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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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