BIOEQUIVALAENCE STUDIES

PRESENTED BY
B.KAVITHA,
PHARMACEUTICS,
M.PHARMACY 1ST YR ,1stSEM
13031SO304
CPS,IST,JNTUH 13031S0304

EQUIVALENCE
PHARMACEUTI
CAL
EQUIVALENCE
THERAPEPEUTI
C
EQUIVALENCE
CHEMICAL
EQUIVALENCE

 Bioequivalence is a relative term which denotes that
the drug substance in two or more identical
DOSAGE FORMS reaches the systemic circulation
at the same relative rate and to the same relative
extent

Pharmaceutical Equivalent
Products
Reference Test
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence

IMPORTANT PHARMACOKINETIC PARAMETERS
AUC:
area under the concentration-time curve
 measure of the extent of absorption
Cmax:
the observed maximum concentration of a drug
 measure of the rate and extent of absorption
tmax:
time at which Cmax is observed
 measure of the rate of absorption

INVITRO
INVIVO
DISSOLUTION STUDIES
PHARMACOKNETIC
AND
PHARMACODYNAMIC
METHODS

 CRITERIA
 Oral Immediate Release products
Critical use medicines
Narrow therapeutic range drug products
Documented BA or BE problems related to API
Non-oral, non-parenteral products designed to act
systemically
 Non oral immediate release products
 Oral Modified Release products

PHARMACO
KINETIC
METHODS
PLASMA LEVEL
TIME STUDIES
URINARY
EXCRECTION
STUDIES
PHARMACO
DYNAMIC
METHODS
ACUTE PHARMA
COLOGICAL
RESPONSE
THERAPEPEUTIC
RESPONSE
INVIVO
STUDIES

PLASMA LEVEL TIME
STUDIES
URINARY EXCRETION
STUDIES
 This method is based on
the assumption that two
dosage forms which
exhibit super imposable
plasma level time profiles
result in identical
therapeutic activity
 C max ,tmax ,AUC are
determined
the principle that urinary
excretion of unchanged
drug is directly
proportional to plasma
concentration of drug
 (dXu/dt) max, ( tu )max,
( Xu )max are determined

Comparative
PD studies
Not recommended when:
In case of local action/
no systemic absorption
- active ingredient is absorbed into the
systemic circulation
- pharmacokinetic study can be
conducted

ACUTE
PHARMACOLOGICAL
METHOD
THERAPEUTIC RESPONSE
METHOD
 In this method acute
pharmacological effect
like ECG,EEG readings is
related to time course of a
given drug
observing the clinical
response to a drug
formulation given to
patients suffering from
disease for which it is
intended to be used

CRITERIA
 If the drug product differs only in strength of API
 If the product meets the following criteria
 Product in the form of solution
 If product contains no excipients which significantly
affect the absorption of API
 Product intended for topical administration for
topical effect

 It is an exemption granted by USFDA from
conducting human BE studies when API meets
certain solubility and permeability criteria
 It is an alternative to in vivo pharmacokinetic BE
Studies

BCS APPROACH FOR BIOWAIVERS
According to BCS
classification
CLASS 1
CLASS 2
CLASS 3
CLASS 4
 Highly soluble , highly
permeable
 Low soluble, high permeable
Dissolution rate limited
 Highly soluble , low permeable
Permeability rate limited
 Low solubility and low
permeability

 Biowaivers uses class 1 and class 3 drugs
 Drugs should be Highly soluble and highly
permeable
 Highest dose strength should be soluble in 250ml
aqueous solution over a pH 1-7.5 at 37۫ oC
 90% of the administered oral dose should be
absorbed
 80% of the drug should dissolve with in 15min at
37 oC

 BIOWAIVERS reduce the need for establishing in
vivo BE When in vitro data provides reasonable
estimate of relative in vivo performance of two
products
 Serves as an alternative to in vivo pharmacokinetic
BE studies

 Drugs with rapid and similar dissolution
 Drugs with high therapeutic window
 Parenterally administered drugs
 If new drug is solution
 If new drug is powder for reconstitution as
solution
 If drug is in gaseous form

1. Title
2. Study objective
3. Study design
4. Study population
5. Bio analytical methods
6. Ethical considerations
7. Facilities
8. Statistical data analysis

Investiga
tor
details
Laborato
ry
details
Sponser
details
Protocol
number
Version
number

 Objective of Bioequivalence study is to compare the
test formulation with reference to standard

Basic design considerations:
minimize variability not
attributable to formulations
goal: compare performance
2 formulations
minimize bias

 Design method
 Drug product
 Dosage regimen
 Sampling
 Fasting schedule
Test
Reference
Single dose
Multiple dose

Completetly randomised design
Randomised block design
Cross over designs
Latin square design

 All the treatments are randomly allocated among all
experimental subjects
ADVANTAGES DISADVANTAGES
1.Easy to construct
2.Can accommodate any
number of treatments and
subjects
Subjects must be
homogeneous

 Subjects are sorted in to homogenous groups called
BLOCKS
 Treatments are then assigned at random with in the
blocks

ADVANTAGES
DISADVANTAGES
1.More precise results than
completely randomized design
2. Easy to construct
3. Simple statistical analysis
Missing observations with in a
block require more statistical
analysis

 It is randomized block design in which same subject
serves as a block
 Administration of two or more treatments one after
the other in a specified or random order to the same
group of patients is called carryover / crossover
design

1. Provide good precision for
comparing treatments
2. Observes same subject at
different points of time
rather than observing same
subject at specified point of
time
Carry over or residual effect
from preceding treatments

LATIN SQUARE DESIGN
BALANCED INCOMPLETE
BLOCK DESIGN
 It is two factor design with
one observation in each
cell
subjects-rows
Treatments-columns
 Each subject receives each
formulation during the
course of experiment
 Each subject receives 2
formulations at different
occasions

GROUP
NUMBER
SUBJEC
TS
TREATM
ENT 1
WASH
OUT
PERIOD
TREATMEN
T 2
WASH
OUT
TREATM
ENT 3
2 WAY
1 1,2,3,4,
5,6
A B
2 7,8,9,10
,11,12
B A
3 WAY
1 1,2,3,4,
5,6
A C B
2 7,8,9,10
,11,12
B A A
3 13,14,1
5,16,17,
18
C B C

1.Minimises inter Subject
variability in plasma drug levels
2.Minimses carry over effects
3.Minimises variations due to
time effect
1.More complex method
2.Takes long time since
washout period is essential
3.More rate of subject drop
outs

SUBJECTS TREATMENT WASHOUT TREATMENT
1 A B
2 B A
3 A C
4 C A
5 B C
6 C B

• New drug formulation /new
dosage form of existing drug
TEST
• Chemical or generic product
approved by USFDA
STANDARD
• Mostly oral route ROUTE OF
ADMINISTRATION

DOSAGE REGIMEN
SINGLE DOSE:
Generally Single
dose regimen is
sufficient
 Multiple dose is required in case
of
Drug too potent
/toxic
Non linear pk at
Extended
/modified release
formulations
steady state
Analytical assay
sensitive
Difference in
rate due to not
extent of abs

♦ Sampling
♦ number of samples
♦ sampling times
♦ time of sampling
♦ wash-out-phase
 Number of samples
 sufficient to “describe” at least 80 % of total AUC
 usually ~12– 18 samples (minimum)

 Confinement of subjects at least 10 h prior to drug
administration
 Last food intake ~10 h prior to drug intake
 No food or fluids ~2 h prior to drug intake
 Drug administration with ~150-200 ml (e.g.) water
 Light standardized meal not before ~4 h post-dose
FED TIME:Define time of drug administration and
food intake, (e. g. drug intake within 30 min. before,
immediately before or after the standardised meal)

 SUBJECTS :Healthy
volunteers
 GENDER :Male
 AGE:20-25 yrs young
 WEIGHT:120-200 lbs
 Medical history should
be considered while
selecting the volunteers
 STUDY
CONDITIONS
 Uniform diet
 Should not consume any
drug prior1week to drug
therapy

ICH Definition
An independent body of medical, scientific and
nonscientific members
Responsibility is to ensure the protection of the rights,
safety and well-being of human subjects involved in a
trial
Among other things, reviewing, approving, and providing
continuing review of trial protocol and amendments and
of the methods and material to be used in obtaining and
documenting informed consent of the trial subjects;

 All BE data are expressed as ratio of AUC /C max
for test and standard
 Statistical criteria for acceptance of generic product is
based on 90% confidence limits i.e.,90% CI of test product
must fall between 80-120% of reference
 Statistical methods are used to evaluate the data in
order to identify different sources of variation

ANOVA
CONFIDENCE INTERVAL
APPROACH
 If probability p is ≤ 0.05
then the difference
between two products are
not considered as
statistically significant
 It is 2 sided test procedure
used to demonstrate if he
if the BA of the test is too
low/too high compared to
the standard
 should lie between 80-
120% CI i.e., difference
between BA of test and
standard should NMT
20%

CONCLUSION
 Ensuring uniformity in standards
of quality ,efficacy of
pharmaceutical products
 To ensure therapeutic
equivalence between reference
product and test product
 Vital concern in drug
development , more significant
in case of narrow therapeutic
index drugs

REFERENCES
 D.M BRAHMANKAR, B.SUNIL
JAISWAL,BIOPHARMACEUTICS AND
PHARMACOKINETICS ,A TRETISE ,Pg.no 285-
295
 LEON SHARGEL,APPLIED
PHARMCOKINETICS AND
BIOPHARMACEUTICS,FIFTH EDITION ,Pg.no
460-465

BIOEQUIVALAENCE STUDIES

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