The document discusses biowaivers for solid oral dosage forms based on the Biopharmaceutics Classification System (BCS). It describes the four BCS classes based on a drug's solubility and permeability characteristics. For highly soluble, highly permeable Class 1 drugs, in vivo bioavailability/bioequivalence studies can be waived if the test and reference products have rapid dissolution. The document outlines methods for determining solubility and permeability to classify drugs. It also discusses potential biowaiver extensions for Class 3 drugs or drugs with pH-dependent solubility if dissolution is very rapid.

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2. Drug products for which BA/BE can be waived
Biowaivers for solid oral dosage form based on
BCS
Biowaiver extensions
Data to support biowaivers
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3. Drug Products for which
bioavailability or bioequivalence can
be waived
Bioavailability is self evident
IVIVC
BCS based biowaivers
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4. Biowaivers for immediate release
solid oral dosage form based on
BCS (FDA Guidance for Industry)
Recommendations provided by guidance
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5. BCS pillars
Solubility Permeability Dissolution
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6. BCS drug substance are classified as
below:
• Class 1: High Solubility, High Permeability
• Class 2: Low Solubility, High Permeability
• Class 3: High Solubility, Low Permeability
• Class 4: Low Solubility, Low Permeability
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7. Biopharmaceutics Classification System
Solubility
 Easy to determine
Permeability
 Harder to determine
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8. Solubility
Objective: to determine equilibrium solubility of a
drug substance under physiological pH conditions.
 pH-solubility profile of test drug at 37oC in aqueous
media with a pH range of 1 to 7.5
 Shake-flask or titration method
 Analysis by validated stability-indicating assay
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9. Permeability
Extent of absorption in humans determined by:
Pharmacokinetic studies in humans:
 Mass-balance studies
 Absolute bioavailability studies
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 or animal
intestinal tissue
 In vitro permeation experiments across epithelial cell
monolayers
Instability in the Gastrointestinal Tract
 Accounts for extent of degradation of a drug in the GI fluid prior
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10. Permeability Standards
IS = Internal standard for Permeability
studies
ES =Efflux pump substrates
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11. DISSOLUTION DETERMINATION
USP apparatus I (basket) at 100 rpm or USP apparatus II
(paddle) at 50 rpm.
Dissolution media (900 ml):
• 0.1 N HCl or simulated gastric fluid USP,
• A pH 4.5 buffer,
• A pH 6.8 buffer or simulated intestinal fluid USP.
Compare dissolution profiles of test and reference products
Using a similarity factor f2.
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12. BCS BIOWAIVER (no in vivo BA/BE
needed)
 Rapid dissolution relative to gastric emptying
 Class 1: High solubility, High permeability
 Wide therapeutic window
 Excipients used in dosage form should be
used previously in FDA approved Immediate
Release (IR) solid dosage forms
 Prodrugs; buccal absorption
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13. No biowaiver for:
locally applied, systemically acting products
non-oral immediate release forms with systemic action
modified release products
transdermal products
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14. Biowaiver Extensions ?!
Provided that ......
 drug solubility is high,
 permeability is limited,
 excipients do not affect kinetics,
 excipients do not interact ,.....
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15. Biowaiver Extensions ?!
....then very rapid dissolution (e.g.>85% in 15 min)
of test and reference may ensure similar product
characteristics
because...
....absorption process is probably independent from
dissolution and not product related…
 limited absorption kinetics due to poor drug
permeability and/or gastric emptying
♦ Biowaiver for BCS class III drugs (e.g. Atenolol)?!
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16. Biowaiver Extensions ?!
For drugs showing ....
 ‘very’ high permeability
 pH-dependent solubility within the physiologically
relevant pH range
.....an ‘intermediate solubility’ class is suggested
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17. Data to support Biowaivers
Data supporting
High solubility
High permeability
Rapid and similar dissolution
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18. Write note on drug products for which BA/BE
studies can be waived. (5 marks)
Write note on BCS based biowaivers. (5 marks)
Enlist the methods to determine the permeability
of drug substance. (2 marks)
Comment on Biowaiver extensions. (2 marks)
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19. REFERENCES
 http://ikev.org/haber/bioav/Barends_Istanbul
%2004-1_korr.pdf
 http://www.absorption.com/site/Services/BCS.as
px
 http://ikev.org/haber/bioav/BA-BE%20Intro-01-
30-color.pdf
 http://medicine.iupui.edu/clinical/F813_spring200
6/S_ClinicalPKF813Lecture1709March2006Bioa
vailabilityandBioequivalencerevised.pdf
 http://www.sfbci.com/SFBC/upload/sfbc/Generat
eur/LeonShargel.pdf
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