INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICALREQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED GUIDELINE

BIOPHARMACEUTICS CLASSIFICATION SYSTEM-BASEDBIOWAIVERS

M9
Final version
Adopted on 20 November 2019

This Guideline has been developed by the appropriate ICH Expert Working Groupand 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.

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M9
Document History

CodeHistory

M9

Adopted by the Regulatory Members of the ICH 20 November
Assembly under Step 4 (document dated 16 2019
November 2019).
Endorsement by the ICH Assembly under Step 2 7 June 2018
and release for public consultation.

M9

Date

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ICH HARMONISED GUIDELINE

BIOPHARMACEUTICS CLASSIFICATION SYSTEM-BASEDBIOWAIVERS
M9
ICH Consensus Guideline
TABLE OF CONTENTS

1.

INTRODUCTION................................................................................................................................. 1

1.1.

Background and Objective ............................................................................................................. 1

1.2.

Scope

2.

....................................................................................................................................... 1

BIOPHARMACEUTICS CLASSIFICATION OF THE DRUG SUBSTANCE.............................. 2

2.1.

Solubility ....................................................................................................................................... 2

2.2.

Permeability.................................................................................................................................... 3

3.

ELIGIBILITY OF A DRUG PRODUCT FOR A BCS-BASED BIOWAIVER ............................... 4

3.1.

Excipients ....................................................................................................................................... 4

3.2.

In vitro Dissolution ......................................................................................................................... 6

4.

DOCUMENTATION ............................................................................................................................ 8

5.

GLOSSARY........................................................................................................................................... 9

ANNEX I: CACO-2 CELL PERMEABILITY ASSAY METHOD CONSIDERATIONS.................... 10
ANNEX

II:

FURTHERINFORMATION

ON

THE

ASSESSMENTOF

EXCIPIENTDIFFERENCES........................................................................................................................................... 13i

ICH M9 Guideline
1. INTRODUCTION
1.1.

Background and Objective

Two drug products containing the same drug substance(s) are considered bioequivalent if theirbioavailabilities (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 AUC (area under the concentration time curve) and C max (maximum
concentration), are generally used to assess the rate and extent of drug absorption.
The BCS (Biopharmaceutics Classification System)-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 performancecan 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(s). 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
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 specified in theguideline, provided they can be supported by a thorough scientific rationale.
1.2.

Scope

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 anarrow therapeutic index are excluded from consideration for 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 2 and 3of this guidance.

-1-ICH M9 Guideline
2. BIOPHARMACEUTICS CLASSIFICATION OF THE DRUG SUBSTANCE
BCS-based biowaivers are applicable to drug products where the drug substance(s) exhibit highsolubility 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 thatboth belong to BCS Class I (high solubility and high permeability). A biowaiver is not applicablewhen the test product contains a different ester, ether, isomer, mixture of isomers, complex orderivative of a drug substance from that of the reference product, since these differences may lead todifferent bioavailabilities not deducible by means of experiments used in the BCS-based biowaiverconcept. Pro-drugs may be considered for a BCS-based biowaiver when absorbed as the pro-drug.
2.1.

Solubility

A drug substance is classified as highly soluble if the highest single therapeutic dose is completely
soluble in 250 ml or less of aqueous media over the pH range of 1.2–6.8 at 37±1°C. In cases where thehighest single therapeutic dose does not meet this criterion but the highest strength of the reference
product is soluble under the 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 substanceshould be evaluated if it is within the specified pH range. These experiments should demonstrate thatsolubility 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.

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ICH M9 Guideline
A minimum of three replicate determinations at each solubility condition/pH using appropriatecompendial 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 beclassified. 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.
2.2.

Permeability

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 canalso 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 thatthey are not produced prior to 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 frombiliary 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 ofavailable data on human pharmacokinetics. If high permeability is inferred by means of an in vitro cellsystem, permeability independent of active transport should be proven as outlined in Annex I, “Caco-2cell 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 massbalance studies are used to demonstrate high permeability, unless ≥85% of the dose is recovered as
3

ICH M9 Guideline
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 isrepresentative of the in vivo contact of the drug substance with these fluids, i.e., one hour in gastricfluid and three hours in intestinal fluid. Drug concentrations should then be determined using asuitably validated method. Significant degradation (>10%) of a drug precludes BCS high permeability
classification.
3. ELIGIBILITY OF A DRUG PRODUCT FOR A BCS-BASED BIOWAIVER
A drug product is eligible for a BCS-based biowaiver provided that the drug substance(s) satisfy thecriteria regarding solubility and permeability (BCS Class I and III), the drug product is animmediate-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 notmeet the high solubility criterion but the highest strength of the reference product is soluble under therequired conditions, BCS-based biowaivers can be supported based on demonstration of dose
proportional pharmacokinetics (i.e., AUC and C max ) 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 ofadministration includes water. If administration without water is also 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 thecomposition (excipients) and in vitro dissolution performance of the drug product should be satisfied.
The drug product acceptance criteria are described in sections 3.1 and 3.2 below.
3.1.

Excipients

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 beconsidered. Excipients that may affect absorption include sugar-alcohols, e.g., mannitol, sorbitol, and4

ICH M9 Guideline
surfactants, e.g., sodium lauryl sulfate. The risk that a given excipient will affect the absorption of adrug 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 specificdrug 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 thepotential 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 thatexhibit 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. Additionally, thecumulative 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 greaternumber 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 andquantitatively similar (except for film coating or capsule shell excipients). Excipients that may affectabsorption should be qualitatively the same and quantitatively similar, i.e., within ± 10% of theamount 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 areshown in Annex II. Differences in colorants and flavoring may be permitted when these constitutevery 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
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ICH M9 Guideline
Class III drugs.
Within the context of quantitative similarity, differences in excipients for drug products containing BCSClass III drugs should not exceed the following targets:
Percent of the amount of excipient in the

Excipient classreference

Excipients which may affect absorption
Per excipient:10%

Sum of differences:

10%
Percent difference relative to core weight*(w/w)

All excipients:
Filler10%

DisintegrantStarch

6%

Other

2%

Binder1%

LubricantStearates

0.5%

Other

2%

Talc

2%

Other

0.2%

Glidant

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.
3.2.

In vitro Dissolution

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 thetest 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 in6

ICH M9 Guideline
vitro dissolution experiments should use compendial apparatus and suitably validated analyticalmethod(s).
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 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 fromthe 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 andtest 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 toovercome issues such as coning, if scientifically substantiated. All experimental results should be
provided.
To qualify for a BCS-based biowaiver for BCS Class I drug substances both the test product andreference 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 thedefined 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.
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ICH M9 Guideline
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)Σ t=1 n (R t - T t )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 labelled amount of the drug is dissolved in 15 minutes,
comparison with an f2 test is unnecessary and the dissolution profiles are considered similar. When thecoefficient 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 andreference product should display very rapid (≥85% for the mean percent dissolved in ≤15 minutes) invitro 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.
4. DOCUMENTATIONThe sponsor should provide complete information on the critical quality attributes of the test drug
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ICH M9 Guideline
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 theanalytical 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, expiry 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, de-aeration, 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).
5. GLOSSARY
AUC: Area under the concentration versus time curve
BCS: Biopharmaceutics Classification System
C max : Maximum concentration
FDC: Fixed-dose combination
QC: Quality control
rpm: rotation per minute

9ICH M9 Guideline
ANNEX I: CACO-2 CELL PERMEABILITY ASSAY METHOD CONSIDERATIONSPermeability assays employing cultured Caco-2 epithelial cell monolayers derived from a humancolon adenocarcinoma cell line are widely used to estimate intestinal drug absorption in humans.
Caco-2 cells undergo spontaneous morphological and biochemical enterocytic differentiation, andexpress 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 cellassays as the sole data in support of high permeability for BCS classification is limited to passivelytransported drugs (see below Assay Considerations).
Method validation
The suitability of the Caco-2 cell assays for BCS permeability determination should be demonstrated
by establishing a rank-order relationship between experimental permeability values and the extent ofdrug 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 tocharacterize 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 establishedrelationship 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, prior to and after an experiment.
In addition, cell monolayer integrity should be demonstrated by means of compounds with provenzero permeability (refer to Table 2).
Reporting of the method validation should include a list of the selected model drugs along with dataon 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) withidentification 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.

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ICH M9 Guideline
Assay considerations
Passive transport of the test compound should be demonstrated. This may be verified using a suitableassay system that expresses known efflux transporters, e.g., by demonstrating independence ofmeasured in vitro permeability on initial drug concentration, e.g., 0.01, 0.1, and 1 times the highest
strength dissolved in 250 ml, or on transport direction (efflux ratio, i.e., ratio of apparent permeability(P app ) between the basolateral-to-apical and apical-to-basolateral directions <2 for the selected drugconcentrations).
Efflux ratio = P appBLAP /P appAP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 establishedduring 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 ofinternal 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 thesame 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 andtesting apparatus.
Evaluation of the test drug permeability for BCS classification may be facilitated by selection of ahigh permeability internal standard with permeability in close proximity to the moderate/highpermeability 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 transportmechanism.

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ICH M9 Guideline
Table 2. Examples of model drugs for permeability assay method validation
Group

Drug

High Permeability

Antipyrine
Caffeine
Ketoprofen
Naproxen
Theophylline
Metoprolol
Propranolol
Carbamazepine
Phenytoin
Disopyramide
Minoxidil
Chlorpheniramine
Creatinine
Terbutaline
Hydrochlorothiazide
Enalapril
Furosemide
Metformin
Amiloride
Atenolol
Ranitidine
Famotidine
Nadolol
Sulpiride
Lisinopril
Acyclovir
Foscarnet
Mannitol
Chlorothiazide
Polyethylene glycol 400
Enalaprilat
FITC-Dextran
Polyethylene glycol 4000
Lucifer yellow
InulinLactulose
Digoxin
Paclitaxel
Quinidine
Vinblastine(f a ≥85%)

Moderate Permeability(f a = 50-84%)

Low Permeability(f a < 50%)

Zero Permeability

Efflux Substrates

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ICH M9 Guideline
ANNEX II: FURTHER INFORMATION ON THE ASSESSMENT OF EXCIPIENTDIFFERENCES

Figure 1. BCS Class I drug substances

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ICH M9 Guideline
Figure 2. BCS Class III drug substances

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ICH M9 Guideline
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 mg to 55 mg basedon 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

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ICH M9 Guideline

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 thetest formulation is within the permitted range of 9 mg to 11 mg based on the amount of sorbitol in thereference formulation (i.e., 10 mg ± 10%). Differences in the amount of other excipients are within thecriteria outlined in Table 1, Section 3.1.
Reference Product

Test Product
Absolute %Proportion

Proportion
Component

Composition

relative toComposition

relative to(mg)core weight(mg)

core weight

Lactose monohydrate(filler)
Sorbitol (filler)
Croscarmellose
sodium (disintegrant)
Magnesium stearate(lubricant)Totalrelative tocore weights(%w/w)(%w/w)
Drug substancedifference

100

49.3%

100

46.5%

--

85

41.9%

97

45.1%

3.2%

10

4.9%

9

4.2%

0.7%

6

3.0%

7

3.3%

0.3%

2

1.0%

2

0.9%

0.1%

203

100%

215

100%
Total
change:16

4.3%