Guidance for Industry 

Waiver of In Vivo Bioavailability and 

Bioequivalence Studies for 

Immediate-Release Solid Oral Dosage 

Forms Based on a Biopharmaceutics 

Classification System

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

August 2000 

BP 

C:\Documents and Settings\STAUFFERP\Desktop\3618FNL.DOC 

02/03/05
Guidance for Industry 

Waiver of In Vivo Bioavailability and 

Bioequivalence Studies for 

Immediate-Release Solid Oral Dosage 

Forms Based on a Biopharmaceutics 

Classification System

Additional copies are available from: 

Office of Training and Communications

Division of Communications Management

Drug Information Branch, HFD-210 

5600 Fishers Lane 

Rockville, MD 20857

(Tel) 301-827-4573

(Internet) http://www.fda.gov/cder/guidance/index.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

August 2000 

BP 
TABLE OF CONTENTS 

I. INTRODUCTION ................................................................................................................................ 1 

II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM ....................................................... 1 

A. SOLUBILITY......................................................................................................................................... 2 

B. PERMEABILITY .................................................................................................................................... 2 

C. DISSOLUTION ...................................................................................................................................... 2 

III. METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR 

DETERMINING THE DISSOLUTION CHARACTERISTICS OF A DRUG PRODUCT ..... 3 

A. DETERMINING DRUG SUBSTANCE SOLUBILITY CLASS ........................................................................ 3 

B. DETERMINING DRUG SUBSTANCE PERMEABILITY CLASS ................................................................... 4 

1. Pharmacokinetic Studies in Humans.............................................................................................. 4 

2. Intestinal Permeability Methods..................................................................................................... 4 

3. Instability in the Gastrointestinal Tract.......................................................................................... 7 

C. DETERMINING DRUG PRODUCT DISSOLUTION CHARACTERISTICS AND DISSOLUTION PROFILE 

SIMILARITY ............................................................................................................................................. 7 

IV. ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER ........................... 8 

A. EXCIPIENTS ......................................................................................................................................... 8 

B. PRODRUGS........................................................................................................................................... 9 

C. EXCEPTIONS ........................................................................................................................................ 9 

1. Narrow Therapeutic Range Drugs ................................................................................................. 9 

2. Products Designed to be Absorbed in the Oral Cavity................................................................... 9 

V. REGULATORY APPLICATIONS OF THE BCS............................................................................ 9 

A. INDS/NDAS........................................................................................................................................ 9 

B. ANDAS............................................................................................................................................. 10 

C. POSTAPPROVAL CHANGES................................................................................................................. 10 

VI. DATA TO SUPPORT A REQUEST FOR BIOWAIVERS........................................................ 10 

A. DATA SUPPORTING HIGH SOLUBILITY .............................................................................................. 11 

B. DATA SUPPORTING HIGH PERMEABILITY.......................................................................................... 11 

C. DATA SUPPORTING RAPID AND SIMILAR DISSOLUTION..................................................................... 12 

D. ADDITIONAL INFORMATION .............................................................................................................. 12 

ATTACHMENT A..................................................................................................................................... 13 
GUIDANCE FOR INDUSTRY1

Waiver of In Vivo Bioavailability and Bioequivalence Studies 

for Immediate-Release Solid Oral Dosage Forms Based on a 

Biopharmaceutics Classification System

I. INTRODUCTION 

This guidance provides recommendations for sponsors of investigational new drug 

applications (INDs), new drug applications (NDAs), abbreviated new drug applications 

(ANDAs), and supplements to these applications who wish to request a waiver of in vivo 

bioavailability (BA) and/or bioequivalence (BE) studies for immediate release (IR) solid 

oral dosage forms. These waivers are intended to apply to (1) subsequent in vivo BA or 

BE studies of formulations after the initial establishment of the in vivo BA of IR dosage 

forms during the IND period, and (2) in vivo BE studies of IR dosage forms in ANDAs. 

Regulations at 21 CFR part 320 address the requirements for bioavailability (BA) and BE 

data for approval of drug applications and supplemental applications. Provision for 

waivers of in vivo BA/BE studies (biowaivers) under certain conditions is provided at 21 

CFR 320.22. This guidance explains when biowaivers can be requested for IR solid oral 

dosage forms based on an approach termed the Biopharmaceutics Classification System

(BCS). 

II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM 

The BCS is a scientific framework for classifying drug substances based on their aqueous 

solubility and intestinal permeability. When combined with the dissolution of the drug 

product, the BCS takes into account three major factors that govern the rate and extent of 

drug absorption from IR solid oral dosage forms: dissolution, solubility, and intestinal 

permeability.

2

 According to the BCS, drug substances are classified as follows:

Class 1: High Solubility – High Permeability 

Class 2: Low Solubility – High Permeability 

Class 3: High Solubility – Low Permeability 

 1

 This guidance has been prepared by the Biopharmaceutics Classification System Working Group 

of the Biopharmaceutics Coordinating Committee in the Center for Drug Evaluation and Research (CDER) 

at the Food and Drug Administration (FDA). This guidance represents the Agency’s current thinking on

the topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or

the public. An alternative approach may be used if such an approach satisfies the requirements of the 

applicable statutes, regulations, or both. 

 2

Amidon, G. L., H. Lennernäs, V. P. Shah, and J. R. Crison, A Theoretical Basis For a 

Biopharmaceutics Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo 

Bioavailability, Pharmaceutical Research, 12: 413-420 (1995). 
Class 4: Low Solubility – Low Permeability 

In addition, IR solid oral dosage forms are categorized as having rapid or slow 

dissolution. Within this framework, when certain criteria are met, the BCS can be used 

as a drug development tool to help sponsors justify requests for biowaivers. 

Observed in vivo differences in the rate and extent of absorption of a drug from two 

pharmaceutically equivalent solid oral products may be due to differences in drug 

dissolution in vivo.2

 However, when the in vivo dissolution of an IR solid oral dosage 

form is rapid in relation to gastric emptying and the drug has high permeability, the rate 

and extent of drug absorption is unlikely to be dependent on drug dissolution and/or 

gastrointestinal transit time. Under such circumstances, demonstration of in vivo BA or 

BE may not be necessary for drug products containing Class 1 drug substances, as long as 

the inactive ingredients used in the dosage form do not significantly affect absorption of 

the active ingredients. The BCS approach outlined in this guidance can be used to justify 

biowaivers for highly soluble and highly permeable drug substances (i.e., Class 1) in IR 

solid oral dosage forms that exhibit rapid in vitro dissolution using the recommended test 

methods (21 CFR 320.22(e)). The recommended methods for determining solubility, 

permeability, and in vitro dissolution are discussed below. 

A. Solubility 

The solubility class boundary is based on the highest dose strength of an IR 

product that is the subject of a biowaiver request. A drug substance is considered 

highly soluble when the highest dose strength is soluble in 250 ml or less of 

aqueous media over the pH range of 1-7.5. The volume estimate of 250 ml is 

derived from typical BE study protocols that prescribe administration of a drug 

product to fasting human volunteers with a glass (about 8 ounces) of water. 

B. Permeability 

The permeability class boundary is based indirectly on the extent of absorption 

(fraction of dose absorbed, not systemic BA) of a drug substance in humans and 

directly on measurements of the rate of mass transfer across human intestinal

membrane. Alternatively, nonhuman systems capable of predicting the extent of 

drug absorption in humans can be used (e.g., in vitro epithelial cell culture 

methods). In the absence of evidence suggesting instability in the gastrointestinal 

tract, a drug substance is considered to be highly permeable when the extent of 

absorption in humans is determined to be 90% or more of an administered dose 

based on a mass balance determination or in comparison to an intravenous 

reference dose. 

C. Dissolution 

In this guidance, an IR drug product is considered rapidly dissolving when no less 

than 85% of the labeled amount of the drug substance dissolves within 30 

2
minutes, using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus 

II at 50 rpm) in a volume of 900 ml or less in each of the following media: (1) 0.1 

N HCl or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and 

(3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes. 

III. METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR 

DETERMINING THE DISSOLUTION CHARACTERISTICS OF A DRUG 

PRODUCT

The following approaches are recommended for classifying a drug substance and 

determining the dissolution characteristics of an IR drug product according to the BCS: 

A. Determining Drug Substance Solubility Class

An objective of the BCS approach is to determine the equilibrium solubility of a 

drug substance under physiological pH conditions. The pH-solubility profile of 

the test drug substance should be determined at 37 ± 1o

C in aqueous media with a 

pH in the range of 1-7.5. A sufficient number of pH conditions should be 

evaluated to accurately define the pH-solubility profile. The number of pH 

conditions for a solubility determination can be based on the ionization 

characteristics of the test drug substance. For example, when the pKa of a drug is 

in the range of 3-5, solubility should be determined at pH = pKa, pH = pKa +1, 

pH = pKa-1, and at pH = 1 and 7.5. A minimum of three replicate determinations 

of solubility in each pH condition is recommended. Depending on study 

variability, additional replication may be necessary to provide a reliable estimate 

of solubility. Standard buffer solutions described in the USP are considered 

appropriate for use in solubility studies. If these buffers are not suitable for 

physical or chemical reasons, other buffer solutions can be used. Solution pH 

should be verified after addition of the drug substance to a buffer. Methods other 

than the traditional shake-flask method, such as acid or base titration methods, can 

also be used with justification to support the ability of such methods to predict 

equilibrium solubility of the test drug substance. Concentration of the drug 

substance in selected buffers (or pH conditions) should be determined using a 

validated stability-indicating assay that can distinguish the drug substance from its 

degradation products.3 If degradation of the drug substance is observed as a 

function of buffer composition and/or pH, it should be reported along with other 

stability data recommended in section III.B.3. 

The solubility class should be determined by calculating the volume of an 

aqueous medium sufficient to dissolve the highest dose strength in the pH range 

of 1-7.5. A drug substance should be classified as highly soluble when the 

highest dose strength is soluble in < 250 ml of aqueous media over the pH range 

of 1-7.5. 

 3 See the FDA guidance for industry on Submitting Documentation for the Stability of Human 

Drugs and Biologics (February 1987), posted at http://www.fda.gov/guidance/index.htm. 

3
B. Determining Drug Substance Permeability Class

The permeability class of a drug substance can be determined in human subjects 

using mass balance, absolute BA, or intestinal perfusion approaches. 

Recommended methods not involving human subjects include in vivo or in situ 

intestinal perfusion in a suitable animal model (e.g., rats), and/or in vitro 

permeability methods using excised intestinal tissues, or monolayers of suitable 

epithelial cells. In many cases, a single method may be sufficient (e.g., when the 

absolute BA is 90% or more, or when 90% or more of the administered drug is 

recovered in urine). When a single method fails to conclusively demonstrate a 

permeability classification, two different methods may be advisable. Chemical 

structure and/or certain physicochemical attributes of a drug substance (e.g., 

partition coefficient in suitable systems) can provide useful information about its 

permeability characteristics. Sponsors may wish to consider use of such 

information to further support a classification. 

1. Pharmacokinetic Studies in Humans 

a. Mass Balance Studies

Pharmacokinetic mass balance studies using unlabeled, stable isotopes or a 

radiolabeled drug substance can be used to document the extent of 

absorption of a drug. Depending on the variability of the studies, a 

sufficient number of subjects should be enrolled to provide a reliable 

estimate of extent of absorption. Because this method can provide highly 

variable estimates of drug absorption for many drugs, other methods 

described below may be preferable. 

b. Absolute Bioavailability Studies 

Oral BA determination using intravenous administration as a reference can 

be used. Depending on the variability of the studies, a sufficient number 

of subjects should be enrolled in a study to provide a reliable estimate of 

the extent of absorption. When the absolute BA of a drug is shown to be 

90% or more, additional data to document drug stability in the 

gastrointestinal fluid is not necessary. 

2. Intestinal Permeability Methods 

The following methods can be used to determine the permeability of a drug 

substance from the gastrointestinal tract: (1) in vivo intestinal perfusion studies 

in humans; (2) in vivo or in situ intestinal perfusion studies using suitable 

animal models; (3) in vitro permeation studies using excised human or animal 

intestinal tissues; or (4) in vitro permeation studies across a monolayer of 

cultured epithelial cells. 

4
In vivo or in situ animal models and in vitro methods, such as those using 

cultured monolayers of animal or human epithelial cells, are considered 

appropriate for passively transported drugs. The observed low permeability of 

some drug substances in humans could be caused by efflux of drugs via 

membrane transporters such as P-glycoprotein (P-gp). When the efflux 

transporters are absent in these models, or their degree of expression is low 

compared to that in humans, there may be a greater likelihood of 

misclassification of permeability class for a drug subject to efflux compared to a 

drug transported passively. Expression of known transporters in selected study 

systems should be characterized. Functional expression of efflux systems (e.g., 

P-gp) can be demonstrated with techniques such as bidirectional transport 

studies, demonstrating a higher rate of transport in the basolateral-to-apical

direction as compared to apical-to-basolateral direction using selected model 

drugs or chemicals at concentrations that do not saturate the efflux system (e.g., 

cyclosporin A, vinblastine, rhodamine 123). An acceptance criterion for 

intestinal efflux that should be present in a test system cannot be set at this time. 

Instead, this guidance recommends limiting the use of nonhuman permeability 

test methods for drug substances that are transported by passive mechanisms. 

Pharmacokinetic studies on dose linearity or proportionality may provide useful 

information for evaluating the relevance of observed in vitro efflux of a drug. 

For example, there may be fewer concerns associated with the use of in vitro 

methods for a drug that has a higher rate of transport in the basolateral-to-apical 

direction at low drug concentrations but exhibits linear pharmacokinetics in 

humans. 

For application of the BCS, an apparent passive transport mechanism can be 

assumed when one of the following conditions is satisfied: 

• A linear (pharmacokinetic) relationship between the dose (e.g., 

relevant clinical dose range) and measures of BA (area under the 

concentration-time curve) of a drug is demonstrated in humans 

• Lack of dependence of the measured in vivo or in situ permeability is 

demonstrated in an animal model on initial drug concentration (e.g., 

0.01, 0.1, and 1 times the highest dose strength dissolved in 250 ml) in 

the perfusion fluid 

• Lack of dependence of the measured in vitro permeability on initial 

drug concentration (e.g., 0.01, 0.1, and 1 times the highest dose 

strength dissolved in 250 ml) is demonstrated in donor fluid and 

transport direction (e.g., no statistically significant difference in the 

rate of transport between the apical-to-basolateral and basolateral-toapical direction for the drug concentrations selected) using a suitable 

in vitro cell culture method that has been shown to express known 

efflux transporters (e.g., P-gp) 

5
To demonstrate suitability of a permeability method intended for application of 

the BCS, a rank-order relationship between test permeability values and the 

extent of drug absorption data in human subjects should be established using a 

sufficient number of model drugs. For in vivo intestinal perfusion studies in 

humans, six model drugs are recommended. For in vivo or in situ intestinal

perfusion studies in animals and for in vitro cell culture methods, twenty model 

drugs are recommended. Depending on study variability, a sufficient number of 

subjects, animals, excised tissue samples, or cell monolayers should be used in a 

study to provide a reliable estimate of drug permeability. This relationship 

should allow precise differentiation between drug substances of low and high 

intestinal permeability attributes. 

For demonstration of suitability of a method, model drugs should represent a 

range of low (e.g., < 50%), moderate (e.g., 50 - 89%), and high (≥ 90%) 

absorption. Sponsors may select compounds from the list of drugs and/or 

chemicals provided in Attachment A or they may choose to select other drugs 

for which there is information available on mechanism of absorption and 

reliable estimates of the extent of drug absorption in humans. 

After demonstrating suitability of a method and maintaining the same study 

protocol, it is not necessary to retest all selected model drugs for subsequent 

studies intended to classify a drug substance. Instead, a low and a high 

permeability model drug should be used as internal standards (i.e., included in 

the perfusion fluid or donor fluid along with the test drug substance). These two 

internal standards are in addition to the fluid volume marker (or a zero 

permeability compound such as PEG 4000) that is included in certain types of 

perfusion techniques (e.g., closed loop techniques). The choice of internal 

standards should be based on compatibility with the test drug substance (i.e., 

they should not exhibit any significant physical, chemical, or permeation 

interactions). When it is not feasible to follow this protocol, the permeability of

internal standards should be determined in the same subjects, animals, tissues, 

or monolayers, following evaluation of the test drug substance. The 

permeability values of the two internal standards should not differ significantly 

between different tests, including those conducted to demonstrate suitability of 

the method. At the end of an in situ or in vitro test, the amount of drug in the 

membrane should be determined. 

For a given test method with set conditions, selection of a high permeability 

internal standard with permeability in close proximity to the low/high 

permeability class boundary may facilitate classification of a test drug 

substance. For instance, a test drug substance may be determined to be highly 

permeable when its permeability value is equal to or greater than that of the 

selected internal standard with high permeability. 

6
3. Instability in the Gastrointestinal Tract 

Determining the extent of absorption in humans based on mass balance studies 

using total radioactivity in urine does not take into consideration the extent of 

degradation of a drug in the gastrointestinal fluid prior to intestinal membrane 

permeation. In addition, some methods for determining permeability could be 

based on loss or clearance of a drug from fluids perfused into the human and/or 

animal gastrointestinal tract either in vivo or in situ. Documenting the fact that 

drug loss from the gastrointestinal tract arises from intestinal membrane 

permeation, rather than a degradation process, will help establish permeability. 

Stability in the gastrointestinal tract may be documented using gastric and 

intestinal fluids obtained from human subjects. Drug solutions in these fluids 

should be incubated at 37o

C for a period that is representative of in vivo drug 

contact with these fluids; for example, 1 hour in gastric fluid and 3 hours in 

intestinal fluid. Drug concentrations should then be determined using a 

validated stability-indicating assay method. Significant degradation (>5%) of a 

drug in this protocol could suggest potential instability. Obtaining 

gastrointestinal fluids from human subjects requires intubation and may be 

difficult in some cases. Use of gastrointestinal fluids from suitable animal 

models and/or simulated fluids such as Gastric and Intestinal Fluids USP can be 

substituted when properly justified. 

C. Determining Drug Product Dissolution Characteristics and 

Dissolution Profile Similarity4

Dissolution testing should be carried out in USP Apparatus I at 100 rpm or 

Apparatus II at 50 rpm using 900 ml of the following dissolution media: (1) 0.1 

N HCl or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and 

(3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes. For 

capsules and tablets with gelatin coating, Simulated Gastric and Intestinal Fluids 

USP (with enzymes) can be used. 

Dissolution testing apparatus used in this evaluation should conform to the 

requirements in USP (<711> Dissolution). Selection of the dissolution testing 

apparatus (USP Apparatus I or II) during drug development should be based on a 

comparison of in vitro dissolution and in vivo pharmacokinetic data available for 

the product. The USP Apparatus I (basket method) is generally preferred for 

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

generally preferred for tablets. For some tablet dosage forms, in vitro (but not in 

vivo) dissolution may be slow due to the manner in which the disintegrated 

product settles at the bottom of a dissolution vessel. In such situations, USP 

Apparatus I may be preferred over Apparatus II. If the testing conditions need to 

be modified to better reflect rapid in vivo dissolution (e.g., use of a different 

rotating speed), such modifications can be justified by comparing in vitro 

 4 See the FDA guidance for industry on Dissolution Testing of Immediate Release Solid Oral

Dosage Forms (August 1997). 

7
dissolution with in vivo absorption data (e.g., a relative BA study using a simple 

aqueous solution as the reference product). 

A minimum of 12 dosage units of a drug product should be evaluated to support a 

biowaiver request. Samples should be collected at a sufficient number of 

intervals to characterize the dissolution profile of the drug product (e.g., 10, 15, 

20, and 30 minutes). 

When comparing the test and reference products, dissolution profiles should be 

compared using a similarity factor (f2). The similarity factor is a logarithmic 

reciprocal square root transformation of the sum of squared error and is a 

measurement of the similarity in the percent (%) of dissolution between the two 

curves. 

f2 = 50 • log {[1 + (1/n)∑t=1n (Rt - Tt)

2

]

-0.5 • 100} 

Two dissolution profiles are considered similar when the f2 value is $50. To 

allow the use of mean data, the coefficient of variation should not be more than 

20% at the earlier time points (e.g., 10 minutes), and should not be more than 

10% at other time points. Note that when both test and reference products 

dissolve 85% or more of the label amount of the drug in #15 minutes using all 

three dissolution media recommended above, the profile comparison with an f2

test is unnecessary. 

IV. ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER 

When requesting a BCS-based waiver for in vivo BA/BE studies for IR solid oral dosage 

forms, applicants should note that the following factors can affect their request or the 

documentation of their request: 

A. Excipients 

Excipients can sometimes affect the rate and extent of drug absorption. In 

general, using excipients that are currently in FDA-approved IR solid oral dosage 

forms will not affect the rate or extent of absorption of a highly soluble and highly 

permeable drug substance that is formulated in a rapidly dissolving IR product. 

To support a biowaiver request, the quantity of excipients in the IR drug product 

should be consistent with the intended function (e.g., lubricant). When new 

excipients or atypically large amounts of commonly used excipients are included 

in an IR solid dosage form, additional information documenting the absence of an 

impact on BA of the drug may be requested by the Agency. Such information can 

be provided with a relative BA study using a simple aqueous solution as the 

reference product. Large quantities of certain excipients, such as surfactants (e.g., 

polysorbate 80) and sweeteners (e.g., mannitol or sorbitol) may be problematic, 

and sponsors are encouraged to contact the review division when this is a factor. 

8
B. Prodrugs 

Permeability of prodrugs will depend on the mechanism and (anatomical) site of

conversion to the drug substance. When the prodrug-to-drug conversion is shown 

to occur predominantly after intestinal membrane permeation, the permeability of 

the prodrug should be measured. When this conversion occurs prior to intestinal 

permeation, the permeability of the drug should be determined. Dissolution and 

pH-solubility data on both prodrug and drug can be relevant. Sponsors may wish 

to consult with appropriate review staff before applying the BCS approach to IR 

products containing prodrugs. 

C. Exceptions

BCS-based biowaivers are not applicable for the following: 

1. Narrow Therapeutic Range Drugs5

This guidance defines narrow therapeutic range drug products as those 

containing certain drug substances that are subject to therapeutic drug 

concentration or pharmacodynamic monitoring, and/or where product labeling 

indicates a narrow therapeutic range designation. Examples include digoxin, 

lithium, phenytoin, theophylline, and warfarin. Because not all drugs subject to 

therapeutic drug concentration or pharmacodynamic monitoring are narrow 

therapeutic range drugs, sponsors should contact the appropriate review division 

to determine whether a drug should be considered to have a narrow therapeutic 

range. 

2. Products Designed to be Absorbed in the Oral Cavity 

A request for a waiver of in vivo BA/BE studies based on the BCS is not 

appropriate for dosage forms intended for absorption in the oral cavity (e.g., 

sublingual or buccal tablets). 

V. REGULATORY APPLICATIONS OF THE BCS 

A. INDs/NDAs

Evidence demonstrating in vivo BA or information to permit FDA to waive this 

evidence must be included in NDAs (21 CFR 320.21(a)). A specific objective is 

to establish in vivo performance of the dosage form used in the clinical studies 

that provided primary evidence of efficacy and safety. The sponsor may wish to 

determine the relative BA of an IR solid oral dosage form by comparison with an 

 5

 This guidance uses the term narrow therapeutic range instead of narrow therapeutic index, 

although the latter is more commonly used. 

9
oral solution, suspension, or intravenous injection (21 CFR 320.25 (d)(2) and 

320.25 (d)(3)). The BA of the clinical trial dosage form should be optimized 

during the IND period. 

Once the in vivo BA of a formulation is established during the IND period, 

waivers of subsequent in vivo BE studies, following major changes in 

components, composition, and/or method of manufacture (e.g., similar to 

SUPAC-IR Level 3 changes6

) may be possible using the BCS. BCS-based 

biowaivers are applicable to the to-be-marketed formulation when changes in 

components, composition, and/or method of manufacture occur to the clinical trial 

formulation, as long as the dosage forms have rapid and similar in vitro

dissolution profiles (see sections II and III). This approach is useful only when 

the drug substance is highly soluble and highly permeable (BCS Class 1), and the 

formulations pre- and postchange are pharmaceutical equivalents (under the 

definition at 21 CFR 320.1 (c)). BCS-based biowaivers are intended only for BE 

studies. They do not apply to food effect BA studies or other pharmacokinetic 

studies. 

B. ANDAs 

BCS-based biowaivers can be requested for rapidly dissolving IR test products 

containing highly soluble and highly permeable drug substances, provided that the 

reference listed drug product is also rapidly dissolving and the test product 

exhibits similar dissolution profiles to the reference listed drug product (see 

sections II and III). This approach is useful when the test and reference dosage 

forms are pharmaceutical equivalents. The choice of dissolution apparatus (USP 

Apparatus I or II) should be the same as that established for the reference listed 

drug product. 

C. Postapproval Changes 

BCS-based biowaivers can be requested for significant postapproval changes 

(e.g., Level 3 changes in components and composition) to a rapidly dissolving IR 

product containing a highly soluble, highly permeable drug substance, provided 

that dissolution remains rapid for the postchange product and both pre- and 

postchange products exhibit similar dissolution profiles (see sections II and III). 

This approach is useful only when the drug products pre- and postchange are 

pharmaceutical equivalents. 

VI. DATA TO SUPPORT A REQUEST FOR BIOWAIVERS

The drug substance for which a waiver is being requested should be highly soluble and 

highly permeable. Sponsors requesting biowaivers based on the BCS should submit the 

following information to the Agency for review by the Office of Clinical Pharmacology 

 6

 See the FDA guidance for industry on Immediate Release Solid Oral Dosage Forms: Scale-Up

and Post-Approval Changes (November 1995). 

10
and Biopharmaceutics (for NDAs) or Office of Generic Drugs, Division of 

Bioequivalence (for ANDAs): 

A. Data Supporting High Solubility 

Data supporting high solubility of the test drug substance should be developed 

(see section III.A). The following information should be included in the 

application:

• A description of test methods, including information on analytical 

method and composition of the buffer solutions 

• Information on chemical structure, molecular weight, nature of the 

drug substance (acid, base, amphoteric, or neutral), and dissociation 

constants (pKa(s)) 

• Test results (mean, standard deviation, and coefficient of variation) 

summarized in a table under solution pH, drug solubility (e.g., mg/ml), 

and volume of media required to dissolve the highest dose strength 

• A graphic representation of mean pH-solubility profile 

B. Data Supporting High Permeability 

Data supporting high permeability of the test drug substance should be developed 

(see section III.B). The following information should be included in the 

application:

• For human pharmacokinetic studies, information on study design and 

methods used along with the pharmacokinetic data 

• For direct permeability methods, information supporting the suitability 

of a selected method that encompasses a description of the study 

method, criteria for selection of human subjects, animals, or epithelial 

cell line, drug concentrations in the donor fluid, description of the 

analytical method, method used to calculate extent of absorption or 

permeability, and where appropriate, information on efflux potential 

(e.g., bidirectional transport data) 

• A list of selected model drugs along with data on extent of absorption 

in humans (mean, standard deviation, coefficient of variation) used to 

establish suitability of a method, permeability values for each model 

drug (mean, standard deviation, coefficient of variation), permeability 

class of each model drug, and a plot of the extent of absorption as a 

function of permeability (mean ± standard deviation or 95% 

confidence interval) with identification of the low/high permeability 

11
class boundary and selected internal standard. Information to support 

high permeability of a test drug substance should include permeability 

data on the test drug substance, the internal standards (mean, standard 

deviation, coefficient of variation), stability information, data 

supporting passive transport mechanism where appropriate, and 

methods used to establish high permeability of the test drug substance. 

C. Data Supporting Rapid and Similar Dissolution 

For submission of a biowaiver request, an IR product should be rapidly 

dissolving. Data supporting rapid dissolution attributes of the test and reference 

products should be developed (see section III.C). The following information 

should be included in the application: 

• A brief description of the IR products used for dissolution testing, 

including information on batch or lot number, expiry date, 

dimensions, strength, and weight 

• Dissolution data obtained with 12 individual units of the test and 

reference products using recommended test methods in section III.C. 

The percentage of labeled claim dissolved at each specified testing 

interval should be reported for each individual dosage unit. The 

mean percent dissolved, range (highest and lowest) of dissolution, 

and coefficient of variation (relative standard deviation) should be 

tabulated. A graphic representation of the mean dissolution profiles 

for the test and reference products in the three media should also be 

included. 

• Data supporting similarity in dissolution profiles between the test 

and reference products in each of the three media, using the f2 metric 

D. Additional Information 

The manufacturing process used to make the test product should be described 

briefly to provide information on the method of manufacture (e.g., wet 

granulation vs. direct compression). A list of excipients used, the amount used, 

and their intended functions should be provided. Excipients used in the test 

product should have been used previously in FDA-approved IR solid oral dosage 

forms. 

12
ATTACHMENT A 

This attachment includes model drugs suggested for use in establishing suitability of a 

permeability method as described in section III. The permeability of these compounds 

was determined based on data available to the FDA. Potential internal standards (IS) 

and efflux pump substrates (ES) are also identified. 

 Drug Permeability Class 

Antipyrine High (Potential IS candidate)

Caffeine High

Carbamazepine High

Fluvastatin High

Ketoprofen High

Metoprolol High (Potential IS candidate)

Naproxen High

Propranolol High 

Theophylline High

Verapamil High (Potential ES candidate)

Amoxicillin Low 

Atenolol Low

Furosemide Low

Hydrochlorthiazide Low

Mannitol Low (Potential IS candidate)

"-Methyldopa Low

Polyethylene glycol (400) Low

Polyethylene glycol (1000) Low 

Polyethylene glycol (4000) Low (Zero permeability marker)

Ranitidine Low

13