Biowaivers

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2. 2/20
Drug products for which BA/BE can be waived

Biowaivers for solid oral dosage form based on
BCS
Biowaiver extensions
Data to support biowaivers

3. 3/20
Drug Products for which
bioavailability or bioequivalence can
be waived
Bioavailability is self evident
IVIVC
BCS based biowaivers

4. 4/20
Biowaivers for immediate release
solid oral dosage form based on
BCS (FDA Guidance for Industry)
Recommendations provided by guidance

5. 5/20
BCS pillars
SolubilityPermeabilityDissolution

6. 6/20
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

7. 7/20
Biopharmaceutics Classification System
Solubility
Easy to determine
Permeability
Harder to determine

8. 8/20
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

9. 9/20
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
to intestinal membrane permeability.

10. 10/20
Permeability Standards
IS = Internal standard for Permeability
studies
ES =Efflux pump substrates

11. 11/20
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 f
2.

12. 12/20
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

13. 13/20
No biowaiver for:
locally applied, systemically acting products
non-oral immediate release forms with systemic action
modified release products
transdermal products

14. 14/20
Biowaiver Extensions ?!Biowaiver Extensions ?!
Provided that ......
drug solubility is high,
permeability is limited,
excipients do not affect kinetics,
excipients do not interact ,.....

15. 15/20
Biowaiver Extensions ?!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)?!

16. 16/20
Biowaiver Extensions ?!Biowaiver Extensions ?!
For drugs showing ....
‘very’ high permeability
pH-dependent solubility within the physiologically
relevant pH range
.....an ‘intermediate solubility’ class is suggested

17. 17/20
Data to support Biowaivers
Data supporting
High solubility
High permeability
Rapid and similar dissolution

18. 18/20
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)

19. 19/20
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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