Download - Regulatory status of biowaivers
REGULATORY STATUS OF BIOWAIVERS:GLOBAL PERSPECTIVE
Ikjot Sodhi
M.S. (Pharmaceutics)
NIPER, Mohali
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CONTENTS:
Background: About Biowaivers Current Pedestals of Biowaivers Regulatory Guidelines and Guidances Conclusion
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BACKGROUND: ABOUT BIOWAIVERS
Therapeutic Equivalence
Bioequivalence
Pharmaceutical
Equivalence
IN VIVO STUDIES
Exemptionto in vivo studies is
BIOWAIVER
IN VITRO STUDIES
Only in vitro studiessufficient assurrogate
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CURRENT PEDESTALS OF BIOWAIVERS
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BCS• Considers the dose:solubility ratio,
permeability and dissolution behaviour.
IVIVC• Based on correlation between in vitro
data and in vivo profile.
Composition Proportionality• New product is qualitatively same and
quantitatively proportional to bio-batch.
Applications for biowaivers are granted on the basis of:
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eBCS BASED BIOWAIVERS
Class I• High Solubility• High Permeability
Class II• Low Solubility• High Permeability
Class III• High Solubility• Low Permeability
Class IV• Low Solubility• Low Permeability
Current Aspects:
• Extension Potential• Risk Assessment• Objections
For grants of solid oral dosage forms of:
• SUPAC-IR products• ANDAs
Along with dissolution behaviour of product
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eIN VITRO - IN VIVO CORRELATION
Level A
Level B
Level C
Level D
Regulatory Acceptance of Biowaiver
Used for biowaiver grants of :•modified release products or•products subject to change in manufacturing procedure.
Multi-Level C
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eCOMPOSITION PROPORTIONALITY
• Basis of biowaivers for additional strength• Criterion: API and excipients must be-
Qualitatively same Quantitatively proportional
• Manufactured by same manufacturing process• Issue of linearity…
1000mg
500mg
250mg
100mg
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DISSOLUTION TESTING - SOUL OF BIOWAIVERS
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DISSOLUTION TESTING
IVIVC
BCSCP
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DISSOLUTION TESTING - SOUL OF BIOWAIVERS
• Different from compendial testingMedia- 900mL 0.1N HCl, pH 4.5, pH 6.8Number of units tested
• Minimum 3 time-points for both profiles• Apparatus: Rotating basket, rotating paddle• Comparative dissolution profile• Acceptance criteria:
f1 value between 0-15f2 not less than 50
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eGUIDELINES OF
REGULATORY AGENCIES
HHS-FDA (USA)• CFR Sec. 320.22(b) ‘Criteria for waiver of
evidence of in vivo bioavailability or bioequivalence.’
EMEA (EU)• Guideline on the Investigation of
Bioequivalence, 2010
PMDA (Japan)• Guideline for Bioequivalence Studies of Generic
Products, 2006
…continued
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eGUIDELINES OF
REGULATORY AGENCIES
CDSCO (India)• Guidelines for Bioavailability and
Bioequivalence Studies, 2005
WHO (International)• Revision of Multi-source (generic)
Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability, 2005
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HHS-FOOD AND DRUG ADMINISTRATION
• Parenterals, solutions, IR solid oral dosage forms
Dosage Forms
• No past bioINequivalence case• Example: Hydroxyzine Hydrochloride
Tablets
Drug Efficacy Study Implementation (DESI)
• If taken on empty stomach• No effect of food
Fed-BE Study
‘Criteria for waiver of evidence of in vivo bioavailability or bioequivalence’, CDER, HHS-FDA, CFR Sec. 320.22(b)
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HHS-FOOD AND DRUG ADMINISTRATION
• Only IR products with class 1 APIs• Post-change products (for minor
changes)
BCS Based Biowaivers
• Else additive change must be NMT 10% or
• Change of API compensated by excipients in different strengths
Proportional Similarity based biowaivers
• For MR products• Post-change products (SUPAC Level 3)
IVIVC based biowaivers
FDA Guidances- 1995, 1997, 1997, 2000, 2003
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Guideline on the Investigation of Bioequivalence, 2010
BIOWAIVERS
• For additional strengths• Some deviations from exact
proportionality allowedComposition
Proportionality
• Acceptable level A correlation• Grants of biowaivers for variationsIVIVC Based
• Class I and IIIBCS based Biowaivers
• Pediatric Investigation Plan(PIP)• Pediatric Committee decides
eligibility of biowaiversBiowaivers of
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EUROPEANS MEDICINES AGENCY
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PHARMACEUTICALS ANDMEDICAL DEVICES AGENCY
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BCS not recognised• No biowaivers to ANDAs in Japan
IVIVC not recognised• IVIVC not real predictor of in vivo absorption behaviour
Japanese Achlorhydic patients• Dosage form performance across physiological pH
carefully reviewed
Multimedia dissolution testing• McIlvaine buffers used to prepare media• Dissolution experimental duration is defined• Passing criteria• Low solubility: Drug product fails to reach 85%
disslutionWider variations allowed• Upto level D, variations are allowed without BE testing
under certain conditions• Separate qualification requirements for core versus
coating layer for coated products.
Guideline for Bioequivalence Studies of Generic Products, PMDA, 2006
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eCDSCO GUIDELINES
• Solutions, gases, nasal sprays, powders for reconstitution
Dosage forms
• All dosage forms must contain essentially same excipients as comparator
Excipient considerations:
BCS based biowaiver: Class I• Highly soluble• Highly permeable• Dissolution: 85% in 15 min
Composition proportionality:• Qualitatively same• Quantitatively proportional• Same method of manufacture• At least one of the strength has been
studied for its bioavailability
Guidelines for Bioavailability and Bioequivalence Studies, CDSCO, 2005
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eWORLD HEALTH ORGANIZATION
• When API shows dose:solubility ratio of less than 250mL over pH range of 1.2-6.8
High solubility
• When API is absorbed to the extent of 85% or more
High permeability
Redefined BCS parameters:BCS Class Dissolution profile Qualification
Criteria
Class I Rapidly dissolving F2>50
Very Rapidly dissolving
Profile comparison not needed
Class II with weak acidic properties
Rapidly dissolving at pH 6.8
Profile comparison at pH 1.2, 4.5, 6.8
Class III Very rapidly dissolving
Risk assessment of bioInequivalency
more critical
WHO Multisource Document, 2005
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Harmonized Compendial Dissolution Monograph
Paddles and/or Baskets (Apparatus 1 and 2)
Biowaivers for High Solubility, High Permeability Drugs Allowed
Drug Product Manufactured at >=10% Commercial Scale
Narrow Therapeutic Drugs are Special Case
F2 Calculation and Criteria Applied
pH 6.8 Media
Twelve tablets (units) tested
Harmonized Compendial Dissolution Monograph
Paddles and/or Baskets (Apparatus 1 and 2)
Biowaivers for High Solubility, High Permeability Drugs Allowed
Drug Product Manufactured at >=10% Commercial Scale
Narrow Therapeutic Drugs are Special Case
F2 Calculation and Criteria Applied
pH 6.8 Media
Twelve tablets (units) tested
COMPARATIVE APPROACH
Regions of Overlap
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eCOMPARATIVE APPROACH
Regions of Diff erencesParameter US EU Japan
Allowed BCS Class I I and III All
Highly permeable >90% >85% Not relevant
Rapidly Dissolving
>85% 30 min, 3 pHs
>85% 15 min, 3 pHs No requirement
Media Surfactant
SUPAC allowed- if justified
None “Strictly discouraged”
Required if low solubility
Intramural Composition
Change
SUPAC- All BCS Classes Variation
Type A-E, Type B, C, E like SUPAC
level 1, 2, 3 Type D unique
IVIVC as Dissolution Regimen/BE Surrogate
Allowed for MR SUPAC Allowed Not permitted
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eCONCLUSION
Issues:International HarmonizationViolation by Sponsors: Need of
Audits
Future approaches to Biowaivers
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A long way still to be traversed…
Thank You!!!
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REGULATORY STATUS OF BIOWAIVERS: GLOBAL PERSPECTIVE
Back-up Slides
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eBIOWAIVER MONOGRAPHS
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eRISK ASSESSMENT
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DISSOLUTION PROFILE COMPARISON
Difference factor(f1):• Difference in percent dissolved between reference and test
at various time intervals.
Similarity factor(f2):• Comparison of closeness of two comparative formulations.
wheren = the number of dissolution time pointsRt = mean % drug dissolved of the reference product at time tTt = mean % drug dissolved of the test product at time t
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EXCIPIENTS
Well established No interaction with the PK of the active
substance 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.
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eBIOPHARMACEUTICS
CLASSIFICATION SYSTEM
Dose-Solubility Ratio (Highly soluble): FDA- Highest dose strength is soluble in ≤ 250mL
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 EMEA - pH 1.2, 4.5, 6.8