The document discusses the Biopharmaceutical Classification System (BCS), which classifies drug substances based on their aqueous solubility and intestinal permeability. The BCS categorizes drugs into four classes and can be used to guide formulation strategies. It provides a framework for biowaivers where in vivo bioequivalence studies are not required for highly soluble, highly permeable Class I drugs and highly soluble Class III drugs, if the drug products dissolve rapidly. The BCS aims to improve drug development efficiency by identifying bioequivalence tests that can be waived.

1. Biopharmaceutical
Classification System
By- Smrati Bhardwaj
M. Pharma (Pharmaceutics)
Swift, School of pharmacy
Smrati Bhardwaj
M. Pharma (Pharmaceutics)
Swift, School of pharmacy

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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9. BCS
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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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17. IVIVC expectations for IR products based
on BCS
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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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