Biowaivers

Basic Information regarding Bio waiver

1. BIOWAIVERBIOWAIVER
PRESENTED BY
Mangesh S.Gawade
Regulatory Affairs Specialist Galpha Laboratories Ltd

2. What it means?
Approach & need for development
Biowaivers based on BCS
Biowaiver criteria
Biowaiver extensions
Data to support biowaiver
Requirements of biowaiver studies
Economic important of biowaiver
Questions?
Contents of presentationContents of presentation

3. Waived
Means
Win
Biowaiver means that in vivo bioavailability
and/or bioequivalence studies may be waived.
What it means?What it means?

4. A generally accepted practical definition of
Bioavailability:
The extent and the rate at which a drug is delivered from
a pharmaceutical form and becomes available in the
general circulation.
Two oral dosage forms are considered to be
bioequivalent if both rate and extent of absorption are
the same.
Approach & need of developmentApproach & need of development

5. In the 1960's several case histories started on issues
related to bioequivalence of medicinal products. It
became evident that differences in rate and extent of
absorption could result in either under medication or
intoxication.
In 1967 the FDA defined criteria for possible 'problem'
drugs, recognizing that bioequivalence is an important
issue in drug development. Bioequivalence is even
more important in the case of Narrow Therapeutic
Index (NTI) drugs.
Approach & need of developmentApproach & need of development

6. What is BCS?
The Biopharmaceutics Classification System (BCS)
was proposed in 1995 by Amidon etal.
It is a scientific framework which divides APIs into
four groups, according to their solubility and
permeability properties.

7. Solubility
Permeability
Dissolution

8. Class 1: High Solubility, High Permeability
Class 2: Low Solubility, High Permeability
Class 3: High Solubility, Low Permeability
Class 4: Low Solubility, Low Permeability
BCS divides drugs into four different classes:

9. Objective:
To determine equilibrium solubility of a
drug substance under physiological pH
conditions.

pH-solubility profile of test drug at 37°C in
aqueous media with a pH range of 1 to
7.5
Shake-flask or titration method
Analysis by validated stability-indicating
assay

10. 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.

11. USP apparatus I (basket) at 100 rpm or USP
apparatus II (paddle) at 50 rpm.
Dissolution media (900 ml):
A pH 1.2 - 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. BCS based Biowaiver – No In vivo/BA/BE Study 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 e.g Sublingual tablets
BIOWAIVER CRITERIABIOWAIVER CRITERIA

13. No Biowaiver for:
Locally applied
Systemically acting products
Non-oral immediate release forms with systemic
action
Modified release products transdermal products
BIOWAIVER CRITERIABIOWAIVER CRITERIA

14. Provided that ......
Drug solubility is high,
Permeability is limited,
Excipients do not affect kinetics,
Excipients do not interact ,.....
BIOWAIVER EXTENTIONSBIOWAIVER EXTENTIONS

15. ....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)
BIOWAIVER EXTENTIONSBIOWAIVER EXTENTIONS

16. For drugs showing ....
‘very’ high permeability
pH-dependent solubility within the physiologically
relevant pH range
.....an ‘intermediate solubility’ class is suggested
BIOWAIVER EXTENTIONSBIOWAIVER EXTENTIONS

17. Data supporting:
High solubility
High permeability
Rapid and similar dissolution
DATA TO SUPPORT BIOWAIVER DATA TO SUPPORT BIOWAIVER

18. Allowance of regulatory authorities like FDA, WHO etc.
Drugs should have high solubility and high permeability
according to bio-pharmaceutics classification system
(BCS I). Other classification systems are part of current
investigations.
Dissolution Test in 3 different media
- Buffer pH
- Buffer pH 4.5,
- Buffer pH 6.8
-------- all in 900ml and at 37°C ± 2
Dissolution Test in 3 different media

19. 12 Samples in each media, paddle 50rpm or basket
100rpm
Sampling time: 10, 15, 20, 30, 45 and 60 minutes.
The profiles of the test and reference products (for
example original tablets if generic products are
tested) must be in all three media.
The products are similar if the factor f2 ? 50 and
both products show? 85% dissolution in 15 min

20. When the BE substitution is done by biowaiver the
cost reductions are enormous, and is allowed by
regulatory authorities $300,000 for a BE study
with in-vivo tests compared to $2,000 for a
Biowaiver study.

21.  Write note on drug products for which BA/BE
studies can be waived.
Write note on BCS based biowaivers.
Enlist the methods to determine the permeability of
drug substance.
Comment on Biowaiver extensions.
QUESTIONS QUESTIONS