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  2. 2. Drug products for which BA/BE can be waivedBiowaivers for solid oral dosage form based onBCSBiowaiver extensionsData to support biowaivers 2/20
  3. 3. Drug Products for whichbioavailability or bioequivalence canbe waived Bioavailability is self evident IVIVC BCS based biowaivers 3/20
  4. 4. Biowaivers for immediate releasesolid oral dosage form based onBCS (FDA Guidance for Industry) Recommendations provided by guidance 4/20
  5. 5. BCS pillars Solubility Permeability Dissolution 5/20
  6. 6. BCS drug substance are classified asbelow:• Class 1: High Solubility, High Permeability• Class 2: Low Solubility, High Permeability• Class 3: High Solubility, Low Permeability• Class 4: Low Solubility, Low Permeability 6/20
  7. 7. Biopharmaceutics Classification SystemSolubility Easy to determinePermeability Harder to determine 7/20
  8. 8. 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 8/20
  9. 9. PermeabilityExtent of absorption in humans determined by:Pharmacokinetic studies in humans: Mass-balance studies Absolute bioavailability studiesIntestinal 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 monolayersInstability in the Gastrointestinal Tract Accounts for extent of degradation of a drug in the GI fluid prior to intestinal membrane permeability. 9/20
  10. 10. Permeability Standards IS = Internal standard for Permeability studies ES =Efflux pump substrates 10/20
  11. 11. 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. 11/20
  12. 12. BCS BIOWAIVER (no in vivo BA/BEneeded)  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 12/20
  13. 13. No biowaiver for: locally applied, systemically acting products non-oral immediate release forms with systemic action modified release products transdermal products 13/20
  14. 14. Biowaiver Extensions ?! Provided that ......  drug solubility is high,  permeability is limited,  excipients do not affect kinetics,  excipients do not interact ,..... 14/20
  15. 15. 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)?! 15/20
  16. 16. Biowaiver Extensions ?! For drugs showing ....  ‘very’ high permeability  pH-dependent solubility within the physiologically relevant pH range ‘intermediate solubility’ class is suggested 16/20
  17. 17. Data to support Biowaivers Data supporting High solubility High permeability Rapid and similar dissolution 17/20
  18. 18. 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) 18/20
  19. 19. REFERENCES %2004-1_korr.pdf px 30-color.pdf 6/S_ClinicalPKF813Lecture1709March2006Bioa vailabilityandBioequivalencerevised.pdf eur/LeonShargel.pdf 19/20
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