This document discusses provisions for waiving in vivo bioavailability and bioequivalence studies under certain conditions according to 21 CFR 320.22. It outlines requirements for biowaivers including same active/inactive ingredients, dosage form and strength. It also discusses potential biowaivers for Class II and III drugs based on solubility and permeability properties. Biowaivers do not apply to locally acting, non-oral or modified release products. The document provides references for further information.

1. BIO WAIVERSBIO WAIVERS
Mr. Nitin KadamMr. Nitin Kadam

2. Will Talk On….Will Talk On….
Provision for waivers of in vivo BA/BE studiesProvision for waivers of in vivo BA/BE studies
Biowaiver extensions forBiowaiver extensions for CLASS II & IIICLASS II & III drugsdrugs
ReferencesReferences

3. Provision for waivers of in vivo BA/BE studies (Biowaiver)Provision for waivers of in vivo BA/BE studies (Biowaiver)
under certain conditions is provided inunder certain conditions is provided in
21 CFR 320.22.21 CFR 320.22.

4. Requirement of Bio waiver….Requirement of Bio waiver….
A.A.
For certain drug products, the in vivo bioavailability orFor certain drug products, the in vivo bioavailability or
bioequivalence of the drug product may bebioequivalence of the drug product may be self-evident.self-evident.

5. A.a.A.a.
Thedrug product:Thedrug product:
 Is a potential solution intended solely forIs a potential solution intended solely for
administration byadministration by injection, or an ophthalmicinjection, or an ophthalmic
or otic solution; andor otic solution; and
 Contains theContains the same active and inactivesame active and inactive
ingredientsingredients in thein the same concentrationsame concentration as a drugas a drug
productproduct that is the subject of an approved fullthat is the subject of an approved full
new drug applicationnew drug application..

6. Thedrug product:Thedrug product:
 Is administeredIs administered by inhalation as a gas,by inhalation as a gas, e.g., ae.g., a
medicinal or an inhalation anesthetic; andmedicinal or an inhalation anesthetic; and
 Contains anContains an active ingredient in the sameactive ingredient in the same
dosage formdosage form as a drug product that is theas a drug product that is the
subject of an approved full new drugsubject of an approved full new drug
application.application.
A.b.A.b.

7. A.cA.c
Thedrug product:Thedrug product:
 Is a solutionIs a solution for application to the skin, an oralfor application to the skin, an oral
solution, elixir, syrup, tincture, or similar othersolution, elixir, syrup, tincture, or similar other
solubilized formsolubilized form..
 Contains anContains an active drug ingredient in the sameactive drug ingredient in the same
concentration and dosage formconcentration and dosage form as a drug product thatas a drug product that
is the subject of an approved full new drugis the subject of an approved full new drug
application; andapplication; and
 Contains no inactive ingredient or other change inContains no inactive ingredient or other change in
formulation from the drug productformulation from the drug product that is the subjectthat is the subject
of the approved full new drug application that may

8. B.B.
 Solid oral dosage formSolid oral dosage form (other than an enteric coated or(other than an enteric coated or
controlled release dosage form)controlled release dosage form) of a drug productof a drug product
determined to bedetermined to be effective for at least one indication in a Drugeffective for at least one indication in a Drug
Efficacy Study Implementation noticeEfficacy Study Implementation notice or which isor which is identical,identical,
related, or similar to such a drug product under § 310.6related, or similar to such a drug product under § 310.6 of thisof this
chapterchapter unless FDA has evaluated the drug productunless FDA has evaluated the drug product under theunder the
criteria set forth in § 320.32, included the drug product in thecriteria set forth in § 320.32, included the drug product in the
Approved Drug ProductswithApproved Drug Productswith
 Therapeutic Equivalence Evaluations List, andTherapeutic Equivalence Evaluations List, and rated the drugrated the drug

9. C.C.
For certain drug products,
bioavailability or
bioequivalence may be
demonstrated by evidence
obtained in vitro in lieu of in
vivo data

10. C.1.C.1.
 The drug product is in theThe drug product is in the same dosagesame dosage
form,form, but in a different strengthbut in a different strength, and is, and is
proportionally similar in its active andproportionally similar in its active and
inactive ingredients to another druginactive ingredients to another drug
product for which theproduct for which the same manufacturersame manufacturer
hasobtained approvalhasobtained approval

11. C.2.C.2.
The drug product is shown toThe drug product is shown to
meet anmeet an in vitro test that hasin vitro test that has
been correlated with in vivobeen correlated with in vivo
datadata

12. The drug product is aThe drug product is a reformulatedreformulated
productproduct that is identical,that is identical, except for aexcept for a
different color, flavor, or preservativedifferent color, flavor, or preservative
thatthat could not affect thecould not affect the
bioavailability of the reformulatedbioavailability of the reformulated
productproduct, to another drug product for, to another drug product for
which the same manufacturer haswhich the same manufacturer has
obtained approval and the followingobtained approval and the following
C.2.C.2.

13. GUIDANCE FOR INDUSTRYGUIDANCE FOR INDUSTRY
(Covered last year……….)(Covered last year……….)

14. BiowaiverExtensionBiowaiverExtension
Potential for ClassPotential for Class
IIDrugs:-IIDrugs:-
These are typicallyThese are typically poorly soluble weak acidspoorly soluble weak acids
with pKavaluesof ≤4.5 and intrinsic solubilitywith pKavaluesof ≤4.5 and intrinsic solubility
(solubility of the un–ionized form) is of ≥ 0.01(solubility of the un–ionized form) is of ≥ 0.01
mg/ ml.mg/ ml. At pH values typical of the fastedAt pH values typical of the fasted
state in thestate in the jejunum (about 6.5), these drugsjejunum (about 6.5), these drugs
will have solubility of ≥ 1 mg/ ml, resulting inwill have solubility of ≥ 1 mg/ ml, resulting in
fast and reliable dissolution of the drugfast and reliable dissolution of the drug..
Currently these drugs are classified as class IICurrently these drugs are classified as class II
drugs because they are poorly soluble atdrugs because they are poorly soluble at

15. BiowaiverExtensionBiowaiverExtension
Potential forClass IIIPotential forClass III
DrugsDrugs Scientific rationale behind suggesting Biowaiver forScientific rationale behind suggesting Biowaiver for
Class III drugs is that the absorption of class III drugs isClass III drugs is that the absorption of class III drugs is
limited by its permeability and less dependent upon itslimited by its permeability and less dependent upon its
formulation and its bioavailability may be determinedformulation and its bioavailability may be determined
by itsin vivo permeability pattern.by itsin vivo permeability pattern.
 If the dissolution of class III products is rapid under allIf the dissolution of class III products is rapid under all
physiological pH conditions, it can beexpected that theyphysiological pH conditions, it can beexpected that they
will behave like an oral solution in vivowill behave like an oral solution in vivo.. BE studies areBE studies are
generally waived off oral solution drug productsgenerally waived off oral solution drug products
because the release of the drug from an oral solution isbecause the release of the drug from an oral solution is

16. NoBiowaiverNoBiowaiver
for….for….
 Locally applied, systemically actingLocally applied, systemically acting
productsproducts
 Non-oral immediatereleaseformswithNon-oral immediatereleaseformswith
systemic actionsystemic action
 Modified releaseproductsModified releaseproducts
 Transdermal productsTransdermal products

17. ReferenceReference
s…s…
 http://ikev.org/haber/bioav/Barends_Istanbul%2004-1_korr.pdf
 http://www.fda.gov/cder/Guidance/3618fnl.pdf
 http://www.absorption.com/site/Services/BCS.aspx
 http://ikev.org/haber/bioav/BA-BE%20Intro-01-30-color.pdf
 http://medicine.iupui.edu/clinical/F813_spring2006/S_Clinical
PKF813Lecture1709March2006BioavailabilityandBioequivale
ncerevised.pdf
 http://www.sfbci.com/SFBC/upload/sfbc/Generateur/LeonSha
rgel.pdf
 WHO document QAS/04.093
 Pharmaceutical processscale- up edited by Michael Levin,
Marcel Dekker .inc New York, page: 447-468,551-564.