2. Content
Introduction
Goals of the BSC guidance
Principle
Biopharmaceutical Classification System
Factors affecting on BCS
Class Boundaries used in BCS
Applications of biopharmaceutics classification system
Biowaivers
Advantages of biowaivers
Limitation of BCS
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3. Introduction
The biopharmaceutical classification system (BCS) is a new concept in the
field of pharmaceutical science and technology
The BCS was first devised in 1995, by Amidon et al. and since then it has
become a benchmark in the regulation of bioequivalence of oral drug
products
The Biopharmaceutics Classification System (BCS) is a scientific framework for
classifying drug substances based on their aqueous solubility and intestinal
permeability
It reduce the need for in vivo bioequivalence studies, utilization of in vitro
dissolution tests as a surrogate for in vivo bioequivalence studies
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4. The BCS serves as a guiding tool for formulation scientists, for recommending
a strategy to improve the efficiency of drug development by proper selection
of dosage form and bioequivalence tests, to recommend a class of immediate
release (IR) solid dosage
The concept of BCS provides a better understanding of the relationship
between drug release from the product and the absorption process
The BCS has also got a place in various guidance documents of regulatory
importance
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5. Goals of the BSC 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) 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 and permeability characteristics of the
drug substance
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6. Principle
The principles of the BCS classification system can be applied to NDA and
ANDA approvals as well as to scaleup and post approval changes in drug
manufacturing
Therefore, can save significant amount of product development time of
pharmaceutical companies and reduces it costs
BCS is a drug development tool that allows estimation of the contributions of
three major factors, dissolution, solubility, and intestinal permeability, which
affect oral drug absorption from immediate release (IR) solid oral products
Knowledge of BCS helps to the formulation scientist to develop a suitable
dosage forms based on mechanistic rather than empirical approaches
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7. 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 concept can be
summarized by application of Fick’s first in the following equation
J = Pw Cw
Where J is the flux across the gut wall, Pw is the permeability of the gut wall
to the drug, and Cw is the concentration profile at the gut wall
In terms of bioequivalence, it is assumed that highly permeable, highly
soluble drugs housed in rapidly dissolving drug products will be bioequivalent
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8. Biopharmaceutical Classification System
The BCS categorizes drug substances into one of four BCS classes as follows:
Class I: high solubility, high permeability
Class II: low solubility, high permeability
Class III: high solubility, low permeability
Class IV: low solubility, low permeability
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10. Factors affecting on BCS
The BCS guidance takes into account three major factors, which govern the
rate and extent of drug absorption from immediate release (IR) solid dosage
forms
Solubility
Intestinal Permeability
Dissolution
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11. Solubility
The solubility is a property of substance by virtue of which it forms mixtures
with other substances, which are chemically and physically homogeneous
throughout
The degree of solubility is the concentration of the solute in a saturated
solution (in equilibrium with solid/drug) at any given temperature
The rate of dissolution and solubility are not the same
The higher single unit dose is completely soluble in 250 ml at pH 1- 6.8 ( 37˚C
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12. Determination of solubility
The solubilities are determined by exposing an excess of solid (drug) to the liquid
in water/buffer and assaying after equilibrium has been established
It usually takes 60 to 72 hours to establish equilibrium; sampling at earlier points
is necessary
The pH solubility profile of the drug is determined at 37 ± 10°C in the aqueous
medium, with pH in the range of 1-7.5
A sufficient number of samples should be evaluated, to accurately define the pH
solubility profile
A minimum of three replicate determinations of solubility in each pH condition
should be carried out
The conc. of the drug substance in the selected buffer or pH condition should be
determined using a validated solubility-indicating assay that can distinguish the
drug substances from their degradation products
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13. Permeability
Permeability along with solubility forms the backbone of BCS that helps in
accessing oral absorption of drug molecules
Permeability of the drug to pass the biological membrane which is the
lipophilic
Permeability is indirectly based on the extent of absorption of a drug
substance
Drug substance is considered to be highly permeable, when the extent of
absorption in human determined to be 90% or more of administered drug or
compare to in vivo reference dose
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14. Determination of permeability
The various methods used for permeability screening are as mentioned below:
Determination of o/w pH partition profile of the drug
Studies of the extent of absorption inhumans - Pharmacokinetic mass balance
and absolute bioavailability studies
In vitro permeation studies using excised human or animal intestinal tissue
Intestinal permeability studies - The following tissues can be used:
i) In-vivo intestinal perfusion studies in human
ii) In-vivo or in-situ perfusion studies in animals
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15. Dissolution
It is process in which solid substance solubilises in given solvent i.e mass
transfer from solid surface to liquid phase
Using USP apparatus I at 100 rpm or USP apparatus II at 50 rpm
Dissolution Media [900 ml]
0.1 N HCl or simulated gastric fluid (pH 1.2) without enzyme
pH 4.5 buffer & pH 6.8 buffer
Simulated intestinal fluid without enzyme
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16. Class Boundaries used in BCS
A drug substance is considered highly soluble when the highest dose strength
is soluble in < 250 ml water over a pH range 1 to 7.5
A drug is considered highly permeable when the extent of absorption in
humans is determined to be 90% of an administered dose, based on the mass
balance or in comparison to an intravenous dose
A drug product is considered to dissolve rapidly when 85% of the labeled
amount of drug substance dissolves within 30 minutes, using USP apparatus I
or II in a volume of < 900 ml buffer solution
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18. Class I Drugs
These 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
Bioavailability and dissolution is very rapid so bioavailability and bio-
equivalency studies are unnecessary for such product.
In vitro- In vivo correlation (IVIVC) cannot be expected
These compounds are highly suitable for design the SR and CR formulations
Examples include Ketoprofen, Propanolol, Metoprolol, Verapamil etc
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19. Class II drugs
These 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
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
In vitro- In vivo correlation (IVIVC) is usually expected for class II drugs
Examples: Phenytoin, Ketoconazole, Mefenamic acid
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20. Method of enhancing the dissolution
Micronization (reduced the particle size to increase the surface)
Solvent deposition (deposition of poorly soluble drugs on inert material)
Solid dispersions (dispersion of poorly soluble drugs in a solid matrix of the
water soluble carrier)
Use of the surfactants(to increasing the surface area by facilitating proper
wetting)
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21. Class III drugs
In these drugs permeability is rate limiting step for drug absorption
These drugs exhibit a high variation in the rate and extent of drug absorption
Since the dissolution is rapid, the variation is attributable to alteration of
physiology and membrane permeability rather than the dosage form factors
These drugs are problematic for controlled release development
These drugs showed the low bioavailability and need enhancement in
permeability
Examples include Acyclovir, Alendronate, Captopril, Neomycin B etc
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22. Following permeation enhancers can be used
Synthetics surfactants : SLS, Polysorbate 20 & 80, Sorbitan laurate
Bile Salts: Sodium deoxycholate, Sodium glycocholate, Sodium fusidate
Fatty acids and derivatives: Oleic acid, Caprylic acid, Lauric acid
Chelators: Sod EDTA, Citric acid, Salicylates
Inclusion complexes: Cyclodextrins and derivatives
Mucoadhesive polymers: Chitosan, Polycarbophil
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23. Class IV drugs
These exhibit poor and variable bioavailability
Several factors such as dissolution rate, permeability and gastric emptying
form the rate limiting steps for the drug absorption
These are unsuitable for controlled release
Examples: Furosemide, Cefuroxime etc
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24. Applications of biopharmaceutics classification system
Drug delivery technologies (Class I systems) : The Class I drugs are not those
in which either solubility or permeability is limiting within the target regions
of the GI tract
The drug release in such cases can be modulated using controlled release
technology. Controlled release technologies for Class I drugs includes number
of products such as -
Microsphere, MODAS (Multiporous oral drug absorption system)
SCOT (Single composition osmotic tablet system)
CONSURF (constant surface area drug delivery shuttle)
Diamatrix (Diffusion controlled matrix system)
DPHS (Delayed pulsatile hydrogel system)
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25. DUREDAS (Dual release drug absorption system)
GMHS (Granulated modulating hydrogel system)
IPDAS (Intestinal protective drug absorption system)
Multipor, Pharmazone (Microparticle Drug Delivery Technology)
PPDS (Pelletized pulsatile delivery system)
BEODAS (Bioerodible enhanced oral drug absorption system)
PRODAS (Programmable oral drug absorption system)
SODAS (Spheroidal oral drug absorption system)
SMHS (Solubility modulating hydrogel system) and SPDS (Stabilized pellet
delivery system)
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26. Class II systems:
This class relates to the cases in which solubility or dissolution rate is limiting,
and thus significantly affects absorption and BA
The technologies under this class include the approaches such as classical
micronization, stabilization of high-energy states (including lyophilized fast-
melt systems), use of surfactants, emulsion or microemulsion systems, solid
dispersion and use of complexing agent such as cyclodextrins
The technologies under this class include:
SoftGel (soft gelatin capsule formulation)
Zer-Os tablet technology (osmotic system)
Triglas and nanosized carriers such as nanoemulsion, nanosuspension and
nanocrystals are treated as hopeful means of increasing solubility and BA of
poorly water-soluble active ingredients
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27. Class III systems:
Manipulating the site or rate of exposure or perhaps by incorporating
functional agents into the dosage form to modify the metabolic activity of the
enzyme systems are included in Class III technologies
The technologies under this class include Oral vaccine system, Gastric
retention system, High-Frequency Capsule and Telemetric Capsule
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28. Class IV systems:
Extreme examples of Class IV compounds are exceptions rather than the rule
and are rarely developed to reach the market
But a number of examples of Class IV drugs do exist, for example,
Cyclosporin A, Furosemide, Ritonavir, Saquinavir and Taxol
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29. Biowaivers
Biowaiver means to obtain waive off for carrying out expensive and time-
consuming BA and BE studies
BCS provides biowaivers for Class I and III drug with some specifications
This waiver is for both pre- and post approval 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
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30. Advantages of biowaivers
Circumvent expensive and sometimes unethically questionable human testing
Reducing time in bringing product to the market
Reduce product cost
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31. The criteria recommended by USFDA BCS
guidance for Biowaiver
The drug substance should be highly soluble and highly permeable (Class I
drugs)
An immediate release drug product
For waiver of an in vivo relative BA study, dissolution should be greater than
85% in 30 minutes in the 3 recommended dissolution media
The drug should not be a narrow therapeutic index drug
Excipients used in the dosage form should have been previously used in a FDA
approved IR solid dosage forms
The drug must be stable in gastrointestinal tract and the product is designed
not to be absorbed in oral cavity
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32. BCS Based Biowaiver Approach
BCS framework – Drug substance categorized into 4 classes
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33. For BCS class 1 drug products
The following should be demonstrated:
The drug substance should be highly soluble (pH 1- 6.8)
The drug substance should be highly permeable
The drug product (test and reference) should be rapidly
dissolving (≥ 85% in 30 min)
The product does not contain any excipients that will affect the rate or
extent of absorption of the drug
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34. For BCS class 3 drug products
The following should be demonstrated:
The drug substance should be highly soluble (pH 1- 6.8)
The drug product (test and reference) should be rapidly dissolving (≥ 85% in
30 min)
The test product formulation is qualitatively the same and quantitatively very
similar
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35. Limitation of BCS
BCS based biowaiver are not applicable for the following:
Narrow therapeutic range drug products
BCS based biowaivers have limited application for the class II drugs
Dosage form meant for absorption in the oral cavity e.g. sublingual or buccal
tablets
Effects of food, absorptive transporters, efflux transporters, and routes of
elimination (renal/biliary) were important determinants of overall drug
absorption and bioavailability for immediate release oral dosage forms, which
are not considered in BCS
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