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