1/20 PRESENTED BY BRAHMABHATT BANSARI K. M. PHARM DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLGY L. M. COLLEGE OF PHARMACY

2/20 Drug products for which BA/BE can be waived Biowaivers for solid oral dosage form based on BCS Biowaiver extensions Data to support biowaivers

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

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

5/20 BCS pillars SolubilityPermeability Dissolution

6/20 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

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

8/20 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

9/20 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.

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

11/20 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 f 2.

12/20 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

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

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

15/20 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)?!

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

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

18/20  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)

19/20 REFERENCES  _korr.pdf _korr.pdf  px px  30-color.pdf 30-color.pdf  06/S_ClinicalPKF813Lecture1709March2006Bioav ailabilityandBioequivalencerevised.pdf 06/S_ClinicalPKF813Lecture1709March2006Bioav ailabilityandBioequivalencerevised.pdf  eur/LeonShargel.pdf eur/LeonShargel.pdf

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