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Biopharmaceutical

Classification SystemPresented by

Aashka Jani

Assit Professor

M.Pharm , Q.A.

Saurashtra University

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INTRODUCTION The BCS is a scientific framework for classifying a

drug substance based on its aqueous solubility andintestinal permeability

According to the BCS the drugs can be

categorized in to four basic groups on the basesof their solubility and permeability GIT mucosa

The introduction of the BiopharmaceuticsClassification System (BCS) in 1995 was the resultof continuous efforts on mathematical analysisfor the elucidation of the kinetics and dynamicsof the drug process in the gastrointestinal (GI)

tract

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INTRODUCTION Since the BCS was introduced, it has been used

as a regulatory tool for the replacement ofcertain BE studies with accurate in vitro

dissolution tests.

This step certainly reduces timelines in the drugdevelopment process, both directly and

indirectly, and reduces unnecessary drug

exposure in healthy volunteers.

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INTRODUCTION

Purpose Of BCS :

1. Expands the regulatory application of the BCS and

recommends methods for classifying drugs.

2. Explains when a waiver for in vivo bioavailability and

bioequivalence studies may be requested based on the

approach of BCS.

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INTRODUCTION

Goals Of The BCS Guidance :

To improve the efficiency of drug development and the

review process by recommending a strategy for

identifying expendable clinical bioequivalence tests

To recommend a class of immediate-release (IR) solidoral 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 and

permeability characteristics of the drug substance.

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INTRODUCTION

Principle Concept Behind BCS:

Principle concept behind BCS is that if two drugs

products yield the same concentration profile along the

gastrointestinal (GI) tract, they will result in the same

plasma profile after oral administration. This conceptcan be summarized by application of Ficksfirst in the

following equation

J = PwCw. (1)

Where J is the flux across the gut wall, Pwis the

permeability of the gut wall to the drug, and Cwis the

concentration profile at the gut wall

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INTRODUCTION

Classifications :

The BCS is a scientific framework for classifying a drug

substance based on its aqueous solubility and intestinal

permeability.

It allows for the prediction of in vivo pharmacokineticsof oral immediate-release (IR) drug products by

classifying drug compounds into four classes based on

their solubility related to dose and intestinal

permeability in combination with the dissolution

properties of the dosage form

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INTRODUCTION

The interest in this classification system stems largelyfrom its application in early drug development and then

in the management of product change through its life

cycle.

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INTRODUCTION In early drug development, knowledge of the class of a

particular drug is an important factor influencing thedecision to continue or stop its development

Therefore , an organization wishing to produce oral

dosage forms will wish to limit development to

molecules with high permeability.

This classification is associated with a drug dissolution

and absorption model, which identifies the key

parameters controlling drug absorption.

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INTRODUCTION Absorption Number (An):

Defined as the ratio of the mean residence time to meanabsorption time.

It denotes the dimensionless dose/solubility ratio for

the particular drug formulation. The dose/solubility ratio indicates whether the capacity

of the GI fluid is sufficient to dissolve the entire dose

administered.

Tresidenceis the mean residence time

Peffis the effective permeability

R is the radius of the intestinal segment.

Residence timeis the

average amount of time

that a particle spends in aparticular system.

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INTRODUCTION Dissolution Number (Dn):

Defined as the ratio of mean residence time to meandissolution time.

Dose Number (D0):Defined as the mass divided by the product of uptake

volume (250 mL) and solubility of drug.

The mean residence time here is the average of the

residence time in the stomach, small intestine and the

colon.

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INTRODUCTION M0is the dose of drug administered, V0 is the

initial gastric volume (250 mL)

Cs is the saturation solubility

Tres is the mean residence time (180 min)

tdissis the time required for a drug particle to

dissolve

Peffis the effective permeability

R is the radius of the intestinal segment.

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Characteristics Of Drugs Of Various BCS

Classes :1. 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 ratedetermining step.

Bioavailability and dissolution is very rapid.

So bioavailability and bioequivalence studies are

unnecessary for such product. These compounds are highly suitable for design the SR and

CR formulations.

Examples include Ketoprofen, Naproxen, Carbamazepine,

Propanolol, Metoprolol, Diltiazem, Verapamil etc

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Classes :2. Class II : ( low solubility , high permeability) drugs have a high absorption number but a low

dissolution number.

In vivo drug dissolution is then a rate limiting step for

absorption.

These drug exhibited variable bioavailability and need

the enhancement in dissolution for increasing the

bioavailability. These compounds are suitable for design the SR and CR

formulations.

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Classes :

In vitro- In vivo correlation (IVIVC) is usually expected forclass II drugs.

Examples include Phenytoin, Danazol, Ketoconazole,Mefenamic acid, Nifedinpine, Felodipine, Nicardipine,Nisoldipine etc.

Method of enhancing the dissolution :

Use of surfactants

Complexation

By making the prodrug

Use of selected polymeric forms

Use of solvates and hydrates

Use of salt of weak acids and weak bases

Buffering the pH of the microenvironment

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Classes : If the formulation does not change the permeability or

gastrointestinal duration time, then Class I criteria can

be applied .

Examples include cimetidine, ranitidine, acyclovir,

neomycin B, atenolol, and captopril

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Classes :4. Class IV : ( low Solubility , low permeability ) The drugs of this class are problematic for effective oral

administration.

These compounds have poor bioavailability.

They are usually not well absorbed through theintestinal mucosa, and a high variability is expected.

Fortunately, extreme examples of Class IV compoundsare the exception rather than the rule, and these arerarely developed and marketed.

Nevertheless, several Class IV drugs do exist.

Examples include hydrochlorothiazide, taxol, andfurosemide.

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Classes :

Absorption Rate limiting process : Release of the drug substances from its dosage form or

drug permeation through the intestinal membrane arethe rate limiting steps for the absorption andbioavailability.

If the permeation through intestinal membrane is ratelimiting, the dissolution properties may be negligibleimportance.

Since the dissolution of the class I drug is very fast so

the BA/BE studies for this class seem to be unnecessary. The class III drug product are seem to be the better for

BA/BE studies as their bioavailability depend on thepermeability properties

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Dissolution Media For Various

Classes Of BCS

Media for Class I substances : Substances that belong to class I possess good aqueous

solubility and are transported through the GI mucosa.

Their bioavailability after oral administration is usually

close to 100 %, provided they are not decomposed in

GIT and do not under go extensive first pass metabolism

After administration, the dosage form quickly passes

into stomach and, usually disintegrates there, so it islogical to use a dissolution medium that reflects the

gastric conditions

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Classes Of BCS

Simulated gastrointestinal fluid (SGF) without enzymesis suitable for many immediate release dosage forms of

this class.

In case of weak acidic drugs simulated intestinal fluid

with out enzyme may be used due to hampereddissolution of this drug by the SGF medium.

Water is less suitable medium because it has a nominal

buffer capacity zero; therefore, the pH may vary duringthe test.

Milk as dissolution media can improve the drug

solubility includes the solubilisation of drugs in the fatty

part of the fluid

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Classes Of BCS

Media for Class II substances : Substances that belong to class II possess poor aqueous

solubility but are easily transported across the GImucosa.

Suitable bio relevant media for class II drugs are:(a) SGF plus surfactant (e.g., Triton X- 100), to simulate the

fasted state in the stomach.

This medium is specifically useful for weak basic drugs,

because these are most soluble under acidic condition.

Presence of surfactant in the gastric may play a role inthe wetting and solubilization of poorly soluble acids inthe stomach

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Classes Of BCS

The dissolution rate of the poorly soluble drug is oftenbetter in FaSSIF and FeSSIF than in the simple aqueous

buffers because of the increased wetting of the drug

surface and micelle solubilization of the drug by the bile

components of these media.(d) Hydroalcoholic mixtures as dissolution media were

popular for the dissolution of poorly soluble drugs.

Particular significance of these media over thesurfactant containing media is that they do not tend to

foam, which makes deaeration and volume adjustment

somewhat less frustrating

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Classes Of BCS

Media for Class III substances Despite their good aqueous solubility, class III

substances fail to achieve complete bioavailability after

oral dosing because of their poor membrane

permeability.

A simple aqueous media can be used

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Classes Of BCS

Media for Class IV substances Class IV drugs combine poor solubility with poor

permeability.

Therefore, similar to class III drugs, they usually do not

approach complete bioavailability.

Two compendial media i.e. SGF & SIF with addition Of a

surfactant to ensure the complete release of drug from

formulation can be used

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Selection Of Agitation Rate An appropriate rotational speed must be selected.

If rotation speed is very low, leading to low rates ofdissolution.

If the rate of rotation is too fast, the test will not be able

to discriminate between acceptable and not acceptable

Batches .

Rotation speed in range 50-75 rpm appear to be

suitable in case of paddle method.

If the basket method is used a rotational speed 75-100rpm may be suitable

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Duration Of Dissolution Tests For

BCS Classes

The duration of dissolution test must be tailored to not

only the site of absorption for the drug but also timingof administration.

If this is best absorbed from the upper small intestine

and is to be administered in the fasted state, dissolutiontest in a medium simulating fasted gastric conditions

with duration of 15 to 30 minutes are appropriate.

if a drug is administered with food and well absorbed

through the small intestine and proximal large intestine,duration of as long as 10 hours

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BCS Class Boundaries Class boundary parameters (i.e., solubility, permeability,

and dissolution) are for easy identification and

determination of BCS classSolubility: A drug substance is considered highly soluble

when the highest dose strength is soluble in 250 mL or less

of water over a pH range of 17.5 at 37 C

Permeability: A drug substance is considered highlypermeable when the extent of absorption in humans is

greater than 90% of an administered dose, based on mass-

balance or compared with an intravenous reference dose .

Dissolution: A drug product is considered rapidly

dissolving when 85% or more of the labeled amount of

drug substance dissolves within 30 min using USP

Apparatus 1 or 2 in a volume of 900 mL or less of buffersolutions

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Methodology For Classifying And Determining The

Dissolution Characteristics Of A Drug Product

A. Determining Drug Substance Solubility Class: Solubility is the amount of a substance that has passed

into solution when equilibrium is attained between the

solution and excess (i.e., undissolved) substance at a

given temperature and pressure.

Solubilities are determined by exposing an excess of

solid (drug) to the liquid in question (water/buffer) and

assaying after equilibrium has been established. It usually takes 6072 h to establish equilibrium.

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Dissolution Characteristics Of A Drug Product An objective of the BCS approach is to determine the

equilibrium solubility of a drug substance under

physiological pH conditions

The pH-solubility profile of the test drug substance

should be determined at 37 1oC in aqueous media

with a pH in the range of 1-7.5

A sufficient number of pH conditions should be

evaluated to accurately define the pH-solubility profile The number of pH conditions for a solubility

determination can be based on the ionization

characteristics of the test drug substance

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For example, when the pKa of a drug is in the range of 3-5,solubility should be determined at pH = pKa, pH = pKa +1,pH = pKa-1, and at pH = 1 and 7.5.

A minimum of three replicate determinations of solubility ineach pH condition is recommended

Standard buffer solutions described in the USP areconsidered appropriate for use in solubility studies.

If these buffers are not suitable for physical or chemicalreasons, other buffer solutions can be used

Methods other than the traditional shake-flask method,such as acid or base titration methods, can also be usedwith justification to support the ability of such methods topredict equilibrium solubility of drug substance.

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If degradation of the drug substance is observed as afunction of buffer composition and/or pH, it should bereported

The solubility class should be determined by calculating

the volume of an aqueous medium sufficient to dissolvethe highest dose strength in the pH range of 1-7.5.

A drug substance should be classified as highly solublewhen the highest dose strength is soluble in < 250 ml of

aqueous media over the pH range of 1-7.5. The volume estimate of 250 mL is derived from the

typical volume of water consumed during the oraladministration of a dosage form, which is about 8

ounces.

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This boundary value is a reflection of the minimum fluidvolume anticipated in the stomach at the time of drug

administration

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B. Determining Drug Substance Permeability Class : The permeability is based directly on the extent of

intestinal absorption of a drug substance in humans orindirectly on the measurements of the rate of mass

transfer across the human intestinal membrane To understand the nature of gastrointestinal

permeability limitations, there are methods andtechniques to both screen and grade these

characteristics A drug substance is considered highly permeable when

the extent of absorption in humans is 90% or more ofan administered dose, based on mass-balance or

compared with an intravenous reference dose.

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The methods that are routinely used for thedetermination of permeability include :

1. Human studies Mass balance pharmacokinetic studies

Absolute bioavailability studies, intestinal perfusionmethods

2. Intestinal permeability methods In vivo intestinal perfusions studies in humans

In vivo or in situ intestinal perfusion studies in animals

In vitro permeation experiments with excised human oranimal intestinal tissue

in vitro permeation studies across a monolayer of culturedepithelial cells. (e.g., Caco-2 cells or TC-7 cells)

3. Instability in the Gastrointestinal Tract

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1. Pharmacokinetic Studies in Humansa Mass Balance Studies :

Pharmacokinetic mass balance studies usingunlabeled, stable isotopes or a radiolabeld drug

substance can be used to document the extent ofabsorption of a drug

Depending on the variability of the studies, a sufficientnumber of subjects should be enrolled to provide a

reliable estimate of extent of absorption

Because this method can provide highly variableestimates of drug absorption for many drugs, othermethods described below may be preferable.

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b. Absolute Bioavailability Studies Oral BA determination using intravenous administration

as a reference can be used

Depending on the variability of the studies, a sufficientnumber of subjects should be enrolled in a study

When the absolute BA of a drug is shown to be 90% or

more, additional data to document drug stability in the

gastrointestinal fluid is not necessary

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2. Intestinal Permeability Methods : In vivo or in situ animal models and in vitro methods, such

as those using cultured monolayers of animal or human

epithelial cells, are considered appropriate for passively

transported drugs The observed low permeability of some drug substances in

humans could be caused by efflux of drugs via membrane

transporters such as P-glycoprotein

When the efflux transporters are absent in these models, or

their degree of expression is low compared to that in

humans, there may be a greater likelihood of

misclassification of permeability class for a drug subject to

efflux compared to a drug transported passively.

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this guidance recommends limiting the use ofnonhuman permeability test methods for drug

substances that are transported by passive mechanisms

For application of the BCS, an apparent passive

transport mechanism can be assumed when one of the

following conditions is satisfied:

1. A linear (pharmacokinetic) relationship between the

dose and measures of BA of a drug is demonstrated inhumans

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2. Lack of dependence of the measured in vivo or in situpermeability is demonstrated in an animal model on

initial drug concentration (e.g., 0.01, 0.1, and 1 times

the highest dose strength dissolved in 250 ml) in the

perfusion fluid

3. Lack of dependence of the measured in vitro

permeability on initial drug concentration (e.g., 0.01,

0.1, and 1 times the highest dose strength dissolved in

250 ml) is demonstrated in donor fluid and transport

direction using a suitable in vitro cell culture method

that has been shown to express known efflux

transporters

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For in vivo intestinal perfusion studies in humans, sixmodel drugs are recommended.

For in vivo or in situ intestinal perfusion studies in

animalsand for in vitro cell culture methods, twenty

model drugs are recommended.

For demonstration of suitability of a method, model

drugs should represent a range of low (e.g., < 50%),

moderate (e.g., 50 - 89%), and high ( 90%) absorption a low and a high permeability model drug should be

used as internal standards

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The choice of internal standards should be based oncompatibility with the test drug substance (i.e., they

should not exhibit any significant physical, chemical, or

permeation interactions)

The permeability values of the two internal standards

should not differ significantly between different tests,

including those conducted to demonstrate suitability of

the method.

At the end of an in situ or in vitro test, the amount of

drug in the membrane should be determined.

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3. Instability in the Gastrointestinal Tract Determining the extent of absorption in humans based

on mass balance studies using total radioactivity in

urine does not take into consideration the extent of

degradation of a drug in the gastrointestinal fluid prior

to intestinal membrane permeation

Stability in the gastrointestinal tract may be

documented using gastric and intestinal fluids obtainedfrom human subjects

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Drug solutions in these fluids should be incubated at37oC for a period that is representative of in vivo drug

contact with these fluids for example, 1 hour in gastric

fluid and 3 hours in intestinal fluid.

Drug concentrations should then be determined using a

validated stability-indicating assay method

Significant degradation (>5%) of a drug in this protocol

could suggest potential instability Use of gastrointestinal fluids from suitable animal

models and/or simulated fluids such as Gastric and

Intestinal Fluids USP can be substituted when properly

justified

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C. Determining Drug Product Dissolution Characteristics andDissolution Profile Similarity

The BCS classifies a drug product as rapidly dissolving whenno less than 85% of the labeled amount of the drugsubstance dissolves in 30 min using the following

USP Apparatus 1 (basket) at 100 rpm or USP Apparatus 2(paddle) at 50 rpm.

Dissolution medium volume of 900 mL or less in each of thefollowing :

1. 0.1 N HCI or simulated gastric fluid (SGF) USP

without enzymes

2. A pH 4.5 buffer

3. A pH 6.8 buffer or simulated intestinal fluid (SIF) USP

without enzymes

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The USP Apparatus I (basket method) is generallypreferred for capsules and products that tend to float

USP Apparatus II (paddle method) is generally preferred

for tablets

For some tablet dosage forms, in vitro (but not in vivo)dissolution may be slow due to the manner in whichthe disintegrated product settles at the bottom of adissolution vessel.

In such situations, USP Apparatus I may be preferredover Apparatus II

A minimum of 12 dosage units of a drug product shouldbe evaluated

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Additional Considerations For Requesting A Bio

waiver

a Biowaiveris a waiver (exemption) of clinicalbioequivalence studies given to a drug product.

When requesting a BCS-based waiver for in vivo BA/BE

studies for IR solid oral dosage forms, applicants should

note that the following factors can affect their request

or the documentation of their request:

1. Excipients

2. Prodrugs

3. Exceptions

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waiver

1. Excipients : Excipients can sometimes affect the rate and extent of

drug absorption.

In general, using excipients that are currently in FDA-approved IR solid oral dosage forms will not affect the

rate or extent of absorption of a highly soluble and

highly permeable drug substance that is formulated in

a rapidly dissolving IR product. To support a biowaiver request, the quantity of

excipients in the IR drug product should be consistent

with the intended function (e.g., lubricant)

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Additional Considerations For Requesting A

Biowaiver

When new excipients or atypically large amounts ofcommonly used excipients are included in an IR solid

dosage form, additional information documenting the

absence of an impact on BA of the drug may be

requested by the Agency.

Large quantities of certain excipients, such as

surfactants (e.g., polysorbate 80) and sweeteners (e.g.,

mannitol or sorbitol) may be problematic, and sponsorsare encouraged to contact the review division when this

is a factor.

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waiver

2. Prodrugs : Permeability of prodrugs will depend on the mechanism

and (anatomical) site of conversion to the drug substance

When the prodrug-to-drug conversion is shown to occur

predominantly after intestinal membrane permeation, the

permeability of the prodrug should be measured

When this conversion occurs prior to intestinal

permeation, the permeability of the drug should be

determined

Dissolution and pH-solubility data on both prodrug and

drug can be relevant.

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Biowaiver

Examples include digoxin, lithium, phenytoin,theophylline, and warfarin.

sponsors should contact the appropriate review division

to determine whether a drug should be considered to

have a narrow therapeutic range.

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Biowaiver

2. Products Designed to be Absorbed in the Oral Cavity: A request for a waiver of in vivo BA/BE studies based on

the BCS is not appropriate for dosage forms intended

for absorption in the oral cavity (e.g., sublingual or

buccal tablets).

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Regulatory Applications Of The BCS

A. INDs/NDAs

B. ANDAs

C. Post approval Changes

A. INDs/NDAs :

BCS-based biowaivers are applicable to the to-be

marketed formulation when changes in components,

composition, or method of manufacture occur to theclinical trial formulation, as long as the dosage forms

have rapid and similar in vitro dissolution profiles

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This approach is useful only when the drug substance is

highly soluble and highly permeable (BCS Class I) andthe pre- and post-change formulations are

pharmaceutical equivalents

A specific objective is to establish in vivo performance of

the dosage form used in the clinical studies thatprovided primary evidence of efficacy and safety

The sponsor may wish to determine the relative BA of

an IR solid oral dosage form by comparison with an oralsolution, suspension, or intravenous injection

The BA of the clinical trial dosage form should be

optimized during the IND period.

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BCS-based biowaivers are intended only for BE studies.

They do not apply to food effect BA studies or otherpharmacokinetic studies

B. ANDAs :

BCS-based biowaivers can be requested for rapidly

dissolving IR test products containing highly soluble and

highly permeable drug substances, provided that the

reference listed drug product is also rapidly dissolving

and the test product exhibits similar dissolution profilesto the reference listed drug product

This approach is useful when the test and reference

dosage forms are pharmaceutical equivalents.

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The choice of dissolution apparatus (USP Apparatus I orII) should be the same as that established for thereference listed drug product.

C. Post approval Changes :

BCS-based biowaivers can be requested for significantpostapproval changes to a rapidly dissolving IR productcontaining a highly soluble, highly permeable drugsubstance, provided that dissolution remains rapid for

the post change product and both pre- and post changeproducts exhibit similar dissolution profiles

This approach is useful only when the drug productspre- and post change are pharmaceutical equivalents

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Applications Of BCS In Oral Drug

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Delivery Technology

In the early development phase, the permeability and

solubility boundaries can be set as selection criteria for

new drug candidates

Solubility is typically measured by the shake-flask

method and permeability by Caco-2 cells. Gastric emptying of the dissolved drug is the rate

limiting step for oral absorption of class I drugs with

rapid dissolution

Class I drugs have favorable absorption properties,

leading to rapid and complete absorption.


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Delivery Technology

IVIVCs cannot be found for IR formulations of class I

drugs if dissolution is faster than gastric emptying.

Thus, the dissolution method can be a simple and

cheap quality control tool.

if a BCS biowaiver is utilized in a regulatory application,dissolution should be tested in three different media

representing the pH range of the gastrointestinal tract.

BCS III drugs have permeability limited absorption.Incomplete absorption due to limited permeability can

rarely be solved by formulation factors, because specific

and non-toxic permeability enhancers are difficult to

develop


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Delivery Technology

bioavailability may be increased by prodrug

derivatization of the parent compound, improving drug

distribution to the target tissue

The role of the dissolution method is to act as a quality

control tool to ensure batch-to-batch consistency.


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Delivery Technology

Formulation and dissolution methods may be similar to

those for class II drugs if dissolution is the rate-limiting

factor.

For permeability-limited absorption, class IV drugs may

be developed like class III drugs. Some class IV drugs may be unsuitable for oral

administration if the fraction absorbed is too low and

oral absorption is highly variable


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Delivery Technology

2. Approval of the generics: As subsequent R & D proceeds, dissolution studies are

done on a new formulation in accordance with the FDA

guidance

The knowledge of BCS can also help the formulation

scientist to develop a dosage form based on mechanistic

approach rather than empirical approach.

This allows determining the potential for invitro invivocorrelation and significantly reducing the in vivo studies

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Data To Support A Request For Biowaivers:

A. Data Supporting High Solubility

Data supporting high solubility of the test drug substanceshould be developed .The following information should beincluded in the application:

1. A description of test methods, including information onanalytical method and composition of the buffer solutions

2. Information on chemical structure, molecular weight,nature of the drug substance (acid, base, amphoteric, orneutral), and dissociation constants (pKa(s))

3. Test results (mean, standard deviation, and coefficient ofvariation) summarized in a table under solution pH, drugsolubility (e.g., mg/ml), and volume of media required todissolve the highest dose strength

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4. A graphic representation of mean pH-solubility profile

B. Data Supporting High Permeability :

Data supporting high permeability of the test drug

substance should be developed The following

information should be included in the application:

1. For human pharmacokinetic studies, information on

study design and methods used along with thepharmacokinetic data

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2. For direct permeability methods, information

supporting the suitability of a selected method that

encompasses a description of the study method,

criteria for selection of human subjects, animals, or

epithelial cell line, drug concentrations in the donorfluid, description of the analytical method, method

used to calculate extent of absorption or permeability,

and where appropriate, information on efflux potential

(e.g., bidirectional transport data)

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3. A list of selected model drugs along with data on

extent of absorption in humans (mean, standarddeviation, coefficient of variation) used to establish

suitability of a method, permeability values for each

model drug (mean, standard deviation, coefficient of

variation), permeability class of each model drug, anda plot of the extent of absorption as a function of

permeability (mean standard deviation or 95%

confidence interval) with identification of the low/high

permeability class boundary and selected internal

standard

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Information to support high permeability of a test drug

substance should include permeability data on the testdrug substance, the internal standards (mean, standard

deviation, coefficient of variation), stability information,

data supporting passive transport mechanism where

appropriate, and methods used to establish highpermeability of the test drug substance

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C. Data Supporting Rapid and Similar Dissolution

For submission of a biowaiver request, an IR product shouldbe rapidly dissolving. Data supporting rapid dissolutionattributes of the test and reference products should bedeveloped

1. A brief description of the IR products used for dissolutiontesting, including information on batch or lot number,expiry date, dimensions, strength, and weight

2. Dissolution data obtained with 12 individual units of thetest and reference products using recommended testmethods in section III.C.

The percentage of labelled claim dissolved at each specifiedtesting interval should be reported for each individualdosage unit

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The mean percent dissolved, range (highest and lowest)

of dissolution, and coefficient of variation (relativestandard deviation) should be tabulated.

A graphic representation of the mean dissolution

profiles for the test and reference products in the three

media should also be included.

3. Data supporting similarity in dissolution profiles

between the test and reference products in each of the

three media, using the f2

metric

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D. Additional Information :

The manufacturing process used to make the test

product should be described briefly to provide

information on the method of manufacture (e.g., wet

granulation vs. direct compression).

A list of excipients used, the amount used, and their

intended functions should be provided.

Excipients used in the test product should have been

used previously in FDA-approved IR solid oral dosageforms.

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REFERENCES

M. Yasir et. al Biopharmaceutical Classification System

:An Account , International J of PharmTech Research,2(3) , July-Sept 2010 , pp 1681-1690

Guidance for Industry , Waiver of In Vivo

Bioavailability and Bioequivalence Studies for

Immediate-Release Solid Oral Dosage Forms Based on

a Biopharmaceutics Classification System U.S.

Department of Health and Human Services , Food and

Drug Administration, Center for Drug Evaluation andResearch (CDER), Aug 2000

Documents

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