20 mg of Rabeprazole

Sodium Delayed-Release tablet, 52% of this drug is absorbed unchanged
systematically as compared to intravenous administration. So, the absolute
bioavailability of this drug product is 52% [7].

Examples of bioequivalence: two medicines are bioequivalent if there is no clinically

significant difference in their bioavailability. Based on the bioequivalence studies under
fasting and fed conditions, Idiazole, Rabeprazolnatrium, and Rodesa 20 mg tablets are
bioequivalent with Pariet 20 mg. Here, Idiazole, Rabeprazolnatrium, and Rodesa 20 mg

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9/6/23, 6:15 PM Difference between Bioavailability and Bioequivalence

tablets are the generic drug product. Pariet is the RLD of Rabeprazole Sodium Delay
Release tablet in the UK and Australian markets and Aciphex is the RLD of
Rabeprazole Sodium Delay Release tablet for the US market.

Summary of the difference between bioavailability and

bioequivalence

Features Bioavailability Bioequivalence

Bioequivalence means the

Bioavailability is the rate and
extent to which the active
ingredient or active moiety is
Definition
absorbed from a drug product
and becomes available at the
site of action.
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.

Short
BA or F BE
expression

Investigational New Drug

Application (IND), New Drug Abbreviated New Drug Application
Require for
Application (NDA), and NDA (ANDA
supplements.

On determining the process On the performance of the drug

and time frame by which a product and usually involve
Main focus drug substance is released comparisons of two drug products:
from the oral dosage form and T (test product) and (Innovator
moves to the site of action. drug product or RLD).

Reference A solution, suspension, or Innovator drug product or

product intravenous (IV) dosage form reference listed drug (RLD).

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9/6/23, 6:15 PM Difference between Bioavailability and Bioequivalence
of the new drug.
A. Bioavailability data provide
an estimation of the fraction of
the drug absorption,
distribution, metabolism,
excretion, and the effects of
food on the absorption of the
drug, dose proportionality, or
linearity in the
pharmacokinetics of the active
moieties and when
appropriate inactive moieties.
Objectives
B. BA provides useful
information to establish
dosage regimens and to
support drug labeling, such as
distribution and elimination
characteristics of the drug.
C. Bioavailability of drug
products aids in the FDA’s
evaluation of the safety and
effectiveness of a product in
IND, NDA, or NDA
supplements.
Measurement Bioavailability is an indirect or
surrogate measure of the rate
and extent to which the drug
substance or active moiety is
absorbed from a drug product
and becomes available at its
target sites of action.
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A. To measure and compare
formulation performance between
two or more drug products.
B. Bioequivalence provides a link
between the pivotal and early
clinical trial formulation.
C. To determine the therapeutic
equivalence between the
pharmaceutical equivalence
generic drug product and a
corresponding reference listed
drug.
D. For an innovator drug product,
bioequivalence studies establish
the performance of the new
formulation product intended for
marketing with an already
approved innovator drug product to
evaluate the safety/efficacy of the
new formulation drug product.
E. To provide information on
product quality and performance
when there are changes in
components, composition, and
method of manufacture after
approval of the drug product.
Bioequivalence (BE) is a surrogate
measure of in vivo drug product
performance and dissolution profile
comparisons as a measure of in
vitro drug product performance. BE
has been established via
bioavailability testing.
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Bioavailability is measured by Bioequivalence is measured based

using three main on the relative bioavailability of
pharmacokinetic variables: the innovator drug
AUC, Cmax, Tmax. product versus the generic drug
product.

Nature of
Expletory study Confirmatory or statutory study
Study

Not assesse via

Interrelation Assess via bioavailability testing.
bioequivalence testing.

Based on the bioequivalence

studies under fasting and fed
After oral administration of 20
conditions, Idiazole,
mg of Rabeprazole Sodium
Rabeprazolnatrium, and Rodesa
Delayed-Release tablet, 52%
20 mg tablets are bioequivalent
of this drug is absorbed
with Pariet 20 mg. Here, Idiazole,
Examples unchanged systematically as
Rabeprazolnatrium, and Rodesa
compared to intravenous
20 mg tablets are the generic drug
administration. So, the
product. Pariet is the RLD of
absolute bioavailability of this
Rabeprazole Sodium Delayed-
drug product is 52%.
Release tablet in the UK and
Australia markets.

References

1. Center for Drug Evaluation and Research (2003). “Guidance for Industry:
Bioavailability and Bioequivalence Studies for Orally Administered Drug Products –
General Considerations”. United States Food and Drug Administration.

2. Center for Drug Evaluation and Research (2003). “Guidance for Industry:
Bioavailability Studies Submitted in NDAs or INDs — General Considerations”.
United States Food and Drug Administration.

3. Center for Drug Evaluation and Research (2003). “Guidance for Industry:
Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under

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9/6/23, 6:15 PM Difference between Bioavailability and Bioequivalence

an ANDA — General Considerations”. United States Food and Drug Administration.

4. Birkett D. Generics – equal or not? Australian Prescriber, 2003(26):85-7.

5. WHO Guidance for organizations performing in vivo bioequivalence studies. WHO

Technical Report Series No. 996, 2016, Annex 9

6. United States Pharmacopeia and National Formulary (USP 43–NF 38). United
States Pharmacopeial Convention; 2020. Accessed January 01, 2021.

7. Highlights of prescribing information of ACIPHEX® (rabeprazole sodium) Delayed-

Release Tablets. Eisai Inc. Retrieved 27 February 2021.

Pharma Difference
Difference between Packing and Packaging
AUC in Pharmacokinetics

DIFFERENCES

Difference between Bioavailability and Bioequivalence

Difference between Packing and Packaging

Difference between Signs and Symptoms

Difference between Drug Design and Drug Development

IV Bolus vs IV Infusion of Parenteral Drug Product

Difference between Compression and Compaction of Tablets

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......................................................................................................

TECHNOLOGY

Friability Test of Tablets, Granules, Spheroids

Quality control tests of tablets or Evaluation of tablets

Tablet Compression Machine: Types, Functional Parts

Excipients for Tablets with examples

Colouring Agents, Colorants, Color Additives in Pharmaceutical

Tablet Coating Defects and Remedies

Examples of suspension (Pharmacy, Chemistry, Food)

Tablet defects

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Vitamin, Pro-vitamin, Antivitamin

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