Biowaivers

In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.

Citation Is done at the end of slide.

Content is up to date & true to my belief.

Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- [email protected]

1. PRESENTED BY :-ANURAG PANDEY
M.PHARM (PHARMACEUTICS)
INSTITUTE OF PHARMACY, NIRMA UNIVERSITY
BIOWAIVERS &
IT’S GUIDELINES
UNDER THE GUIDANCE OF:-DR. MAYUR PATEL
ASSOCIATE PROFESSOR AT DEPT. OF PHARMACEUTICS
INSTITUTE OF PHARMACY, NIRMA UNIVERSITY
Wednesday, April 11, 20181

2. HISTORY OF BIOWAIVER
Wednesday, April 11, 20182
1.Theterm“biowaiver”isappliedtoaregulatorydrugapprovalprocess
whenthedossier(application)isapprovedbasedonevidenceof
equivalenceotherthanthroughIn-vivoequivalencetesting.
2.In1995,theAmericanDepartmentofHealthandHumanServices,US
FoodandDrugAdministration(HHS-FDA)instigatedthe
BiopharmaceuticsClassificationSystem(BCS),withtheaimof
grantingso-calledbiowaiversforSUPACs.
3.AtthattimethebiowaiverwasonlyconsideredforSUPACto
pharmaceuticalproducts.
4.Morerecently,theapplicationofthebiowaiverconcepthasbeen
extendedtoapprovalofcertainorallyadministeredgenericproducts

3. INTRODUCTION
Wednesday, April 11, 20183
ABiowaivermeansthatinvivobioavailabilityand/orbioequivalence
studiesmaybewaived(notconsiderednecessaryforproduct
approval).Inshort,In-vitroinsteadofIn-vivo“Bioequivalence”testing.
Insteadofconductingexpensiveandtimeconsuminginvivo
studies,adissolutiontestcouldbeadoptedasthesurrogatebasisfor
thedecisionastowhetherthetwopharmaceuticalproductsare
equivalent.
OnlyAPIswithhighsolubilityandhighpermeabilityandwhichare
formulatedinsolid,immediaterelease(IR)oralformulationscanbe
approvedonthebasisoftheBiowaiverprocedure.
AmajoradvantageoftheBiowaiverprocedureisthesimplification
andreductionoftimerequiredforproductapproval,thusreducing
thecostofbringingnewproductstomarket.

4. CONT…
Wednesday, April 11, 20184
Theriskoftherapeuticinequivalenceoftwoimmediaterelease
productscanneverbereducedtozero,evenifafullclinicalstudyis
performed.
Theconclusionofcomparativeclinicalstudies,invivobioequivalence
studies,invitroequivalencetestsandbiowaiversisbasedonstatistics
andscientificdatathatareassumedtoberepresentativefortheproducts
atissue.
Theaimofbiowaiverguidanceistoreducetheriskofbioinequivalence
toanacceptablelevel.
Pharmaceuticaldevelopmentworkaimsatreducingtheprobabilityof
manufacturinginequivalentformulationstakingintoaccountthecritical
aspectsoftheproductatissue.
Inthiscontext,theabsorptionphaseisregardedasthecriticalprocess
determiningtheequivalenceofthepharmacokineticprofilesand
therebythetherapeuticequivalenceofthetestandreferenceproduct

5. BIOWAIVERS TYPE OF PRODUCTS
Wednesday, April 11, 20185
1. SOLUTIONS
2. IV PRODUCTS
3. IMMEDIATE RELEASE PRODUCTS
LOWER STRENGTH
BCS CLASS I
BCS CLASS II?
BCS CLASS III?
4. EXTENDED RELEASE PROCDUCTS
LOWER STRENGTH
5. TOPICAL DOSAGE FORMS
SOLUTIONS
AEROSOLS
ANTIFUNGALS
6. INHALATION & NASAL DOSAGE FORMS (AERSOLS)
SOLUTIONS

6. SCOPE & ADVANTAGES OF BIOWAIVER
Wednesday, April 11, 20186
SCOPE
Inside a product:
• Scale up processes
• Line extensions
• Variation after marketing authorization
Between different products:
• Application of generics without clinical data
ADVANTAGE’S
Circumvent expensive and sometimes unethically questionable human
testing.
Reducing time in bringing product to the market.
Reduce product cost
Fig. Source: INTERNET

7. LIMITATION/EXCEPTION OF
BCS-BASED BIOWAIVER
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BCS based biowaiver are not applicable for the following:
1.Narrowtherapeuticrangedrugproducts.(It’sdefinitionisnot
mentionedintheguidelinesacc.ToEMAitmustbedecidedcaseby
case.)
2.BCSbasedbiowaivershavelimitedapplicationfortheclassIIdrugs
andnotapplicableforclassIII.
3.Dosageformmeantforabsorptionintheoralcavitye.g.sublingualor
buccaltablets.
4.Effectsoffood,absorptivetransporters,effluxtransporters,and
routesofelimination(renal/biliary)wereimportantdeterminantsof
overalldrugabsorptionandbioavailabilityforimmediatereleaseoral
dosageforms,whicharenotconsideredinBCS.

8. BCS-BASED BIOWAIVER
Wednesday, April 11, 20188
According to the HHS-FDA definitions,
the four possible categories for an API according to the BCS:
HIGH
SOLUBILITY
HIGH PERMEABILITY LOW PERMEABILITY
LOW
SOLUBILITY
Source: INTERNET

9. BRIEF ABOUT BCS CLASS
Wednesday, April 11, 20189
BCS CLASS-1
Compoundarewellabsorption&highabsorptionrateascomparedtoexcretion.
DrugsexhibitHighAbs.number&Highdissolutionnumber.
RLS–Dissolution
If,dissolutionisrapidthengastricemptyingratewillbeRLS.
Examples: Metoprolol, Diltiazem, Verapamil, Propranolol
BCS CLASS-2
Bioavailability of these products is limited by their solvation rate.
Drugs have a high absorption number but a low dissolution number.
The absorption for class II drugs is usually slower than class I and occurs over a
longer period of time.

10. Wednesday, April 11, 201810
BCS CLASS-3
The absorption is limited by the permeation rate but the drug is solvated very fast..
If the formulation does not change the permeability or gastro-intestinal duration
timethen class I criteria can be applied.
High variation in the rate and extent of drug absorption.
Since the dissolution is rapid, the variation is an aspect to alteration of physiology
and membrane permeability rather than the dosage form factors.
Examples: Cimetidine, Acyclovir, Neomycin B and Captopril.
BCS CLASS-4
Thesecompoundshaveapoorbioavailabilityandnotgoodabsorbedoverthe
intestinalmucosaproperly
Lot of problems for effective oral administration.
Examples : Hydrochlorothiazide and Taxol.

11. BCS CLASS BOUNDARIES: OBJECTIVES
Wednesday, April 11, 201811
DISSOLUTION
(PRODUCT)
SOLUBILITY
(DRUG)
PERMEABILITY
(DRUG)
This
information is taken from the: WHO workshop on
pre
-
qualification of medicines
programme
,
Abu
dhabi
, 11
-
13
october
, 2010 presented by Dr, JAN WELINK
Veryrapid/rapiddissolution-ensure
thatinvivodissolutionisnotlikelyto
bethe“ratedetermining”step
Highsolubility-ensurethatsolubility
isnotlikelytolimitdissolutionand,
therefore,absorption
Highpermeability-ensurethatdrug
iscompletelyabsorbedduringthe
limitedtransittimethroughthesmall
intestine

12. DATA TO SUPPORT REQUEST FOR
BIOWAIVERS
Wednesday, April 11, 201812
HIGH SOLUBILITY DEFINITION:
Thehighestsingleunitdoseiscompletelysolublein250mlorlessofaqueous
solutionatpH1–7.5(37°C)
250ml:derivedfromtypicalBEstudyprotocolsthatprescribetheadministration
ofadrugproducttofastinghumanvolunteerswithaglass(approx.250ml)water
HIGH PERMEABILITY DEFINITION:
AccordingtoHHS-FDA,when90%ormoreoftheorallyadministereddoseis
absorbedinthesmallintestine.
Permeabilitycanbeassessedbypharmacokineticstudies(forexample,mass
balancestudies),orintestinalpermeabilitymethods,e.g.intestinalperfusionin
humans,animalmodels,Caco2celllinesorothersuitable,validatedcelllines.

13. Wednesday, April 11, 201813
Dissolution:
Inthreedifferentmedia:pH1.2HCl,pH4.5AcetatebufferandpH6.8Phosphate
buffer,compositioninapaddle(50rpm)orbasket(100rpm)apparatusat37°C
andavolumeof900ml.
A. Very Rapid Dissolution:
AnIRdrugproductisconsideredVERYRAPIDLYDISSOLVINGwhen>85%
ofthelabeledamountofdrugsubstancedissolveswithin15minutes.
B. Rapid Dissolution:
AnIRdrugproductisconsideredRAPIDLYDISSOLVINGwhen>85%ofthe
labeledamountofdrugsubstancedissolveswithin30minutes.
CONT….

14. REQUIREMENTS FOR A
BCS-BASED BIOWAIVER
Wednesday, April 11, 201814
Therehavebeencertainrequirementsforabiowaiverstudythatinclude
allowanceofregulatoryauthoritieslikeFDAandWHOetc.Thedrugs
shouldhavehighsolubilityandhighpermeabilityaccordingtoBCS.
Requirements for a BCS-based biowaiver study include:
1. Dissolution Test in 3 different media (in 900 ml and at 37°C)which are:
Buffer pH 1.2, Or simulated gastric fluid without enzymes or 0.1N HCl.
Buffer pH 4.5.
Buffer pH 6.8 or simulated intestinal fluid without enzymes.
2. 12 samples in each media, paddle rotating at 50 rpm or basket at 100 rpm.
3. Samplingtimes are 10, 15, 20, 30, 45 and 60 minutes.
4. The profiles of the testand referenceproducts must be similar in all
three media.

15. ADDITIONAL CONSIDERATIONS
FOR REQUESTING A BIOWAIVER
Wednesday, April 11, 201815
A. Excipients
BCSclassificationisrelatedtoAPIwithoutexcipients.However,
literatureevidenceillustrateshowexcipientsmayaffectthefractionof
doseabsorbedbymodulatingdisintegration,solubilizationorstabilizinga
specificpolymorphicform,therebychangingthedissolutioncharacteristics
oftheAPI.
Theeffectofexcipientsisstrictlylimitedbytheguidancedocuments:
qualitativedifferencesinexcipientsfromwhichaneffectonthe
bioavailabilitycouldbeexpectedarenotaccepted,whereasscientific
reasoningmayjustifylargerandstillsafedeviations.

16. CONT..
Wednesday, April 11, 201816
Excipientsusedinthedosageformmusthavebeenusedinapreviously
approvedimmediatereleasesolidoraldosageformbytheFDA.
ThequantityofexcipientsintheIRproductshouldbeconsistentwith
theirintendedfunction.Largequantitiesofcertainexcipients,suchas
surfactants(e.g.,sodiumlaurylsulfate)orosmoticingredients(e.g.,
sorbitol)maybeproblematic.
B. Prodrugs
Conversionsiteofprodrugtodrugmustbeconsidered,ifitoccurs
beforeintestinalabsorptionthenpermeabilitystudyofdrugmustbe
doneotherwisepermeabilitystudyofprodrugmustbedone.

17. To be considered bioequivalent according to the
HHS-FDA biowaiver procedure
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Or,
Eligibility criteria for biowaiver acc. to HHS-FDA
1.BCSClassofAPI:-CLASS1
2.Dissolutioncharacteristics:Rapidlydissolving,inthreedifferentmedia
•FirstOption:Veryrapidlydissolvingandnofurtherprofilecomparison
•SecondOption:RapidlydissolvingandProvingsimilarityofdissolutionprofiles
ofTandR(e.g.usingf2-test).
3.Excipients:-MustnotinfluencetheabsorptionoftheAPI(affectingmotilityor
permeability).
4.TherapeuticIndex:-Notcontain’sanAPIwithanarrowT.I
5.Formulation:-Productshouldnotbedesignedtobeabsorbedfromtheoral
cavity.

18. To be considered bioequivalent according to the
WHO biowaiver procedure
Wednesday, April 11, 201818
Or,
Eligibility criteria for biowaiver acc. to WHO
1. BCS Class of API:-Class II acids with D:S ratio in 250ml or lower at pH 6.8
or >85% dissolved within 30 minutes at pH (75rpm) .
Class III compounds are eligible, if they dissolved within 15 minutes in buffer
media ph 1.2-6.8 (75rpm).
2.FILLINGPROCEDURE:-
MUSTNOTFOLLOWFDA,SHOULDBESTICKTOWHOGUIDELINES
3.pHFORSOLUBILTIYDETERMINATION :-1.2TO6.8
4.PERMEABILITY:-MUSTBEHIGH(i.e.,>85%)

19. REGULATORY PROVISONS OF BIOWAIVERS :
GLOBAL PERSPECTIVE;
A COMPARATIVE APPROACH
Wednesday, April 11, 201819
PARAMETERS US EU JAPAN
ALLOWED BCS
CLASS
I I & III All
HIGHLY
PERMEABLE
>90% >85% Not relevant
RAPIDLY
DISSOLVING
>85%in 30 min,
at pH 3
(pH 1.0, 4.6 , 6.8)
>85%in 15 min,
at pH 3
(pH 1.2, 4.5 , 6.8)
Norequirement
MEDIA
SURFACTANT
SUPAC allowed-if
justified.
None “strictly
discouraged”.
Required if low
solubility
INTRA-MURAL
COMPOSITION
CHANGE
SUPAC allowed-for
all BCS classes.
Variation Type A-E,Type B, C, E
like SUPAC level 1,2,3
Type D unique
IVIVC ASDOSAGE
REGIMEN/BE
SURROGATE
Allowedfor Moderate
Release SUPAC
Allowed Not permitted
Source: INTERNET

20. CURRENT PEDESTALS OF BIOWAIVERS
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C.P :-COMPOSITION PROPORTIONALITY
SOURCE ;-INTERNET
BCS
•CONSIDER THE DOSE:SOLUBILITY RATIO,
PERMEABILITY& DISSOLUTION BEHAVIOUR .
IVIVC
•BASED ON CORRELATION BETWEEN IN -VITRO
DATA TO IN-VIVO PROFILE.
C.P
•NEW PRODUCT IS QUALITATIVELY SAME &
QUANTITATIVELY PROPORTIONAL TO BIO -BATCH.

21. APPLICATION OF BIOWAIVER
Wednesday, April 11, 201821
1 & 2
•FOR CHECKING VARIATIONS IN DRUG PRODUCTS
•FOR GENERIC DRUG APPLICATION
3
•DEVELOPING NEW DRUG PRODUCTS e.g., BRIDGING
STUDIES, PILOT BATCH v/s PRODUCTION BATCH.
4
•BIOWAIVERMEANSTOOBTAINWAIVEOFFFOR
CARRYINGOUTEXPENSIVEANDTIME-CONSUMINGBA
ANDBESTUDIES.

22. CONCLUSION
Wednesday, April 11, 201822
AnimportantapplicationofBCSintheregulatorydocumentsistheuseof
BCSintheguidanceforbiowaiverprocedures.Oneofthemostimportant
criteriafordecidingwhetheraBCS-basedbiowaiverisappropriateis
theBCSclassoftheAPI.
Forinstance,productscontainingBCSclassIVAPIsareexcludedfrom
theBCS-basedbiowaiverprocedure.
Additionally,productscontainingclassIIIAPIscannot,asofthis
writing,beapprovedintheUSAbythebiowaiverprocedure.Inthe
EUandcountriesusingtheWHOcriteria,productscontainingClass
IIIAPIsareonlyeligibleforbiowaivingiftheyareveryrapidly
dissolving.
ClassIIAPIsareonlyeligibleforthebiowaiverprocedureincountries
usingtheWHOcriteriaandthenonlyinthecaseofaweakacidthatis
highlysolubleatpH6.8.
Bycontrast,ClassIAPIsareeligibleforthebiowaiverprocedureinall
jurisdictionsthatapplyit(Japan,notably,isacountrythatdoesnot
yetallowapprovalofdrugproductsusingtheBCS-basedbiowaiver
procedure).

23. REFERENCE
Wednesday, April 11, 201823
REVIEW ARTICLES
Biowaivers-anupdatedreviewBy,Abilash.N*,Chandramouli.R,“Departmentof
QualityAssurance”,KrupanidhiCollegeofPharmacy,#12/1,Chikkabellandur,Carmelaram
Post,VarthurHobli,Bangalore-560035,KA
POWERPOINT PRESENTATION
Basis for BCS-based BiowaiverBy Mohamed Abdeen, “R&D department”,
Azalpharmaceutical Co.LTD
Biowaiver monograph for Immediate release Solid oral dosage forms:
Ibuprofen by H.POTTHAST*, Federal institute for drug & medical devices,
(BfArm), kurtgeorg-kiesinger-Allee3, Bonn, Germany
BIOWAIVERS: CRITERIA AND REQUIREMENTS, “Prepared by Dr. Mazen
Kurdi”, “Reviewed by Dr. Rita Karam 2015

24. Wednesday, April 11, 201824