Guidance for Industry
`Extended Release Oral Dosage Forms:
`Development, Evaluation, and
`Application of In Vitro/In Vivo
`Correlations
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`September 1997
`BP 2
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`Page 1
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`SHIRE EX. 2039
`KVK v. SHIRE
`IPR2018-00293
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`

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`Guidance for Industry
`Extended Release Oral Dosage Forms:
`Development, Evaluation, and
`Application of In Vitro/In Vivo
`Correlations
`
`Additional copies are available from:Office of Training and Communications Division of Communications ManagementThe Drug Information Branch, HFD-2105600 Fishers LaneRockville, MD 20857
`
`(Tel) 301-827-4573
`(Internet) http://www.fda.gov/cder/guidance/index.htm
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`September 1997
`BP 2
`
`Page 2
`
`

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`Table of Contents
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`I.
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`II.
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`INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
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`BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
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`III.
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`CATEGORIES OF IN VITRO/IN VIVO CORRELATIONS . . . . . . . . . . . . . . . . . . 3
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`A.
`B.
`C.
`D.
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`Level A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
`Level B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
`Level C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
`Multiple Level C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
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`IV.
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`GENERAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
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`V.
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`DEVELOPMENT AND EVALUATION OF A LEVEL A IN VITRO/IN VIVO
`CORRELATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
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`A.
`B.
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`Developing the Correlation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
`Evaluating the Predictability of a Level A Correlation . . . . . . . . . . . . 6
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`VI.
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`DEVELOPMENT AND EVALUATION OF A LEVEL C IN VITRO/IN VIVO
`CORRELATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
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`VII. APPLICATIONS OF AN IVIVC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
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`A.
`B.
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`Biowaivers for Changes in the Manufacturing of a Drug Product . . 11
`Setting Dissolution Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
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`REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
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`DEFINITION OF TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
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`GUIDANCE FOR INDUSTRY1
`
`Extended Release Oral Dosage Forms:
`Development, Evaluation, And Application
`Of In Vitro/In Vivo Correlations
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`I.
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`INTRODUCTION
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`This guidance provides recommendations to pharmaceutical sponsors who intend to developdocumentation in support of an in vitro/in vivo correlation (IVIVC) for an oral extended release(ER) drug product for submission in a new drug application (NDA), abbreviated new drugapplication (ANDA), or antibiotic drug application (AADA). The guidance presents acomprehensive perspective on (1) methods of developing an IVIVC and evaluating itspredictability; (2) using an IVIVC to set dissolution specifications; and (3) applying an IVIVC asa surrogate for in vivo bioequivalence when it is necessary to document bioequivalence during theinitial approval process or because of certain pre- or postapproval changes (e.g., formulation,equipment, process, and manufacturing site changes).
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`II.
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`BACKGROUND
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`The concept of IVIVC, particularly for ER drug products, has been extensively discussed bypharmaceutical scientists. The ability to predict, accurately and precisely, expected bioavailabilitycharacteristics for an ER product from dissolution profile characteristics is a long sought aftergoal. Several workshops and publications have provided information in support of this goal. These are discussed briefly as follows:
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`Workshop on CR Dosage Forms: Issues and Controversies
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` (1987) indicated that the stateof science and technology at that time did not permit consistently meaningful IVIVC forER dosage forms and encouraged IVIVC as a future objective. Dissolution testing wasconsidered useful only for process control, stability, minor formulation changes, andmanufacturing site changes.
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` This guidance has been prepared by the Extended Release Dissolution Working Group of the1Biopharmaceutics Coordinating Committee (BCC) in the Center for Drug Evaluation and Research (CDER) at the Foodand Drug Administration (FDA). This guidance represents the Agency’s current thinking on in vitro/in vivo correlationsfor extended release oral dosage forms. It does not create or confer any rights for or on any person and does not operateto bind FDA or the public. An alternative approach may be used if such approach satisfies the applicable statute,regulations, or both.
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`Report of the
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`A report from a 1987 ASCPT/DIA/APS/FDA-sponsored workshop entitled
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`A USP PF Stimuli Article in July 1988 established the classification of IVIVC into LevelsA, B and C, which are currently in use.
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`(1990) concluded that, while the science and technology may not always permitmeaningful IVIVC, the development of an IVIVC was an important objective on aproduct-by-product basis. Procedures for development, evaluation, and application of anIVIVC were described. Validation of dissolution specifications by a bioequivalence studyinvolving two batches of product with dissolution profiles at the upper and lowerdissolution specifications was suggested.
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`USP Chapter 1088 similarly describes techniques appropriate for Level A, B, and Ccorrelations and methods for establishing dissolution specifications.
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`Further information related to IVIVCs was developed in a USP/AAPS/FDA-sponsoredworkshop, which resulted in a report entitled
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`In vitro/In
`vivo Testing and Correlation for Oral Controlled/Modified Release Dosage Forms
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`Extended Release Dosage Forms
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`Workshop II Report: Scale-up of Oral
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` (1993). This report identified the objectives of anIVIVC to be the use of dissolution as a surrogate for bioequivalency testing, as well as anaid in setting dissolution specifications. The report concluded that dissolution may beused as a sensitive, reliable, and reproducible surrogate for bioequivalence testing. Thereport gave support to the concepts of USP Chapter 1088 and further found that anIVIVC may be useful for changes other than minor changes in formulation, equipment,process, manufacturing site, and batch size.These reports document increasing confidence in IVIVC to estimate the in vivo bioavailabilitycharacteristics for an ER drug product. In this regard, increased IVIVC activity in NDAsubmissions has been apparent. Still, the complete process of developing an IVIVC with highquality and predictability and identifying specific applications for such correlations has not beenwell defined. As part of the process of developing this guidance, the Agency conducted several surveys ofNDA submissions for ER drug products to find out the number of times that IVIVCs weredeveloped. The first survey included NDA submissions from 1982-1992 and found 9 IVIVCs in60 submissions. A more recent survey included NDA submissions from October 1994 to October1995 and found 9 IVIVCs in 12 submissions. This guidance is based on these prior deliberations and publications as well as on currentunderstanding at the FDA and elsewhere on approaches to developing reliable and useful IVIVCs. This guidance describes the levels of correlations that can be established with varying degrees ofusefulness, important considerations for in vivo and in vitro experimentation, evaluation of thecorrelation by focusing on the critical feature of predictability, and practical applications that canbe achieved using the IVIVC. With the availability of this guidance, sponsors are encouraged to
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`A report from a 1990 ASCPT/DIA/APS/FDA-sponsored workshop entitled
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`III.
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`CATEGORIES OF IN VITRO/IN VIVO CORRELATIONS
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`A.
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`Level A
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`A Level A correlation is usually estimated by a two-stage procedure: deconvolution2followed by comparison of the fraction of drug absorbed to the fraction of drug dissolved. A correlation of this type is generally linear and represents a point-to-point relationshipbetween in vitro dissolution and the in vivo input rate (e.g., the in vivo dissolution of thedrug from the dosage form). In a linear correlation, the in vitro dissolution and in vivoinput curves may be directly superimposable or may be made to be superimposable by theuse of a scaling factor. Nonlinear correlations, while uncommon, may also be appropriate. Alternative approaches to developing a Level A IVIVC are possible. One alternative isbased on a convolution procedure that models the relationship between in vitro dissolutionand plasma concentration in a single step. Plasma concentrations predicted from themodel and those observed are compared directly. For these methods, a referencetreatment is desirable, but the lack of one does not preclude the ability to develop anIVIVC.Whatever the method used to establish a Level A IVIVC, the model should predict theentire in vivo time course from the in vitro data. In this context, the model refers to therelationship between in vitro dissolution of an ER dosage form and an in vivo responsesuch as plasma drug concentration or amount of drug absorbed.
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` Level A correlations are the most common type of correlation developed in NDAs submitted to the FDA. 2Level B correlations are rarely seen in NDAs; multiple Level C correlations are seen infrequently.3develop IVIVCs for ER products in the expectation that the information will be useful inestablishing dissolution specifications and will permit certain formulation and manufacturingchanges without an in vivo bioequivalence study.
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`B.
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`Level B
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`A Level B IVIVC uses the principles of statistical moment analysis. The mean in vitrodissolution time is compared either to the mean residence time or to the mean in vivodissolution time. A Level B correlation, like a Level A, uses all of the in vitro and in vivodata, but is not considered to be a point-to-point correlation. A Level B correlation doesnot uniquely reflect the actual in vivo plasma level curve, because a number of different invivo curves will produce similar mean residence time values.
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`C.
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`Level C
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`A Level C IVIVC establishes a single point relationship between a dissolution parameter,for example, t, percent dissolved in 4 hours and a pharmacokinetic parameter (e.g.,50%AUC, C, T). A Level C correlation does not reflect the complete shape of the plasmamax maxconcentration time curve, which is the critical factor that defines the performance of ERproducts.
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`D.
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`Multiple Level C
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`A multiple Level C correlation relates one or several pharmacokinetic parameters ofinterest to the amount of drug dissolved at several time points of the dissolution profile.
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`IV.
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`GENERAL CONSIDERATIONS
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`:The following general statements apply in the development of an IVIVC in an NDA orANDA/AADA:
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`Bioavailability studies for IVIVC development should be performed with enough subjectsto characterize adequately the performance of the drug product under study. In prioracceptable data sets, the number of subjects has ranged from 6 to 36. Although crossoverstudies are preferred, parallel studies or cross-study analyses may be acceptable. Thelatter may involve normalization with a common reference treatment. The referenceproduct in developing an IVIVC may be an intravenous solution, an aqueous oral solution,or an immediate release product.
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`IVIVCs are usually developed in the fasted state. When a drug is not tolerated in thefasted state, studies may be conducted in the fed state.
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`Any in vitro dissolution method may be used to obtain the dissolution characteristics ofthe ER dosage form. The same system should be used for all formulations tested.
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`The preferred dissolution apparatus is USP apparatus I (basket) or II (paddle), used atcompendially recognized rotation speeds (e.g., 100 rpm for the basket and 50-75 rpm forthe paddle). In other cases, the dissolution properties of some ER formulations may bedetermined with USP apparatus III (reciprocating cylinder) or IV (flow through cell). Appropriate review staff in CDER should be consulted before using any other type ofapparatus.
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`Human data should be supplied for regulatory consideration of an IVIVC.
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`An aqueous medium, either water or a buffered solution preferably not exceeding pH 6.8,is recommended as the initial medium for development of an IVIVC. Sufficient datashould be submitted to justify pH greater than 6.8. For poorly soluble drugs, addition ofsurfactant (e.g., 1% sodium lauryl sulfate) may be appropriate. In general, nonaqueous andhydroalcoholic systems are discouraged unless all attempts with aqueous media areunsuccessful. Appropriate review staff in CDER should be consulted before using anyother media.
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`The dissolution profiles of at least 12 individual dosage units from each lot should bedetermined. A suitable distribution of sampling points should be selected to defineadequately the profiles. The coefficient of variation (CV) for mean dissolution profiles of asingle batch should be less than 10%.
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`A Level A IVIVC is considered to be the most informative and is recommended, ifpossible.
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`Multiple Level C correlations can be as useful as Level A correlations. However, if amultiple Level C correlation is possible, then a Level A correlation is also likely and ispreferred.
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`Level C correlations can be useful in the early stages of formulation development whenpilot formulations are being selected.
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`Rank order correlations are qualitative and are not considered useful for regulatorypurposes.
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`V.
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`DEVELOPMENT AND EVALUATION OF A LEVEL A IN VITRO/IN VIVO
`CORRELATION
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`A.
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`Developing the Correlation
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`The most commonly seen process for developing a Level A IVIVC is to (1) developformulations with different release rates, such as slow, medium, fast, or a single releaserate if dissolution is condition independent; (2) obtain in vitro dissolution profiles and invivo plasma concentration profiles for these formulations; (3) estimate the in vivoabsorption or dissolution time course using an appropriate deconvolution technique foreach formulation and subject (e.g., Wagner-Nelson, numerical deconvolution). These threesteps establish the IVIVC model. Alternative approaches to developing Level A IVIVCsare possible. Further general information follows:
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`Level B correlations are least useful for regulatory purposes.
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`The IVIVC relationship should be demonstrated consistently with two or moreformulations with different release rates to result in corresponding differences inabsorption profiles. Although an IVIVC can be defined with a minimum of twoformulations with different release rates, three or more formulations with differentrelease rates are recommended. Exceptions to this approach (i.e., use of only oneformulation) may be considered for formulations for which in vitro dissolution isindependent of the dissolution test conditions (e.g., medium, agitation, pH).
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`If one or more of the formulations (highest or lowest release rate formulations)does not show the same relationship between in vitro dissolution and in vivoperformance compared with the other formulations, the correlation may still beused within the range of release rates encompassed by the remaining formulations.
`The in vitro dissolution methodology should adequately discriminate amongformulations. Dissolution testing can be carried out during the formulationscreening stage using several methods. Once a discriminating system is developed,dissolution conditions should be the same for all formulations tested in thebiostudy for development of the correlation and should be fixed before furthersteps towards correlation evaluation are undertaken.
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`During the early stages of correlation development, dissolution conditions may bealtered to attempt to develop a 1-to-1 correlation between the in vitro dissolutionprofile and the in vivo dissolution profile.
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`Time scaling may be used as long as the time scaling factor is the same for allformulations. Different time scales for each formulation indicate absence of anIVIVC.
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`B.
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`Evaluating the Predictability of a Level A Correlation
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`An IVIVC should be evaluated to demonstrate that predictability of in vivo performanceof a drug product from its in vitro dissolution characteristics is maintained over a range ofin vitro dissolution release rates and manufacturing changes. Since the objective ofdeveloping an IVIVC is to establish a predictive mathematical model describing therelationship between an in vitro property and a relevant in vivo response, the proposedevaluation approaches focus on the estimation of predictive performance or, conversely,prediction error. Depending on the intended application of an IVIVC and the therapeuticindex of the drug, evaluation of prediction error internally and/or externally may beappropriate. Evaluation of internal predictability is based on the initial data used to definethe IVIVC model. Evaluation of external predictability is based on additional test data
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`Ideally, formulations should be compared in a single study with a crossover design.
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`7sets. Application of one or more of these procedures to the IVIVC modeling processconstitutes evaluation of predictability. An important concept is that the less data available for initial IVIVC development andevaluation of predictability, the more additional data may be needed to define completelythe IVIVC's predictability. Some combination of three or more formulations withdifferent release rates is considered optimal.Another significant factor is the range of release rates studied. The release rates, asmeasured by percent dissolved, for each formulation studied, should differ adequately(e.g., by 10%). This should result in in vivo profiles that show a comparable difference, forexample, a 10% difference in the pharmacokinetic parameters of interest (C or AUC)maxbetween each formulation.
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`Methodology for the evaluation of IVIVC predictability is an active area of investigationand a variety of methods are possible and potentially acceptable. A correlation shouldpredict in vivo performance accurately and consistently. Once this relationship has beenachieved, in vitro dissolution can be used confidently as a surrogate for in vivobioequivalence of ER drug products in the situations described below.1.Experimental Data Considerationsa.Dosage Form Properties: Dependence of In Vitro Release onExperimental Conditions
`: If in vitro dissolution is shown to beindependent of dissolution conditions (e.g., pH and agitation) and if the in vitrodissolution profile is shown to be equal to the in vivo absorption or in vivodissolution profile, then the results for a single formulation (one release rate) maybe sufficient. Evaluation of data for this formulation and evaluation of additionaltest data sets, as appropriate, for the purpose of estimation of internal and/orexternal predictability are recommended.
`: In all other instances where an IVIVC model ispresented, results from a single formulation (one release rate) should be consideredinsufficient. To estimate internal and/or external predictability, evaluation of datafrom two or more formulations with different release rates is recommended.b.Internal and External PredictabilityTwo distinct aspects of predictability can be considered. However, both aspectsare not recommended in all instances.
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`Condition independent dissolution
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`Condition dependent dissolution
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`Estimation of prediction error internally
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`Estimation of prediction error externally:
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`: The first aspect relates to evaluatinghow well the model describes the data used to define the IVIVC and is appropriatein all instances.If formulations with three or more release rates are used to develop the IVIVCmodel, no further evaluation beyond this initial estimation of prediction error maybe necessary for non-narrow therapeutic index drugs (Category 2 a and bapplications, see page 12). However, depending on the results of this internalprediction error calculation, determination of prediction error externally may beappropriate.If only two formulations with different release rates are used, the application of theIVIVC is further limited to Category 2a applications (see page 12). In thiscircumstance, determination of prediction error externally is recommended forcomplete evaluation and subsequent full application of the IVIVC.
`The second aspect relates to how wellthe model predicts data when one or more additional test data sets are used thatdiffer from those used to define the correlation. This is appropriate in somesituations, particularly when only two formulations with different release rates areused to develop the IVIVC model, when calculation of prediction error internallyis inconclusive, or when a narrow therapeutic index drug is studied.The additional test data sets used for external prediction error calculation mayhave several differing characteristics compared to the data sets used in IVIVCdevelopment. Although formulations with different release rates provide theoptimal test of an IVIVC's predictability, a formulation need not be prepared solelyfor this purpose. In the absence of such a formulation, data from other types offormulations may be considered. In each case, bioavailability data should beavailable for the data set under consideration.The following represent, in decreasing order of preference, formulations that maybe used to estimate prediction error externally:
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`A formulation with a different release rate than those used in IVIVCdevelopment. The release rate of the test formulation may be either withinor outside the range used to define the IVIVC relationship.
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`A formulation with the same or similar release rate, but involving somechange in manufacture of this batch (e.g., composition, process, equipment,manufacturing site).
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`A formulation with the same or similar release rate obtained from anotherbatch/lot with no changes in manufacturing.c.Pharmacologic Properties of the Drug (Therapeutic Index)
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`Narrow therapeutic index drugs
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`: If an IVIVC model is to be used in estimatingthe in vivo performance of formulations of narrow therapeutic index drugs, themodel's predictability should be tested further with a data set that differs fromthose data sets used to define the correlation. In other words, the externalpredictability of the correlation should be evaluated.
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`Non-narrow therapeutic index drugs
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`: If an IVIVC model is to be used inestimating the in vivo performance of formulations of non-narrow therapeuticindex drugs, testing the model’s predictability with a data set that differs fromthose data sets used to define the correlation may be desirable, but is notconsidered as important as for a narrow therapeutic index drug.Note — If the classification of a drug as a narrow therapeutic index drug isuncertain, appropriate review staff in CDER should be consulted. 2.Methods for Evaluation of PredictabilityThe objective of IVIVC evaluation is to estimate the magnitude of the error inpredicting the in vivo bioavailability results from in vitro dissolution data. Thisobjective should guide the choice and interpretation of evaluation methods. Anyappropriate approach related to this objective may be used for evaluation ofpredictability.
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`Internal predictability
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`: All IVIVCs should be studied regarding internalpredictability. One recommended approach involves the use of the IVIVC modelto predict each formulation’s plasma concentration profile (or C and/or AUC formaxa multiple Level C IVIVC) from each respective formulation’s dissolution data.This is performed for each formulation used to develop the IVIVC model. Thepredicted bioavailability is then compared to the observed bioavailability for eachformulation and a determination of prediction error is made.
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`Criteria
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`Average absolute percent prediction error (% PE) of 10% or less for Cmaxand AUC establishes the predictability of the IVIVC. In addition, the %PE for each formulation should not exceed 15%.
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`External predictability
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`If these criteria are not met, that is, if the internal predictability of theIVIVC is inconclusive, evaluation of external predictability of the IVIVCshould be performed as a final determination of the ability of the IVIVC tobe used as a surrogate for bioequivalence.
`: Most important when using an IVIVC as a surrogate forbioequivalence is confidence that the IVIVC can predict in vivo performance ofsubsequent lots of the drug product. Therefore, it may be important to establishthe external predictability of the IVIVC. This involves using the IVIVC to predictthe in vivo performance for a formulation with known bioavailability that was notused in developing the IVIVC model.
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`Criteria
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`% PE of 10% or less for C and AUC establishes the externalmaxpredictability of an IVIVC.
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`% PE between 10 - 20% indicates inconclusive predictability and the needfor further study using additional data sets. Results of estimation of PEfrom all such data sets should be evaluated for consistency of predictability.
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`% PE greater than 20% generally indicates inadequate predictability, unlessotherwise justified.With the exception of narrow therapeutic index drugs, the externalpredictability step in the IVIVC evaluation process may be omitted if theevaluation of internal predictability indicates acceptable % PE. However,when the evaluation of internal predictability is inconclusive, evaluation ofexternal predictability is recommended.
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`VI.
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`DEVELOPMENT AND EVALUATION OF A LEVEL C IN VITRO/IN VIVO
`CORRELATION
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`A single point Level C correlation allows a dissolution specification to be set at the specified timepoint. While the information may be useful in formulation development, waiver of an in vivobioequivalence study (biowaiver) is generally not possible if only a single point correlation isavailable. A multiple point Level C correlation may be used to justify a biowaiver, provided thatthe correlation has been established over the entire dissolution profile with one or morepharmacokinetic parameters of interest. This could be achieved by correlating the amountdissolved at various time points with C, AUC, or any other suitable parameter. A relationshipmaxshould be demonstrated at each time point with the same parameter such that the effect on the invivo performance of any change in dissolution can be assessed. If such a multiple Level C
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`VII. APPLICATIONS OF AN IVIVC
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`In vitro dissolution testing is important for (1) providing process control and quality assurance;(2) determining stable release characteristics of the product over time; and (3) facilitating certainregulatory determinations (e.g., absence of effect of minor formulation changes or of change inmanufacturing site on performance). In certain cases, especially for ER formulations, thedissolution test can serve not only as a quality control for the manufacturing process but also asan indicator of how the formulation will perform in vivo. Thus, a main objective of developingand evaluating an IVIVC is to establish the dissolution test as a surrogate for humanbioequivalence studies, which may reduce the number of bioequivalence studies performed duringthe initial approval process as well as with certain scale-up and postapproval changes. However,for the applications outlined below, the adequacy of the in vitro dissolution method to act as asurrogate for in vivo testing should be shown through an IVIVC for which predictability has beenestablished.
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`11correlation is achievable, then the development of a Level A correlation is likely. A multiple LevelC correlation should be based on at least three dissolution time points covering the early, middle,and late stages of the dissolution profile. The recommendations for assessing the predictability ofLevel C correlations will depend on the type of application for which the correlation is to be used.These methods and criteria are the same as those for a Level A correlation (see Section V B2).
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`1.Category 1: Biowaivers Without an IVIVCFor formulations consisting of beads in capsules, with the only difference betweenstrengths being the number of beads, approval of lower strengths without anIVIVC is possible, provided bioavailability data are available for the higheststrength.Where the guidance for industry
` recommends a biostudy, biowaivers for the same changes made onlower strengths are possible without an IVIVC if (1) all strengths arecompositionally proportional or qualitatively the same, (2) in vitro dissolutionprofiles of all strengths are similar, (3) all strengths have the same releasemechanism, (4) bioequivalence has been demonstrated on the highest strength(comparing changed and unchanged drug product), and (5) dose proportionalityhas been demonstrated for this ER drug product. In the last circumstance (5),documentation of dose proportionality may not be necessary if bioequivalence hasbeen demonstrated on the highest and lowest strengths of the drug product,
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`A.
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`Biowaivers for Changes in the Manufacturing of a Drug Product
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`SUPAC-MR: Modified Release Solid Oral
`Dosage Forms; Scale-Up and Postapproval changes: Chemistry, Manufacturing,
`and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence
`Documentation
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`Comparison of dissolution profiles
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`12comparing changed and unchanged drug product for both strengths, asrecommended in SUPAC-MR. For the above situations, waivers can be granted without an IVIVC if dissolutiondata are submitted in the application/compendial medium and in three other media(e.g., water, 0.1N HCl, and USP buffer at pH 6.8, comparing the drug productafter the change to the drug product before the change).Biowaivers, as defined in SUPAC-MR, that do not necessitate eitherbioequivalence testing or an IVIVC will likely be granted in preapproval situationsfor both narrow and non-narrow therapeutic index ER drug products if dissolutiondata, as described in SUPAC-MR, are submitted.
`: Dissolution profiles can be compared usingmodel independent or model dependent methods. A model independent approachusing a similarity factor, and comparison criteria are described in SUPAC-MR. 2.Category 2: Biowaivers Using an IVIVC: Non-Narrow Therapeutic IndexDrugs a.Two Formulations/Release RatesA biowaiver will likely be granted for an ER drug product using an IVIVCdeveloped with two formulations/release rates for (1) Level 3manufacturing site changes as defined in SUPAC-MR; (2) Level 3nonrelease controlling excipient changes as defined in SUPAC-MR, withthe exception of complete removal or replacement of excipients (seebelow). b.Three Formulations/Release RatesA biowaiver will likely be granted for an ER drug product using an IVIVCdeveloped with three formulations/release rates (or developed with twoformulations/release rates with establishment of external predictability) for(1) Level 3 process changes as defined in SUPAC-MR; (2) completeremoval of or replacement of nonrelease controlling excipients as defined inSUPAC-MR; and (3) Level 3 changes in the release controlling excipientsas defined in SUPAC-MR.c.Biowaivers for Lower StrengthsIf an IVIVC is developed with the highest strength, waivers for changesmade on the highest strength and any lower strengths may be granted if
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`Bioequivalence has been established for all strengths of thereference listed product.
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`13these strengths are compositionally proportional or qualitatively the same,the in vitro dissolution profiles of all the strengths are similar, and allstrengths have the same release mechanism.d.Approval of New StrengthsThis biowaiver is applicable to strengths lower than the highest strength,within the dosing range that has been established to be safe and effective, ifthe new strengths are compositionally proportional or qualitatively thesame; have the same release mechanism; have similar in vitro dissolutionprofiles; and are manufactured using the same type of equipment and thesame process at