Pharmaceutical
`Dissolution Testing
`
`
`
`© 2005 by Taylor & Francis Group, LLC© 2005 by Taylor & Francis Group, LLC
`
`MYLAN EXHIBIT 1030
`
`

`

`Pharmaceutical
`Dissolution Testing
`
`Edited by
`
`Jennifer Dressman
`Johann Wolfang Goethe University
`Frankfurt, Germany
`
`Johannes Krämer
`Phast GmbH
`Homburg/Saar, Germany
`
`
`
`© 2005 by Taylor & Francis Group, LLC© 2005 by Taylor & Francis Group, LLC
`
`

`

`Published in 2005 by
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`

`4
`
`The Role of Dissolution Testing in
`the Regulation of Pharmaceuticals:
`The FDA Perspective
`
`VINOD P. SHAH
`
`Office of Pharmaceutical Science, Center for
`Drug Evaluation and Research, Food and Drug
`Administration, Rockville, Maryland, U.S.A.
`
`INTRODUCTION
`
`Over the last quarter century the dissolution test has
`emerged as a most powerful and valuable tool to guide formu-
`lation development, monitor the manufacturing process,
`assess product quality, and in some cases to predict in vivo
`performance of solid oral dosage forms. Under certain condi-
`tions, the dissolution test can be used as a surrogate measure
`for bioequivalence (BE) and to provide biowaivers, assuring
`BE of the product. Dissolution test has turned out to be a
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`critical test for measuring product performance. Generally,
`dissolution testing of solid oral dosage form is carried out by
`the basket (USP Apparatus 1) or paddle (USP Apparatus 2)
`method under mild agitation (100 rpm with the basket or
`50–75 rpm with the paddle), in an aqueous buffer in the pH
`range 1.2–6.8. Dissolution samples are analyzed at 15 min
`intervals for immediate-release (IR) products or at hourly
`intervals for extended-release products until at least 85%
`dissolution is achieved. For water-insoluble drug products,
`small amounts of surfactants are often employed to achieve
`sink conditions.
`Dissolution is also used to identify bioavailability (BA)
`problems and to assess the need for further BE studies relative
`to scale-up and post-approval Changes (SUPAC), where it func-
`tions as a signal of bioinequivalence. In vitro dissolution studies
`for all product formulations investigated (including prototype
`formulations) are encouraged, particularly if in vivo absorption
`characteristics can be defined for the different product formula-
`tions. With such efforts, it may be possible to achieve an in
`vitro/in vivo correlation. When an in vitro correlation or asso-
`ciation is available, the in vitro test can serve not only as a qual-
`ity control (QC) specification for the manufacturing process,
`but also as an indicator of in vivo product performance.
`Several in vitro tests are currently employed to assure
`drug product quality. These include purity, potency, assay,
`content uniformity, and dissolution specifications. For a phar-
`maceutical product to be consistently effective, it must meet
`all of its quality test criteria. When used as a QC test, the
`in vitro dissolution test provides information for marketing
`authorization. The dissolution test forms the basis for setting
`specifications (test, methodology, acceptance criteria) to allow
`batch release into the market place. Dissolution tests also
`provides a useful check on a number of physical characteris-
`tics, including particle size distribution, crystal form, etc.,
`which may be influenced by the manufacturing procedure.
`In vitro dissolution tests and QC specifications should be
`based on the in vitro performance of the test batches used
`in in vivo studies or on suitable compendial specifications.
`For conventional-release products, a single-point dissolution
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`© 2005 by Taylor & Francis Group, LLC
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`Dissolution Testing in Regulation of Pharmaceuticals
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`83
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`test is commonly used as a compendial specification. How-
`ever, a two-point test or a profile is suggested for characteriz-
`ing the dosage form. For extended-release products, a three to
`four-point dissolution test is recommended as a routine QC
`test. The dissolution test or the drug-release test is also
`employed for evaluating other non-oral (special) dosage forms
`such as topicals and transdermals, suppositories, implants,
`etc. It is anticipated that the drug-release test for these pro-
`ducts will also be of value in assuring drug product quality.
`For the test to be useful, the dissolution test should be
`simple, reliable and reproducible, and should be able to discri-
`minate between different degrees of in vivo product perfor-
`mance. The value of the test is significantly enhanced when
`product performance is evaluated as a function of time, i.e.,
`when the dissolution profile is determined rather than a
`single-point determination. Increasingly, dissolution profile
`comparison is used for assuring product sameness under
`SUPAC-related changes and for granting biowaivers. Thus,
`an increasing role of dissolution is seen in regulating the
`quality of pharmaceutical drug products.
`
`DISSOLUTION-RELATED FDA GUIDANCES
`
`Because of the importance of dissolution, FDA has developed
`dissolution-related guidances that provide information and
`recommendations on the development of dissolution test
`methodology, setting dissolution specifications, and the regu-
`latory applications of dissolution testing (1,2). In addition, it
`provides information with respect to when a single-point
`dissolution test is adequate as a QC test and when two points
`or a dissolution profile is needed to characterize the drug
`product. A procedure for establishing a predictive relation-
`ship between dissolution and in vivo performance and setting
`specifications for extended-release drug products is also
`discussed (2). A recent FDA guidance on biowaiver based on
`Biopharmaceutics Classification System (BCS) suggests that
`documentation of BE via dissolution studies is appropriate
`for orally administered IR drug products which are highly
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`Shah
`
`soluble, highly permeable, and rapidly dissolving (3). The
`FDA dissolution-related guidances are:
`
` Guidance
`Industry: Dissolution Testing of
`for
`Immediate Release Solid Oral Dosage Form, August
`1997.
` Guidance for Industry: Extended Release Solid Oral
`Dosage Forms: Development, Evaluation and Applica-
`tion of In Vitro/In Vivo Correlations, September 1997.
` Guidance for Industry: Waiver of In Vivo Bioavailabil-
`ity and Bioequivalence Studies for Immediate-Release
`Solid Oral Dosage Forms Based on a Biopharmaceutics
`Classification System, August 2000. (BCS Guidance).
`
`A recent FDA guidance on Bioavailability and Bioequiva-
`lence Studies for Orally Administered Drug Products—Gen-
`eral Considerations (4) provides ‘‘how to’’ information for
`conducting BA and BE studies, defines proportionally similar
`formulations, and provides provision for biowaivers for lower
`strength(s) of IR as well as modified-release (MR) drug pro-
`ducts. The guidance lowers regulatory burden without sacrifi-
`cing product quality. The general BA and BE guidance and
`BCS guidance clearly establish a trend whereby the dissolu-
`tion test has moved from traditional QC test to a surrogate
`in vitro BE test. Figure 1 for IR and Figure 2 for MR dosage
`forms summarize the BE and dissolution requirements as
`discussed in this guidance.
`A dissolution profile or at least a two-point determination
`should be used to characterize the in vitro performance of an
`IR drug product. Because a MR dosage form is a more com-
`plex formulation, three to four dissolution time points are
`needed to characterize the product. In addition, SUPAC gui-
`dances also rely on dissolution testing and profile comparison
`to assure product sameness between pre- and post-approval
`change for drug products. In order to avoid subjective evalua-
`tion of dissolution profile comparison, FDA has adopted a sim-
`ple method to compare dissolution profiles, termed the
`similarity factor, f2. The pharmaceutical industry has used
`this approach extensively to assure product sameness for
`changes in manufacturing site (SUPAC-related changes).
`
`© 2005 by Taylor & Francis Group, LLC
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`Dissolution Testing in Regulation of Pharmaceuticals
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`Figure 1 The IR dosage forms.
`
`Figure 2 The MR dosage forms.
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`Shah
`
`CHANGES IN DISSOLUTION
`SCIENCE PERSPECTIVES
`
`As more experience and knowledge is gained in understand-
`ing of the dissolution science and mechanism, the dissolution
`test has undergone a shift in its application and value. The
`current regulatory perspective on dissolution is depicted in
`Figure 3. In this new era of dissolution, dissolution tests
`can be used not only for QC but also as a surrogate marker
`for BE test, as outlined in a recent BCS guidance (3). The
`possibility of using dissolution testing as a tool for providing
`biowaivers has considerably enhanced the value of the test.
`The BCS guidance takes into account three major factors, dis-
`solution, solubility, and intestinal permeability, which govern
`the rate and extent of drug absorption from IR solid dosage
`forms. The BCS provides a scientific framework for classifying
`drug substances based on aqueous solubility and intestinal
`permeability, and in combination with dissolution data, pro-
`vides a rationale for biowaiver of IR drug products. In addi-
`tion,
`the General Bioavailability
`and Bioequivalence
`Guidance (4) allows biowaivers for lower strength(s) of IR as
`
`Figure 3 Current regulatory perspective on dissolution.
`
`© 2005 by Taylor & Francis Group, LLC
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`Dissolution Testing in Regulation of Pharmaceuticals
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`87
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`well as MR drug products based on formulation proportional-
`ity and dissolution profile comparison. These changes in BE
`requirements, moving away from in vivo study requirement
`in certain cases and relying more on dissolution test, clearly
`establish a change in dissolution testing applications. In all
`cases where the dissolution test is used as a BE test, an
`anchor with a bioavailable product is established or a rational
`for waiving in vivo studies is provided. Further, the reliance
`on dissolution testing can be extended to improve drug pro-
`duct quality in developing countries. In several instances, bio-
`waivers can be justified on the basis of a dissolution profile
`comparison with a reference product.
`
`DISSOLUTION-BASED BIOWAIVERS—
`DISSOLUTION AS A SURROGATE
`MARKER OF BE
`
`The BCS provides a new perspective to the dissolution testing
`(3,5). It provides scientific rationale to lower regulatory bur-
`den and justifies a biowaiver under certain circumstances.
`It is based on aqueous solubility and intestinal permeability
`of the drug substance and dissolution of the drug product.
`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 dosage
`forms namely dissolution, solubility, and intestinal perme-
`ability. It classifies the drug substance (and therefore the
`drug product) into four classes, class 1: high solubility/high
`permeability (HS/HP), class 2: low solubility/high permeabil-
`ity (LS/HP), class 3: high solubility/low permeability (HS/
`LP) and class 4:
`low solubility/low permeability (LS/LP).
`BCS takes into consideration GI physiological factors such
`as pH, gastric fluid volume, gastric emptying, intestinal tran-
`sit time, etc and permeability factors (5). According to the
`BCS guidance:
`
` the 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;
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` the drug substance is considered highly permeable
`when the extent of drug absorption in humans is
`determined to be 90% or more of an administered dose
`based on a mass balance determination or in compar-
`ison to an intravenous reference dose; and
` an IR drug product is considered rapidly dissolving
`when 85% or greater of the labeled amount of the
`drug substance dissolves within 30 min, using basket
`method (Apparatus I) at 100 rpm or paddle method
`(Apparatus II) at 50 rpm in a volume of 900 mL or less
`in each of the following media: (i) 0.1 N HCl or simu-
`lated gastric fluid USP without enzymes (ii) a pH
`4.5 buffer and (iii) a pH 6.8 buffer or simulated Intest-
`inal Fluid USP without enzymes.
`
`The BCS also predicts the possibility of obtaining an in
`vitro/in vivo correlation. Justification of a biowaiver is based
`on a combination of the BCS classification of the drug sub-
`stance and a drug product dissolution profile comparison. In
`all these instances, an anchor with a bioavailable product is
`established. Specifically, to obtain a biowaiver for an IR gen-
`eric product:
`
` the reference product should belong to Class 1, HS/
`HP;
` the test and reference drug products should dissolve
`rapidly (85% or greater in 30 min or less) under mild
`test conditions in pH 1.2, 4.5, and 6.8 and
` the test product and the reference product should
`meet the profile comparison criteria under all test
`conditions.
`
`Dissolution-based biowaivers for generic IR and MR drug
`products are discussed in the General BA and BE Guidance (4).
`For IR Products,
`
`1. A biowaiver is applicable for drug products meeting
`the BCS Class 1 criteria, HS/HP/RD (Rapid Dissolu-
`tion).
`2. A biowaiver is applicable for lower strength(s) when
`the highest strength is shown to be BE to the innova-
`
`© 2005 by Taylor & Francis Group, LLC
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`Dissolution Testing in Regulation of Pharmaceuticals
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`tor product and the formulation(s) of the generic pro-
`duct is (are) proportional to the highest strength and
`meets dissolution profile comparison criteria.
`
`For MR products,
`
`1. A biowaiver is applicable for beaded capsules when
`the lower strength differs only in number of beads
`of active drug and the dissolution profile is similar
`in the recommended dissolution test media and con-
`ditions.
`2. A biowaiver is applicable for extended-release tablet
`formulations, where the lower strength(s) are compo-
`sitionally similar to the highest strength and uses
`the same release mechanism and the dissolution pro-
`file is similar in pH 1.2, 4.5, and 6.8.
`
`The biowaiver criteria described in BCS guidance (3) are
`regarded as very conservative. Discussions are underway to
`consider relaxing some of the requirements for biowaiver of
`the drug product. These dissolution-based biowaivers exem-
`plify the role of dissolution in regulating pharmaceutical drug
`products.
`
`DISSOLUTION/IN VITRO RELEASE OF
`SPECIAL DOSAGE FORMS
`
`In the last decade, the application of dissolution testing has
`been extended to oral and non-oral ‘‘special’’ dosage forms,
`such as transdermal patches, semisolid preparations such as
`creams, ointments and gels, orally disintegrating dosage
`forms, suppositories,
`implants, microparticles,
`liposomes,
`etc. Can the principles and applications of dissolution/in vitro
`drug release be extended to these ‘‘special’’ dosage forms?
`Current scientific knowledge suggests that the drug release
`from the formulation is the crucial first step for the therapeu-
`tic activity of the drug product. Thus, the principles of dissolu-
`tion, i.e., in vitro drug release from the special dosage forms
`can at least be used as a QC tool to assure batch-to-batch
`reproducibility. The goal of these in vitro release tests is
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`
`analogous to that for solid oral dosage forms, i.e., to use
`the in vitro-release test as a regulatory tool to assure
`consistent product quality in the market place. A final report
`is out and would prefer to give the final reference report pub-
`lished by FIP Dissolution Working Group summarizes the
`current status of test procedures and developments in this
`area (6).
`The in vitro drug release from semisolid preparations,
`creams, ointments, and gels can be determined using vertical
`diffusion cell system and synthetic membrane. The method is
`simple, rugged, and easily reproducible. The method is applic-
`able to all creams, ointments, and gels (7). In vitro drug
`release from transdermal patches can be easily determined
`using simple modification of paddle method, paddle over disk
`method (8). This is also simple, rugged, reproducible, and
`applicable to all marketed transdermal patches. In several
`cases, modification of the paddle method is used for drug
`release of suppositories (6,9).
`Going beyond the application of the in vitro-release test
`as a QC tool for special dosage forms to biowaivers and in
`vitro–in vivo correlations will require more research.
`
`DISSOLUTION PROFILE COMPARISON
`
`In recent years, FDA has placed more emphasis on dissolution
`profile comparison in the area of post-approval changes and
`biowaivers. Under appropriate test conditions, a dissolution
`profile can characterize the product more precisely than a
`single-point dissolution test. A dissolution profile comparison
`between (i) pre-change (reference) and post-change (test)
`products for SUPAC-related changes, or (ii) with different
`strengths of a given manufacturer, or (iii) comparison
`between manufacturers for BCS class 1 (HS/HP/RD) drug
`products, evaluates similarity in product performance, with
`poor results signaling bioinequivalence.
`Among several methods investigated for dissolution
`profile comparison, the f2 factor is the simplest and widely
`applicable (1). Moore and Flanner (10) proposed a model inde-
`
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`Dissolution Testing in Regulation of Pharmaceuticals
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`
`pendent mathematical approach to compare the dissolution
`profile using two factors, f1 and f2.
`
`f1 ¼ f½t¼1njRt TtjŠ=½t¼1nRtŠg 100
`t¼1ðRt TtÞ2Š0:5 100g
`f2 ¼ 50 logf½1 þ ð1=nÞn
`where Rt and Tt are the cumulative percentage dissolved
`at each of the selected n time points of the reference and test
`product, respectively. The factor f1 is proportional to the aver-
`age difference between the two profiles, where as factor f2 is
`inversely proportional to the average squared difference
`between the two profiles, with emphasis on the larger differ-
`ence among all the time points. The factor f2 measures the
`closeness between the two profiles. Because of the nature of
`measurement, f1 was described as a difference factor, and f2
`as a similarity factor (11). The similarity factor, f2 (10–12),
`has been adopted by the FDA in its Guidances, since the
`regulatory interest is to know whether the dissolution profiles
`of the test and reference products are similar. When the two
`profiles are identical, f2 ¼ 100. A plot of f2 values determined
`using computer-simulated average differences between the
`reference and test dissolution profiles indicated that an aver-
`age difference of 10% at all measured time points between the
`value of 50 (Fig. 4). FDA has set a
`two profiles results in a f2
`public standard of f2 value between 50 and 100 to indicate
`similarity between two dissolution profiles. (Further discus-
`sion of the advantages and limitations of the f2 factor and other
`measures of profile similarity can be found in Chapter 13.)
`For a dissolution profile comparison:
`
` At least 12 units should be used for each profile deter-
`mination. Mean dissolution values can be used to esti-
`mate the similarity factor, f2. To use mean data, the
`percentage coefficient of variation at the earlier point
`should not be more than 20% and at other time points
`should not be more than 10%.
` For circumstances where wide variability is observed,
`or a statistical evaluation of f2 metric is desired, a
`bootstrap approach to calculate a confidence interval
`can be performed (8).
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`
`Figure 4 Dissolution profile comparison model
`analysis.
`
`independent
`
` The dissolution measurements of the two products
`(test and reference, pre- and post-change,
`two
`strengths) should be made under the same test condi-
`tions. The dissolution time points for both the profiles
`should be the same, e.g., for IR products 15, 30, 45,
`and 60 min, for extended-release products 1, 2, 3, 5,
`and 8 hr.
` Because f2 values are sensitive to the number of disso-
`lution time points, only one measurement should be
`considered after 85% dissolution of the product.
` For drug products dissolving 85% or greater in 15 min
`or less, a profile comparison is not necessary.
`
`A f2 value of 50 or greater (50–100) ensures sameness or
`equivalence of the two curves and, thus, the performance of
`
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`Dissolution Testing in Regulation of Pharmaceuticals
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`
`the two products. From a public health point of view, and as a
`regulatory consideration, a conservative approach of f2  50 is
`appropriate. The f2 comparison metric with a value of 50 or
`greater is a conservative, but reliable basis for granting a bio-
`waiver, and for assuring product and product performance
`sameness. A value below 50 may be acceptable based on addi-
`tional information available about the drug substance and
`drug product. Additional research and data mining are
`needed to address the general question of what can be done
`if the f2 value is <50.
`
`FUTURE DIRECTIONS
`
`One of the major efforts of the FDA is to reduce regulatory
`requirements and unnecessary in vivo testing, without sacri-
`ficing the quality of the product. The BCS guidance is a step
`in the right direction, but future extensions of the BCS
`remain a major challenge. Appropriate data need to be col-
`lected and evaluated before biowaiver extensions in other
`classes can be considered. Principles of BCS, especially solubi-
`lity information, can be utilized in the selection of an appro-
`priate dissolution medium. In addition, based on the BCS,
`the dissolution specification for class 1 drug products (HS/
`HP) can be set at 85% dissolution in 30 min to improve the
`quality of pharmaceutical products in the market place. A
`good knowledge and understanding of GI physiology, excipi-
`ent effects on drug absorption and GI motility, and the use
`of biorelevant dissolution media may be useful in this evalua-
`tion. The dissolution test using a biorelevant dissolution
`medium may be especially helpful in product development,
`establishing in vitro–in vivo correlation, determining appro-
`priate dissolution test media (particularly for drugs belonging
`to BCS class 2 and 4), and also in predicting food effects
`(13–15). The use of biorelevant dissolution media can serve
`as an excellent prognostic tool in these areas.
`Further, there is an increased reliance on use of in vitro
`dissolution as a surrogate marker for in vivo blood level data.
`When dissolution is used as a QC test for IR products, it is
`generally a single-point dissolution test and is represented
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`
`as X % dissolved in Y minutes. But when the dissolution test
`is used as a BE test, it is different: comparison of the dissolu-
`tion profile with a bioavailable product is crucial.
`The value of dissolution test can be further appropri-
`ately utilized in developing countries where it can be used
`as a ‘‘BE test.’’ The question is raised: ‘‘Can dissolution test
`alone be used as a BE test for approval of IR products in
`developing countries’’? Generally in developing countries,
`the technology and other resources are very limited to con-
`duct an appropriate in vivo BE studies. Under these circum-
`stances, appropriate dissolution studies,
`for e.g., profile
`comparison between the local generic product and the refer-
`ence product in pH 1.2, 4.5, and 6.8 media under mild test
`conditions, e.g., basket method at 100 rpm or paddle method
`at 50 rpm, may be used to assure product quality. This
`appears to be a practical approach that can be easily consid-
`ered and adopted for BE test in developing countries (16).
`The research in the area of dissolution/in vitro release test
`for non-oral (special) dosage forms will lead to its application
`as a QC test for batch-to-batch uniformity as well as other
`regulatory applications.
`
`IMPACT OF DISSOLUTION TESTING
`
`The art and science of dissolution testing have come a long
`way since its inception about 30 years ago. The procedure is
`well established, reliable, and reproducible. Application of
`dissolution testing as a QC test, to guide formulation develop-
`ment, to use as a manufacturing/process control tool and as a
`test for product sameness under SUPAC-related changes is
`well established. Increasingly, in vitro dissolution testing
`and profile comparison are relied on to assure product quality
`and performance and to provide a biowaiver. An appropriate
`dissolution test procedure is identified as a simple and eco-
`nomical method that can be utilized effectively in developing
`countries to assure acceptable drug product quality. An increas-
`ing role of dissolution in regulating pharmaceutical drug
`product quality is becoming clearly evident. The dissolution test
`
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`Dissolution Testing in Regulation of Pharmaceuticals
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`is currently being used as a both QC test (generally single point
`for IR products and 3-to-4 points for extended-release pro-
`ducts), as well as an in vitro BE test (generally dissolution pro-
`file and profile comparison). Since dissolution testing plays a
`different role when it is used as a QC test than when it is used
`as a surrogate for BE, the discussion and assessment of dissolu-
`tion in these roles should be carefully separated.
`
`REFERENCES
`
`1. Guidance for Industry: Dissolution Testing of Immediate
`Release Solid Oral Dosage Form. Aug. 1997.
`
`2. Guidance for Industry: Extended Release Solid Oral Dosage
`Forms: Development, Evaluation and Application of In Vitro/
`In Vivo Correlations. Sep. 1997.
`
`3. Guidance for Industry: Waiver of In Vivo Bioavailability and
`Bioequivalence Studies for Immediate-Release Solid Oral
`Dosage Forms Based on a Biopharmaceutics Classification
`System. Aug. 2000.
`
`4. Guidance for Industry: Bioavailability and Bioequivalence
`Studies for Orally Administered Drug Products—General Con-
`siderations. Oct. 2000.
`
`5. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical
`basis for a biopharmaceutics drug classification: the correlation
`of in vitro drug product dissolution and in vivo bioavailability.
`Pharm Res 1995; 12:413–420.
`
`6. Siewert M, Dressman J, Brown CK, Shah VP. FIP/AAPS
`Guidelines for dissolution in vitro release testing of novel/spe-
`cial dosage forms. AAPS Pharm Sci Tech 2003; 4(1):43–52;
`Pharm Ind 2003; 65:129–134; Dissolut Technol 2003; 10(1):6–15.
`
`7. Shah VP, Elkins JS, Williams RL. Evaluation of the test
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