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Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 8
COMPARISON OF GLOBAL REGULATORY GUIDELINES FOR AVAILABILITY OF
DIFFERENT BIOWAIVER PROVISIONS AND APPLICATION REQUIREMENTS OF
BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) BASED BIOWAIVER.
Available Internet at www.ijdra.com
REVIEW ARTICLE
1Patel Jimi, 1Mehta Priti*, 2Kothari Vaishali
1 Dept of Pharm. Analysis, Institute of Pharmacy, Nirma University, Ahmedabad - 382481
2 International Regulatory Affairs, Cadila Healthcare Limited,, Ahmedabad - 380059
*Corresponding Author’s E-mail: drpritimehta@nirmauni.ac.in
INTRODUCTION
As per survey of FDA, every year only 18 to 26
New Chemical Entities (NCEs) get approved as
a New Drug Application (NDA). Whereas,
pharmaceutical companies file thousands of
Abbreviated New Drug Applications (ANDAs)
to get an approval as a generic version of
innovators every year. To get an approval for
ANDAs, generic formulation should be proven
bioequivalent to that of Reference Listed Drug
(RLD). For market authorization of generics,
instead of non-clinical and clinical studies, only
Bioequivalence (BE) study is required. At drug
development stage, only one formulation
becomes eligible for marketing from many of
formulations. In that case, Biowaiver concept
comes into picture to reduce unnecessary time
and expense of BE study for each formulation.
Biowaiver is a kind of ANDA filing, which
applies to reduce time and cost from a complete,
systemic BE study.
Biowaiver
Simply, Biowaiver is considered as waiver of
clinical bioequivalence studies. As per WHO
guidance, “The term Biowaiver is applied to a
regulatory drug approval process when the
dossier (application) is approved based on
evidence of equivalence other than In-vivo
bioequivalence test.”
Different Approaches for Biowaiver
Different drug regulatory authorities approve
Biowaiver for different conditions, which are
summarized in Figure 1 and described below in
brief.
ABSTRACT
To waive a complete and systemic Bioequivalence (BE) study, Biowaiver or Request for a Biowaiver is a fast track
approach to boost the drug development process. Over the past three-four years the Biowaiver market shows greater
number of Biowaiver submissions and the wider use of In-vitro permeability study. Biowaiver is a beneficial
approach for getting approval of Abbreviated New Drug Application (ANDA) while, BCS based Biowaiver is the
novel approach to gain approval for New Drug Application (NDA) as well as ANDA. A Biopharmaceutics
Classification System (BCS) based Biowaiver is an exemption from conducting human bioequivalence studies when
active ingredient and dosage form meet criteria of solubility, permeability and dissolution. The Paper covers different
kind of Biowaiver approaches and the criteria for the applicability of BCS based Biowaivers in the different
geographic scopes with regard to global development strategy. There is a comparison of global guidelines on
provisions availability for different types of Biowaiver approaches as well as for requirements of Biowaiver based on
BCS. From comparison of different global guidelines it is reviewed that most of the guidance resembles to the
USFDA, EU and WHO guidelines because most of the regulatory authorities are following the BCS based Biowaiver
concept as one of the three main guidance documents (USFDA, EMA, WHO) or a combination of specific
requirements.
Keywords: Bioequivalence, Biowaiver, BCS based Biowaiver.
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 9
Figure1. Different Approaches of Biowaiver
1) Biowaiver for Specific Dosage Forms
Due to certain characteristics of some specific
formulations, BE study may not be required. In
that case, bioequivalence between the test and
the reference product can be presumed without
any further In-vivo experiments. This kind of
Biowaiver can be possible for aqueous oral
solutions, parenteral solutions and topical
solutions (e.g. eye drops). One of the major
prerequisite is that the excipients should not
influence the bioavailability of the active drug
substance. The conditions for this Biowaiver are
identical in most countries.
2) Biowaiver for Additional Dose Strengths
If several strengths of a generic drug product are
developed for the same formulation then under
this approach, it can be sufficient to demonstrate
bioequivalence of test versus the reference
product only with one or two strengths,
depending on certain product characteristics,
rather than performing BE study for all designed
strengths. Also for this Biowaiver, the basic
requirements are identical in most countries.
For this type of Biowaiver, BE study is
performed either for the highest or lowest
strength among several strengths, in the case of
linear Pharmacokinetic profile. The highest or
lowest strength study based on pharmacokinetic
profile of different strength means that if there is
linear relationship between dose Vs response of
several strengths, then only BE study can be
performed either for highest or lowest strength.
Choice of strength for BE study: (In case of
Additional Strength) (1)
Highest Strength: Mostly highest strength is
used for BE study. Moreover, if lowest strength
is undetectable by analytical method then also
highest strength is used to perform BE study.
Lowest Strength: When highest strength is not
tolerated by patient or if the highest strength is
the issue of patient safety in that case lowest
strength is used for BE study.
When highest and lowest both strengths are
issue in that case, strength other than highest
and lowest is used for BE study among several
strengths.
If there is some deviation from quantitatively
proportional composition, then one or more of
the following criteria applies to the strength
used in the bioequivalence study and the
strength(s) for which a waiver is to be granted.
(1)
The amount of the active substance(s) is less
than 5% of the tablet core weight, the weight
of the capsule content.
The amounts of the different core excipients
or capsule content are the same for the
concerned strength and the amount of active
substance is changed.
The amount of filler is changed to account
for the change in amount of active
substance. The amounts of other core
excipients or capsule content should be the
same for the concerned strengths.
Types of Biowaiver
Specific
Dosage
Form
Additional
Strength
Other
Strength SUPAC BCS based
Biowaiver
Same
Product Bridging
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 10
Appropriate In-vitro dissolution data should
confirm the adequacy of waiving additional
In-vivo bioequivalence testing.
3) Biowaiver for Other Strengths
If several strengths (which are already
approved) are designed for same formulation
then it is called “Biowaiver based on Other
Strength”. Mostly highest or lowest strength (In
case of linear pharmacokinetic) are used for BE
study.
There are two approaches under Biowaiver for
Other Strengths.
First approach called “Look a Like” is used
under Biowaiver for other strength, where
difference of total weight and size of different
strengths is minor. Waiver of In-vivo studies for
different strengths of a drug product can be
granted under 21CFR 320.22 (d) (2) when (1)
The drug product is in the same dosage
form, but in a different strength;
This different strength is proportionally
similar in its active and inactive ingredients
to the strength of the product for which the
same manufacturer has conducted an
appropriate In-vivo study;
The composition of strengths are
quantitatively proportional, i.e. the ratio
between the amount of each excipient to the
amount of active substance(s) is the same
for all strengths (for immediate release
products coating components, capsule shell,
color agents and flavors are not required to
follow this rule).
A second approach is called “Dose
Proportional.” For that guidance defines
proportionally similar in the following ways: (1)
All active and inactive ingredients are in
exactly the same proportion between
different strengths (e.g., a tablet of 50 mg
strength has all the inactive ingredients,
exactly half that of a tablet of 100 mg
strength, and twice that of a tablet of 25 mg
strength).
Active and inactive ingredients are not in
exactly the same proportional between
different strengths as stated above, but the
ratios of inactive ingredients to total weight
of the dosage form are within the limits
defined by the SUPAC-IR and SUPAC-MR
guidance up to and including Level II.
For high potency drug substances, where are
amount of the active drug substance in the
dosage form is relatively low, the total
weight of the dosage form remains nearly
the same for all strengths (within ± 10% of
the total weight of the strength on which a
biostudy was performed), the same inactive
ingredients are used for all strengths and the
change in any strength is obtained by
altering the amount of the active ingredients
and one or more of the inactive ingredients.
The changes in the inactive ingredients are
within the limits defined by the SUPAC-IR
and SUPAC-MR guidance up to and
including Level II.
4) Biowaiver based on BCS
For drug substances belonging to a BCS class
(Mostly Class I or Class III), a complete
Biowaiver for bioequivalence studies might be
possible if criteria of solubility, permeability
and dissolution are met. The eligibility criteria
for BCS based Biowaivers differs between
USA, EU and WHO as well as in other
countries which have been compared in table 3
on basis of solubility, permeability, dissolution
and BCS Classification.
5) Biowaiver for Scale Up and Post
Approval Changes (SUPAC)
During the life cycle of a medicinal product,
there usually are several post approval changes
which may require bioequivalence study to
prove the equivalence of the new generic
medicinal product to the reference product.
However, under this approach there is no need
of additional BE study as the applicant can
justify that certain preconditions are fulfilled or
comparable in different geographical scopes.
This kind of Biowaiver is applicable to mostly
minor post approval changes and few of the
moderate changes.
Information of the types of In-vitro dissolution
testing in the presence of specified post approval
changes are provided in FDA guidance for
industry entitled SUPAC-IR: Immediate Release
Solid Oral Dosage Forms - Scale Up and Post
Approval Changes. For post approval changes,
we recommended that the In-vitro comparison
be made between the pre-change and post-
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 11
change products. In instances where dissolution
profile comparisons are suggested, we also
recommended an f2 test be used. An f2 value of
>50 suggests a sufficiently similar dissolution
profile such that no further In-vivo studies are
needed. When In-vivo BE studies are called for,
we recommend that the comparison be made for
ANDAs between the post-change and RLD.
6) Biowaiver for Same Product
Biowaiver for same product can be granted if
the generic medicinal product is a one-to-one
copy of the reference product, bioequivalence
between the test and reference product can be
presumed based on demonstration of identity
and comparative In-vitro dissolution data. The
basis for this Biowaiver approach is the
equivalence of the test and reference product.
Although not officially described in regulatory
guidance documents, in theory it is possible
only if the generic applicant knows exact
quantitative and qualitative composition (with
regard to active substance(s) and excipients) as
well as the galenical characteristics and
manufacturing process of the reference product.
In practice, however, it is often not feasible due
to patent issues to develop quantitatively and
qualitatively the same product as the innovator.
Altogether, this approach is not very common
but it sometimes is possible (e.g. simple gelatin
capsules filled only with the active ingredient
without any excipients). Regulatory authorities
worldwide must be convinced of this Biowaiver
approach on a case by case basis.
7) Bridging – Biowaiver for National
Bioequivalence Study based on
Bioequivalence Study versus Foreign
reference Product
There is the so called “Bridging” approach used
to waive unnecessary national bioequivalence
studies. Many countries require so-called local
bioequivalence studies that are bioequivalence
studies of test product versus the local reference
product; very often performed with subjects
from the local population. Asian countries
(instance e.g., China, South Korea, Thailand and
Japan) usually require such local bioequivalence
studies. Other countries such as Russia, Canada,
Australia, Brazil, Mexico require bio-
equivalence studies versus the corresponding
local reference product. In the case of ethnic
sensitivity relating to the metabolism of the drug
substance, it makes sense to demonstrate
bioequivalence in different ethnic populations.
However, the need to use the local reference
product is not always justified or necessary
because innovator products are very often
identical in different countries around the world.
Under this “Bridging” Biowaiver concept,
regulatory authorities accept the results of
bioequivalence studies which have been
performed for test versus a foreign reference
product rather than national reference product
approved in the country where the application is
made. The study results versus the foreign
reference product are “bridged” via product
likeness to the locally /nationally approved
reference product. If the foreign and local/
national reference products are demonstrated to
be essentially the same, an additional
bioequivalence study may not be required.
However, one prerequisite is that general study
requirements like GCP are fulfilled and that
potential ethnic differences in pharmacokinetics
can be excluded.
DISSCUSSION
Various Biowaiver approaches have been
described. These approaches are compared
against global regulatory authorities in Table 1.
The symbol “+” indicates availability of
provision in the guideline for the corresponding
authority. The symbol “-“ indicates absence of
provision in the guideline for the corresponding
authority.
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 12
Table 1: Comparison on Provisions Available for Different Biowaiver Approaches
Parameter
Regulatory
Authority
Specific
Dosage
Form
Additional
strengths
-Lower
-higher
Other
Strengths
BCS
Based
Post
Approval
Changes
Same
Product
Bridging
USA
+
+
+
+
Class I
+
+
+
EU
+
+
Highest &
Lowest
+
+
Class I &
Class III
+
+
+
WHO
+
+
-
+
Class I,
Class III
& Class II
weak acid
+
+
-
ASEAN
+
+
Highest &
Lowest
+
+
Class I
+
+
-
Australia
+
+
Highest &
Lowest
+
+
Class I &
Class III
+
+
+
Brazil
+
+
Highest &
Lowest
-
+
Class I
+
+
-
Canada
+
+
-
+
Class I &
Class III
+
+
-
China
Translated Guidance from Regulatory Authority of China is not available.
India
+
+
-
+
Class I
+
+
-
Japan
+
+
+
Not
Available
+
+
-
Malaysia
+
+
Highest &
Lowest
+
+
Class I
+
+
+
Russia
+
+
-
+
Class I
+
+
-
Saudi
Arabia
+
+
-
+
Class I
+
+
+
South
Africa
+
+
-
+
Class I
+
+
-
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 13
From comparison of availability of Biowaiver
approaches, it can be seen that provisions of
specific dosage form, BCS based, Post Approval
Changes, Same Product based Biowaiver and
Additional Strength Biowaiver (Highest or
Lowest) are available in multiple regulatory
authorities. However, in most countries, y
highest strength BE study is essential to
perform. Moreover, BCS based Biowaiver
approach is not available in all countries,
specifically Japan and Switzerland among the
compared regulatory authorities. In addition,
BCS class (Mostly BCS Class I or Class III)
requirement for Biowaiver also varies. It is
significant to note that Biowaiver based on
Other Strengths is available only in the EU,
ASEAN, Australia and Malaysia. Biowaiver
based on “Bridging Approach” is available in
only the USA, EU, Malaysia and Saudi Arabia.
BCS BASED BIOWAIVER
A Biowaiver can currently be requested for solid
orally administered immediate release product
containing the drug having high solubility and
high permeability (BCS based Biowaiver).
Statistics on generic drug products approved by
USFDA between 2000 and 2011 based on BCS
classification include 263 approvals, of which
110 approvals were for BCS Class I, 55
approvals for BCS Class II and 98 approvals for
BCS Class III. (2)
It is estimated that the In-vivo bioavailability
and bioequivalence studies cost up to $ 250,000
each and require up to 2 months to complete,
whereas the In-vitro laboratory tests are rather
inexpensive and fast. BCS based Biowaiver is
applicable to ANDA as well as NDA filing
whichever applies, exempting from performing
In-vivo bioequivalence (BE) study and reducing
cost and time to complete BE study.
A BCS based Biowaiver is an exemption from
conducting human bioequivalence studies if
active ingredient and dosage form meet
solubility, In-vitro permeability and dissolution
criteria. As per Biopharmaceutics Classification
System (BCS), Drugs are classified into four
classes having different solubility and
permeability criteria, described in Table 2.
Table 2: Biopharmaceutical Classification
BCS Class I
High Solubility
High Permeability
BCS Class II
Low Solubility
High Permeability
BCS Class III
High Solubility
Low Permeability
BCS Class IV
Low Solubility
Low Permeability
Different guidelines for regulatory authorities
have their own requirements and criteria for
submitting dossier to get BCS based Biowaiver,
and for carrying out study needed for BCS
based Biowaiver. The Approval criteria vary by
regulatory authority, but most of the guidelines
have the same requirements for permeability,
solubility and dissolution because most of them
are adopted from USFDA, EMEA and WHO
guidance on BCS based Biowaiver.
Jurisdictions like Brazil, Australia, Association
of Southeast Asian Nations (ASEAN), South
Africa, India, and Saudi Arabia have adopted
the BCS based Biowaiver concept based on one
of the three main guidance documents (USFDA,
EMA, WHO) or a combinations of specific
requirements from each guidance. As per WHO
guideline, BCS based Biowaiver can be granted
either for BCS Class I or Class III or Class II
weak acids. But most of drug regulatory
authority are granting BCS based Biowaiver for
BCS class I drugs. Whereas EU, Australia and
Canada regulatory guideline have provision to
grant Biowaiver for BCS Class I as well as BCS
Class III.
Although most of the requirements for BCS
based Biowaiver are the same for solubility,
permeability and dissolution, the pH range for
solubility study, extent of absorption and BCS
Class vary by regulatory authority, indicated in
bold fonts in Table 3. Table 3 presents the
comparison between requirements for data to
support BCS based Biowaiver is given.
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 14
Table 3: Comparison of Key Factors or Requirement Criteria for BCS Based Biowaiver
Regulatory
Authority
Solubility of Drug Substance
Permeability of Drug Substance
BCS Class
of Drug
Substance
In-vitro Dissolution Similarity of Test and Reference
Product
USA (3) *
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-7.5
Temp.:
37 ±1°C
Methodology:
Shake Flask Method
Acid or Base Titration
Highly Permeable: Extent of
absorption in humans is ≥ 90%
Methodology:
Absolute Bioavailability study
Mass Balance study
In-vivo perfusion study
In-vitro excised human or
animal Intestinal study
In-vitro epithelial cell culture
study
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 50 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
EU (4)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-6.8
Temp.:
37 ±1°C
Methodology:
Shake Flask Method
Highly Permeable: Extent of
absorption in humans is ≥ 85%
Methodology:
Absolute Bioavailability study
Mass Balance study
Class I,
Class III
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Class III
Very Rapidly Dissolving: ≥85% of the labeled amount
of the drug substance dissolves within 15 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 50 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 15
Regulatory
Authority
Solubility of Drug Substance
Permeability of Drug Substance
BCS Class
of Drug
Substance
In-vitro Dissolution Similarity of Test and Reference
Product
WHO (5)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-6.8
Temp.:
37 ±1°C
Methodology:
Shake Flask Method
Highly Permeable: Extent of
absorption in humans is ≥ 85%
Methodology:
Absolute Bioavailability study
Mass Balance study
Class I,
Class III
and Class
II weak
acid
Rapidly Dissolving:
Class I:
≥85% of the labeled amount of the drug substance
dissolves within 30 minutes.
Class III:
≥85% of the labeled amount of the drug substance
dissolves within 15 minutes.
Class II(Weak Acid):
≥85% of the labeled amount of the drug substance
dissolves within 30 minutes at
pH 6.8
Apparatus: USP Type I at 100 rpm or
Type II at 75 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
ASEAN (6)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-7.5
Temp.:
37 ±1°C
Highly Permeable: Extent of
absorption in humans is ≥ 90%
Methodology:
Absolute Bioavailability study
Mass Balance study
In-vivo perfusion study
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 50 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 16
Regulatory
Authority
Solubility of Drug Substance
Permeability of Drug Substance
BCS Class
of Drug
Substance
In-vitro Dissolution Similarity of Test and Reference
Product
Methodology:
Shake Flask Method,
Acid or Base Titration
In-vitro excised human or
animal Intestinal study
In-vitro epithelial cell culture
study
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
Australia(4)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-6.8
Temp.:
37 ±1°C
Methodology:
Shake Flask Method
Highly Permeable: Extent of
absorption in humans is ≥ 85%
Methodology:
Absolute Bioavailability study
Mass Balance study
Class I,
Class III
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Class III
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 15 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 50 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
Brazil (7)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-6.8
Temp.:
37 ±1°C
Highly Permeable: Extent of
absorption in humans is ≥ 85%
Methodology:
Absolute Bioavailability study
Mass Balance study
In-vitro epithelial cell culture
study
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 50 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 17
Regulatory
Authority
Solubility of Drug Substance
Permeability of Drug Substance
BCS Class
of Drug
Substance
In-vitro Dissolution Similarity of Test and Reference
Product
Methodology:
Shake Flask Method
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
Canada (8)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-6.8
Temp.:
37 ±1°C
Methodology:
Shake Flask Method or
similar method with
justification.
Highly Permeable: Extent of
absorption in humans is ≥ 85%
Methodology:
Absolute Bioavailability study
Mass Balance study
Class I
and
Class III
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Class III
Very Rapidly Dissolving: ≥85% of the labeled amount
of the drug substance dissolves within 15 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 50 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
China
Guidance from Regulatory Authority of China is not available in Translated Language or English Language.
India (9)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-7.5
Temp.:
37 ±1°C
Methodology:
Highly Permeable: Extent of
absorption in humans is ≥ 90%
Methodology:
Absolute Bioavailability study
Mass Balance study
In-vivo perfusion study
In-vitro excised human or
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 50 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 18
Regulatory
Authority
Solubility of Drug Substance
Permeability of Drug Substance
BCS Class
of Drug
Substance
In-vitro Dissolution Similarity of Test and Reference
Product
Shake Flask Method
Acid or Base Titration
animal Intestinal study
In-vitro epithelial cell culture
study
without enzymes.
N = 12
Japan (10)
Regulatory Authority of Japan has introduced the concept of BCS based Biowaiver but it hasn’t particular guideline for that.
Malaysia
(11)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-6.8
Temp.:
37 ±1°C
Methodology:
Shake Flask Method or
similar method with
justification
Highly Permeable: Extent of
absorption in humans is ≥ 85%
Methodology:
Absolute Bioavailability study
Mass Balance study
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 75 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
Russia (12)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-6.8
Temp.:
37 ±1°C
Methodology:
Shake Flask Method or
similar method with
justification
Highly Permeable: Extent of
absorption in humans is ≥ 85%
Methodology:
Absolute Bioavailability study
Mass Balance study
In-vivo perfusion study
In-vitro excised human or
animal Intestinal study
In-vitro epithelial cell culture
study
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 75 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 19
Regulatory
Authority
Solubility of Drug Substance
Permeability of Drug Substance
BCS Class
of Drug
Substance
In-vitro Dissolution Similarity of Test and Reference
Product
Saudi
Arabia (13)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-6.8
Temp.:
37 ±1°C
Methodology:
Shake Flask Method or
similar method with
justification
Highly Permeable: Extent of
absorption in humans is ≥ 85%
Methodology:
Absolute Bioavailability study
Mass Balance study
In-vitro epithelial cell culture
study
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 75 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
South
Africa (14)
Highest dose strength is
soluble in ≤ 250 ml of
buffers
pH range:
1-7.5
Temp.:
37 ±1°C
Methodology:
Shake Flask Method or
similar method with
justification
Highly Permeable: Extent of
absorption in humans is ≥ 90%
Absolute Bioavailability study
Mass Balance study
In-vitro epithelial cell culture
study
Class I
Rapidly Dissolving: ≥85% of the labeled amount of the
drug substance dissolves within 30 minutes.
Apparatus: USP Type I at 100 rpm or Type II at 50 rpm
Dissolution Media: 900 ml of following media
(1) 0.1 N HCl or Simulated Gastric Fluid USP without
enzymes;
(2) pH 4.5 buffer;
(3) pH 6.8 buffer or Simulated Intestinal Fluid USP
without enzymes.
N = 12
(Note: * Recently US FDA proposed draft guidance on “Waiver of In-vivo Bioavailability and Bioequivalence studies for Immediate Release Solid Oral
Dosage Forms based on a Biopharmaceutics Classification System – Guidance for Industry” (May 2015). As per this guidance, BCS class I as well as BCS
class III drugs can get Biowaiver approval. Moreover, the same requirements from EU guidance for pH range for solubility study, extent of absorption and
dissolution criteria have been proposed.)
Jimi et al. International Journal of Drug Regulatory Affairs; 2015, 3(3), 8-20 ISSN: 2321 - 6794
© 2015 IJDRA Publishing Group, All rights reserved Page 20
CONCLUSION
It is concluded that the Biowaiver is an
advantage for generic companies as it exempts
BE study. In addition, Biowaiver is a time and
cost saving fast track approach for ANDA
filing. BCS based Biowaiver is employed to
waive In-vivo BE testing for new as well as
generic drugs application. Granting Biowaivers
under systems such as the BCS eliminates
unnecessary In-vivo studies and provides fast
approval, while maintaining the high public
health standard for therapeutic equivalence to
the innovator drug. Using the rationale of BCS,
it can be argued that Biowaivers can also be
granted on the basis of standard
pharmacokinetic data, such as when a drug
exhibits dose-linear pharmacokinetics and a
sufficiently fast dissolution profile. However,
BCS based Biowaiver does not apply to food
effects bioavailability studies and other
pharmacokinetic studies as they are intended
only for BE studies. Thus, BCS based
Biowaiver is not applicable to waive all types of
clinical studies.
Research is ongoing in this field by exploring
different strategies and methods to increase the
utilization of the Biowaiver approach (mostly
BCS based Biowaiver). In the future, the
Biowaiver monograph project will extend to
fixed dose combinations and science based risk
calculations. However, further global
harmonization for Biowaiver regulations and
guidelines is needed for wider implementation
of best science practices in the area of
Biowaiver.
ACKNOWLEDGEMENT
I’m thankful to Dr. Priti Mehta, Dept. of
Pharmaceutical Analysis, Institute of Pharmacy,
Nirma University, India, & Ms. Vaishali
Kothari, International Regulatory Affairs,
Cadila Healthcare Limited, New Sigma PTC,
Ahmedabad for his kind assistance for the
preparation of this manuscript.
CONFLICTS OF INTEREST
Author declares that there are no conflict of
interest in this work.
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