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
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.
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 f2.
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
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.
QUESTIONSQUESTIONS