Regulatory status of biowaivers
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Regulatory status of biowaivers

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A brief review of the major global guidelines regarding biowaivers.

A brief review of the major global guidelines regarding biowaivers.

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Regulatory status of biowaivers Presentation Transcript

  • 1. REGULATORY STATUS OF BIOWAIVERS:GLOBAL PERSPECTIVE Ikjot Sodhi M.S. (Pharmaceutics) NIPER, Mohali
  • 2. CONTENTS: Background: About Biowaivers Current Pedestals of Biowaivers Perspective Regulatory Status of Biowaivers: Global Regulatory Guidelines and Guidances Conclusion 2
  • 3. BACKGROUND: ABOUT BIOWAIVERS Pharmaceutical Equivalence Perspective Regulatory Status of Biowaivers: Global Bioequivalence Therapeutic Equivalence 3
  • 4. CURRENT PEDESTALS OF BIOWAIVERS Applications for biowaivers are granted on the basis of: BCS • Considers the dose:solubility ratio, permeability and dissolution Perspective Regulatory Status of Biowaivers: Global behaviour. IVIVC • Based on correlation between in vitro data and in vivo profile. Composition Proportionality • New product is qualitatively same and 4 quantitatively proportional to bio-batch.
  • 5. BCS BASED BIOWAIVERS Class I Class II of solid oral For grants • High Solubility • Low Solubility of: dosage forms • High • High Perspective Regulatory Status of Biowaivers: Global Permeability • Permeability products SUPAC-IR • ANDAs Class III Class IVAspects: Current • High Solubility • Low Solubility • Low •• Low Extension Potential Permeability • Permeability Risk Assessment • Objections Along with dissolution behaviour of product 5
  • 6. IN VITRO - IN VIVO CORRELATION Level A Perspective Regulatory Status of Biowaivers: Global Level B Level C Multi-Level C Level D Used for biowaiver grants of : •modified release products or 6 •products subject to change in manufacturing procedure.
  • 7. Regulatory Status of Biowaivers: Global Perspective 7 1000 mgCOMPOSITION PROPORTIONALITY 500 mg 250 mg 100 mg
  • 8. DISSOLUTION TESTING - SOUL OF BIOWAIVERS Perspective Regulatory Status of Biowaivers: Global CP BCS IVIVC DISSOLUTION TESTING 8
  • 9. Regulatory Status of Biowaivers: Global Perspective 9DISSOLUTION TESTING - SOUL OF BIOWAIVERS
  • 10. GUIDELINES OF REGULATORY AGENCIESHHS-FDA (USA)• CFR Sec. 320.22(b) „Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.‟ Perspective Regulatory Status of Biowaivers: GlobalEMEA (EU)• Guideline on the Investigation of Bioequivalence, 2010PMDA (Japan)• Guideline for Bioequivalence Studies of Generic Products, 2006 10 …continued
  • 11. GUIDELINES OF REGULATORY AGENCIESCDSCO (India) Perspective Regulatory Status of Biowaivers: Global• Guidelines for Bioavailability and Bioequivalence Studies, 2005WHO (International)• Revision of Multi-source (generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability, 2005 11
  • 12. HHS-FOOD AND DRUG ADMINISTRATION Dosage Forms • Parenterals, solutions, IR solid oral dosage forms Perspective Regulatory Status of Biowaivers: Global Drug Efficacy Study Implementation (DESI) • No past bioINequivalence case • Example: Hydroxyzine Hydrochloride Tablets Fed-BE Study • If taken on empty stomach • No effect of food 12„Criteria for waiver of evidence of in vivo bioavailability or bioequivalence‟, CDER, HHS-FDA, CFR Sec. 320.22(b)
  • 13. HHS-FOOD AND DRUG ADMINISTRATION BCS Based Biowaivers • Only IR products with class 1 APIs • Post-change products (for minor changes) Perspective Regulatory Status of Biowaivers: Global Proportional Similarity based biowaivers • Else additive change must be NMT 10% or • Change of API compensated by excipients in different strengths IVIVC based biowaivers • For MR products • Post-change products (SUPAC Level 3) 13FDA Guidances- 1995, 1997, 1997, 2000, 2003
  • 14. EUROPEANS MEDICINES AGENCY • For additional strengths Composition • Some deviations from exactProportionality proportionality allowed Perspective Regulatory Status of Biowaivers: Global • Acceptable level A correlation IVIVC Based • Grants of biowaivers for variations • Class I and III BCS based Biowaivers • Pediatric Investigation Plan(PIP) Biowaivers of • Pediatric Committee decides eligibilityPediatric Study of biowaivers 14 Guideline on the Investigation of Bioequivalence, 2010
  • 15. PHARMACEUTICALS AND MEDICAL DEVICES AGENCYBCS not recognised testingMultimedia dissolution Perspective Regulatory Status of Biowaivers: Global• •McIlvaine buffersANDAsto prepare media No biowaivers to used in Japan• Dissolution experimental duration is definedIVIVC not recognised• Passing criteria• •Low solubility: predictor of in vivo absorption 85% disslution IVIVC not real Drug product fails to reach behaviourWider variations allowedJapanese Achlorhydic patients• Upto level D, variations are allowed without BE testing under • Dosage form performance across physiological pH carefully certain conditions reviewed• Separate qualification requirements for core versus coating layer for coated products. 15 Guideline for Bioequivalence Studies of Generic Products, PMDA, 2006
  • 16. CDSCO GUIDELINESBCS based biowaiver: Class I Dosage forms• Highly soluble• Highly permeable nasal sprays, powders Perspective Regulatory Status of Biowaivers: Global • Solutions, gases,• Dissolution: 85% in 15 min for reconstitutionComposition proportionality: Excipient considerations:• Qualitatively same• • All dosage forms must Quantitatively proportionalcontain essentially• same excipients as comparator Same method of manufacture• At least one of the strength has been studied for its bioavailability 16 Guidelines for Bioavailability and Bioequivalence Studies, CDSCO, 2005
  • 17. WORLD HEALTH ORGANIZATION BCS Class Dissolution profile Qualification Criteria High solubility Class I Rapidly dissolving F2>50 Perspective Regulatory Status of Biowaivers: Global • When API shows dose:solubility ratio of less Very Rapidly dissolving Profile comparison not than 250mL over pH range of 1.2-6.8 neededClass II with weak acidic Rapidly dissolving at pH Profile comparison at High permeability properties 6.8 pH 1.2, 4.5, 6.8 • WhenIIIAPI is absorbed to the extent of assessment of Class Very rapidly dissolving Risk 85% or more bioInequivalency more critical 17 WHO Multisource Document, 2005
  • 18. Regulatory Status of Biowaivers: Global Perspective 18COMPARATIVE APPROACH
  • 19. COMPARATIVE APPROACH Parameter US EU JapanAllowed BCS Class I I and III AllHighly permeable >90% >85% Not relevant Perspective Regulatory Status of Biowaivers: Global Rapidly >85% 30 min, 3 >85% 15 min, 3 No requirement Dissolving pHs pHs SUPAC allowed- None “Strictly Required if lowMedia Surfactant if justified discouraged” solubility Type A-E, Type B, Intramural SUPAC- All BCS C, E like SUPAC Composition Variation Classes level 1, 2, 3 Type D Change unique IVIVC as Dissolution Allowed for MR Allowed Not permitted Regimen/BE SUPAC Surrogate 19
  • 20. Regulatory Status of Biowaivers: Global Perspective 20CONCLUSION
  • 21. Regulatory Status of Biowaivers: GlobalPerspective 21
  • 22. Perspective Regulatory Status of Biowaivers: Global REGULATORY STATUS OF BIOWAIVERS: GLOBAL PERSPECTIVE22 Back-up Slides
  • 23. Regulatory Status of Biowaivers: Global Perspective 23BIOWAIVER MONOGRAPHS
  • 24. Regulatory Status of Biowaivers: Global Perspective 24RISK ASSESSMENT
  • 25. Regulatory Status of Biowaivers: Global Perspective 25DISSOLUTION PROFILE COMPARISON
  • 26. EXCIPIENTS Well established No interaction with the PK of the active substance Perspective Regulatory Status of Biowaivers: Global expected Not affect the rate and extent of absorption In case of atypically large amounts of known excipients or new excipients being used, additional documentation has to be submitted. 26
  • 27. BIOPHARMACEUTICS CLASSIFICATION SYSTEM Dose-Solubility Ratio (Highly soluble):  FDA- Highest dose strength is soluble in ≤ 250mL Perspective Regulatory Status of Biowaivers: Global aqueous media over pH range of 1-7.5, 37±1⁰C.  EMEA- same except for 1-6.8 Permeability (Highly permeable):  FDA- 90%  EMEA- 85% Dissolution behaviour:  FDA - pH 1.0, 4.6, 6.8 27  EMEA - pH 1.2, 4.5, 6.8