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1. Bioavailability and bioequivalence of Drug Product
Introduction
Bioavailability quantifies the proportion of a drug which is absorbed and available to
produce systemic effects .
 Bioavailability is a fundamental property of a pharmaceutical product for a given
route of administration.
 It should be known and shown to be reproducible for all drug products intended to
produce a systemic effects.
 Bioequivalence is a term in pharmacokinetics used to access the used to access the
expected in vivo biological equivalence of two proprietary preparation of a drug.
 If two products are said to be bioequivalent it means that they would be expected to
be ,for all intents and purposes, the same.
 Two pharmaceutical products are bioequivalent if they are pharmaceutically
equivalent and their bioavailability after administration in the same molar dose are
similar to such a degree that their effects, with respect to both efficacy and safety ,
can be expected to be essentially the same.
 Ensuring uniformity in standards of quality , efficacy and safety of pharmaceutical
products is the fundamental responsibility of central drugs standard control
organization (CDSCO).
DRUG PRODUCT PERFORMANCE
 Drug product performance , in vivo, may be defined as the release of the drug
substance from the drug product leading to bioavailability of the drug.
 The assessment of drug product performance is important since bioavailability is
related both to the pharmacodynamic response and to adverse events.
 Performance tests relate the quality of a drug product to clinical safety and efficacy

2.  Bioavailability studies are drug product performance studies used to define the effect
of changes in the physiochemical properties of the drug substances , the
formulation of the drug , and thev manufacture process of the drug product ( dosage
form ).
 Drug product performance studies are used in the development of new and generic
drug products.
BIOAVALABILITY
“ The term bioavailability is defined as a rate and extent (amount) of absorption of drug
from its dosage form “
OR
“ Bioavailability is a term used to indicate the fractional extent to which a dose of drug
reaches it is site of action or a biological fluid from which the drug has access to its site of
action “
Absorption is the process of movement of unchanged drug from the site of administration
to systemic circulation or site of measurement that is plasma.
The amount of intestinal absorption is dependent on lipophilicity, drug stability , aqueous
solubility and intestinal permeability.
The drug bioavailability is affects its pharmacological effect due to drug.
Figure - A typical plasma Concentration – time profile showing pk and pd parameter

3. DEFINITION
Brand name drug
A brand name drug is a drug marketed under a properiatory, trademark- protected name.
Generic drug
A generic drug is the same as a brand- name drug in dosage , safety , strength, how is taken,
quality , performance , and intended use.
OBJECTIVES
 Entity Determination of influence of excipients patient related factors and possible
reaction with other drug on efficient of absorption.
 primary stages of development of a suitable dosages form for a new drug entity.
 development of new formulation of existing drug.
 control of quality of drug product during early marketing in order to determine the
influence of processing factors, storage and stability on drug absorption.
SIGNIFICANCE
 Drugs having low therapeutic index , e.g cardiac glycoside , quinidine, phenytoin etc.
and narrow margin of safety e.g antiarrythmics , antidiabetics, adrenal steroids.
 Drugs whose peak levels are required for the effect of drugs, e.g phenytoin
 Drugs that are absorbed by an active transport , e.g amino acid analogues
 In addition , any new formulation has to be tested for its bioavailability profile
 Drugs which are disintegrated in the alimentary canal and liver , e.g chlorpromazine
etc.
CONSIDERATIONS IN BIOAVAILABILITY STUDY DESIGN

4. Absolute bioavailability
“ When the systemic availability of a drug administered orally is determined in comparison
to its intravenous administration , is called as absolute bioavailability “.
% Absorption = Dose (iv) * Dose( oral ) * 100
Dose( oral ) * Dose (iv)
Relative bioavailability
When the systemic bioavailability of a drug after administered orally is compared with that
of an oral standard of the same drug ( aqueous or non aqueous solutions ).
It is denoted by symbol (Fr).
FR = [AUC] test D Std
[AUC] std D test
It is used to characterize absorption of a drug from its formulation . F and Fr are generally
expressed in percentage (%).
MEASUREMENT OF BIOAVAILABILITY
The methods available are classified as pharmacokinetic methods and pharmacodynamic
methods.
Pharmacokinetic ( indirect )
1) Plasma level time studies
2) Urinary excretion studies
Pharmacodynamic ( direct )
1) Acute pharmacological response
2) Therapeutic response

5. Based on the plasma concentration-time curve, the following measurements are
important for bioavailability studies.
 MINIMUM EFFECTIVE PLASMA CONCENTRATION
The minimum plasma concentration of the drug required to achieve a given
pharmacological or therapeutic response. This value varies from drug to drug and
from individual to individual as well as with the type and severity of the disease.
 MAXIMUM SAFE CONCENTRATION
The plasma concentration of the drug beyond which adverse effects are likely to
happen.
 THERAPEUTIC RANGE
The range of plasma drug concentration in which the desired response is achieved yet
avoiding adverse effect. The aim is clinical practice is to maintain plasma drug
concentration within the therapeutic range.
 ONSET OFACTION
On set of action is the time required to achieve the minimum effective plasma
concentration following administration of drug formulation.
 DURATION OFACTION
Duration of action of the therapeutic effect of the drug is defined as the time period
during which the plasma concentration of the drug exceeds the minimum effective
level.
 INTENSITY OFACTION
In general, the difference between the peak plasma concentration and the minimum
effective plasma concentration provides a relative measure of the intensity of the
therapeutic response of the drug.

6. Peak concentration (Cmax)
represents the highest concentration attained by the drug in the plasma. At this concentration,
rate of drug input becomes equal to rate of drug output.
It is clear that formulation A should produce pain relief than formulation B, even though it
seemed well absorbed, would not produce the desired pharmacological effect and would be
ineffective in producing analgesia.

7. On the other hand, if the two curves represent blood concentrations following equal
doses of two different formulations of the same cardiac glycoside

8. 1. Pharmacokinetics Method (Indirect)
a) Plasma Level Time Studies
Plasma level time curve describes the situation of drug concentration in our body after
administration with time (specific time intervals).
During clinical trials, the patient’s plasma drug concentration-time profile can be drawn by
assessing the plasma concentration at specific time points.
By using appropriate blood sampling, an accurate description of the plasma drug
concentration-time profile of the pharmacologically active drug substance(s) can be achieved
using a validated drug assay.
The plasma level time curve is obtained by plotting the concentration of the drug in plasma
after administration of a drug (Y-axis) and the corresponding time at which the plasma
sample was collected (X-axis). IV Bolus vs IV Infusion
Generally, plasma or serum is utilized the most frequently for direct drug measurement. A
drug or drug product enters the systemic circulation after delivery, and over time, plasma
drug concentrations increase.
The drug is distributed to the intracellular and extracellular regions of the body’s tissues from
the systemic circulation after absorption from the GIT, and it is also eliminated at the same
time either by excretion, biotransformation, or both processes. Plasma level time curve also
known as plasma drug.
Definition of the Plasma Level Time Curve
Plasma level time curve is a drug concentration versus time curve that graphically describes
the state of drug concentration in our body with time using the pharmacokinetic parameters
like peak plasma level (Cmax), time for peak plasma level (tmax), and area under the curve
(AUC) as well as pharmacodynamics parameters like onset time, the onset of action, the
intensity of action, duration of action, termination of the action, therapeutic range/window,
sub-therapeutic level, toxic level, MEC, and MTC /MSC and generally helps to predict
dosage regimens and assess the bioavailability of a drug product. Bioavailability vs
Bioequivalence
Concentration vs Time Graph of different dosage forms
Plasma level time curve of single immediate release dosage forms

9. Parameters of the plasma drug concentration-time profile
A typical plasma drug concentration vs. time graph is obtained after a drug dose is
administered. A plasma concentration-time profile may be used to examine two different
types of parameters:
Plasma level time curve describes the situation of drug concentration in our body after
administration with time (specific time intervals). During clinical trials, the patient’s plasma
drug concentration-time profile can be drawn by assessing the plasma concentration at
specific time points. By using appropriate blood sampling, an accurate description of the
plasma drug concentration-time profile of the pharmacologically active drug substance(s) can
be achieved using a validated drug assay. The plasma level time curve is obtained by plotting
the concentration of the drug in plasma after administration of a drug (Y-axis) and the
corresponding time at which the plasma sample was collected (X-axis). IV Bolus vs IV
Infusion
Generally, plasma or serum is utilized the most frequently for direct drug measurement. A
drug or drug product enters the systemic circulation after delivery, and over time, plasma
drug concentrations increase. The drug is distributed to the intracellular and extracellular
regions of the body’s tissues from the systemic circulation after absorption from the GIT, and
it is also eliminated at the same time either by excretion, biotransformation, or both
processes. Plasma level time curve also known as plasma drug concentration-time profile,
plasma concentration-time curve, blood concentration–time curve, blood concentration-time
profiles, concentration vs time graph, plasma drug concentration vs. time curve, plasma
concentration-time curve, drug concentration vs time graph.
Table of Contents
Plasma drug concentration vs time graph
Figure: Plasma level time curve of immediate release dosage forms after oral administration
of a single dose

10. Drug concentration vs time graph of multiple doses
Plasma-Level–Time-Curve-of-Immediate-release-dosage-forms-after-oral-administration-of-
a-multiple-dose
Figure: Drug concentration vs time graph of multiple doses of immediate-release dosage
forms

11. Plasma level time curve of a single intravenous bolus dose
Plasma Level–Time Curve of a single intravenous bolus dose of a drug
of a single intravenous bolus dose of a drug
Figure: Plasma level time curve
Plasma drug concentration-time profile for constant IV infusion
Plasma level vs time graph for constant IV infusion
Figure: Plasma drug concentration-time profile for constant IV infusion

12. Drug concentration vs time graph of single sustained release dosage forms
concentration vs time graph of controlled release sustained release dosage forms after
administration of a single dose.
Figure: Drug concentration vs time graph of controlled release / sustained release dosage
forms after administration of a single dose
Parameters of the plasma drug concentration-time profile
A typical plasma drug concentration vs. time graph is obtained after a drug dose is
administered. A plasma concentration-time profile may be used to examine two different
types of parameters:
A. PHARMACOKINETIC PARAMETERS
Three important parameters are related to drug movement in assessing the bioavailability of a
drug from its formulation:

13. Peak plasma concentration (Cmax)
The peak plasma drug concentration is the maximum drug concentration in plasma after the
administration of drugs.
It is crucial for assessing the safety of drugs. Additionally, it reflects the drug’s toxicity level
in the body.
Cmax is frequently used in bioequivalence studies as a surrogate measure for the rate of drug
bioavailability.
The magnitude of the pharmacological effect was correlated with the peak plasma drug
concentration. For the intended therapeutic response, Cmax should be higher than MEC but
lower than MSC.
The peak plasma drug concentration depends on the administered dose and rates of
absorption and elimination.
The concentration units used to represent the units of Cmax are mg/mL, g/mL, and ng/mL.
Time of peak concentration (tmax)
The time of peak plasma concentration is the time required to reach peak plasma drug
concentration (Cmax) after drug administration and is a rough marker of the average rate of
drug absorption.
At tmax, the rate of drug absorption precisely equals the rate of drug elimination.
As the drug’s absorption rate increases, the value for tmax will decrease (indicating less time
is needed to reach peak plasma concentration).
It is useful in estimating the onset of action and rate of absorption. Units of time used to
express the units of tmax are hours and minutes.
Area under the curve (AUC)
The area under curve (AUC) or area under the blood (or plasma) concentration–time curve is
a measurement of the extent of drug bioavailability i.e. the total amount of the drug that has
effectively reached the systemic circulation after its administration.
The actual body exposure to a drug after administration of dosage is represented by the area
under the plasma drug concentration-time curve (AUC), which is expressed in mg*h/L, or
μg/ml x hours, or mg*hr*L-1. The drug’s clearance is negatively correlated (inversely
proportional) with the AUC

14. B. PHARMACODYNAMIC PARAMETERS
These crucial parameters are related to drug action.
Minimum Effective Concentration (MEC)
Minimum Effective Concentration (MEC) is the minimum concentration of drug in plasma or
at the receptor site required to produce the desired therapeutic effect.
Maximum safe concentration (MSC) or Minimum Toxic Concentration (MTC)
The minimum toxic concentration is the minimum drug concentration needed to just barely
produce a toxic effect.
In other words, drug concentration in plasma at which undesirable effects begin to manifest.
Onset time
Onset time is the time at which a drug is initiated to induce pharmacological responses.
In other words, the onset time is the time for the plasma concentration to reach MEC after
the administration of a drug.
Lag time
The time delay prior to the commencement of first-order drug absorption is known as lag
time.
Some people have delayed drug absorption after a single oral dosage due to physiological
variables such as intestinal motility and stomach emptying time.
Onset of action
Onset of action is the commencement of pharmacologic effects. It happens when the plasma
drug concentration barely goes above the necessary MEC.
Duration of action
Duration of action is the time period for which the plasma concentration of the drug remains
above the MEC level.
In other words, the duration of drug action is the difference between the onset time and the
time for the drug to decline back from the MEC.

15. Termination of action
Termination of action is the end of pharmacologic responses. When the plasma drug
concentration falls back from the MEC, it happens.
Intensity of action
Intensity of action is the extreme pharmacologic response produced by the peak plasma
concentration (Cmax) of a drug.
Therapeutic Range/Window
The therapeutic range is the drug concentration between MEC and MSC. It is the drug’s
safest concentration at which it will have the optimum therapeutic responses.
Drugs produce undesirable or unpleasant effects if its concentration exceeds therapeutic
windows, and if its concentration falls below, drugs produce sub-therapeutic effects.
Subtherapeutic Level
Drug concentrations below MEC are considered sub-therapeutic levels, and at these
concentrations, the drug will have sub-therapeutic effects.
Toxic Level
The term “toxic level” refers to the concentration of a substance that causes toxic or adverse
or unwanted effects when it is higher than the MTC or MSC. or toxic effects.
Significance of Plasma Level Time Curve
 The plasma drug concentration versus time curve is most frequently used to determine
the systemic bioavailability of a drug from a drug product.
 Helps to predict dosage regimens for single oral and IV bolus doses, multiple-dose
regimens, IV infusions etc.
 Allows for the development of a drug product that consistently delivers a drug in a
predictable manner .
 Used to characterize the therapeutic effect of a drug for a specific dosage or
formulation.

16. b) Urinary Excretion Study
In a cumulative urinary excretion study, urine is collected upon administration of a drug
product until the unchanged drug is more or less excreted from the body (at least 7 ⋅ t1/2
when> 99% of the drug is eliminated).
In each urine sample of a collecting period, the drug concentration per milliliter is
determined.
It is base on the principle that the urinary excretion of unchanged drug is directly proportional
to plasma concentration of drug .
Method
Collection of urine at regular intervals for a time span equal to 7biological half life .
Analysis of unchanged drug in collected sample and determined the amount of drug excreted
in each interval and cumulative amount excreted .
At each sample collection , total emptying of the bladder is necessary to avoid errors resulting
from additional of residual amount to the next urine sample.
Figure – Plot of urinary excretion rate versus time

17. The three major parameters examined in urinary excretion data obtained with single dose
study are-
1) (dXu/dt) max – it gives the rate of appearance of drug in the urine is proportional to its
concentration in systemic circulation.
It value increases as the rate of and / or extent of absorption increases
2) (tu) max – it is analogous to the plasma level data , its value decreases as the absorption
rate increases.
3) Xu – it is related to the AUC of plasma level data and increases as the extent of
absorption increases.
2. Pharmacodynamics Method (Direct )
a) Acute pharmacological response
When bioavailability measurement by pharmacokinetics method is difficult ,
inaccurate or non-predictable , an acute pharmacological effect such as change in EEg
or ECG reading , pupil diameter etc.
It is related to the time course of given drug bioavailability can then be determined by
constriction of pharmacological effect time curve as well as dose response graph.
The method require measurement of response for at least 3 biological half live of the
drug in order to obtain a good estimation of AUC.
DISADVANTAGE
The pharmacological response tends to be more variable and accurate correlation
between measured response and drug available from the formulation is difficult .
b) Therapeutic response
Theoretically the most definite this method is based on observing the clinical response
to the drug formulation given to patient suffering diseases for which it is intend to be
used.

18. DISADVANTAGE
 In that Quantization of observed response is too improper to allow for
reasonable assessment of relative bioavailability between two dosages forms
of the same drugs.
 Many patients receive more than one drug, and the result obtained from a
bioavailability study could be compromised because of a Drug- Drug
interaction.
BIOEQIVALENCE
Therapeutic equivalence Two pharmaceutical products are therapeutically equivalent if they
are pharmaceutically equivalent and after administration in the same molar dose their effects,
with respect to both efficacy and safety, will be essentially the same as can be derived from
appropriate studies (bioequivalence, pharmacodynamic, clinical or in-vitro studies).
Therapeutically equivalent drug product are interchangeable.
Target of BA and BE study
Bioavailability and Bioequivalence studies are required by regulations to ensure therapeutic
equivalence between a pharmaceutically equivalent test drug and reference drugs.
TYPES OF STUDIES REQUIRED IN BIOEQUIVALENCE STUDIES
IN VIVOm STUDIES
For certain drugs, in vivo documentation of equivalence, through either a bioequivalence
study, a comparative clinical pharmacodynamic study , is regarded as especially important.
 Oral immediate release drug formulations with systemic action when one or more of
the following
 Indicates for serious condition
 Narrow therapeutic window

19.  Pharmacokinetics complicated by variable or incomplete absorptionor absorption
window, non linear pharmacokinetics , pre systemic elimination.
 Unfavourable physicochemical properties , e.g – low solubility, instability, etc
 Documented evidence for bioavailability problems related to the drug or drugs of
similar chemical structure or formulations.
 Where a high ratio of excipients to active ingredients exists.
Bioequivalence documentation is also needed to establish links between:
 Early and late clinical trial formulation.
 Formulations used in clinical trials and stability studies.
 Clinical trial formulations and to be marketed drug products.
WHEN NO NEED OF BIOEQUIVALENCE STUDIES
In the following formulations and circumstances , bioequivalence between a test drug
and a reference drug may be considered self evident with no further requirement for
documentation.
 When a gas is in the form of test drug.
 When test drug are to be administered parenterally as aqueous solution and contain
the same active ingredients in the same concentration and the same excipients in
comparable concentrations.
 When test drug is in the form of solution for oral use
 When the test drug is in form of powder for reconstitution as a solution and the
solution meets either above second and third points
 When a test drug is in the form of an inhalation [roduct or a nasal spray , tested to be
administered with or without the same device as the reference drug , prepared as
aqueous solutions,
and contains the same active ingredients in the same concentration and essentially the same
excipients in comparable concentrations.

20. CRITERIA FOR BIOEQUIVALENCE
To establish bioequivalence , the calculated 90% confidence interval for AUC and Cmax
should fall with in the bioequivalence range , usually 80.00 – 125.00%.
The non- parametric 90% confidence interval for T max should lie with in a clinically
acceptable range.
Tighter limits for permissible differences in bioavailability may be required for drug that
have:
 A narrow therapeutic index
 A serious , dose – related toxicity
 A steep dose / effect curve
 A non linear pharmacokinetics with in the therapeutic dose range A wider acceptance
range may be acceptable if it is based on sound clinical justification.
DESIGN AND CONDUCT OF PHARMACOKINETIC STUDIES
a) Study Design
According to following points the design of an in vivo bioavailability study is determined :
 The nature of reference drug and the dosage form to be tested.
 Benefit risk ratio considerations in regard to testing in humans.
 The availability of analytical methods .
 What is the scientific questions to be answered
Single dose studies generally suffice . however situations as described below may demand a
steady state study design:
 Some modified release drugs

21.  Where problems of sensitivity preclude sufficiently precise plasma concentration
measurements after single dose administration.
 Dose or time dependent pharmacokinetics.
Selection of the number of subjects
The number of subjects required for should be statistically significant and is
determined by the following considerations:
 The level of significant should be 0.05.
 The error variance associate with the primary characteristics to be studies as
estimated from a pilot experiment, from previous studies.
 The expected deviation from the reference drug compatible with
bioequivalence.
 The required power, normally > 80% to detect the maximum allowable
difference in primary characteristics to be studies.
Selection criteria for subjects
The studies should be normally performed on healthy adult volunteers with aim to
minimize variability and permit detection of differences between the study drugs.
Subjects may be males or
females; however the choice of gender should be consistent with usage and safety
criteria.
To minimize intra and inter individual variation subjects should be consistent with
usage and safety criteria.
Genetic phenotyping
Phenotyping and genotyping of subjects should be considered for exploratory
bioavailability studies and all studies using parallel group design.
Study Condition
Standardization of the study environment , diet , fluid intake, post dosing postures,
exercise, sampling schedules etc.
It is important in all studies.

22. Selection of Blood Sampling Schedules
The blood sampling period in single dose trials of an immediate release product
should extent to at least three elimination half lives.
Sampling should be continued for a sufficient period to ensure that the area extrapol -
ated from the time last measured concentration to infinite time only a small
percentage of the total AUC .
The use of a truncated AUC is undesirable except in certain circumstances such as in
the accurately.
Fasting and fed state consideration
Generally, a single dose study should be conducted after an overnight (at least 10
hours), with subsequent fast of 4 hours following dosing.
For multiple dose fasting state studies, when an evening dose must be given, two
hours of fasting before and after the dose is considered acceptable.
However, when it is recommended that the study drug be given with food (as would
be in routine clinical practice), or where the dosage from is a modified release
product, fed state studies need to be carried out in addition to the fasting state studies.
Fed state studies are also required the consumption of a high fat breakfast before
dosing.
Such a breakfast must be designed to provide 950 to 1000 Kcals.
At least 50% of these calories must come from fat, 15 to 20% from proteins and the
rest from carbohydrates.
The vast ethic and cultural variations of the Indian sub continent preclude the
recommendation of any single standard high fat breakfast.
Protocol should specify the suitable and appropriate diet.
The high fat breakfast must be consumed approximately 15 minutes before dosing.
Characteristics to Be Investigated During Bioequivalence Studies
In most cases evaluation of bioavailability and bioequivalence will be based upon the
measured concentrations of the active drug substances in the biological matrix.

23. In some situations, the measurements of an active or inactive metabolite may be
necessary.
These situations include:
 Where the concentrations of the drugs may be too low to accurately measure in
the biological matrix.
 Limitations of the analytical method .
 Unstable drugs.
 Drugs with a very short half life.
Racemates should be measured using an achiral assay method. Measurement of individual
enantiomers in bioequivalence studies is recommended where all of the following criteria are
met;
 The enantiomers exhibit different pharmacodynamic characteristics.
 The enantiomers exhibit different pharmacokinetic characteristics.
 Primary efficacy / safety activity resides with the minor enantiomer.
 Non linear absorption is present for at least one of the enantiomers.
The plasma time concentration curve is mostly used to assess the rate and extend of absorption
of the study drug.
These include pharmacokinetic parameters such as the Cmax, Tmax, AUC0-t and AUC0-&.
For studies in the steady state state AUC0-t, Cmax, Cmin, and degree of fluctuation should be
calculated.

24. b) The Crossover Design
A crossover design is a modified, randomized block design in which each block receives
more than one formulation of a drug at different time periods. A block may be a subject or a
group of subjects.
Subjects in each block receive a different sequence of formulations.
There are several situations, where it is essential to go for the crossover designs like:
(i) the formulations do not have a serious damaging effect on the subjects
(ii) subjects require special training over a long period of time
(iii) objective of the experiment is to find out the effect of different subjects
(iv) homogeneous subjects are scarce
(v) budget constraint
EVALUATION OF DATA:
ANALYTICAL METHOD:
The analytical method for measurement of drug must be validated for accuracy, precision,
sensitivity and specificity.
The use of more than one analytical method during BE studies may not be valid because
different methods may yield different values.
PHARMACOKINETIC EVALUATION OF DATA:
For single dose studies, including fasting study or food interaction study, pharmacokinetic
analysis include calculation of each subject of (AUC0→t) and to infinity (AUC0→∞),
Tmax and Cmax. Additionally, elimination rate constant K and elimination half life (T1/2)
may be estimated. For multiple dose studies, analysis include calculation for each subject
of (AUC0→t), Tmax , Cmin, Cmax and percent fluctuation.
After data has been collected , statistical methods must be applied to determine the level of
significance of any observed difference in the rate and extent of drug absorption.
The commonly adopted approaches to determine statistical difference are:
ANOVA(Analysis of variance)
Is a statistical procedure used to test the data for differences within and between control and
groups.
A stastical difference between the pk obtained from two or more drug product is
statistical significant if there is probability is 0.005.
If P < 0.05 the differences between products are not statistical significant.

25. Confidence Interval approach :
The 90% confidence limits are estimated for sample based on Student’s t distribution of
data
A confidence interval about the ratio of means of the two drug products must be within
± 20% for bioavailability i.e. the difference between the bioavailability of the test product
should not be greater than ±20% of the average of reference product
Limitations:
 Difficult for drugs with a long elimination half life.
 Highly variables drug may required a far greater number of subjects.

26. Biopharmaceutics classification system
 It is a scientific framework for classifying drug substances based on their aqueous
solubility and intestinal permeability.
 It is a drug-development tool that allows estimation of the contributions of three major
factors, dissolution, solubility and intestinal permeability that affect oral drug
absorption from IR solid oral dosage forms.
 It was first introduced into regulatory decision-making process in the guidance
document on immediate release solid oral dosage forms: Scale-up and postapproval
changes.
 The drugs are divided into high/low-solubility and permeability classes. Currently, BCS
guidelines are provided by USFDA, WHO and EMEA.
Three necessary steps for a drug to be absorbed are:
 Release of drug from dosage forms.
 Maintenance of dissolved state through gastro-intestinal tract.
 Permeation through G.I membrane into hepatic circulation.
Concept Behind BCS
 The in- vivo performance of orally administered drug depends upon their solubility and
tissue permeability characteristics
 The release rate or solubility of the drug substance will not be a partameter if the
absorption of the drug is permeation rate limited and in such cases the in-
vitrodissolution study can be used to demonstrate the bioavailability or bioequivalence
of the drug product through in vitro- in vivo correlation (IVIVC)
 On the other hand if absorption of the drug is dissolution rate limited that means the
drug in the gastrointestinal fluid passes freely through the bio-membrane at a rate higher
than it dissolves or is released from the dosage form.
 The specifically designed in-vivo study will be rquired in such a cases to access the
absorption rate, and hence its bioavailability and to demonstrate the bioequivalence
ultimately.
Purpose of the BCS guidance
 Expands the regulatory application of the BCS and recommends method for
classifying drugs

27.  Explains when a waiver for in vivo bioavailability and bioequivalence studies
may be requested based on the approach of BCS
Objective of BCS
 To improve the efficiency of the drug development and review process by
recommending , a strategy for identifying expendable clinical bioequivalence
test.
 To recommended a class of immediate release solid oral dosage forms for which
bioequivalence may be assessed based on in-vitro dissolution tests.
 To recommend methods for classification according to dosage form dissolution
along with the solubility- permeabilty characteristics of the drug products.
Biopharmaceutics classification system
 It is a scientific framework for classifying drug substances based
on their aqueous solubility and intestinal permeability.
 It is a drug-development tool that allows estimation of the contributions of
three major factors, dissolution, solubility and intestinal permeability
that affect oral drug absorption from IR solid oral dosage forms.
 It was first introduced into regulatory decision-making process in
the guidance document on immediate release solid oral dosage
forms: Scale-up and postapproval changes.
 The drugs are divided into high/low-solubility and permeability classes.
Currently, BCS guidelines are provided by USFDA,WHO and EMEA.
Classification
According to BCS, drug substances or APIs are divided into high/
low solubility and permeability classes as follow:
Class I : High Solubility - High Permeability
Class II : Low Solubility - High Permeability
Class III : High Solubility - Low Permeability
Class IV : Low Solubility - Low Permeability

28. In combination with the dissolution, the BCS takes into account
the three major factors governing BA, viz. dissolution, solubility and
permeability.
The BCS in accordance with WHO guideline is shown in
This classification is associated with drug dissolution and
absorption model, which identifies the key parameters controlling
drug absorption as a set of dimensionless numbers.
Absorption number, An 5 mean residence time/mean absorption
Time Dissolution number, Dn 5 mean residence time/mean dissolution
time.
Dose number, Do 5 (maximum dose strength/250)/solubility
Class I drugs exhibit a high absorption number and a high
dissolution number.
The rate-limiting step is drug dissolution and
if dissolution is very rapid then gastric emptying rate becomes the
rate-determining step.
Class II drugs have a high absorption number
but a low dissolution number.
In vivo drug dissolution is then a
rate-limiting step for absorption except at a very high dose number.
The absorption for Class II drugs is usually slower than Class I and
occurs over a longer period of time.
In the case of Class III drugs,
permeability is a rate-limiting step for drug absorption.
These drugs exhibit a high variation in the rate and extent of drug absorption.
Because the dissolution is rapid, the variation is attributable to
alteration of physiology and membrane permeability rather than
the dosage form factors. Generally,
Class IV drugs exhibit problems
for effective oral administration. Examples of drugs for different
classes are given in Table.

29. Biowaivers
The term biowaiver is applied to a regulatory drug approval process when the dossier
(application) is approved based on evidence of equivalence other than through in vivo
equivalence testing.
Biowaiver means to obtain waive off for carrying out expensive and time-consuming BA and
BE studies.
BCS provides biowaivers for Class I, II and III drug with some specifications.
This waiver is for both pre- and postapproval phases. BCS-based biowaivers are applicable
for immediate-release solid oral dosage formulations containing one or more of the API(s),
identified by WHO prequalification of medicines programme (PQP) to be eligible, if the
required data ensure the similarity of the submitted pharmaceutical product and the
appropriate comparator product. Comparator products used in BCS-biowaiver applications
should be selected from the current list of WHO PQP recommended comparator products,
including the appropriate fixed-dose combination product.

30. Parameters of BCS
Drugs are classified in BCS on the basis of following parameters-
 Solubility
 Permeability
 Dissolution
Solubility class Boundaries –
It is based on the highest dose strength of an immediate release product.
A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or
less of aqueous media over the pH range of 1 to 7.5
Permeability class boundaries –
It is based indirectly on the extend of absorption of a drug substance in humans and directly
on the measurement of rates of mass transfer across human intestinal membrane
Dissolution class boundaries –
An immediate release product is considered rapidly dissolving when no less than 85% of the
labeled amount of the drug substances dissolve with in 15 minutes using USP dissolution
Apparatus – I at 100 RPM or apparatus -II at 50 RPM in a volume of 900 ml or less in the
following media: 0.1 N HCL or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or
simulated intestinal fluid.
SUBMITTED BY- SUBMITTED TO -
Kritika Singh Mrs. Anupriya Adhikari Mam
Roll No - (Associate Proffessor)
220420801008
TOPIC –
Bioavailability and Bioequivalence of Drug Product.
Date of Submission –
26 - May - 2023