3618fnl.pdf

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
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 (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
TABLE OF CONTENTS
INTRODUCTION .1
THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM.1
METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR
DETERMINING THE DISSOLUTION CHARACTERISTICS OF A DRUG PRODUCT.3
DETERMINING DRUG SUBSTANCE SOLUBILITY CLASS. 3 DETERMINING DRUG SUBSTANCE PERMEABILITY CLASS. 4 Pharmacokinetic Studies in Humans.4 Intestinal Permeability Methods .4 Instability in the Gastrointestinal Tract .7 C. DETERMINING DRUG PRODUCT DISSOLUTION CHARACTERISTICS AND DISSOLUTION PROFILE ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER.8
Products Designed to be Absorbed in the Oral Cavity .9 REGULATORY APPLICATIONS OF THE BCS.9
DATA TO SUPPORT A REQUEST FOR BIOWAIVERS .10
DATA SUPPORTING RAPID AND SIMILAR DISSOLUTION . 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
INTRODUCTION
This guidance provides recommendations for sponsors of investigational new drugapplications (INDs), new drug applications (NDAs), abbreviated new drug applications(ANDAs), and supplements to these applications who wish to request a waiver of in vivobioavailability (BA) and/or bioequivalence (BE) studies for immediate release (IR) solidoral dosage forms. These waivers are intended to apply to (1) subsequent in vivo BA orBE studies of formulations after the initial establishment of the in vivo BA of IR dosageforms 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 BEdata for approval of drug applications and supplemental applications. Provision forwaivers of in vivo BA/BE studies (biowaivers) under certain conditions is provided at 21CFR 320.22. This guidance explains when biowaivers can be requested for IR solid oraldosage forms based on an approach termed the Biopharmaceutics Classification System(BCS).
THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM
The BCS is a scientific framework for classifying drug substances based on their aqueoussolubility and intestinal permeability. When combined with the dissolution of the drugproduct, the BCS takes into account three major factors that govern the rate and extent ofdrug absorption from IR solid oral dosage forms: dissolution, solubility, and intestinalpermeability.2 According to the BCS, drug substances are classified as follows: 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 onthe topic. It does not create or confer any rights for or on any person and does not operate to bind FDA orthe public. An alternative approach may be used if such an approach satisfies the requirements of theapplicable statutes, regulations, or both.
2Amidon, G. L., H. Lennernäs, V. P. Shah, and J. R. Crison, AA Theoretical Basis For a Biopharmaceutics Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In VivoBioavailability,@ Pharmaceutical Research, 12: 413-420 (1995).
In addition, IR solid oral dosage forms are categorized as having rapid or slowdissolution. Within this framework, when certain criteria are met, the BCS can be usedas 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 twopharmaceutically equivalent solid oral products may be due to differences in drugdissolution in vivo.2 However, when the in vivo dissolution of an IR solid oral dosageform is rapid in relation to gastric emptying and the drug has high permeability, the rateand extent of drug absorption is unlikely to be dependent on drug dissolution and/orgastrointestinal transit time. Under such circumstances, demonstration of in vivo BA orBE may not be necessary for drug products containing Class 1 drug substances, as long asthe inactive ingredients used in the dosage form do not significantly affect absorption ofthe active ingredients. The BCS approach outlined in this guidance can be used to justifybiowaivers for highly soluble and highly permeable drug substances (i.e., Class 1) in IRsolid oral dosage forms that exhibit rapid in vitro dissolution using the recommended testmethods (21 CFR 320.22(e)). The recommended methods for determining solubility,permeability, and in vitro dissolution are discussed below.
Solubility
The solubility class boundary is based on the highest dose strength of an IRproduct that is the subject of a biowaiver request. A drug substance is consideredhighly soluble when the highest dose strength is soluble in 250 ml or less ofaqueous media over the pH range of 1-7.5. The volume estimate of 250 ml isderived from typical BE study protocols that prescribe administration of a drugproduct to fasting human volunteers with a glass (about 8 ounces) of water.
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 anddirectly on measurements of the rate of mass transfer across human intestinalmembrane. Alternatively, nonhuman systems capable of predicting the extent ofdrug absorption in humans can be used (e.g., in vitro epithelial cell culturemethods). In the absence of evidence suggesting instability in the gastrointestinaltract, a drug substance is considered to be highly permeable when the extent ofabsorption in humans is determined to be 90% or more of an administered dosebased on a mass balance determination or in comparison to an intravenousreference dose.
Dissolution
In this guidance, an IR drug product is considered rapidly dissolving when no lessthan 85% of the labeled amount of the drug substance dissolves within 30 minutes, using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or ApparatusII at 50 rpm) in a volume of 900 ml or less in each of the following media: (1) 0.1N 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.
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 anddetermining the dissolution characteristics of an IR drug product according to the BCS: Determining Drug Substance Solubility Class
An objective of the BCS approach is to determine the equilibrium solubility of adrug substance under physiological pH conditions. The pH-solubility profile ofthe test drug substance should be determined at 37 ± 1oC in aqueous media with apH in the range of 1-7.5. A sufficient number of pH conditions should beevaluated to accurately define the pH-solubility profile. The number of pHconditions for a solubility determination can be based on the ionizationcharacteristics of the test drug substance. For example, when the pKa of a drug isin 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 determinationsof solubility in each pH condition is recommended. Depending on studyvariability, additional replication may be necessary to provide a reliable estimateof solubility. Standard buffer solutions described in the USP are consideredappropriate for use in solubility studies. If these buffers are not suitable forphysical or chemical reasons, other buffer solutions can be used. Solution pHshould be verified after addition of the drug substance to a buffer. Methods otherthan the traditional shake-flask method, such as acid or base titration methods, canalso be used with justification to support the ability of such methods to predictequilibrium solubility of the test drug substance. Concentration of the drugsubstance in selected buffers (or pH conditions) should be determined using avalidated stability-indicating assay that can distinguish the drug substance from itsdegradation products.3 If degradation of the drug substance is observed as afunction of buffer composition and/or pH, it should be reported along with otherstability data recommended in section III.B.3.
The solubility class should be determined by calculating the volume of anaqueous medium sufficient to dissolve the highest dose strength in the pH rangeof 1-7.5. A drug substance should be classified as highly soluble when thehighest dose strength is soluble in < 250 ml of aqueous media over the pH rangeof 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.
Determining Drug Substance Permeability Class
The permeability class of a drug substance can be determined in human subjectsusing mass balance, absolute BA, or intestinal perfusion approaches.
Recommended methods not involving human subjects include in vivo or in situintestinal perfusion in a suitable animal model (e.g., rats), and/or in vitropermeability methods using excised intestinal tissues, or monolayers of suitableepithelial cells. In many cases, a single method may be sufficient (e.g., when theabsolute BA is 90% or more, or when 90% or more of the administered drug isrecovered in urine). When a single method fails to conclusively demonstrate apermeability classification, two different methods may be advisable. Chemicalstructure and/or certain physicochemical attributes of a drug substance (e.g.,partition coefficient in suitable systems) can provide useful information about itspermeability characteristics. Sponsors may wish to consider use of suchinformation to further support a classification.
Pharmacokinetic mass balance studies using unlabeled, stable isotopes or aradiolabeled drug substance can be used to document the extent ofabsorption of a drug. Depending on the variability of the studies, asufficient number of subjects should be enrolled to provide a reliableestimate of extent of absorption. Because this method can provide highlyvariable estimates of drug absorption for many drugs, other methodsdescribed below may be preferable.
Oral BA determination using intravenous administration as a reference canbe used. Depending on the variability of the studies, a sufficient numberof subjects should be enrolled in a study to provide a reliable estimate ofthe extent of absorption. When the absolute BA of a drug is shown to be90% or more, additional data to document drug stability in thegastrointestinal fluid is not necessary.
The following methods can be used to determine the permeability of a drugsubstance from the gastrointestinal tract: (1) in vivo intestinal perfusion studiesin humans; (2) in vivo or in situ intestinal perfusion studies using suitableanimal models; (3) in vitro permeation studies using excised human or animalintestinal tissues; or (4) in vitro permeation studies across a monolayer ofcultured epithelial cells.
In vivo or in situ animal models and in vitro methods, such as those usingcultured monolayers of animal or human epithelial cells, are consideredappropriate for passively transported drugs. The observed low permeability ofsome drug substances in humans could be caused by efflux of drugs viamembrane transporters such as P-glycoprotein (P- gp). When the effluxtransporters are absent in these models, or their degree of expression is lowcompared to that in humans, there may be a greater likelihood ofmisclassification of permeability class for a drug subject to efflux compared to adrug transported passively. Expression of known transporters in selected studysystems should be characterized. Functional expression of efflux systems (e.g.,P-gp) can be demonstrated with techniques such as bidirectional transportstudies, demonstrating a higher rate of transport in the basolateral-to-apicaldirection as compared to apical-to-basolateral direction using selected modeldrugs or chemicals at concentrations that do not saturate the efflux system (e.g.,cyclosporin A, vinblastine, rhodamine 123). An acceptance criterion forintestinal efflux that should be present in a test system cannot be set at this time.
Instead, this guidance recommends limiting the use of nonhuman permeabilitytest methods for drug substances that are transported by passive mechanisms.
Pharmacokinetic studies on dose linearity or proportionality may provide usefulinformation 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 vitromethods for a drug that has a higher rate of transport in the basolateral-to-apicaldirection at low drug concentrations but exhibits linear pharmacokinetics inhumans.
For application of the BCS, an apparent passive transport mechanism can beassumed 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 theconcentration-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) inthe 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 dosestrength dissolved in 250 ml) is demonstrated in donor fluid andtransport direction (e.g., no statistically significant difference in therate of transport between the apical-to-basolateral and basolateral-to-apical direction for the drug concentrations selected) using a suitablein vitro cell culture method that has been shown to express knownefflux transporters (e.g., P-gp) To demonstrate suitability of a permeability method intended for application ofthe BCS, a rank-order relationship between test permeability values and theextent of drug absorption data in human subjects should be established using asufficient number of model drugs. For in vivo intestinal perfusion studies inhumans, six model drugs are recommended. For in vivo or in situ intestinalperfusion studies in animals and for in vitro cell culture methods, twenty modeldrugs are recommended. Depending on study variability, a sufficient number ofsubjects, animals, excised tissue samples, or cell monolayers should be used in astudy to provide a reliable estimate of drug permeability. This relationshipshould allow precise differentiation between drug substances of low and highintestinal permeability attributes.
For demonstration of suitability of a method, model drugs should represent arange of low (e.g., < 50%), moderate (e.g., 50 - 89%), and high (≥ 90%)absorption. Sponsors may select compounds from the list of drugs and/orchemicals provided in Attachment A or they may choose to select other drugsfor which there is information available on mechanism of absorption andreliable estimates of the extent of drug absorption in humans.
After demonstrating suitability of a method and maintaining the same studyprotocol, it is not necessary to retest all selected model drugs for subsequentstudies intended to classify a drug substance. Instead, a low and a highpermeability model drug should be used as internal standards (i.e., included inthe perfusion fluid or donor fluid along with the test drug substance). These twointernal standards are in addition to the fluid volume marker (or a zeropermeability compound such as PEG 4000) that is included in certain types ofperfusion techniques (e.g., closed loop techniques). The choice of internalstandards should be based on compatibility with the test drug substance (i.e.,they should not exhibit any significant physical, chemical, or permeationinteractions). When it is not feasible to follow this protocol, the permeability ofinternal standards should be determined in the same subjects, animals, tissues,or monolayers, following evaluation of the test drug substance. Thepermeability values of the two internal standards should not differ significantlybetween different tests, including those conducted to demonstrate suitability ofthe method. At the end of an in situ or in vitro test, the amount of drug in themembrane should be determined.
For a given test method with set conditions, selection of a high permeabilityinternal standard with permeability in close proximity to the low/highpermeability class boundary may facilitate classification of a test drugsubstance. For instance, a test drug substance may be determined to be highlypermeable when its permeability value is equal to or greater than that of theselected internal standard with high permeability.
Instability in the Gastrointestinal Tract Determining the extent of absorption in humans based on mass balance studiesusing total radioactivity in urine does not take into consideration the extent ofdegradation of a drug in the gastrointestinal fluid prior to intestinal membranepermeation. In addition, some methods for determining permeability could bebased on loss or clearance of a drug from fluids perfused into the human and/oranimal gastrointestinal tract either in vivo or in situ. Documenting the fact thatdrug loss from the gastrointestinal tract arises from intestinal membranepermeation, rather than a degradation process, will help establish permeability.
Stability in the gastrointestinal tract may be documented using gastric andintestinal fluids obtained from human subjects. Drug solutions in these fluidsshould be incubated at 37oC for a period that is representative of in vivo drugcontact with these fluids; for example, 1 hour in gastric fluid and 3 hours inintestinal fluid. Drug concentrations should then be determined using avalidated stability-indicating assay method. Significant degradation (>5%) of adrug in this protocol could suggest potential instability. Obtaininggastrointestinal fluids from human subjects requires intubation and may bedifficult in some cases. Use of gastrointestinal fluids from suitable animalmodels and/or simulated fluids such as Gastric and Intestinal Fluids USP can besubstituted when properly justified.
Determining Drug Product Dissolution Characteristics and
Dissolution Profile Similarity4
Dissolution testing should be carried out in USP Apparatus I at 100 rpm orApparatus II at 50 rpm using 900 ml of the following dissolution media: (1) 0.1N 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. Forcapsules and tablets with gelatin coating, Simulated Gastric and Intestinal FluidsUSP (with enzymes) can be used.
Dissolution testing apparatus used in this evaluation should conform to therequirements in USP (<711> Dissolution). Selection of the dissolution testingapparatus (USP Apparatus I or II) during drug development should be based on acomparison of in vitro dissolution and in vivo pharmacokinetic data available forthe product. The USP Apparatus I (basket method) is generally preferred forcapsules and products that tend to float, and USP Apparatus II (paddle method) isgenerally preferred for tablets. For some tablet dosage forms, in vitro (but not invivo) dissolution may be slow due to the manner in which the disintegratedproduct settles at the bottom of a dissolution vessel. In such situations, USPApparatus I may be preferred over Apparatus II. If the testing conditions need tobe modified to better reflect rapid in vivo dissolution (e.g., use of a differentrotating 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 dissolution with in vivo absorption data (e.g., a relative BA study using a simpleaqueous solution as the reference product).
A minimum of 12 dosage units of a drug product should be evaluated to support abiowaiver request. Samples should be collected at a sufficient number ofintervals 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 becompared using a similarity factor (f2). The similarity factor is a logarithmicreciprocal square root transformation of the sum of squared error and is ameasurement of the similarity in the percent (%) of dissolution between the twocurves.
2 = 50 i log {[1+(1/n)Ót=1 (Rt - Tt)2]-0.5 i 100} Two dissolution profiles are considered similar when the f2 value is $50. Toallow the use of mean data, the coefficient of variation should not be more than20% at the earlier time points (e.g., 10 minutes), and should not be more than10% at other time points. Note that when both test and reference productsdissolve 85% or more of the label amount of the drug in #15 minutes using allthree dissolution media recommended above, the profile comparison with an f2test is unnecessary.
ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER
When requesting a BCS-based waiver for in vivo BA/BE studies for IR solid oral dosageforms, applicants should note that the following factors can affect their request or thedocumentation of their request: Excipients
Excipients can sometimes affect the rate and extent of drug absorption. Ingeneral, using excipients that are currently in FDA-approved IR solid oral dosageforms will not affect the rate or extent of absorption of a highly soluble and highlypermeable drug substance that is formulated in a rapidly dissolving IR product.
To support a biowaiver request, the quantity of excipients in the IR drug productshould be consistent with the intended function (e.g., lubricant). When newexcipients or atypically large amounts of commonly used excipients are includedin an IR solid dosage form, additional information documenting the absence of animpact on BA of the drug may be requested by the Agency. Such information canbe provided with a relative BA study using a simple aqueous solution as thereference 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.
Prodrugs
Permeability of prodrugs will depend on the mechanism and (anatomical) site ofconversion to the drug substance. When the prodrug-to-drug conversion is shownto occur predominantly after intestinal membrane permeation, the permeability ofthe prodrug should be measured. When this conversion occurs prior to intestinalpermeation, the permeability of the drug should be determined. Dissolution andpH-solubility data on both prodrug and drug can be relevant. Sponsors may wishto consult with appropriate review staff before applying the BCS approach to IRproducts containing prodrugs.
Exceptions
BCS-based biowaivers are not applicable for the following: This guidance defines narrow therapeutic range drug products as thosecontaining certain drug substances that are subject to therapeutic drugconcentration or pharmacodynamic monitoring, and/or where product labelingindicates a narrow therapeutic range designation. Examples include digoxin,lithium, phenytoin, theophylline, and warfarin. Because not all drugs subject totherapeutic drug concentration or pharmacodynamic monitoring are narrowtherapeutic range drugs, sponsors should contact the appropriate review divisionto determine whether a drug should be considered to have a narrow therapeuticrange.
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 notappropriate for dosage forms intended for absorption in the oral cavity (e.g.,sublingual or buccal tablets).
REGULATORY APPLICATIONS OF THE BCS
INDs/NDAs
Evidence demonstrating in vivo BA or information to permit FDA to waive thisevidence must be included in NDAs (21 CFR 320.21(a)). A specific objective isto establish in vivo performance of the dosage form used in the clinical studiesthat provided primary evidence of efficacy and safety. The sponsor may wish todetermine the relative BA of an IR solid oral dosage form by comparison with anoral solution, suspension, or intravenous injection (21 CFR 320.25 (d)(2) and 5 This guidance uses the term narrow therapeutic range instead of narrow therapeutic index, although the latter is more commonly used.
320.25 (d)(3)). The BA of the clinical trial dosage form should be optimizedduring 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 incomponents, composition, and/or method of manufacture (e.g., similar toSUPAC-IR Level 3 changes6) may be possible using the BCS. BCS-basedbiowaivers are applicable to the to-be-marketed formulation when changes incomponents, composition, and/or method of manufacture occur to the clinical trialformulation, as long as the dosage forms have rapid and similar in vitrodissolution profiles (see sections II and III). This approach is useful only whenthe drug substance is highly soluble and highly permeable (BCS Class 1), and theformulations pre- and postchange are pharmaceutical equivalents (under thedefinition at 21 CFR 320.1 (c)). BCS-based biowaivers are intended only for BEstudies. They do not apply to food effect BA studies or other pharmacokineticstudies.
BCS-based biowaivers can be requested for rapidly dissolving IR test productscontaining highly soluble and highly permeable drug substances, provided that thereference listed drug product is also rapidly dissolving and the test productexhibits similar dissolution profiles to the reference listed drug product (seesections II and III). This approach is useful when the test and reference dosageforms are pharmaceutical equivalents. The choice of dissolution apparatus (USPApparatus I or II) should be the same as that established for the reference listeddrug product.
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 IRproduct containing a highly soluble, highly permeable drug substance, providedthat dissolution remains rapid for the postchange product and both pre- andpostchange products exhibit similar dissolution profiles (see sections II and III).
This approach is useful only when the drug products pre- and postchange arepharmaceutical equivalents.
DATA TO SUPPORT A REQUEST FOR BIOWAIVERS
The drug substance for which a waiver is being requested should be highly soluble andhighly permeable. Sponsors requesting biowaivers based on the BCS should submit thefollowing 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).
and Biopharmaceutics (for NDAs) or Office of Generic Drugs, Division ofBioequivalence (for ANDAs): 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 theapplication: • 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 dissociationconstants (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 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 theapplication: • 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 studymethod, criteria for selection of human subjects, animals, or epithelialcell line, drug concentrations in the donor fluid, description of theanalytical method, method used to calculate extent of absorption orpermeability, 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 toestablish suitability of a method, permeability values for each modeldrug (mean, standard deviation, coefficient of variation), permeabilityclass of each model drug, and a plot of the extent of absorption as afunction of permeability (mean ± standard deviation or 95%confidence interval) with identification of the low/high permeability class boundary and selected internal standard. Information to supporthigh permeability of a test drug substance should include permeabilitydata on the test drug substance, the internal standards (mean, standarddeviation, coefficient of variation), stability information, datasupporting passive transport mechanism where appropriate, andmethods used to establish high permeability of the test drug substance.
Data Supporting Rapid and Similar Dissolution
For submission of a biowaiver request, an IR product should be rapidlydissolving. Data supporting rapid dissolution attributes of the test and referenceproducts should be developed (see section III.C). The following informationshould 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 andreference products using recommended test methods in section III.C.
The percentage of labeled claim dissolved at each specified testinginterval should be reported for each individual dosage unit. Themean percent dissolved, range (highest and lowest) of dissolution,and coefficient of variation (relative standard deviation) should betabulated. A graphic representation of the mean dissolution profilesfor the test and reference products in the three media should also beincluded.
Data supporting similarity in dissolution profiles between the testand reference products in each of the three media, using the f2 metric Additional Information
The manufacturing process used to make the test product should be describedbriefly to provide information on the method of manufacture (e.g., wetgranulation vs. direct compression). A list of excipients used, the amount used,and their intended functions should be provided. Excipients used in the testproduct should have been used previously in FDA-approved IR solid oral dosageforms.
ATTACHMENT A
This attachment includes model drugs suggested for use in establishing suitability of apermeability method as described in section III. The permeability of these compoundswas determined based on data available to the FDA. Potential internal standards (IS)and efflux pump substrates (ES) are also identified.
Permeability Class

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