THE BIOPHARMACEUTICS
CLASSIFICATION SYSTEM
(BCS)
M.PHARM – I YEAR
DEPT. OF PHARMACEUTICS
2
CONTENTS
➢Introduction
➢Biopharmaceutical Classification System(BCS) Criteria
➢Biopharmaceutical Drug Disposition Classification System(BDDCS)
➢Understanding the terms
➢Drug Products for Which Bioavailability or Bioequivalence May Be Self-Evident
➢Generic Biologics
➢Biosimilarity vs Interchangeability
➢Clinical significance of Bioequivalence studies
➢Special concerns in Bioavailability and Bioequivalence studies
➢Generic Substitution
➢References
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INTRODUCTION
➢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.
➢These factors are dissolution, solubility and
intestinal permeability.
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CLASS SOLUBILITY PERMEABILITY COMMENTS
Drug dissolves rapidly and is well
Class I High High absorbed. Bioavailability problem is not
expected for IR drug approaches.
Drug is dissolution limited and well
absorbed. Bioavailability is controlled
Class II Low High
by the dosage form and the rate of
release of the drug substance.
Drug is permeability limited.
Bioavailability may be incomplete if
Class III High Low
drug is not dissolved or released within
the absorption window.
Difficulty in formulating a drug product
that will deliver a consistent drug
Class IV Low Low
bioavailability. An alternative route of
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INTRODUCTION
• The classification system is based on Fick’s first law applied to a membrane:
Jw = Pw Cw
• where Jw is the drug flux (mass/area/time) through the intestinal wall at any position and
time, Pw is the permeability of the membrane, and Cw is the drug concentration at the
intestinal membrane surface.
• It showed the solubility and permeability characteristics of various representative drugs.
Biopharmaceutics drug classification is very useful in predicting the in vitro drug
dissolution of IR solid oral drug products with in vivo absorption.
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SOLUBILITY
➢An objective of the BCS approach is to determine the equilibrium solubility of a drug
under approximate physiologic conditions.
➢For this purpose, determination of pH–solubility profiles over a pH range of 1–8 is
suggested.
➢The solubility class is determined by calculating what volume of an aqueous medium is
sufficient to dissolve the highest anticipated dose strength.
➢A drug substance is considered highly soluble when the highest dose strength is soluble in
250 mL or less of aqueous medium over the pH range 1–8.
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PERMEABILITY
• Study of extent of absorption in humans and intestinal permeability methods can be used in
determining the permeability class of a drug.
• To be classified as highly permeable, a test drug should have an extent of absorption >90% in
humans.
• Supportive information on permeability characteristics of the drug substance should also be derived
from its physical–chemical properties (eg, octanol: water partition coefficient).
• Some methods to determine the permeability of a drug from the gastrointestinal tract include
(1) in vitro permeation experiments using excised human or animal intestinal tissues
(2) in vitro permeation experiments across a monolayer of cultured human intestinal cells.
(3) in vivo intestinal perfusion studies in humans;
(4) in vivo or in situ intestinal perfusion studies in animals;
• When using these methods, the experimental permeability data should correlate with the known
extent-of-absorption data in humans.
• After oral drug administration, in vivo permeability can be affected by the effects of efflux and
absorptive transporters in the gastrointestinal tract, food and possibly by the various excipients
present in the formulation.
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IN-VITRO METHODS
A) EVERTED SMALL INTESTINAL
SAC TECHNIQUE
➢ This method involves isolating a small segment of the intestine of a laboratory animal
such as rat, everting the intestine and filling the sac with a small volume of drug free
buffer solution.
➢ Both the segments are tied off and the sac is immersed in an Erlenmeyer flask
containing a large volume of buffer solution that contains the drug.
➢ The flask and its contents are then oxygenated and the whole preparation is
maintained at 37°C and shaken mildly.
➢ At predetermined time intervals, the sac is removed and the concentration of drug in the
serosal fluid is determined/assayed for drug content.
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A) EVERTED SMALL INTESTINAL
SAC TECHNIQUE
Advantages
-The epithelial cells of the mucosal surface are exposed directly to the oxygenated mucosal
fluid.
-Prolongs the viability and integrity of the preparation after removal from the animal.
-Convenience and accuracy with respect to drug analysis.
Disadvantage
– Difficulty in obtaining more than one sample per intestinal segment
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Fig. Everted sac technique
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B) EVERTED SAC MODIFICATION
➢ In this method, the test animal is fasted for a period of 20-24 hr and water is allowed.
➢ The animal is killed and the entire small intestine is everted.
➢ Segments, 5-15 cm in length are cut from a specific region of the intestine.
➢ The distal end of the segment is tied and the proximal end is attached to the cannula. The
segment is suspended in a solution which contains the drug.
➢ A drug free buffer is then placed in the serosal compartment.
➢ For determining the rate of drug transfer, the entire volume of serosal solution is removed
from the sac at each time interval with the help of a syringe and replaced with fresh buffer
solution.
➢ The amount of drug that permeates the intestinal mucosa is plotted against time to
describe the absorption profile of drug at any specific pH.
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B) EVERTED SAC MODIFICATION
Fig. Everted sac modification
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B) EVERTED SAC MODIFICATION
Advantages
A number of different solutions may be tested with a single segment of the intestine.
Simple and reproducible.
It distinguishes between active and passive diffusion.
It determines the region of small intestine where absorption is optimal, in the case of
active transport.
Used to study the effect of pH, surface active agents, complexation and enzymatic
hydrolysis.
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B) EVERTED SAC MODIFICATION
Disadvantages
• The intestinal preparation is removed from the animal as well as from its normal blood
supply. Under these conditions, the permeability characteristics of the membrane are
significantly altered.
• The rate of transport of drug as determined from the everted sac technique, may
be slower than in the intact animal.
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CELL CUTURE TECHNIQUES
➢ Cell culture is the complex process by which cells are grown under controlled conditions,
generally outside their natural environment.
➢ In this technique, differentiated cells of the intestine, originating from cells of carcinoma
of colon are placed on synthetic polycarbonate membrane previously treated with an
appropriate material such as collagen, which on incubation, aids reproduction of cells
while not retarding drug permeation characteristics.
➢ These models are based on the assumption that passage of drugs across the intestinal
epithelium is the main barrier for drugs to reach the circulation.
➢ Cells of carcinoma of colon is the most widely used cell line and is a continuous cell line.
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CELL CUTURE TECHNIQUES
➢ These cells differentiate spontaneously under
normal culture conditions and hence are polarized
(i.e. apical and basolateral surface), have tight
junctions and brush border.
➢ Solution of drug is placed on this layer of cultured
cells and the system is placed in a bath of buffer
solution.
➢ The drug that reaches the latter compartment is
sampled and analysed periodically.
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IN VIVO METHODS
➢ In vitro and in situ techniques gives us an idea about absorption, but in vivo method
gives us an idea about some important factor that influence absorption such as gastric
emptying, intestinal motility and the effects of drugs on the GIT can be determined.
➢ The in vivo method can be classified into:
1. Direct method
2. Indirect method
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DIRECT METHOD
➢ The drug levels in blood or urine is determined as a function of time.
➢ For this, a suitable sensitive reproducible analytical procedure should be developed to
determine the drug in the biological fluid.
➢ In this method, blank urine or blood sample is taken from the test animal before the
experiment.
➢ The test dosage form is administered to the animal and at appropriate intervals of
time the blood or urine sample are collected and assayed for the drug content.
➢ From the data, we can determine the rate and extent of drug absorption.
➢ In this method, the experimental animal chosen should bear some resemblence to
man.
➢ It is reported that pigs most closely resemble to man but are not used due to the handling
problems.
➢ The other animal that can be used are dogs, rabbits and rats.
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INDIRECT METHOD
➢ When the measurement of drug concentration in blood or urine is difficult or not
possible, but a sensitive method is available to test the activity, then absorption studies
can be done by this indirect method.
➢ In this method, pharmacological response of the drug is related to the amount of drug in
the body.
➢ The response is determined after the administration of a test dosage form, LD 50 appears
to be dependent on the rate of the absorption of drug.
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IN SITU METHODS
• These methods simulates the in vivo conditions for drug absorption and are based on
perfusion of a segment of GIT by drug solution and determination of amount of drug
diffused through it.
• The most important advantage of in situ methods compared to the in vitro techniques consists
of intact blood and nerve supply.
• Accordingly, this methodology is highly accurate for predicting the permeability of passively
transported compounds, while the use of a scaling factor is recommended for predicting
permeability of carrier-mediated compounds.
• TYPES – 1) Doluisio method
2) Single pass perfusion technique
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DOLUISIO METHOD
• In this method, the upper and lower parts of the
small intestine of anaesthetised and dissected rat
are connected by means of tubing to syringes of
capacity 10 – 30 ml.
• After washing the intestinal segment with normal
saline, the syringe is filled with a solution of
radiolabelled drug and a non-absorbable
marker which is used as an indicator of water
flux during perfusion.
• Part of the content of the syringe containing drug
is delivered to the intestinal segment which is
then collected in the second syringe and analysed
for drug.
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SINGLE PASS PERFUSION TECHNIQUE
• It is generally considered superior to the Doluisio
method giving better control of the
hydrodynamics and increased surface area.
• The drug solution is perfused continuously (via an
infusion pump) down a set length of intestine through
the duodenal end cannula and perfusate collected
from the ileal-end cannula, at flow rates of between
0.1 and 0.3 ml/min.
• The samples collected at outflow are assayed
for drug content.
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DISSOLUTION
• The dissolution class is based on the in vitro dissolution rate of an IR drug product under
specified test conditions and is intended to indicate rapid in vivo dissolution in relation to
the average rate of gastric emptying in humans under fasting conditions.
• An IR drug product is considered rapidly dissolving when not less than 85% of the label
amount of drug substance dissolves within 30 minutes using USP Apparatus I at 100 rpm or
Apparatus II at 50 rpm in a volume of 900 mL or less in each of the following media: (1)
acidic media such as 0.1 N HCl or simulated gastric fluid USP without enzymes (2) pH 4.5
buffer and (3) pH 6.8 buffer or simulated intestinal fluid USP without enzymes.
• The FDA is in the process of revising the BCS guidance to permit biowaivers for generic
formulations of Class 3 drugs.
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ORAL CRITERIA ON
CLASS HIGHLY SOLUBLE DISSOLUTION
BIOAVAILABILITY EXCIPIENTS
Test and reference
≥85% in 30 minutes at should be
Highest strength, over pH 1.0, 4.5, 6.8 pharmaceutical
range of pH 1.0–6.8 (“rapidly dissolving”) equivalents
≥85%
Class I Volume = 900 mL Test and reference
Paddles at 50 rpm, or should not differ in
basket at 100 rpm amounts of excipients
known to affect
bioavailability
Test and reference
≥85% in 15 minutes at
should be
pH 1.0, 4.5, 6.8 (“very
Highest strength, over pharmaceutical
rapidly dissolving)
Class III range of pH 1.0–6.8 ≥85% equivalents
Volume = 900 mL
Test and reference
Paddles at 50 rpm, or
formulations should be
basket at 100 rpm
the same
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BIOPHARMACEUTICS DRUG
DISPOSITION CLASSIFICATION
SYSTEM
➢The major aspects of BCS are the consideration of solubility and permeation.
➢According to BCS, permeability in vivo is considered high when the active drug is systemically
absorbed ≥90%.
➢Wu and Benet (2005) and Benet et al (2008) have proposed modification of the BCS system known as
the Biopharmaceutics Drug Disposition Classification System (BDDCS), which takes into account
drug metabolism (hepatic clearance) and transporters in the gastrointestinal tract for drugs that are
orally administered.
➢For BCS 1 drugs (high solubility and high permeability), transporter effects will be minimal.
➢However, BCS 2 drugs (low solubility and high permeability), transporter effects are more important.
➢These investigators suggest that the BCS should be modified on the basis of the extent of drug
metabolism, overall drug disposition, including routes of drug elimination and the effects of
efflux and absorptive transporters on oral drug absorption.
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BIOPHARMACEUTICS DRUG
DISPOSITION CLASSIFICATION
SYSTEM
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UNDERSTANDING THE TERMS
REFERENCE PRODUCT
A reference product is the single biological product,
already approved by FDA, against which a proposed
biosimilar product is compared to and evaluated to ensure
that the product is highly similar and has no clinically
meaningful differences.
BIOSIMILAR PRODUCT
A biosimilar is a biological product that is highly similar
to and has no clinically meaningful differences from an
existing FDA-approved reference product.
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UNDERSTANDING THE TERMS
PHARMACEUTICAL EQUIVALENTS
Drug products in identical dosage forms that contain the same active ingredient(s), that is, the
same salt or ester, are of the same dosage form, use the same route of administration, and are
identical in strength or concentration (eg, Chlordiazepoxide hydrochloride 5-mg capsules).
PHARMACEUTICAL ALTERNATIVES
Drug products that contain the same therapeutic moiety but as different salts, esters, or
complexes. For example, Tetracycline phosphate and Tetracycline hydrochloride equivalent to
250-mg tetracycline base are considered pharmaceutical alternatives.
PHARMACEUTICAL SUBSTITUTION
The process of dispensing a pharmaceutical alternative for the prescribed drug product. For
example, ampicillin suspension is dispensed in place of ampicillin capsules.
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UNDERSTANDING THE TERMS
THERAPEUTIC EQUIVALENTS
Drug products are considered to be therapeutic equivalents only if they are pharmaceutical
equivalents and if they can be expected to have the same clinical effect and safety profile
when administered to patients under the conditions specified in the labeling.
THERAPEUTIC ALTERNATIVES
Drug products containing different active ingredients from the same pharmacologic class and
are expected to have the same therapeutic effect when administered to patients for such
condition of use. For example, ibuprofen is given instead of aspirin; cimetidine may be given
instead of ranitidine.
BIOEQUIVALENT DRUG PRODUCTS
This term describes pharmaceutical equivalent or pharmaceutical alternative products that
display comparable bioavailability when studied under similar experimental conditions.
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DRUG PRODUCTS FOR WHICH
BIOAVAILABILITY OR BIOEQUIVALENCE
MAY BE SELF-EVIDENT
1. The drug product (a) is a solution intended solely for intravenous administration and (b)
contains an active drug ingredient or therapeutic moiety combined with the same solvent
and in the same concentration as in an intravenous solution that is the subject of an
approved, full NDA.
2. The drug product is a topically applied preparation (eg, a cream, ointment, or gel
intended for local therapeutic effect). The FDA has released guidances for the performance
of bioequivalence studies on topical corticosteroids and antifungal agents. The FDA is
also considering performing dermatopharmacokinetic (DPK) studies on other topical
drug products. In addition, in vitro drug release and diffusion studies may be required.
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DRUG PRODUCTS FOR WHICH
BIOAVAILABILITY OR BIOEQUIVALENCE
MAY BE SELF-EVIDENT
3. The drug product is in an oral dosage form that is not intended to be absorbed (eg, an
antacid or a radiopaque medium). Specific in vitro bioequivalence studies may be
required by the FDA. For example, the bioequivalence of cholestyramine resin is
demonstrated in vitro by the binding of bile acids to the resin.
4. The drug product meets both of the following conditions:
a) It is administered by inhalation as a gas or vapor (eg, as a medicinal or as an inhalation
anesthetic).
b) It contains an active drug ingredient or therapeutic moiety in the same dosage form as a drug
product that is the subject of an approved, full NDA.
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DRUG PRODUCTS FOR WHICH
BIOAVAILABILITY OR BIOEQUIVALENCE
MAY BE SELF-EVIDENT
5. The drug product meets all of the following conditions:
a) It is an oral solution, elixir, syrup, tincture, or similar other solubilized form.
b) It contains an active drug ingredient or therapeutic moiety in the same concentration as a drug
product that is the subject of an approved, full NDA.
c) It contains no inactive ingredient that is known to significantly affect absorption of the active
drug ingredient or therapeutic moiety.
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GENERIC BIOLOGICS
➢Biologics, or biotechnology-derived drugs, are derived from living sources such as
humans, animals or microorganisms.
➢Many biologics are complex mixtures that are not easily identified or characterized and
are manufactured using biotechnology or are purified from natural sources.
➢Other biological drugs, such as insulin and growth hormone, are proteins derived by
biotechnology and have been well characterized.
➢Advances in analytical sciences enable some protein products to be characterized
extensively in terms of their physicochemical and biological properties.
➢These analytical procedures have improved the ability to identify and characterize not only
the desired product but also product-related substances and product and process-related
impurities.
➢Advances in manufacturing science and production methods may enhance the likelihood that
a product will be highly similar to another product by better targeting the original
product’s physiochemical and functional properties.
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FACTORS
➢The FDA recommends the following factors that must be considered in assessing whether
products are highly similar.
EXPRESSION SYSTEM
✓Therapeutic protein products can be produced by microbial cells (prokaryotic, eukaryotic),
cell lines of human or animal origin or tissues derived from animals or plants.
✓It is expected that the expression construct for a proposed biosimilar product will encode
the same primary amino acid sequence as its reference product.
ASSESSMENT OF PHYSICOCHEMICAL PROPERTIES:
✓Physicochemical assessment of the proposed biosimilar product and the reference product
should consider all relevant characteristics of the protein product (eg. the primary,
secondary, tertiary, and quaternary structure, post-translational modifications, and functional
activity).
✓The objective of this assessment is to maximize the potential for detecting differences in
quality attributes between the proposed biosimilar product and the reference product.
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FACTORS
MANUFACTURING PROCESS
✓A comprehensive understanding of all steps in the manufacturing process for the proposed
biosimilar product should be established during product development.
FUNCTIONAL ACTIVITIES
✓Functional assays act to complement physicochemical analyses and are a quality measure
of the function of the protein product.
RECEPTOR BINDING AND IMMUNOCHEMICAL PROPERTIES
✓When binding or immunochemical properties are part of the activity attributed to the protein
product, analytical tests should be performed to characterize the product in terms of these
specific properties.
IMPURITIES
✓The applicant should characterize, identify, and quantify impurities (product and process
related) in the proposed biosimilar product and the reference product.
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FACTORS
REFERENCE PRODUCT AND REFERENCE STANDARDS
✓A thorough physicochemical and biological assessment of the reference product should
provide a base of information from which to develop the proposed biosimilar product and
justify reliance on certain existing scientific knowledge about the reference product.
FINISHED DRUG PRODUCT
✓Product characterization studies should be performed on the most downstream
intermediate best suited for the analytical procedures used.
STABILITY
✓ An appropriate physicochemical and functional comparison of the stability of the
proposed biosimilar product with that of the reference product should be initiated including
accelerated and stress stability studies, or forced degradation studies.
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BIOSIMILARITY VS
INTERCHANGEABILITY
➢The new legislation establishes two distinct categories of biosimilar products
✓ (1) biological products that are “biosimilar” to a reference biological product
✓ (2) biological products that are “interchangeable” with the reference product.
BIOSIMILAR BIOLOGICAL DRUG PRODUCTS
➢Biological products that are highly similar to the reference product notwithstanding minor
differences in clinically inactive components.
➢In addition, there are no clinically meaningful differences between the biological product
and the reference product in terms of the safety, purity, and potency of the product.
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BIOSIMILARITY VS
INTERCHANGEABILITY
➢INTERCHANGEABLE BIOLOGICAL DRUG PRODUCTS
➢Biological products that are interchangeable with a reference biological product if
(1) it meets the criteria for being biosimilar to the reference product
(2) it can be expected to produce the same clinical result as the reference product in any given
patient
(3) the risk in terms of safety or diminished efficacy in alternating or switching between use of
the biological and reference product is not greater than the risk of using the reference
product without such alteration or switch.
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BIOSIMILARITY VS
INTERCHANGEABILITY
❖FDA regulatory approval of a biosimilar drug product is based on a stepwise approach
includes a comparison of the proposed product and the reference product including
✓Analytical studies that demonstrate that the biological product is highly similar to the reference
product notwithstanding minor differences in clinically inactive components.
✓Animal studies (including the assessment of toxicity)
✓Clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or
pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency.
❖After FDA approval, the manufacturer must provide robust postmarketing safety monitoring
as an important component in ensuring the safety and effectiveness of biological products
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CLINICAL SIGNIFICANCE OF
BIOEQUIVALENCE STUDIES
➢Bioequivalence of different formulations of the same drug substance involves equivalence
with respect to the rate and extent of systemic drug absorption.
➢Clinical interpretation is important in evaluating the results of a bioequivalence study.
➢Generally, two formulations whose rate and extent of absorption differ by 20% or less are
considered bioequivalent.
➢The Report by the Bioequivalence Task Force (1988) considered that differences of less
than 20% in AUC and Cmax between drug products are “unlikely to be clinically
significant in patients.”
➢The Task Force further stated that “clinical studies of effectiveness have difficulty detecting
differences in doses of even 50%–100%.” Therefore, normal variation is observed in
medical practice and plasma drug levels may vary among individuals greater than 20%.
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CLINICAL SIGNIFICANCE OF
BIOEQUIVALENCE STUDIES
• A small, statistically significant difference in drug bioavailability from two or more dosage
forms may be detected if the study is well controlled and the number of subjects is
sufficiently large.
• When the therapeutic objectives of the drug are considered, an equivalent clinical response
should be obtained from the comparison dosage forms if the plasma drug concentrations
remain above the minimum effective concentration (MEC) for an appropriate interval and
do not reach the minimum toxic concentration (MTC).
• Therefore, the investigator must consider whether any statistical difference in bioavailability
would alter clinical efficiency.
• Special populations, such as the elderly or patients on drug therapy, are generally not used
for bioequivalence studies.
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CLINICAL SIGNIFICANCE OF
BIOEQUIVALENCE STUDIES
➢Normal, healthy volunteers are preferred for bioequivalence studies, because these subjects
are less at risk and may more easily endure the discomforts of the study, such as blood
sampling.
➢Furthermore, the objective of these studies is to evaluate the bioavailability of the drug from
the dosage form and use of healthy subjects should minimize both inter and intrasubject
variability. It is theoretically possible that the excipients in one of the dosage forms tested
may pose a problem in a patient who uses the generic dosage form.
➢For the manufacture of a dosage form, specifications are set to provide uniformity of dosage
forms.
➢With proper specifications, quality control procedures should minimize product-to-product
variability by different manufacturers and lot-to-lot variability with a single manufacturer.
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SPECIAL CONCERNS IN 43
BIOAVAILABILITY AND
BIOEQUIVALENCE STUDIES
➢The general bioequivalence study designs and evaluation, such as the comparison of AUC,
Cmax and tmax may be used for systemically absorbed drugs and conventional oral dosage
forms.
➢However, for certain drugs and dosage forms, systemic bioavailability and bioequivalence
are difficult to ascertain.
➢Drugs and drug products (eg, cyclosporine, chlorpromazine) are considered to be highly
variable if the intrasubject variability in bioavailability parameters is greater than 30%
by analysis of variance coefficient of variation.
➢The number of subjects required to demonstrate bioequivalence for these drug products may
be excessive, requiring more than 60 subjects to meet current FDA bioequivalence criteria.
➢The intrasubject variability may be due to the drug itself or to the drug formulation or to
both. The FDA has held public forums to determine whether the current bioequivalence
guidelines need to be changed for these highly variable drugs .
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ISSUES IN ESTABLISHING IN
BIOAVAILABILITY AND
BIOEQUIVALENCE
• Drugs with high intrasubject variability
• Drugs with long elimination half-life
• Biotransformation of drugs – Stereoselective drug metabolism , Drugs with active
metabolites ,Drugs with polymorphic metabolism
• Nonbioavailable drugs (drugs intended for local effect) – Antacids , Local anesthetics , Anti-
infectives , Anti-inflammatory steroids
• Dosage forms for nonoral administration – Transdermal , Inhalation, Ophthalmic,
Intranasal
• Bioavailable drugs that should not produce peak drug levels – Potassium supplements
• Endogenous drug levels – Hormone replacement therapy
• Biotechnology-derived drugs – Erythropoietin interferon , Protease inhibitors
• Complex drug substances – Conjugated estrogens
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GENERIC SUBSTITUTION
• Drug product selection and generic drug product substitution are major responsibilities for
physicians, pharmacists, and others who prescribe, dispense, or purchase drugs.
• To facilitate such decisions, the FDA publishes annually, in print and on the Internet, Approved
Drug Products with Therapeutic Equivalence Evaluations, also known as the Orange Book.
• The Orange Book identifies drug products approved on the basis of safety and effectiveness by
the FDA and contains therapeutic equivalence evaluations for approved multisource
prescription drug products.
• These evaluations serve as public information and advice to state health agencies,
prescribers, and pharmacists to promote public education in the area of drug product selection
and to foster containment of healthcare costs.
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GENERIC SUBSTITUTION
➢To contain drug costs, most states have adopted generic substitution laws to allow
pharmacists to dispense a generic drug product for a brand-name drug product that has
been prescribed.
➢Some states have adopted a positive formulary, which lists therapeutically equivalent or
interchangeable drug products that pharmacists may dispense.
➢Other states use a negative formulary, which lists drug products that are not therapeutically
equivalent, and/or the interchange of which is prohibited.
➢If the drug is not in the negative formulary, the unlisted generic drug products are assumed
to be therapeutically equivalent and may be interchanged.
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APPROVED DRUG PRODUCTS WITH
THERAPEUTIC EQUIVALENCE
EVALUATIONS (ORANGE BOOK)
➢The Orange Book contains therapeutic equivalence evaluations for approved drug
products made by various manufacturers.
➢These marketed drug products are evaluated according to specific criteria.
➢The drug products are divided into two major categories: “A” codes apply to drug products
considered to be therapeutically equivalent to other pharmaceutically equivalent products,
and “B” codes apply to drug products that the FDA, at this time, does not consider to be
therapeutically equivalent to other pharmaceutically equivalent products.
➢A list of therapeutic-equivalence-related terms and their definitions is also given in the
monograph.
➢According to the FDA, evaluations do not mandate that drugs be purchased, prescribed, or
dispensed, but provide public information and advice.
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ABOUT THE ORANGE BOOK
➢ Fulfills a mandate to list drug products approved as
safe and effective under section 505(c) of the Federal
Food, Drug, and Cosmetic Act .
➢ Contains information with respect to substitution of
generic drug products for brand-name (“innovator”)
products.
CONTENTS OF THE ORANGE BOOK
✓ Prescription Products
✓ Over-the-Counter (OTC)
✓ Discontinued Drug Products
✓ Patents
✓ Exclusivity
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ABOUT THE ORANGE BOOK
Available on the internet: http://www.fda.gov/cder/ob/default.htm
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UPDATES TO THE ORANGE BOOK
➢Daily (Website and App)
✓Generic Drug approvals & Patents
➢Monthly (Website, App, and Publication)
✓Additions: NDA approvals and New exclusivities
✓Changes: Active ingredient, discontinued products,
strength, dosage form, route, therapeutic equivalence
(TE) code, Trade name
➢Annually (Website, App, and Publication)
✓Annual Orange Book Edition Publication
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COMPARISON
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REFERENCES
• Applied Biopharmaceutics and Pharmacokinetics by Leon Shargel, Andrew B.C Yu, 7th
Edition, Appleton & Lange; 2005.
• Biopharmaceutics & Pharmacokinetics; D.M. Brahmankar, S.B. Jaiswal; 1st edition, 12th
reprint; Vallabh Prakashan.
• Textbook of Biopharmaceutics and Pharmacokinetics, Dr. Shobha Rani R, Hiremath, Prism
Book.
• https://www.fda.gov/Drugs/DevelopmentApprovalProcess/default.htm
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THANK YOU
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