5. Equivilence
It is a relative term that compares drug products with
respect to a specific characteristic or function or to a
defined set of standards
Definition
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Chemical equivalence
It indicates that two or more drug
products contain the same
labelled chemical substance as
an active ingredient in the
same amount.
+
Definition
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The FDA (USP DIB Volume III) defines the term as:
Drug products are considered pharmaceutical
equivalents if they contain the same active
ingredient(s), are of the same dosage form, route of
administration and are identical in strength or
concentration (for example chlordiazepoxide
hydrochloride, 5 mg capsules)
(USP DIB Volume III)
Pharmaceutical equivalent
Pharmaceutical equivalent product
Possible differences
Excipients, drug particle size,
manufacturing site, equipment, batch size
etc.
Reference
product
Test
product
Definition
9. Pharmaceutical Equivalents
Test Reference
Possible Differences
Drug particle size
Excipients
Manufacturing
Equipment or
Process
Site of
manufacture
Could lead to differences in product performance
in vivo
Possible Bioinequivalence
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Bioequivalent
The rate and extent of absorption of the test drug
do not show a significant difference from the
rate and extent of absorption of the reference
drug when administered at the same molar
dose of the therapeutic ingredient under
similar experimental conditions in either a
single dose or multiple doses.
(USP DI® Volume III):
Definition
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Therapeutic
equivalent
The FDA classifies as
therapeutically equivalent those
products that meet the following
general criteria:
This term indicates that two or more drug
products that contain the same
therapeutically active ingredient elicit
identical pharmacological effects and can
control the disease to the same extent.
+
Definition
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Biopharmaceutical
classification system
BCS
The BCS is a scientific framework for classifying
drug substances based on their aqueous
solubility and intestinal permeability. When
combined with the dissolution of the drug
product, the BCS takes into account three major
factors that govern the rate and extent of drug
absorption from IR solid oral dosage forms.
Definitions
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Drug
bioavailability
Bioavailability refers to the extent and
rate at which the active moiety (drug
or metabolite) enters systemic
circulation, thereby accessing the site
of action
Definitions
16. Path of drug: From tablet
to blood
(Bioavailability)
• Drug move from oral cavity direct into
blood(sublingual tablets) or move to
stomach
• In stomach drug will disintegrate and then
move towards small intestine having basic
pH
• In small intestine, the drug will absorb and
move towards liver by HPV and then
become the part of systemic circulation
17. Scheme of Oral Dosage Form
Oral Bioavailability(%F)
Human Intestinal
Absorption(HIA)
1,2 – Stability + Solubility 3
– Passive + Active Tr.
4 – Pgp efflux + CYP 3A4
18. Purpose of Bioavailability Studies
• To ensure safety of the drug
• To ensure efficacy of the drug
• To establish recommended dosage regimen.
• To define the effect of changes in the physicochemical properties of
the drug substance, the formulation of the drug, and the
manufacture process of the drug product (dosage form).
• To establish the effect of food on the pharmacokinetics of drugs.
• To provide indirect information regarding the presystemic and
systemic metabolism and the role of drug transporters
19. WHEN BIOAVAILABILITY AND
BIOEQUIVALENCE TESTING IS ESSENTIAL?
For new indication
For new dosage regimen or dosage
strength
For new formulations
A
B
C
For new dosage form
For new salt or ester of a drug.
For all new molecules
A
B
C
For a change in the manufacturing
process of the drug or drug product.
C
For administration in special
population, e.g. pediatrics
C
20. 06
01
02
03
04
05
To evaluate absolute
bioavailability of dosage
form compared to with
reference dosage form
To determine if equipotent drug
treatments administered at
different dose strength of the
market form produce equiva ent
drug bioavailability,
To determine if
bioavailability parameters
are linear over proposed
dosage range
Intervention study to
examine effect of food
and other factors
Inter/intra subject
variability
Bioequivalence stucy
reeded as a result of
changes in theformulation
or manufacturing
processes.
Importance of bioequivalence study
21. Important for post-
approval changes in the
marketed drug
formulation
Important for linking the
commercial drug product
to clinical trial material at
time of NDA
Establish that the new
formulation has
therapeutic equivalence
in the rate and extent of
absorption to the
reference drug product
Goals of bioequivalence
22. Plasma drug
concentration
Urinary drug excretion
In vivo pharmacodynamic (PD)
comparison
Clinical endpoint study
In vitro binding studies
IN VIVO MEASUREMENT OF
ACTIVE MOIETY OR MOIETIES
IN BIOLOGICAL FLUIDS
03
02
01
04
05
23. 1- PLASMA DRUG CONCENTRATION
The most direct and objective
way to determine systemic drug
bioavailability.
27. Parameters
2- URINE DRUG EXCRETION DATA
• Urinary drug excretion data is
an indirect method for
estimating bioavailability. The
drug must be excreted in
significant quantities as
unchanged drug in the urine.
Cumulative amount of
drug excreted in the
urine (Du)
Rate of drug
excretion in the
urine (dDu/dt)
Time for maximum
urinary excretion (t)
2
1 3
28. 3-
In
vivo
pharmacodynamic
comparison • If the quantitative measurement of a drug in plasma is not
available or in vitro approaches are not applicable, then
pharmacodynamic (PD) effects are monitored. A dose-
response relationship is demonstrated.
• Sufficient measurements should be taken to assure an
appropriate PD response profile
30. 4 This approach may be
considered acceptable only
when analytical methods
cannot be developed to permit
use of one of the other
approaches
2- The FDA considers this approach
only when analytical methods and
pharmacodynamic methods are not
available to permit use of one of the
approaches described above
3- recommended for
those products that have
negligible systemic
uptake
1- the least accurate, least
sensitive to
bioavailability
differences, and most
variable
4- Clinical endpoint study
31. Option 3
Option 4
Option 1
Option 2
4- For drugs whose dissolution rate
is related to the rate of systemic
absorption, the test formulation that
demonstrates the most rapid rate of
drug dissolution in vitro will
generally have the most rapid rate of
drug bioavailability in vivo.
3- Comparative dissolution
profiles may be considered
similar if the similarity factor
(f2) is greater than 50..
2- Ideally, the in vitro drug dissolution rate
should correlate with in vivo drug
bioavailability (in vivo-in vitro correlation,
IVIVC).
1- Comparative drug
release/dissolution studies under
certain conditions may give an
indication of drug bioavailability
and bioequivalence
5- IN VITRO STUDIES
32. LOREM IPSUM
Potential Situations where an In Vitro BE
Determination May be of Use
Generic drug
applications
1
When the innovator
wishes modify an
existing formulation
2
When BE needs to be
determined for a
combination drug product
where one component is
systemically absorbed and
the other is a locally acting
compound
3
33. IVIVC is the predictive, mathematical models
relating an in-vitro property such as
dissolution and an in-vivo response, e.g.,
amount of drug absorbed, thus allowing an
evaluation of the QC specifications, change
in process, site, formulation and application
for a biowaiver etc. –
US FDA
IVIVC
35. Dissolution profile comparison
The test and reference products for
which in vitro release rates form
the basis of the bioequivalence
usually demonstrate Q1/Q2
sameness (qualitatively same
inactive ingredients in the
quantitative same amounts).
Comparative
dissolution studies
are often performed
on several test
formulations of the
same drug during
drug development.
Comparative dissolution
profiles may be
considered similar if
the similarity factor
(f) is greater than 50
1 2 3
36.
37. 1 2
To Develop in-vitro in-
vivo correlation which
can help to reduce
costs, speed-up
product development
and reduce the need
to perform costly
bioavailability human
volunteer studies
Establish the similarity of
pharmaceutical dosage
forms, for which
composition, manufacture
site, scale of manufacture,
manufacture process and/or
equipment may have
changed within defined
limits
Objective of dissolution profile Comparison
38. Example
For the acyclovir topical ointment, recommended
BE approaches consist of comparative in vitro
release testing and physicochemical
characterization
(US-FDA, CDER, 2012b).
Any other approach deemed acceptable (by the FDA)
• The FDA may also use in vitro
approaches other than comparative
dissolution for establishing
bioequivalence.
• The FDA accepts various other in
vitro approaches for BE
assessment of proposed generic
locally acting drug products.
40. The nature of the
reference material and
the dosage form to be
tested
The availability of
analytical methods
The route of drug
administration
The pharmacokinetics
and pharmacodynamics
of the drug substance
The scientific questions
and objectives to be
answered
Benefit-risk and ethical
considerations with
regard to testing in
humans.
01
02
03
04
05
06
BE Study
considerations
42. 1- Analytical methood
2- Pharmacokinetic
evaluation of data
3- Statistical evaluation of data
4- Analysis of variance
Evaluation of bioequivalence studies
45. 1-Crossover study design
1. Complete crossover design is usually employed, in which each subject receives
the test drug product and the reference product.
2. In this design, each subject is his own control, and subject-to-subject variation is
reduced.
3. The order in which the drug treatments are given should not stay the same in
order to prevent any bias in the data due to a residual effect from the previous
treatment.
4. In two-period study is a study that is performed on two different days (time
periods) separated by a washout period during which most of the drug is
eliminated from the body-generally about 10 elimination half-lives.
47. 2- Replicated crossover study design
1. The standard bioequivalence
criterion using the two-way crossover
design does not give an estimate of
within-subject
(intrasubject)variability.
2. By giving the same drug product
twice to the same subject, the
replicate design provides a measure
for within-subject variability•
Replicate design studies may be used
for highly variable drugs and for
narrow therapeutic index drugs.
3. Replicated crossover designs are used
for the determination of individual
bioequivalence, to estimate within-
subject variance for both the test and
reference drug products, and to
provide an estimate of the subject by
formulation interaction variance.
49. 3- Parallel study design
1. Multiple doses of the
same drug are given
consecutively to reach
steady-state plasma. In
this design, two separate
groups of volunteers are
used. One group will be
given the test product
and the other group will
be given the reference
product.
2. multiple-dose study is
designed as a steady-
state, randomized, two-
treatment, two-way,
crossover study
comparing equal doses
of the test and reference
products in healthy
adult subjects.
3. The area under the
curve during a dosing
interval at steady state
should be the same as
the area under the curve
extrapolated to infinite
time after a single dose.
51. 4- Multiple dose study design
1. A non-replicate, parallel depot
injections in which the drug is slowly
released over weeks or months design
is used for drug products that contain
drugs that have a long elimination
half-life or drug products such as
2. In this design, two separate groups of
volunteers are used. One group will
be given the test product and the
other group will be given the
reference product.
3. Blood sample collection time should
be adequate to ensure completion of
gastrointestinal transit
(approximately 2-3 days) of the drug
product and absorption of the drug
substance.
4. This design is not recommended for
drugs that have high intrasubject
variability in distribution and
clearance.
52. AUC Cmax Cav
tmax Cmin
Degree of
fluctuation
PK analyses for multiple for multiple dose structured
studies includes calculation of following parameters for
each subject
53. Biowaivers
In some cases, in vitro dissolution testing may be used in
lieu of in vivo bioequivalence studies. When the drug
product is in the same dosage form but in different
strengths and is proportionally similar in active and
inactive ingredients, an in vivo bioequivalence study of
one or more of the lower strengths can be waived bases
on dissolution testing and an in vivo bioequivalence
study on highest strength.
54. An acceptable BE study is
conducted on at least one
strength.
.The strength(s) for which
the biowaiver sought should
be proportionally similar to
the strength on which BE
wasdemonstrated.
Acceptable in vitro
dissolution should be
demonstrated for the
strength(s) for which the
biowaiver is sought.
01 02 03
Regulatory perspective for biowaivers
55. appropriate in vitro
dissolution data should
confirm the adequacy of
waiving additional in vivo
bioequivalence testing
qualitative composition
of the different strengths
is the same
composition of the
strengths are quantitatively
proportional,
Products are manufactured
by the same manufacturing
process
General requirements must be met where a
waiver for additional strength(s) is claimed
58. ‘
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Patent
• Protects the investment of the drug
company that developed the brand-
name drug
• Gives the drug company the sole right
to sell the drug while the patent is in
effect
Definition
59. ‘
When the patent on a brand-name drug
nears expiration, drug companies that want
to manufacture a generic can apply to FDA
to sell a generic version of the drug
Patent protection
60.
61. CREDITS: This presentation template was created by
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Thanks!
Do you have any questions?
62. ● Leon Shargel; Andrew B.C Yu, Applied
Bio pharmaceutics ar
pharmacokinetics, Fourth edition,pp
256-271.•
● D.M.Brahmankar, Sunil b. jaiswal,
Biopharmaceutics and
Pharmacokinetics, A Treatise, second
edition, vallabh prakashan,pp336-344..
References
