Biowaivers
Transcript of Biowaivers
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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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Drug Products for which bioavailability or bioequivalence can be waived
Bioavailability is self evident
IVIVC
BCS based biowaivers
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Biowaivers for immediate release solid oral dosage form based on BCS (FDA Guidance for Industry)
Recommendations provided by guidance
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BCS pillars
Solubility Permeability Dissolution
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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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Biopharmaceutics Classification System
Solubility
Easy to determine
Permeability
Harder to determine
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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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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.
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Permeability Standards
IS = Internal standard for PermeabilitystudiesES =Efflux pump substrates
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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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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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No biowaiver for:
locally applied, systemically acting productsnon-oral immediate release forms with systemic
actionmodified release productstransdermal products
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Biowaiver Extensions ?!Biowaiver Extensions ?!
Provided that ......
drug solubility is high, permeability is limited, excipients do not affect kinetics, excipients do not interact ,.....
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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
fromdissolution 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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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
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Data to support Biowaivers
Data supporting
High solubilityHigh permeabilityRapid and similar dissolution
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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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REFERENCES
http://ikev.org/haber/bioav/Barends_Istanbul%2004-1_korr.pdf
http://www.absorption.com/site/Services/BCS.aspx
http://ikev.org/haber/bioav/BA-BE%20Intro-01-30-color.pdf
http://medicine.iupui.edu/clinical/F813_spring2006/S_ClinicalPKF813Lecture1709March2006BioavailabilityandBioequivalencerevised.pdf
http://www.sfbci.com/SFBC/upload/sfbc/Generateur/LeonShargel.pdf
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