Biowaiver

guidance for
sponsors
Mamoon Rashid and Fakhrul
Ahsan

hat does this guideline recommend?

This guidance provides recommendations
for sponsors of
Investigational new drug applications (INDs),
New drug applications (NDAs),
Abbreviated new drug applications (ANDAs),
and
Supplements to these applications who wish to
request a waiver of in vivo bioavailability
(BA) and/or bioequivalence (BE) studies for
immediate release (IR) solid oral dosage forms.

hat does this guideline recommend?

These waivers are intended to apply to
Subsequent in vivo BA or BE studies of
formulations after the initial establishment of
the in vivo BA of IR dosage forms during the
IND period,
In vivo BE studies of IR dosage forms in ANDAs.
Regulations address the requirements for bioavailability
(BA) and BE data for approval of drug applications and
supplemental applications.

cont

BCS fundamentals (recap)

Classifications:
Class 1: High Solubility High Permeability
Class 2: Low Solubility High Permeability
Class 3: High Solubility Low Permeability
Class 4: Low Solubility Low Permeability
IR solid oral dosage forms are categorized as
having rapid or slow dissolution.
Within this framework, when certain
criteria are met, the BCS can be used as a
drug development tool to help sponsors
justify requests for biowaivers.

saying Pharmaceutically equivalent

e mean
Drug products that contain the same
active ingredients and are identical in
strength or concentration, dosage form
and route of administration.
Identical amounts of the identical active drug
ingredient, i.e., the salt or ester of the same
therapeutic moiety, in identical dosage forms,
but
Not necessarily containing the same
inactive ingredients,
Meet the identical compendial or other applicable

Two pharmaceutically equivalent

solid oral drugs may have different
drug dissolution in vivo.
This may lead to different rate and extent
of absorption.
When the in vivo dissolution of an IR solid oral
dosage form is rapid in relation to gastric
emptying and the drug has high permeability,
the rate and extent of drug absorption is
unlikely to be dependent on drug
dissolution and/or gastrointestinal transit
time.
Under such circumstances, demonstration of in
vivo BA or BE may not be necessary for drug
products containing Class 1 drug substances,
as long as the inactive ingredients used in the

Methods
Solubility
Based on highest dose strength of an IR
product.
Highly soluble means, highest dose is soluble
in 250 mL or less amount of aqueous medium in
pH range of 1 to 7.5.
250 mL = 8 ounce = 1 glass of water
Permeability
Is based indirectly on the extent of absorption
(fraction of dose absorbed) in human
Directly on measurements of the rate of mass
transfer across human intestinal membrane.
Alternative non-human systems available

Methods (cont.)
Dissolution:
Rapidly dissolving means no less than 85% of
the labeled drug is dissolved within 30 minutes
using apparatus I at x rpm, or apparatus II at y
rpm.
In a medium of
0.1 N HCl or Simulated Gastric Fluid USP
without enzymes;
a pH 4.5 buffer; and
a pH 6.8 buffer or Simulated Intestinal Fluid
USP without enzymes.

FDA guideline for dissolution

testing apparatus:
Apparatus must conform to the
requirements in USP.
Selection of the dissolution testing apparatus
(USP Apparatus I or II) during drug development
should be based on a comparison of in vitro
dissolution and in vivo pharmacokinetic data
available for the product.
Apparat

us I or II
?

App. I is generally preferred for

capsules and products that tend to
float, and USP Apparatus II
(paddle method) is generally

FDA guideline for dissolution

testing apparatus: (cont.)
For some tablet dosage forms, in vitro (but not
in vivo) dissolution may be slow due to the
manner in which the disintegrated product
settles at the bottom of a dissolution vessel.
In such situations, USP Apparatus I may be
preferred over Apparatus II. If the testing
conditions need to be modified to better reflect
rapid in vivo dissolution (e.g., use of a different
rotating speed), such modifications can be
justified by comparing in vitro dissolution with in
vivo absorption data (e.g., a relative BA study
using a simple aqueous solution as the
reference product).

FDA guideline for dissolution

testing apparatus: (cont.)
Minimum
# of
dosage
units

A minimum of 12 dosage units

of a drug product should be
evaluated to support a biowaiver
request.
Samples should be collected at a
sufficient number of intervals to
characterize the dissolution
profile of the drug product (e.g.,
10, 15, 20, and 30 minutes).

FDA guideline for dissolution

testing apparatus: (cont.)
When comparing the test and reference
products

Dissolution profiles should be

compared using a similarity
factor (f2).
So, what is this f2?

The similarity factor, f2

f 2 50 log

100
1 n
2
1 Rt Tt
n t 1

What is
the
highest
value of f2?

It is the logarithmic reciprocal square root

transformation of the sum of squared error and
is a measurement of the similarity in the
percent (%) of dissolution between the two
curves.

Two dissolution profiles are

considered similar when the f2 value
is 50 or higher.

Additional considerations for

requesting BW

Excipients
can sometimes affect the rate and extent of
drug absorption.
To support a biowaiver request, the quantity
of excipients in the IR drug product should
be consistent with the intended function (e.g.,
lubricant).
When new excipients or atypically large
amounts of commonly used excipients are
included, additional information documenting
the absence of an impact on BA of the drug may
be requested by the Agency. Such information
can be provided with a relative BA study using a

Additional considerations for

requesting BW
Excipients cont.
Large quantities of certain
excipients, such as surfactants
(e.g., polysorbate 80) and
sweeteners (e.g., mannitol or
sorbitol) may be problematic, and
sponsors are encouraged to
contact the review division
when this is a factor.

Additional considerations for

requesting BW
Prodrug
Permeability of prodrugs will depend on the
mechanism and (anatomical) site of
conversion to the drug substance.
When the prodrug-to-drug conversion is shown
to occur predominantly after intestinal
membrane permeation, the permeability of
the prodrug should be measured. When this
conversion occurs prior to intestinal
permeation, the permeability of the drug
should be determined.
Dissolution and pH-solubility data on both prodrug
and drug can be relevant. Sponsors may wish to

Additional considerations for

requesting
BW
Exceptions
Narrow Therapeutic Range Drugs
Examples include
digoxin,
lithium,
phenytoin,
theophylline, and
warfarin.
Because not all drugs subject to therapeutic drug
concentration or pharmacodynamic monitoring are
narrow therapeutic range drugs, sponsors should contact
the appropriate review division to determine whether a
drug should be considered to have a narrow therapeutic
range

Additional considerations for

requesting BW
Exceptions
Products Designed to be Absorbed in the
Oral Cavity
A request for a waiver of in vivo BA/BE studies
based on the BCS is not appropriate for dosage
forms intended for absorption in the oral cavity
(e.g., sublingual or buccal tablets).

REGULATORY APPLICATIONS
OF THE BCS

INDs/NDAs

Evidence demonstrating in vivo BA or

information to permit FDA to waive this
evidence must be included in NDAs.
A specific objective is to establish in vivo
performance of the dosage form used in the
clinical studies that provided primary
evidence of efficacy and safety. The sponsor
may wish to determine the relative BA of an IR
solid oral dosage form by comparison with an
oral solution, suspension, or intravenous
injection.

REGULATORY APPLICATIONS OF
THE BCS
ANDAs

BCS-based biowaivers can be requested for

rapidly dissolving IR test products containing
highly soluble and highly permeable drug
substances, provided that the reference
listed drug product is also rapidly
dissolving and the test product exhibits similar
dissolution profiles to the reference listed drug
product .
This approach is useful when the test and
reference dosage forms are pharmaceutical
equivalents. The choice of dissolution
apparatus (USP Apparatus I or II) should be the

REGULATORY APPLICATIONS OF
THE BCS
Post-approval Changes
BCS-based biowaivers can be requested for
significant postapproval changes to a rapidly
dissolving IR product containing a highly
soluble, highly permeable drug substance,
provided that dissolution remains rapid for the
postchange product and both pre- and
postchange products exhibit similar
dissolution profiles.

DATA TO SUPPORT A
REQUEST FOR
BIOWAIVERS

Essential data by the sponsor

Sponsors requesting biowaivers based on the

BCS should submit the following information to
the Agency for review by
The Office of Clinical Pharmacology
and Biopharmaceutics (for NDAs) or
The Office of Generic Drugs, Division of
Bioequivalence (for ANDAs)

Essential data by the sponsor

Data Supporting High Solubility
Please include
A description of test methods, including
information on analytical method and
composition of the buffer solutions
Information on chemical structure, molecular
weight, nature of the drug substance (acid,
base, amphoteric, or neutral), and dissociation
constants (pKa(s))
Test results (mean, standard deviation, and
coefficient of variation) summarized in a table
under solution pH, drug solubility (e.g., mg/ml),
and volume of media required to dissolve the
highest dose strength

Essential data by the sponsor

Data Supporting High Permeability
Please include
For human pharmacokinetic studies,
information on study design and
methods used along with the
pharmacokinetic data.

Essential data by the sponsor

Data Supporting High Permeability
For direct permeability methods
Information supporting the suitability of a
selected method that encompasses a
description of the study method, criteria for
selection of human subjects, animals, or
epithelial cell line, drug concentrations in the
donor fluid, description of the analytical
method, method used to calculate extent of
absorption or permeability, and where
appropriate, information on efflux potential
(e.g., bidirectional transport data)

Essential data by the sponsor

Data Supporting High Permeability
A list of selected model drugs along with
data on extent of absorption in humans
(mean, standard deviation, coefficient of
variation) used to establish suitability of a
method;
Permeability values for each model drug
(mean, standard deviation, coefficient of
variation), permeability class of each
model drug, and a plot of the extent of
absorption as a function of permeability
(mean standard deviation or 95%
confidence interval) with identification of the

Essential data by the sponsor

Data Supporting High Permeability
contd.
Information to support high
permeability of a test drug substance
should include:
Permeability data on the test drug
substance, the internal standards (mean,
standard deviation, coefficient of
variation), stability information, data
supporting passive transport mechanism
where appropriate, and methods used to
establish high permeability of the test

Essential data by the sponsor

Data Supporting Rapid and Similar
Dissolution
A brief description of the IR products used for
dissolution testing, including information on batch
or lot number, expiry date, dimensions, strength,
and weight.
Dissolution data obtained with 12 individual
units of the test and reference products. The
percentage of labeled claim dissolved at each
specified testing interval should be reported for
each individual dosage unit. The mean percent
dissolved, range (highest and lowest) of
dissolution, and coefficient of variation (relative
standard deviation) should be tabulated. A

Essential data by the sponsor

Additional information
The manufacturing process used to make
the test product should be described
briefly to provide information on the
method of manufacture (e.g., wet
granulation vs. direct compression).
A list of excipients used, the amount used,
and their intended functions should be
provided. Excipients used in the test
product should have been used
previously in FDA-approved IR solid
oral dosage forms.

Part II
Guideline for
preparing Biowaiver
monographs

What is a monograph?
By definition, monograph is a detailed and
documented treatise on a particular
subject.
Objectives of the monograph:
ONE: Gather and organize all relevant data
on a particular API, which have to be taken into
consideration when
A decision is to be made as to whether a new
formulation of that API (either a
reformulation or a new, multi-source
product) needs to be tested in an in vivo
bioequivalence study, or whether a biowaiver

Objectives (cont.)
So, what are those relevant data?
Solubility, pharmacokinetics (especially with
respect to absorption and bioavailability) and
permeability of the API and the dissolution of
dosage forms as per current BCS rules;
Therapeutic use and therapeutic window of the
API; any history of problems with BA/BE and, if it
exists, data on excipient interactions. In specific
cases, it may be desirable to introduce and
discuss further information relevant to a
biowaiver decision.
The risks associated with an inappropriate
biowaiver decision will be addressed.

Objectives (cont.)
TWO:
To assess the validity of the present BCS
Guidances on the basis of the gathered data. To
illustrate some of the possibilities: the results
may show that there is a need to re-define the
present BCS Classes (e.g. relax permeability
requirements or D:S limits), to invoke other
dissolution test conditions than those currently
recommended or to change the specifications
used for dissolution test results
THREE:
To assess the biopharmaceutical relevance
of dissolution testing according to the
compendial method in the USP (where one

Sourcing your data

The structure of the monographs is that of a
classical scientific literature review!
Googling or pubmedding?
A search in PubMed using as keywords:
absolute, absorption, aqueous, bioavailability,
permeability, pharmacokinetics, solubility and
the name of the API, in different combinations,
would be a good starting point. Whenever
possible, original literature is to be consulted in
order to evaluate the quality of the data. Data
from secondary sources can be included for
completeness or when original literature cannot
be located. When no data on an item has
been found, this should be stated.

Sourcing

cont.

Although these monographs are basically

literature reviews,
Some might want to add relevant results of
their own experimental work, for instance, on
the solubility of the API.
On a limited scale, these experimental results
can be fitted into the monograph, if the
experimental methodology used is standard.

Title

Abbre
v.

Organization of the
monograph
Biowaiver Monographs for Immediate
Release Solid Oral Dosage Forms:
xxxx
BCS Biopharmaceutics Classification
System
IR Immediate Release
MA Marketing Authorization
BE Bioequivalence
GI Gastrointestinal
API Active Pharmaceutical
Ingredient
BA Bioavailability
DEGermany
NL The Netherlands

Organization
Abstr
act

cont.

Literature (and experimental) data relevant

to the decision to allow a waiver of in vivo
bioequivalence testing for the approval of
immediate release (IR) solid oral dosage
forms containing API are reviewed.
According to the current Biopharmaceutics
Classification System (BCS), API would be
assigned to Class x . Also, API`s therapeutic
use and therapeutic index, its
pharmacokinetic properties, data related to
the possibility of excipient interactions and
reported bioequivalence/ bioavailability
problems are taken into consideration. On
the basis of this evidence, a biowaiver
can currently be [recommended] /

Organization of the monograph

Key
Words

Suggested:
API;
Absorption;
Biopharmaceutics Classification
System (BCS); Permeability;
Solubility.

Organization of the monograph

Introducti
on

A monograph based on literature data is

presented on API, with respect to its
biopharmaceutical properties and the risk of
waiving in vivo bioequivalence testing in the
approval of new Immediate Release (IR) solid oral
dosage forms containing API (biowaiving),
including both reformulated products and new,
multisource products.
The aim is to evaluate all pertinent data
available from literature sources, to assess the
risk of such a biowaiver and recommend whether

Organization of the monograph

General
Characteris
tics

Indicati
on

APIs INN name and chemical name

Structure (as a Figure)
Stereochemistry (if applicable)
Salts, esters, polymorphs
Where relevant, define which
stereoisomers/salts/ esters/polymorphs are
covered by this monograph
Therapeutic indication
Therapeutic Index
Wide dosing range ?
Adverse drug reactions (ADRs) after
overdosage?
Need to monitor blood levels?

Organization of the monograph

Chemical properties
Solubility
in water
Solubility in organic solvents are not relevant.
in aqueous buffers
Most relevant to the biowaiver discussion would be: pH 1.2,
pH 4.5, pH 6.8.
dose:solubility ratio for WHO dose at pH 1.2 pH 4.5, pH 6.8
In many cases, data in this field will be incomplete. If so, this
should be stated, indicating which data are missing

Polymorphism

Partition coefficient
State which organic solvent was used to determine logP. If only
the distribution coefficient (logD) is known, give this with the
pH value at which it was determined.

Organization of the monograph

Chemical properties
pKa
State whether the compound is a weak acid, weak
base or does not ionize under usual gastrointestinal
conditions (i.e. has no pKa below 9).

Available dose/tablet
WHO recommended dose.
Strengths available on studied market(s) and special
dosing Instructions (e.g. with food) on that market
Name the market(s) that were studied.

Organization of the monograph

Pharmacokinetic
properties
Absolute bioavailability versus i.v.
Describe how studies were done (was radioactive API used?)
report animal data only if no human data is available.

Relative bioavailability versus oral solution

Describe how studies were done (was radioactive API used?)
report animal data only if no human data is available.

Human permeability data?

CaCo II cell permeability data.
Was a validation set included in the study?

Distribution, metabolism, elimination

Not extensive, because only nice to know Only a short
summary on the volume of distribution, protein binding, serum
half-life, plasma clearance, elimination half-life, extent of
biotransformation.

Organization of the monograph

Dosage form performance
Excipients
Excipients present in registered innovator drug
product or market leader in studied market(s)
Excipients present in other registered IR drug
products.
In vivo comparisons of different formulations
Are the compositions of these formulations known?
Their in vitro dissolution? By which method?

Organization of the monograph

Dosage form performance

Dissolution
USP dissolution methodology
Comparative studies of different formulations in
vitro
Known attempts to optimize dissolution from the
dosage form:
e.g. micronization of drug, addition of surfactants to
formulation.

Organization of the monograph

Discussion
Solubility
Discuss quality of the data
D:S ratios for maximum available dosage strength
and for WHO dosage strength
Any D:S changes with pH?
Conclusion about classification with respect to
solubility according to the current BCS criteria

Organization of the monograph

Discussion
Permeability
Discuss quality of the data
Discuss concordance of data
Do the permeability data support the absorption
data?
Variability in fraction absorbed among studies and
within studies.
Concentration/dose dependent absorption?
If appropriate, mechanism of absorption.
Evidence for an GI absorption window?
Conclusion about classification with respect to
permeability, where possible, according to the
current BCS criteria

Organization of the monograph

Risks with respect to excipient and/or
manufacturing variations
Discuss the evidence for, and likelihood of
an influence on bioavailability of excipients
and/or manufacturing methods (particle size,
hydration state, polymorphic forms, compression
force etc.!).

Is there evidence to suggest that there are

in

bio
equivalencies among products
already in the marketplace?

Organization of the monograph

Patient's risks associated with
bioinequivalence
Discuss data on the therapeutic indication
(critical use?) and therapeutic index (narrow
therapeutic index?) and discuss how crucial it is
for new formulations of API to be bioequivalent to
the reference product in terms of patient safety.
What conclusions, if any, can be drawn for IR drug
products which conform to the USP dissolution test
specification (if one exists)?
Is the USP test similar to the tests recommended
in the BCS/Biowaiver Guidances?
Have USP tests been shown to dsicriminate between

Organization of the monograph

Conclusion
BCS classification for API under the present BCS
rules
Stipulate degree of certainty of classification.

Can a biowaiver be
recommended?
Under which restrictions?
Where applicable, comment on current BCS rules
and class boundaries
What are the risks associated with associated with

Organization of the monograph

Conclusion

cont.

When the formulation is found to be bioequivalent,

established by in vitro or in vivo testing, can you
make recommendations for in vitro dissolution
testing for the batch-to-batch control?
Is the USP dissolution test method and specification
appropriate, i.e. sufficiently biorelevant, for batch to
batch control purposes?

Part III

Case
studies