M9 Biopharmaceutics Classification System-Based Biowaivers

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

M9 Biopharmaceutics
Classification System-
Based Biowaivers
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 2021
ICH

M9 Biopharmaceutics
Classification System-
Based Biowaivers
Guidance for Industry
Additional copies are available from:
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Center for Drug Evaluation and Research
Food and Drug Administration
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Silver Spring, MD 20993-0002
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https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
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Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 2021
ICH

Contains Nonbinding Recommendations
FOREWORD
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use (ICH) has the mission of achieving greater regulatory harmonization
worldwide to ensure that safe, effective, and high-quality medicines are developed, registered,
and maintained in the most resource-efficient manner. By harmonizing the regulatory
expectations in regions around the world, ICH guidelines have substantially reduced
duplicative clinical studies, prevented unnecessary animal studies, standardized safety
reporting and marketing application submissions, and contributed to many other
improvements in the quality of global drug development and manufacturing and the products
available to patients.
ICH is a consensus-driven process that involves technical experts from regulatory authorities
and industry parties in detailed technical and science-based harmonization work that results in
the development of ICH guidelines. The commitment to consistent adoption of these
consensus-based guidelines by regulators around the globe is critical to realizing the benefits
of safe, effective, and high-quality medicines for patients as well as for industry. As a
Founding Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a
major role in the development of each of the ICH guidelines, which FDA then adopts and
issues as guidance to industry.

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TABLE OF CONTENTS
I. INTRODUCTION (1)............................................................................................ 1
A. Background and Objective (1.1) ................................................................................ 1
B. Scope (1.2) ............................................................................................................... 2
II. BIOPHARMACEUTICS CLASSIFICATION OF THE DRUG SUBSTANCE (2)
............................................................................................................................... 2
A. Solubility (2.1).......................................................................................................... 2
B. Permeability (2.2) ..................................................................................................... 3
III. ELIGIBILITY OF A DRUG PRODUCT FOR A BCS-BASED BIOWAIVER (3)
............................................................................................................................... 4
A. Excipients (3.1) ........................................................................................................ 5
B. In Vitro Dissolution (3.2) .......................................................................................... 7
IV. DOCUMENTATION (4) ....................................................................................... 8
V. GLOSSARY (5) ..................................................................................................... 9
ANNEX I: CACO-2 CELL PERMEABILITY ASSAY METHOD CONSIDERATIONS
............................................................................................................................. 10
ANNEX II: FURTHER INFORMATION ON THE ASSESSMENT OF EXCIPIENT
DIFFERENCES .............................................................................................................. 13

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M9 Biopharmaceutics Classification System-Based Biowaivers
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency)
on this topic. It does not establish any rights for any person and is not binding on FDA or the public.
You can use an alternative approach if it satisfies the requirements of the applicable statutes and
regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance
as listed on the title page.
I. INTRODUCTION (1)2
A. Background and Objective (1.1)
Two drug products containing the same drug substance or substances are considered
bioequivalent if their bioavailabilities (rate and extent of drug absorption) after administration
in the same molar dose lie within acceptable predefined limits. These limits are set to
ensure comparable in vivo performance, i.e., similarity in terms of safety and efficacy. In in
vivo bioequivalence studies, the pivotal pharmacokinetic parameters area under the
concentration time curve (AUC)3 and maximum concentration (Cmax), are generally used to
assess the rate and extent of drug absorption.
The biopharmaceutics classification system (BCS)-based biowaiver approach is intended to
reduce the need for in vivo bioequivalence studies, i.e., it can provide a surrogate for in vivo
bioequivalence. In vivo bioequivalence studies may be exempted if an assumption of
equivalence in in vivo performance can be justified by satisfactory in vitro data. The BCS is
a scientific approach based on the aqueous solubility and intestinal permeability
characteristics of the drug substance or substances. The BCS categorizes drug substances
into one of four BCS classes as follows:
• Class I: high solubility, high permeability
• Class II: low solubility, high permeability
• Class III: high solubility, low permeability
• Class IV: low solubility, low permeability
1 This guidance was developed within the Expert Working Group (Multidisciplinary) of the International
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and has been
subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been
endorsed by the ICH Assembly at Step 4 of the ICH process, November 2019. At Step 4 of the process, the
final draft is recommended for adoption to the regulatory members of the ICH regions.
2 Arabic numbers reflect the organizational breakdown of the document endorsed by the ICH Steering
Committee at Step 4 of the ICH process, November 2019.
3 Words found in the GLOSSARY (p. 9) are bolded at first use in this guidance.

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This guidance provides recommendations to support the biopharmaceutics classification of
drug substances and the BCS-based biowaiver of bioequivalence studies for drug products.
The BCS-based biowaiver principles may be applied to bioequivalence purposes not
explicitly noted in the guidance, provided they can be supported by a thorough scientific
rationale.
The contents of this document do not have the force and effect of law and are not meant to
bind the public in any way, unless specifically incorporated into a contract. This document
is intended only to provide clarity to the public regarding existing requirements under the
law. FDA guidance documents, including this guidance, should be viewed only as
recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in FDA guidances means that something is suggested or recommended, but
not required.
B. Scope (1.2)
BCS-based biowaivers may be used to substantiate in vivo bioequivalence. Examples
include comparison between products used during clinical development through
commercialization, post-approval changes, and applications for generic drug products in
accordance with regional regulations.
The BCS-based biowaiver is only applicable to immediate release, solid orally administered
dosage forms or suspensions designed to deliver drug to the systemic circulation. Drug
products having a narrow therapeutic index are excluded from consideration fo r a BCS-based
biowaiver in this guidance. Fixed-dose combination (FDC) products are eligible for a BCS-
based biowaiver when all drug substances contained in the combination drug product meet
the criteria as defined in sections II. (2) and III. (3) of this guidance.
II. BIOPHARMACEUTICS CLASSIFICATION OF THE DRUG SUBSTANCE (2)
BCS-based biowaivers are applicable to drug products where the drug substance or
substances exhibit high solubility and, either high permeability (BCS Class I) or low
permeability (BCS Class III).
A biowaiver is applicable when the drug substance(s) in test and reference products are
identical. A biowaiver may also be applicable if test and reference products contain
different salts provided that both belong to BCS Class I (high solubility and high
permeability). A biowaiver is not applicable when the test product contains a different ester,
ether, isomer, mixture of isomers, complex or derivative of a drug substance from that of the
reference product, because these differences may lead to different bioavailabilities not
deducible by means of experiments used in the BCS-based biowaiver concept. Pro-drugs
may be considered for a BCS-based biowaiver when absorbed as the pro-drug.
A. Solubility (2.1)
A drug substance is classified as highly soluble if the highest single therapeutic dose is
completely soluble in 250 milliliter (mL) or less of aqueous media over the pH range of 1.2–
6.8 at 37±1°C. In cases where the highest single therapeutic dose does not meet this
criterion, but the highest strength of the reference product is soluble under the

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aforementioned conditions, additional data should be submitted to justify the BCS-based
biowaiver approach.
The sponsor is expected to establish experimentally the solubility of the drug substance over
the pH range of 1.2–6.8 at 37±1ºC. At least three pHs within this range, including buffers at
pH 1.2, 4.5 and 6.8, should be evaluated. In addition, solubility at the pH of lowest
solubility of the drug substance should be evaluated if it is within the specified pH range.
These experiments should demonstrate that solubility is maintained over relevant timeframes
to accommodate the expected duration of absorption.
Solubility should be evaluated by a method appropriate to the properties of the drug
substance.
Equilibrium solubility experiments may be performed, using a shake-flask technique or an
alternative method, if justified. Small volumes of solubility media may be employed if the
available experimental apparatus will permit it. The pH for each test solution should be
measured after the addition of the drug substance and at the end of the equilibrium solubility
study to ensure the solubility measurement is conducted under the specified pH. The pH
should be adjusted if necessary. The experiment should be conducted over a suitable
timeframe to reach equilibrium.
Alternatively, solubility experiments where the highest therapeutic single dose is examined in
a 250 mL volume, or a proportionally smaller amount examined in a proportionally smaller
volume of buffer, can be considered.
The lowest measured solubility over the pH range of 1.2–6.8 will be used to classify the drug
substance.
A minimum of three replicate determinations at each solubility condition/pH using
appropriate compendial media is necessary to demonstrate solubility using a suitably
validated method.
In addition, adequate stability of the drug substance in the solubility media should be
demonstrated. In cases where the drug substance is not stable with >10% degradation over
the extent of the solubility assessment, solubility cannot be adequately determined and thus
the drug substance cannot be classified. In addition to experimental data, literature data may
be provided to substantiate and support solubility determinations, keeping in mind that peer
reviewed articles may not contain the necessary details of the testing to make a judgement
regarding the quality of the studies.
B. Permeability (2.2)
The assessment of permeability should preferentially be based on the extent of absorption
derived from human pharmacokinetic studies, e.g., absolute bioavailability or mass balance.
High permeability can be concluded when the absolute bioavailability is ≥85%. High
permeability can also be concluded if ≥85% of the administered dose is recovered in urine as
unchanged (parent drug), or as the sum of parent drug, Phase 1 oxidative and Phase 2
conjugative metabolites. Regarding metabolites in feces, only oxidative and conjugative
metabolites can be considered. Metabolites produced through reduction or hydrolysis
should not be included, unless it can be demonstrated that they are not produced before

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absorption, e.g., by microbial action within the gastrointestinal tract. Unchanged drug in
feces cannot be counted toward the extent of absorption, unless appropriate data supports that
the amount of parent drug in feces to be accounted for absorbed drug material is from biliary
excretion, intestinal secretion or originates from an unstable metabolite, e.g., glucuronide,
sulphate, N-oxide, that has been converted back to the parent by the action of microbial
organisms.
Human in vivo data derived from published literature (e.g., product knowledge and
bioavailability studies) may be acceptable, keeping in mind that peer reviewed articles may
not contain the necessary details of the testing to make a judgement regarding the quality of
the results.
Permeability can be also assessed by validated and standardized in vitro methods using Caco-
2 cells (see Annex I). The results from Caco-2 permeability assays should be discussed in
the context of available data on human pharmacokinetics. If high permeability is inferred
by means of an in vitro cell system, permeability independent of active transport should be
proven as outlined in Annex I, “Caco-2 cell permeability assay method considerations.”
If high permeability is not demonstrated, the drug substance is considered to have low
permeability for BCS classification purposes.
Drug Substance Stability in the Gastrointestinal Tract
Additional data to document the drug’s stability in the gastrointestinal tract should be
provided if mass balance studies are used to demonstrate high permeability, unless ≥85% of
the dose is recovered as unchanged drug in urine. Demonstration of stability in the
gastrointestinal tract is required if in vitro Caco-2 studies are used to support high
permeability. Stability in the gastrointestinal tract may be documented using compendial or
simulated gastric and intestinal fluids. Other relevant methods may be used with suitable
justification. Drug solutions should be incubated at 37ºC for a period that is representative
of the in vivo contact of the drug substance with these fluids, i.e., one hour in gastric fluid
and three hours in intestinal fluid. Drug concentrations should then be determined using a
suitably validated method. Significant degradation (>10%) of a drug precludes BCS high
permeability classification.
III. ELIGIBILITY OF A DRUG PRODUCT FOR A BCS-BASED BIOWAIVER (3)
A drug product is eligible for a BCS-based biowaiver provided that the drug substance or
substances satisfy the criteria regarding solubility and permeability (BCS Class I and III), the
drug product is an immediate-release oral dosage form with systemic action, and the drug
product is the same dosage form and strength as the reference product. In cases where the
highest single therapeutic dose does not meet the high solubility criterion, but the highest
strength of the reference product is soluble under the required conditions, BCS-based
biowaivers can be supported based on demonstration of dose proportional pharmacokinetics
(i.e., AUC and Cmax) over a dose range that includes the highest single therapeutic dose.
Drug products with buccal or sublingual absorption are not eligible for a BCS-based
biowaiver application. Furthermore, the BCS-based biowaiver approach is applicable only
when the mode of administration includes water. If administration without water is also

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intended (e.g., orodispersible products), a bioequivalence study in which the product is dosed
without water should be conducted.
In order for a drug product to qualify for a BCS-based biowaiver, criteria with respect to the
composition (excipients) and in vitro dissolution performance of the drug product should be
satisfied. The drug product acceptance criteria are described in sections III.A. (3.1) and
III.B. (3.2) below.
A. Excipients (3.1)
Ideally, the composition of the test product should mimic that of the reference product.
However, where excipient differences exist, they should be assessed for their potential to
affect in vivo absorption. This should include consideration of the drug substance properties
as well as excipient effects. To be eligible for a BCS-based biowaiver, the sponsor should
justify why the proposed excipient differences will not affect the absorption profile of the
drug substance under consideration, i.e., rate and extent of absorption, using a mechanistic
and risk-based approach. The decision tree for performing such an assessment is outlined in
Figures 1 and 2 in Annex II.
The possible effects of excipients on aspects of in vivo absorption such as solubility,
gastrointestinal motility, transit time, and intestinal permeability, including transporter
mechanisms, should be considered. Excipients that may affect absorption include sugar-
alcohols, e.g., mannitol, sorbitol, and surfactants, e.g., sodium lauryl sulfate. The risk that a
given excipient will affect the absorption of a drug substance should be assessed
mechanistically by considering:
• The amount of excipient used
• The mechanism by which the excipient may affect absorption
• Absorption properties (rate, extent, and mechanism of absorption) of the drug
substance
The amount of excipients that may affect absorption in the test and reference formulations
should be addressed during product development, such that excipient changes are kept to a
minimum. Small amounts included in the tablet coating, or levels below documented
thresholds of effect for the specific drug substance, are of less concern.
By definition, BCS Class I drugs are highly absorbed, and have neither solubility nor
permeability limited absorption. Therefore, they generally represent a low risk group of
compounds in terms of the potential for excipients to affect absorption, compared to other
BCS classes. Consideration of excipient effects for BCS Class I drug products should focus
on potential changes in the rate or extent of absorption. For example, if it is known that the
drug has high permeability due to active uptake, excipients that can inhibit uptake
transporters are likely to be of concern. For BCS Class I drugs that exhibit slow absorption,
the potential for a given excipient to increase absorption rate should also be considered.
For BCS Class I drugs, qualitative and quantitative differences in excipients are permitted,
except for excipients that may affect absorption, which should be qualitatively the same and
quantitatively similar, i.e., within ± 10% of the amount of excipient in the reference product.

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Additionally, the cumulative difference for excipients that may affect absorption should be
within ± 10%.
BCS Class III drug substances are considered to be more susceptible to the effects of
excipients. These drugs are not considered highly permeable and may have site-specific
absorption, so there are a greater number of mechanisms through which excipients can affect
their absorption than for BCS Class I drugs. For BCS Class III drugs, all of the excipients
should be qualitatively the same and quantitatively similar (except for film coating or capsule
shell excipients). Excipients that may affect absorption should be qualitatively the same and
quantitatively similar, i.e., within ± 10% of the amount of excipient in the reference product,
and the cumulative difference for these excipients should be within ± 10%. This is defined
in Table 1. Examples of acceptable differences in excipients are shown in Annex II.
Differences in colorants and flavoring may be permitted when these constitute very small
amounts of the formulation.
It is recognized that there are limitations to the application of Table 1, e.g., difficulty in
determining the film coat weight for the reference product. Table 1 is provided as a target to
give clarity to sponsors. Deviations from this will require appropriate justification, based on
the principles described above.
Table 1: Criteria Expected to Demonstrate Quantitative Similarity for Products
Containing BCS Class III Drugs.
Within the context of quantitative similarity, differences in excipients for drug products containing
BCS Class III drugs should not exceed the f ollowing targets:
Excipient Class Percent of the Amount of Excipient in the
Reference
Excipients which may affect absorption
Per excipient:
Sum of differences:
10%
10%
Percent Difference Relative to Core
Weight* (w/w)
All excipients:
Filler 10%
Disintegrant
Starch 6%
Other 2%
Binder 1%
Lubricant
Stearates 0.5%
Other 2%
Glidant
Talc 2%
Other 0.2%

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Total % change permitted for all excipients (including
excipients which may affect absorption): 10%
*Note: Core does not include tablet film coat or capsule shell.
BCS-based biowaivers are applicable to FDCs which are the same dosage form and strength .
FDC formulations containing only BCS Class I drugs should meet criteria regarding
excipients for a BCS Class I drug. FDC formulations containing only BCS Class III drugs,
or BCS Class I and BCS Class III drugs, should meet criteria regarding excipients for a BCS
Class III drug.
B. In Vitro Dissolution (3.2)
When applying the BCS based biowaiver approach, comparative in vitro dissolution tests
should be conducted using one batch representative of the proposed commercial
manufacturing process for the test product relative to the reference product. The test
product should originate from a batch of at least 1/10 of production scale or 100,000 units,
whichever is greater, unless otherwise justified. During a (clinical) development phase,
smaller batch sizes may be acceptable, if justified. The comparative in vitro dissolution
experiments should use compendial apparatus and suitably validated analytical method or
methods.
The following conditions should be employed in the comparative dissolution studies to
characterize the dissolution profile of the product:
• Apparatus: paddle or basket.
• Volume of dissolution medium: 900 mL or less (it is recommended to use the volume
selected for the quality control (QC) test).
• Temperature of the dissolution medium: 37±1°C.
• Agitation: paddle apparatus - 50 revolutions per minute (rpm).
basket apparatus - 100 rpm.
• At least 12 units of reference and test product should be used for each dissolution
profile determination.
• Three buffers: pH 1.2, pH 4.5, and pH 6.8. Pharmacopoeial buffers should be
employed. Additional investigation may be required at the pH of minimum
solubility (if different from the buffers above).
• Organic solvents are not acceptable, and no surfactants should be added.
• Samples should be filtered during collection, unless in situ detection methods are
used.
• For gelatin capsules or tablets with gelatin coatings where cross-linking has been
demonstrated, the use of enzymes may be acceptable, if appropriately justified.
When high variability or coning is observed in the paddle apparatus at 50 rpm for both
reference and test products, the use of the basket apparatus at 100 rpm is recommended.
Additionally, alternative methods (e.g., the use of sinkers or other appropriately justified
approaches) may be considered to overcome issues such as coning, if scientifically
substantiated. All experimental results should be provided.

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To qualify for a BCS-based biowaiver for BCS Class I drug substances, both the test product
and reference product should display either very rapid (≥85% for the mean percent dissolved
in ≤ 15 minutes) in vitro dissolution characteristics, or rapid (≥85% for the mean percent
dissolved in ≤ 30 minutes) and similar in vitro dissolution characteristics (i.e., based on f2
comparison), under all of the defined conditions. In cases where one product has rapid
dissolution and the other has very rapid dissolution, similarity of the profiles should be
demonstrated as below.
For the comparison of dissolution profiles, where applicable, the similarity factor f2 should
be estimated by using the following formula:
f2 = 50 • log {[1 + (1/n)Σt=1n (Rt - Tt)2]-0.5 • 100}
In this equation, f2 is the similarity factor, n is the number of time points, R(t) is the mean
percent reference drug dissolved at time t after initiation of the study, and T(t) is the mean
percent test drug dissolved at time t after initiation of the study.
The evaluation of the similarity factor is based on the following conditions:
• A minimum of three time points (zero excluded).
• The time points should be the same for the two products.
• Mean of the individual values for every time point for each product.
• Not more than one mean value of ≥85% dissolved for either of the products.
• To allow the use of mean data, the coefficient of variation should not be more than
20% at early time-points (up to 10 minutes) and should not be more than 10% at other
time points.
Two dissolution profiles are considered similar when the f2 value is ≥50 . When both test
and reference products demonstrate that ≥85% of the labeled amount of the drug is dissolved
in 15 minutes, comparison with an f2 test is unnecessary, and the dissolution profiles are
considered similar. When the coefficient of variation is too high, f2 calculation is
considered inaccurate and a conclusion on similarity in dissolution cannot be made.
To qualify for a BCS-based biowaiver for BCS Class III drug substances, both the test
product and reference product should display very rapid (≥85% for the mean percent
dissolved in ≤15 minutes) in vitro dissolution characteristics under the defined conditions.
For FDC formulations, dissolution profiles should meet the criteria for all drug substances in
the FDC to be considered. FDC formulations containing only BCS Class I drugs should
meet dissolution criteria for a BCS Class I drug. FDC formulations containing only BCS
Class III drugs should meet dissolution criteria for a BCS Class III drug. For FDCs
containing both BCS Class I and BCS Class III drugs, the dissolution criteria for the
applicable BCS class for each component should be applied.
For products with more than one strength, the BCS approach should be applied for each
strength, i.e., it is expected that test and reference product dissolution profiles are compared
at each strength.
IV. DOCUMENTATION (4)

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The sponsor should provide complete information on the critical quality attributes of the test
drug substance(s) and drug product, and as much information as possible for the reference
product, including, but not limited to: polymorphic form and enantiomeric purity; and any
information on bioavailability or bioequivalence problems with the drug substance(s) or drug
product, including literature surveys and sponsor-derived studies. All study protocols and
reports should be provided. Information on validated test methods should be appropriately
detailed according to current regulatory guidances and policies.
The reporting format should include tabular and graphical presentations showing individual
and mean results and summary statistics.
The report should include all excipients, their qualitative, and, where appropriate, quantitative
differences between the test and reference products.
A full description of the analytical methods employed, including validation and qualification
of the analytical parameters, should be provided. A detailed description of all test methods
and media, including test and reference batch information [unit dose (strength and assay),
batch number, manufacturing date and batch size where known, expiration date] should also
be provided. The dissolution report should include a thorough description of experimental
settings and analytical methods, including information on the dissolution conditions, such as
apparatus, deaeration, filtration during sampling, volume, etc.
In addition, complete information with full description of the methods applied should be
provided for the Caco-2 cell permeability assay method, if applicable (see Annex I).
V. GLOSSARY (5)
AUC: Area under the concentration versus time curve
BCS: Biopharmaceutics Classification System
Cmax: Maximum concentration
FDC: Fixed-dose combination
QC: Quality control
rpm: Revolutions per minute

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ANNEX I: CACO-2 CELL PERMEABILITY ASSAY METHOD CONSIDERATIONS
Permeability assays employing cultured Caco-2 epithelial cell monolayers derived from a
human colon adenocarcinoma cell line are widely used to estimate intestinal drug absorption
in humans. Caco-2 cells undergo spontaneous morphological and biochemical enterocytic
differentiation, express cell polarity with an apical brush border, tight intercellular junctions,
and several active transporters as in the small intestine. Due to a potential for low or absent
expression of efflux (e.g., P-gp, BCRP, MRP2) and uptake (e.g., PepT1, OATP2B1, MCT1)
transporters, the use of Caco-2 cell assays as the sole data in support of high permeability for
BCS classification is limited to passively transported drugs (see Assay Considerations).
Method Validation
The suitability of the Caco-2 cell assays for biopharmaceutics classification system (BCS)
permeability determination should be demonstrated by establishing a rank-order relationship
between experimental permeability values and the extent of drug absorption in human
subjects using zero, low (<50%), moderate (50–84%), and high (≥85%) permeability model
drugs. A sufficient number of model drugs are recommended for the validation to
characterize high, moderate, and low permeability (a minimum 5 for each), plus a zero-
permeability marker; examples are provided in Table 2. Further, a sufficient number
(minimum of 3) of cell assay replicates should be employed to provide a reliable estimate of
drug permeability. The established relationship should permit differentiation between low,
moderate, and high permeability drugs.
Caco-2 cell monolayer integrity should be confirmed by comparing transepithelial electrical
resistance (TEER) measures and/or other suitable indicators, before and after an experiment.
In addition, cell monolayer integrity should be demonstrated by means of compounds with
proven zero permeability (see Table 2).
Reporting of the method validation should include a list of the selected model drugs, along
with data on extent of absorption in humans (mean, standard deviation, coefficient of
variation) used to establish suitability of the 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 high permeability class
boundary and selected high permeability model drug used to classify the test drug substance.
In addition, a description of the study method, drug concentrations in the donor fluid,
description of the analytical method, and equation used to calculate permeability, should be
provided. Additionally, information on efflux potential, e.g., bidirectional transport data,
should be provided for a known substrate.
Assay Considerations
Passive transport of the test compound should be demonstrated. This may be verified using
a suitable assay system that expresses known efflux transporters, e.g., by demonstrating
independence of measured in vitro permeability on initial drug concentration, e.g., 0.01, 0.1,
and 1 times the highest strength dissolved in 250 milliliter (mL), or on transport direction
(efflux ratio, i.e., ratio of apparent permeability (Papp) between the basolateral-to-apical and
apical-to-basolateral directions <2 for the selected drug concentrations).

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Efflux ratio = PappBL→AP/PappAP→BL.
Functional expression of efflux transporters should be verified by using bidirectional
transport studies demonstrating asymmetric permeability of selected efflux transporter
substrates, e.g., digoxin, vinblastine, rhodamine 123, at non-saturating concentrations.
The test drug substance concentrations used in the permeability studies should be justified.
A validated Caco-2 method used for drug permeability determinations should employ
conditions established during the validation and include a moderate and a high permeability
model drug in the donor fluid along with the test drug as internal standards to demonstrate
consistency of the method. The choice of internal standards should be based on
compatibility with the test drug, i.e., they should not exhibit any significant physical,
chemical, or permeation interactions. The permeability of the internal standards may be
determined following evaluation of the test drug in the same monolayers or monolayers in the
same plate, when it is not feasible to include internal standards in the same cell culture well
as the test drug permeability evaluation. The permeability values of the internal standards
should be consistent between different tests, including those conducted during method
validation. Acceptance criteria should be set for the internal standards and model efflux
drug. Mean drug and internal standards recovery at the end of the test should be assessed.
For recoveries <80%, a mass balance evaluation should be conducted, including
measurement of the residual amount of drug in the cell monolayer and testing apparatus.
Evaluation of the test drug permeability for BCS classification may be facilitated by selection
of a high permeability internal standard with permeability in close proximity to the
moderate/high permeability class boundary. The test drug is considered highly permeable
when its permeability value is equal to or greater than that of the selected internal standard
with high permeability.
Information to support high permeability of a test drug substance (mean, standard deviation,
coefficient of variation) should include permeability data on the test drug substance, the
internal standards, in vitro gastrointestinal stability information, and data supporting passive
transport mechanism.
Table 2. Examples of Model Drugs for Permeability Assay Method Validation
Group Drug
High Permeability
(fa ≥85%)
Antipyrine
Caffeine
Ketoprofen
Naproxen
Theophylline
Metoprolol
Propranolol
Carbamazepine
Phenytoin
Disopyramide
Minoxidil
Moderate Permeability
(fa = 50-84%)
Chlorpheniramine
Creatinine

Contains Nonbinding Recommendations
12
Group Drug
Terbutaline
Hydrochlorothiazide
Enalapril
Furosemide
Metformin
Amiloride
Atenolol
Ranitidine
Low Permeability
(fa < 50%)
Famotidine
Nadolol
Sulpiride
Lisinopril
Acyclovir
Foscarnet
Mannitol
Chlorothiazide
Polyethylene glycol 400
Enalaprilat
Zero Permeability FITC-Dextran
Polyethylene glycol 4000
Lucifer yellow
Inulin
Lactulose
Efflux Substrates Digoxin
Paclitaxel
Quinidine
Vinblastine

Contains Nonbinding Recommendations
13
ANNEX II: FURTHER INFORMATION ON THE ASSESSMENT OF EXCIPIENT
DIFFERENCES
Figure 1. BCS Class I Drug Substances

Contains Nonbinding Recommendations
14
Figure 2. BCS Class III Drug Substances

Contains Nonbinding Recommendations
15
EXAMPLES OF ACCEPTABLE DIFFERENCES IN EXCIPIENTS
Example 1: BCS Class I Biowaiver
The formulation of the test product is qualitatively the same as that of the reference product.
Additionally, it contains sorbitol, an excipient with known or suspected effects on drug
absorption. The amount of sorbitol in the test formulation is within the permitted range of
45 milligrams (mg) to 55 mg based on the amount of sorbitol in the reference formulation
(i.e., 50 mg ± 10%).
Component Amount (mg)
Reference Amount (mg) Test
Drug substance 100 100
Microcrystalline cellulose (filler) 100 95
Sorbitol (filler) 50 55
HPMC (binder) 10 10
Talc (glidant) 5 5
Total 265 265

Contains Nonbinding Recommendations
16
Example 2: BCS Class III Biowaiver
The test formulation is qualitatively the same as the reference formulation. Additionally, it
contains sorbitol, an excipient with known or suspected effects on drug absorption. The
amount of sorbitol in the test formulation is within the permitted range of 9 mg to 11 mg
based on the amount of sorbitol in the reference formulation (i.e., 10 mg ± 10%).
Differences in the amount of other excipients are within the criteria outlined in Table 1,
Section III.A. (3.1).
Component
Reference Product Test Product Absolute
%
difference
relative to
core
weights
Composition
(mg)
Proportion
relative to
core weight
(%w/w)
Composition
(mg)
Proportion
relative to
core weight
(%w/w)
Drug substance 100 49.3% 100 46.5% --
Lactose
monohydrate
(filler)
85 41.9% 97 45.1% 3.2%
Sorbitol (filler) 10 4.9% 9 4.2% 0.7%
Croscarmellose
sodium
(disintegrant)
6 3.0% 7 3.3% 0.3%
Magnesium
stearate
(lubricant)
2 1.0% 2 0.9% 0.1%
Total 203 100% 215 100%
Total
change: 4.3%

M9 BIOPHARMACEUTICS
CLASSIFICATION SYSTEM-BASED
BIOWAIVERS
Guidance for Industry
Questions and Answers
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 2023
ICH - Multidisciplinary
This document has been developed by the appropriate ICH Expert Working Group and
has been subject to consultation by the regulatory parties, in accordance with the ICH
Process. 	At Step 4 of the Process the final draft is recommended for adoption to the
regulatory bodies of ICH regions.

i
M9 BIOPHARMACEUTICS
CLASSIFICATION SYSTEM-BASED
BIOWAIVERS
Guidance for Industry
Questions and Answers
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4 th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 2023
ICH – Multidisciplinary

ii
To facilitate the implementation of the M9 Guideline, the
EWG has developed a series of Q&As:
M9 Q&As
Document History
Code 	History 	Date
M9 Q&As 	Adoption by the Regulatory Members of the ICH
Assembly under Step 4
20 November
2019
Legal notice: This document is protected by copyright and may, with the exception of the ICH
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The above-mentioned permissions do not apply to content supplied by third parties. Therefore,
for documents where the copyright vests in a third party, permission for reproduction must be
obtained from this copyright holder.

iii
FOREWORD
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
has the mission of achieving greater regulatory harmonization worldwide to ensure that safe, effective, and high-
quality medicines are developed, registered, and maintained in the most resource-efficient manner. By harmonizing
the regulatory expectations in regions around the world, ICH guidelines have substantially reduced duplicative clinical
studies, prevented unnecessary animal studies, standardized safety reporting and marketing application submissions,
and contributed to many other improvements in the quality of global drug development and manufacturing and the
products available to patients.
ICH is a consensus-driven process that involves technical experts from regulatory authorities and industry parties in
detailed technical and science-based harmonization work that results in the development of ICH guidelines. The
commitment to consistent adoption of these consensus-based guidelines by regulators around the globe is critical to
realizing the benefits of safe, effective, and high-quality medicines for patients as well as for industry. As a Founding
Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a major role in the development of each
of the ICH guidelines, which FDA then adopts and issues as guidance to industry.

iv
TABLE OF CONTENTS
1. 	INTRODUCTION - SCOPE ........................................................................................... 3
2. 	BIOPHARMACEUTICS CLASSIFICATION OF THE DRUG SUBSTANCE ........ 4
2.1 	Solubility ......................................................................................................... 4
2.2 	Permeability ..................................................................................................... 5
3. 	ELIGIBILITY OF A DRUG PRODUCT FOR A BCS-BASED BIOWAIVER ......... 6
3.1 	Excipients ........................................................................................................ 7
3.2 	In vitro Dissolution .......................................................................................... 8
4. 	ANNEX: Q&AS LINKED TO THE RESPECTIVE SECTIONS OF ICH M9
GUIDELINE .................................................................................................................. 12

3
ICH M9 Q&As
1. 	INTRODUCTION - SCOPE1
# Date of
Approval Questions 	Answers
1.1 	Nov. 2019
Are drug substances that exhibit non-
linear pharmacokinetics eligible for a
Biopharmaceutic Classification
System (BCS)-based biowaiver?
Drug substances that exhibit non-linear
pharmacokinetics are eligible for a BCS-based
biowaiver if they meet the solubility and
permeability criteria for BCS I or III
classification.
1.2 	Nov. 2019
Why does the guideline allow for
regional differences in applications
for BCS-based biowaivers for
generic products?
The guideline focuses on BCS-based biowaiver
principles to be applied for bioequivalence
purposes provided they are supported by a sound
scientific rationale. The provision in the
guideline that accommodates exceptions to
existing regulations that do not permit BCS-
based biowaivers for generic product
applications, at this time, does not disqualify
implementation of these harmonized technical
requirements to demonstrate BCS based
biowaivers for other product applications unless
explicitly stated.
1.3 	Nov. 2019
For fixed-dose combination
products, can one of the drug
substances qualify for a BCS-based
biowaiver, while the other does not?
All drug substances in a fixed-dose combination
product must fulfill the criteria for either BCS
Class I or III to qualify for a biowaiver. If one
of the drug substances is not a BCS Class I or III
drug substance, the possibility that the FDC
formulation may influence in vivo performance
cannot be excluded.
1 This guidance was developed within the Expert Working Groups (Efficacy and Safety) of the International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (formerly the International Conference on
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to
consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH
Assembly at Step 4 of the ICH process, February 2022. At Step 4 of the process, the final draft is recommended for adoption to
the regulatory bodies of the ICH regions. Docket No. FDA-2018-D-3614.
M9 Questions and Answers

3
1.4 	Nov. 2019
Why are drugs with a narrow
therapeutic index excluded from
eligibility for a BCS-based
biowaiver, especially if rate and
extent of absorption of BCS Class I
and III drug substances are a directly
attributed function of solubility and
permeability?
Drugs with a narrow therapeutic index can be
defined as those drugs where small differences in
dose or blood concentration may lead to dose and
blood concentration dependent, serious
therapeutic failures or adverse drug reactions.
They are characterized by a steep drug dose-
response relationship within the usual dose range
or a narrow span between effective drug
concentrations and concentrations associated
with serious toxicity. Thus, doses must be titrated
and monitored carefully. Although there is no
international list of narrow therapeutic index
drugs, the demonstration of in vivo
bioequivalence for these drugs is generally
subject to specific requirements such as tightened
acceptance criteria (e.g., Cmax and/or AUC: 90–
111%) and particular study design features in
some regions. BCS-based biowaiver principles
are not designed to take into account more
stringent criteria for a biowaiver. Therefore, the
BCS-based biowaiver approach is not
considered a suitable surrogate for the
establishment of bioequivalence of narrow
therapeutic index drugs.

4
2. 	BIOPHARMACEUTICS CLASSIFICATION OF THE DRUG SUBSTANCE
# Date of
Approval Questions 	Answers
2.1 	Nov. 2019
Is a BCS-based biowaiver applicable
if the test and reference products
contain different salt forms of the
same drug substance?
A BCS-based biowaiver may be applicable if the
test and reference products contain different
(simple) salts, provided that both belong to BCS
Class I (high solubility and high permeability).
This biowaiver approach is not applicable when
the test product contains a different ester, ether,
isomer, mixture of isomers, complex or derivative
of a drug substance from that of the reference
product, since these differences may lead to
differences in bioavailability that may not be
deducible by means of experiments used to
support a BCS-based biowaiver.
In addition to the scientific aspects, the legal basis
for submission and regulatory requirements
should be considered.
2.2 	Nov. 2019
How is weight change associated
with a different salt accounted for
when assessing solubility?
The BCS classifies a specific drug substance. The
dose of the specific active moiety needs to be
identical irrespective of the salt forms. Hence,
there is no relevance for weight change.
2.3 	Nov. 2019
Why is a BCS-based biowaiver
applicable only when a pro-drug is
absorbed as the pro-drug?
The BCS is based on solubility and permeability
criteria for a specific drug substance. The
classification cannot be conferred to different
compounds, e.g., a parent drug and a metabolite.
Moreover, the solubility criterion considers oral
intake with a defined amount of aqueous liquid
which is not relevant for a metabolite unless it is
formed immediately following intake and prior to
absorption. BCS classification should refer to
the drug substance in the drug product since in
vitro dissolution of the same moiety is utilized to
demonstrate product similarity.
2.1 	Solubility
# Date of
Approval Questions 	Answers
2.1.1 	Nov. 2019
How should the pH be adjusted
during the solubility experiment?
There are various acceptable methods to adjust
the pH of the solution. When a pH adjustment is
necessary, the sponsor should justify the chosen
method. A deviation in pH of ±0.1 is
considered acceptable.
2.1.2 	Nov. 2019
How is the duration of the solubility
measurement determined?
For an equilibrium solubility assessment, the
duration over which the solubility is established
should be supported by sufficient scientific
justification based on the time required to reach
equilibrium. In cases where equilibrium
solubility cannot be determined, the duration of
the solubility experiment should be supported by
sufficient scientific justification based on the
expected time for absorption in vivo.

5
2.1.3 	Nov. 2019
How are common ion effects
associated with certain buffers
accounted for when testing
solubility?
Common ion effects are not expected to affect
solubility.
2.1.4 	Nov. 2019
If there is significant variability
among individual results, should the
lowest solubility be based on the
mean of the replicates at a given pH,
or the lowest result obtained for a
single replicate?
Typically, significant variability should not be
observed in individual replicates for highly
soluble drug substances. The determination of the
lowest solubility should be based on the mean of
the replicates.
2.1.5 	Nov. 2019
Can literature data or alternative
scientific justification for solubility
be used as pivotal data to qualify a
drug substance for a BCS-based
biowaiver?
Experimental solubility data should be provided
to establish the solubility of the drug substance.
Literature data may be submitted to further
support the solubility data.
2.1.6 	Nov. 2019
Why does the guideline set a limit for
degradation of a drug substance to
not more than 10% when assessing
solubility?
The 10% cutoff is set to ensure that the
determination of solubility is not over estimated
due to degradation of the drug substance.
This limit is considered well achievable
experimentally.
2.2 	Permeability
# Date of
Approval Questions 	Answers
2.2.1 	Nov. 2019
Why are permeability assessments
restricted to Caco-2 cell lines? Can
other fully validated cell-lines, e.g.,
MDCKII, LLC-PK1, be used to
provide an estimate of permeability
for BCS classification?
It is acknowledged that permeability can be
estimated by other in vitro (other cell lines, such
as MDCKII) or in situ (Loc-I-Gut)/ex-vivo
(everted rat gut sac model) tools, however, as the
assessment of permeability by in vitro approaches
was not established at any other regulatory agency
beyond the US FDA, it was agreed to rely initially
on the method for which the most experience
exists. In the future, when regulators have gained
more experience with in vitro data, other cell-lines
or animal ex vivo and in situ methods may be
considered, but only with rigorous validation and
standardization according to the principles as
outlined in Annex I of the current draft guideline.
2.2.2 	Nov. 2019
For certain drugs that demonstrate
moderate permeability (50-84%) in
validated Caco-2 cell line studies, but
in practice are observed to be
unstable in the GI tract and would
otherwise be highly permeable, why
are these drugs designated as low
permeability?
As only highly permeable drugs will benefit from
a BCS I classification (which gives additional
flexibility for excipient changes and broader
dissolution criteria (i.e., ≥85% within 30
minutes)), further differentiation of permeability
classifications other than highly permeable (i.e.,
moderate or low permeability) is not relevant in
the context of BCS-based biowaivers. For drugs
with instability in the GI tract, it is not possible to
demonstrate high permeability in vivo. In cases
where high permeability cannot be conclusively
demonstrated by one of the methods described in
the guideline, a biowaiver can still be obtained by
following the principles of a BCS III
classification 	(i.e., 	restrictions 	on 	excipient
changes and very rapid dissolution (i.e., ≥85%
within 15 minutes).

6
2.2.3 	Nov. 2019
Comment on the sample size
required to provide a reliable
estimate of drug permeability.
An estimated number of replicates needed to
correctly delineate the permeability classification
is difficult to define as it depends on the
individual assay variability. Inter-lab variability
is considered high and potential sources of
variability have been described (Volpe, J Pharm
Sci) (97), 2008;(Lee et al, Eur J
Pharm&Biopharm (114), 2017). However, inter-
lab variability is substantially lower for BCS
Class I compared to Class III drug substances
(Lee et al.). For drug substances with a Papp >
10 x 10 -6 cm/s, variability is reported to be
moderate (5–20% ; Peng et al., Eur J Pharm Sci
(56), 2014; Jin et al. J Pharmcol & Toxicol
Methods (70), 2014). It is therefore unlikely that
high variability would result in misclassification
of high permeability. Therefore, the minimum
number of three replicates defined for assays
based on Caco-2 epithelial cell
monolayers is considered justified.
2.2.4 	Nov. 2019
If the Papp values obtained for low,
moderate and high permeability
drugs overlap, how are they
statistically differentiated when
comparing the individual values for
drugs of each group?
In the context of this guidance a dichotomic
outcome is the goal, i.e., the drug substance
demonstrates high permeability or not. The in
vivo permeability of the reference drug
substances listed in Annex 1 has been confirmed
in human studies, which demonstrate that the
mean values are clearly differentiated into low,
moderate and high permeability. Furthermore,
numerous laboratories have successfully
validated Caco-2 cell line systems for BCS
classification using these reference drug
substances, which necessitates differentiation
between the high, moderate and low permeability
drug substances in vitro. If the mean values for
low, moderate and high drugs are overlapping
when experimentally determined, this is likely an
indication of an issue with the setup or
performance of the Caco-2 cell line assay used.
For demonstration of permeability classification
of the test drug substance, the assay is
standardized to these reference drug substances,
and the test drug substance has to demonstrate an
apparent permeability (Papp) equal or greater
than the high permeability reference drug
substance(s) to be classified as highly permeable.
No further statistics need to be applied.
3. 	ELIGIBILITY OF A DRUG PRODUCT FOR A BCS-BASED BIOWAIVER
# Date of
Approval Questions 	Answers
3.1 	Nov. 2019
Why are different dosage forms of
test and reference products not
eligible for BCS-based biowaivers?
Differences in formulations of the same drug
substance can influence in vivo performance.
Specific recommendations regarding the dosage
forms and excipients have been considered in the
context of this BCS-based biowaiver guideline to
accommodate the impact of formulation
differences on in vivo performance to

7
mitigate the risk associated with incorrect
conclusions of bioequivalence. However, the
principles of the guideline may be applied to
bridge different dosage forms during product
development, if sufficiently justified, e.g., based
on previous in vivo data.
3.2 	Nov. 2019
Why are orodispersible tablets
(ODT) not eligible for a BCS-based
biowaiver if they are administered
without water?
As residual gastric volume is well below 250 ml,
the estimation of solubility of the drug substance
in 250 ml of liquid media is not applicable to
products that are taken without water. Defining
the volume of media required to establish the
solubility classification would be challenging for
ODTs that are taken without water.
Furthermore, the current dissolution
methodology is of limited value for a product
that is to be dispersed in the mouth without the
intake of a glass of water. For such products, a
bioequivalence study with the
ODT dosed without water should be conducted.
3.1 	Excipients
# Date of
Approval Questions 	Answers
3.1.1 	Nov. 2019
In silico PBPK absorption modelling
is widely used in industry to assess
the risk of changes in formulation
performance. Can a robust risk
assessment be used to assess the
potential impact (inclusion/
exclusion) of an excipient change
beyond the recommended ranges?
Although it is recognized that in silico PBPK
absorption modelling is used to assess the risk in
product performance due to formulation changes,
currently such models cannot comprehensively
predict all potential differences in absorption due
to critical excipients. Validation of in silico
models for such purposes is further limited by a
lack of mechanistic understanding for some
observed excipient effects, including a lack of
high-quality in vivo data for some excipient
classes. Therefore, a risk assessment based on
model predicted effects would not support a
change in excipient beyond the recommended
range. However, in some circumstances in silico
PBPK modelling may provide useful supporting
evidence as part of a wider excipient risk
assessment, for example sensitivity analysis using
an appropriately validated PBPK absorption
model for excipients where the mechanism of
effect is well understood.
3.1.2 	Nov. 2019
Please clarify if the excipients listed
under the heading “All excipients” in
Table 1, are expected to affect
absorption?
Table 1 provides criteria to demonstrate
quantitative similarity for products containing
BCS Class III drug substances. The excipient
classes listed in the table are functional classes;
however, within such a class an excipient can be
an excipient which may affect absorption. In
that case the difference in the % of the amount of
this excipient compared to the reference
should be within 10%.
3.1.3 	Nov. 2019
What may be an ‘appropriate
justification’ for a deviation of an
acceptable difference in excipients as
listed in Table 1?
Typically, a lot of data on the in vivo performance
of a formulation is obtained during a product
development program. Such data, e.g.
formulations with different ranges of excipients
showing no effect on drug absorption, including a

8
thorough mechanistic assessment, may support
changes in excipients beyond those mentioned in
Table 1.
3.1.4 	Nov. 2019
For BCS Class III drug substances,
excipients are required to be
qualitatively the same and
quantitatively similar. What is the
consideration on an excipient with
the same type but different grade?
Is this excipient considered as
“qualitatively the same”?
If appropriate, a difference in grade of excipient
should be assessed relative to the functional
properties of the excipient in the formulation.
For some excipient types, a change in excipient
grade would not be expected to impact product
performance. For others, a modification in grade
can potentially impact drug product dissolution
(e.g., changes in HPMC particle size distribution,
viscosity and substitution; changes in specific
surface area of stearate lubricants). The
assessment of excipient comparability requires a
case-by-case decision to conclusively
demonstrate “qualitative similarity”.
3.1.5 	Nov. 2019
Why are limits not defined for
allowable differences for sugar
alcohol excipients?
Currently, sufficient data is not available to
qualify thresholds of effect for these excipients.
Furthermore, the impact of the changes caused by
these excipients will vary depending on the
properties of the drug substance (i.e., sensitivity
of the pharmacokinetic profile to alterations in
intestinal transit). Changes in the level of these
excipients are therefore subject to the same
restriction as other excipients that may affect
absorption, i.e., within ± 10% of the amount of
excipient in the reference product.
3.1.6 	Nov. 2019
For BCS Class III drugs, all
excipients should be qualitatively the
same and quantitatively similar
(except for film coating or capsule
shell excipients, colorant, flavor
agent, or preservatives) Can
representative examples be provided
that meet and do not meet these
criteria?
Examples demonstrating excipient quantitative
similarity can be found in Annex II of the
guidance. Additionally, many of the
recommendations for allowable excipient
differences in Table 1, Section 3.1, of the
guidance are expressed as percent difference
relative to core weight (w/w). If a test product
meets these recommendations, but there are large
differences in absolute amounts of excipients (for
example, if core weight is not similar between the
test and reference products), additional
justification may be requested.
3.2 	In vitro Dissolution
# Date of
Approval Questions 	Answers
3.2.1 	Nov. 2019
Can the use of sinkers be justified for
situations other than for coning, i.e.,
sticking, floating etc.?
Yes, if appropriately justified, sinkers may be
used to overcome issues noted during dissolution
experiments. The same experimental conditions
should be applied for the reference and test
formulations.
3.2.2 	Nov. 2019
What is the approach to compare
dissolution profiles for BCS Class I
products, where one meets the
criteria for very rapid (≥85% for the
mean percent dissolved in ≤15
minutes) and the other for rapid
(≥85% for the mean percent
If one product exhibits dissolution at greater than
85% at 15 minutes but the other does not,
sufficient sampling points should be taken to
calculate f2 to demonstrate similarity.

9
dissolved in ≤30 minutes) in vitro
characteristics?
3.2.3 	Nov. 2019
For dissolution profile comparisons
not enough sampling points may be
valid for the calculation of f2 due to
a high variability at the earlier time
points. How can this be addressed?
For BCS Class I drug substances, high variability
in dissolution is not expected and alternate
statistical methodologies, e.g., boot strapping, to
demonstrate similarity is therefore not considered
applicable. In cases where high variability
occurs due to coning, alternative methods (e.g.,
the use of sinkers or other appropriately justified
approaches) may be considered to overcome
issues such as coning, if scientifically justified.
3.2.4 	Nov. 2019
For dissolution profile comparisons,
in some cases, different time-points
may result in different f2 values,
although the time-points may meet
the criteria and conditions listed in
the guideline. For example, time-
points of 10, 20, 30min result in a
f2<50, whereas time-points of 8, 20,
30min yield a f2>50. 	How can
this
situation be reconciled?
This situation should only occur in exceptional
cases. The time points for the calculation of the f2
value have to be pre-specified. In general, all
pre- specified sampling points should be used
and justified.
3.2.5 	Nov. 2019
When the dissolution profiles are
different (rapid and very rapid)
between test and reference products,
do the same dissolution time points
have to be used for a f2 calculation to
demonstrate comparability?
The same time points should be used for the f2
calculation.
See also response to 3.2.4.
3.2.6 	Nov. 2019
Can a BCS-based biowaiver for one
product strength be extended to other
strengths in the product series?
No; a BCS-based biowaiver requires supporting
data for each strength in a product series. In
vitro comparison of the test product strengths to
respective strengths of the reference product
excludes possible drift that may occur when an
additional waiver is made without comparison to
the respective reference strength.
3.2.7 	Nov. 2019
Are comparisons between the
following dosage forms eligible for a
BCS-based biowaiver?
- Uncoated tablets versus film-coated
tablets?
- Tablets versus capsules?
- Uncoated tablets and non-functional film-coated
tablets are considered to be the same dosage form;
a comparison between these dosage forms would
be eligible for a BCS-based biowaiver.
- Tablets and capsules are not considered to be the
same dosage form and in principle a BCS-based
biowaiver 	may 	not 	be 	acceptable 	(see 	also
response to 3.1).
3.2.8 	Nov. 2019
What is the recommended agitation
requirement for comparative
dissolution 	assessments 	for
suspension dosage forms?
For suspensions, a rotational speed of 50 rpm is
recommended with the paddle apparatus. A
lower rotation speed may be used but is not
required.
ANNEX I: CACO-2 CELL PERMEABILITY ASSAY METHOD CONSIDERATIONS
# Date of
Approval Questions 	Answers
A.1 	Nov. 2019
The guideline states that the BCS
classification through in vitro
permeability demonstration is
limited to passively transported
In a comparison between 24 human jejunal
permeabilities and Caco-2 permeabilities the in
vivo and in vitro drug permeability measurements
correlated well for passively absorbed drugs but

10
drugs. However 12 of the 40 model
drugs (see Table 2) for method
validation of Caco-2 cells are
transported actively: Four of these 12
are efflux markers (digoxin,
paclitaxel, 	quinidine 	and
vinblastine), the other eight are
transported actively (Furosemide =
OAT3; Metformin OCT1 and OCT2;
Amiloride=OCT2; Famotidine=
OCT2; Acyclovir =OAT1 and OCT1,
Theophylline =OAT2; and Enalapril
= PepT1 and 2). Can the apparent
contradiction be explained?
less well for actively transported drugs (Sun et al.
Pharm Res (19) 2002). Caco-2 monolayers can
be, thus, used to predict passive drug transport in
humans, whereas prediction of transport by
carrier mediated systems might be inaccurate,
owing to an altered expression of carriers in this
cell line (Di et al., Drug Discover Today (17)
2012). Accordingly, the reference drugs defining
high permeability are rapidly (passively)
permeating drugs such as naproxen, antipyrine
and metoprolol with comparable permeability
coefficients in Caco-2 cells and in human
jejunum.
Although some of the example model drugs may
in some part undergo active transport, the
permeabilities of these drug substances in Caco-
2 monolayers have been shown to reliably
correlate with in vivo permeability. Because
carrier expression in cell lines may be different
from in vivo conditions, this correlation is not
universally observed for all actively transported
drugs. Therefore, without meaningful in vivo
data, in vitro data cannot be the sole means to
determine the permeability classification of
actively transported drugs. The final conclusion
of a drug substance being classified as highly
permeable by means of the Caco-2 cell
monolayer assay would be feasible only for drug
substances devoid of any active transport.
A.2 	Nov. 2019
In situations where a drug substance
is subject to efflux in Caco-2, but the
apparent Km value is much lower
than 	the 	relevant 	intestinal
concentrations, efflux activity can be
saturated at all concentrations and
permeability is then only driven by
passive diffusion. In vitro data
could be used in such cases,
especially if human 	clinically
observed pharmacokinetics is linear.
Can products with low Km qualify
for a BCS-based 	biowaiver
based 	on supportive 	data, e.g.
human pharmacokinetics,
Absorption- Distribution-
Metabolism- Elimination (ADME)
data?
Lack of efflux or saturation of efflux transporters
cannot be differentiated if the applied
physiologically-relevant concentrations (see
Annex I e.g., 0.01, 0.1 and 1x highest strength
dissolved in 250 ml medium) exceed a drug’s Km
value. In that case, a drug substance may
qualify for high permeability if the apparent
permeability, Papp, is ≥ the high permeability
reference standard.
Additionally, the Caco-2 assay must be validated
demonstrating the bi-directional transport of
known probes (Table 2) proving functional
activity of efflux transporter(s). If in vivo data
can be presented that demonstrate high
permeability according to the guidance (i.e.,
ADME or absolute bioavailability), a high
permeability classification may still be granted.
For drug substances that do not qualify for a high
permeability designation, it needs to be
emphasized that a BCS Class III waiver option is
also available if all other conditions according to
the guidance are fulfilled.
A.3 	Nov.2019
Since Caco-2 cells predict
permeability of actively transported
drugs why are these drugs excluded
See response A1; actively transported drugs are
not excluded if the human in vivo data support the
classification as highly permeable. The use of the
Caco-2 cell assay only would be not adequate for

11
from qualification for a BCS-based
biowaiver?
this purpose (as transporter expression in Caco-2
systems may differ from in vivo expression).
A.4 	Nov.2019
For some validated Caco-2 cell
monolayer models, an efflux ratio
greater than 2 might be more
appropriate as the threshold for
observed efflux. Can an efflux ratio
threshold of greater than 2 be
justified based on the model
compounds/dataset from validation
results?
In the of absence of any active transport whether
uptake or efflux, the ratio between Papp apical
(A) to basolateral (B) –absorptive- and B to A is
expected to be 1 or close to 1. Any deviation
from 1 would indicate some contribution of an
active transport. An efflux ratio of greater than
2 has been adopted as indicative of the drug
being a substrate for efflux transporter
(Giacomini, et al. Nat Rev Drug Discov. 2010;
9:215-236).
Provide examples of references for
the model drugs for permeability
assay method validation.
Please refer to:
o Volpe DA. Application of Method
Suitability for Drug Permeability
Classification. AAPS J. 2010;12(4):670-8.”
o Li C. et al. Development of In Vitro
Pharmacokinetic Screens Using Caco-2,
Human Hepatocyte, and Caco-2/Human
Hepatocyte Hybrid Systems for the Prediction
of Oral Bioavailability in Humans. Journal
of Biomolecular Screening 2007;
12(8):1084-
1091
o Peng Y. et al. Applications of a 7-day Caco-
2 cell model in drug discovery and
development. European Journal of
Pharmaceutical Sciences 2014; 56: 120-130
A.5 	Nov. 2019 o Kasim NA et al. Molecular Properties of
WHO Essential Drugs and Provisional
Biopharmaceutical Classification. Molecular
Pharmaceutics 2004; 1(1): 85-96
o Lennernäs, H. 'Intestinal permeability and
its relevance for absorption and elimination',
Xenobiotica 2007; 37(10): 1015 – 1051
o Thiel-Demby VE. Biopharmaceutics
Classification System: Validation and
Learnings of an In Vitro Permeability Assay.
Molecular Pharmaceutics 2009; 6(1): 11-18
o Giacomini, et al. Nat Rev Drug Discov.
2010; 9:215-236
o FDA, United States In Vitro Metabolism-
and Transporter- Mediated Drug-Drug
Interaction Studies Guidance for Industry
(October 2017)2
2 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

12
4. 	ANNEX: Q&As linked to the respective Sections of ICH M9 Guideline
Sections of	
ICH M9 Guideline	
1: Introduction-Scope	
2.0: BIOPHARMACEUTICS CLASSIFICATION	
OF THE DRUG SUBSTANCE	
2.1: Solubility	
2.2: Permeability	
3.0: ELIGIBILITY OF A DRUG PRODUCT FOR A	
BCS-BASED BIOWAIVER Title	
3.1: Excipients	
7: Title
Annex I: CACO-2 CELL PERMEABILITY ASSAY	
METHOD CONSIDERATIONS Glossary	
Other ICH Guidelines
1. Introduction – Scope
1 	1.1
2 	1.2
3 	1.3
4 	1.4
2.0 BIOPHARMACEUTICS CLASSIFICATION OF THE DRUG
SUBSTANCE
1 	2.1
2 	2.2
3 	2.3
2.1. Solubility
1 	2.1.1
2 	2.1.2
3 	2.1.3
4 	2.1.4
5 	2.1.5
6 	2.1.6
2.2. Permeability
1 	2.2.1
2 	2.2.2
3 	2.2.3
4 	2.2.4
3.0 ELIGIBILITY OF A DRUG PRODUCT FOR A BCS-BASED
BIOWAIVER Title
1 	3.1
2 	3.2
3.1. Excipients
1 	3.1.1
2 	3.1.2
3 	3.1.3
4 	3.1.4
5 	3.1.5
6 	3.1.6
3.2. In Vitro Dissolution
1 	3.2.1
2 	3.2.2
3 	3.2.3
4 	3.2.4
5 	3.2.5
6 	3.2.6
7 	3.2.7
8 	3.2.8
Annex I. CACO-2 CELL PERMEABILITY ASSAY METHOD
CONSIDERATIONS
1 	A.1
2 	A.2
3 	A.3
4 	A.4
5 	A.5