1. 1/20

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
2/20

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

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

5. BCS pillars
Solubility Permeability Dissolution
5/20

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
6/20

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

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
8/20

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
to intestinal membrane permeability. 9/20

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

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.
11/20

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
12/20

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

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

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)?!
15/20

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

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

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)
18/20

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
19/20

20. 20/20