Guidance for Industry
`
`Dissolution Testing of Immediate
`Release Solid Oral Dosage Forms
`
`U.S. Department of Health and Human Services
`Food aud Drug Administration
`Center for Drng Evaluation and Research (CDER)
`August 1997
`
`BPl
`
`MYLAN EXHIBIT 1015
`
`

`

`Guidance for Industry
`Dissolution Testing of Immediate
`Release Solid Oral Dosage Forms
`
`Additional copies are available from:
`
`Office of Training and Communications
`Division of Communications Management
`The Drug Information Branch, HFD-210
`5600 Fishers Lane
`Rockville, MD 20857
`
`(Tel) 301-827-4573
`(lnterne t) http://wwwjda.gov/cder!guidance. htm
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`August 1997
`
`BPl
`
`

`

`Table of Contents
`
`I.
`
`II.
`
`INTRODUCTION , ........................... , .. , ..................... 1
`
`BACKGROUND ............................... , ................... , .. 1
`
`III.
`
`BIOPHARMACEUTICS CLASSIFICATION SYSTEM .... , .................. 2
`
`IV.
`
`V.
`
`SETTING DISSOLUTION SPECIFICATIONS .............................. 3
`A.
`Approaches for Setting Dissolution Specifications for a New Chemical Entity .. , 4
`B.
`Approaches for Setting Dissolution Specifications for Generic Products ....... 5
`C.
`Special Cases .......... , ................................. , ...... 6
`D.
`Mapping or Response Surface Methodology ......... , ......... , ...... , . 7
`E.
`In Vivo-In Vitro Correlations ........................... , ........... 7
`F.
`Validation and Verification of Specifications ................... , , ....... 8
`
`DISSOLUTION PROFILE COMPARISONS ................................ 8
`A.
`Model Independent Approach Using a Similarity Factor ....... , ........... 8
`B.
`Model Independent Multivariate Confidence Region Procedure .. , ..... , .. , 10
`C.
`Model Dependent Approaches ..... , ..... , , ........................ 10
`
`VI.
`
`DISSOLUTION AND SUPAC-IR ... , , ............. , , ............. , ..... 11
`
`VII. BIOW AIVERS .. , ................................................... 11
`
`Appendix A ................... , ..................... , .................... A-1
`
`REFERENCES
`
`

`

`GUIDANCE FOR INDUSTRY1
`
`Dissolution Testing of Immediate Release
`Solid Oral Dosage Forms
`
`I.
`
`INTRODUCTION
`
`This guidance is developed for immediate release (IR) dosage forms and is intended to provide
`(I) general recommendations for dissolution testing; (2) approaches for setting dissolution
`specifications related to the biophannaceutic characteristics of the drug substance; (3) statistical
`methods for comparing dissolution profiles; and (4) a process to help determine when dissolution
`testing is sufficient to grant a waiver for an in vivo bioequivalence study. This document also
`provides recommendations for dissolution tests to help ensure continuous drug product quality
`and performance after certain postapproval manufacturing changes. Summary information on
`dissolution methodology, apparatus, and operating conditions for dissolution testing ofJR
`products is provided in summary form in Appendix A. This guidance is intended to complement
`the SUP AC - IR guidance for industry: Immediate Release Solid Oral Dosage Forms: Scale-up
`and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution
`Testing, and In Vivo Bioequivalence Documentation, with specific reference to the generation of
`dissolution profiles for comparative purposes.
`
`II.
`
`BACKGROUND
`
`Drug absorption from a solid dosage form after oral administration depends on the release of the
`drug substance from the drug product, the dissolution or solubilization of the drug under
`physiological conditions, and the permeability across the gastrointestinal tract. Because of the
`critical nature of the first two of these steps, in vitro dissolution may be relevant to the prediction
`of in vivo performance. Based on this general consideration, in vitro dissolution tests for
`immediate release solid oral dosage forms, such as tablets and capsules, are used to (1) assess the
`lot-to-lot quality of a drug product; (2) guide development of new formulations;
`
`1This guidance has been prepared by the Immediate Release Expert Working Group of the Biopharmaceutics
`Coordinating Committee in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.
`This guidance document represents the Agency's current thinking on the dissolution testing of immediate release solid
`oral dosage forms. It does not create or confer any rights for or on any person and does not operate to bind FDA or the
`public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute,
`regulations, or both.
`
`

`

`and (3) ensure continuing product quality and performance after cetiain changes, such as changes
`in the formulation, the manufacturing process, the site of manufacture, and the scale-up of the
`manufacturing process.
`
`Current knowledge about the solubility, permeability, dissolution, and pharmacokinetics of a drug
`product should be considered in defining dissolution test specifications for the drug approval
`process. This knowledge should also be used to ensure continued equivalence of the product, as
`well as to ensure the product's sameness under certain scale-up and postapproval changes.
`
`New drug applications (NDAs) submitted to the Food and Drug Administration (FDA) contain
`bioavailability data and in vitro dissolution data, that, together with chemistry, manufacturing, and
`controls (CMC) data, characterize the quality and performance of the drug product. In vitro
`dissolution data are generally obtained from batches that have been used in pivotal clinical and/or
`bioavailability studies and from other human studies conducted during product development.
`Acceptable bioequivalence data and comparable in vitro dissolution and CMC data are required
`for approval of abbreviated new drug applications (AND As) (21 CPR 314.94). The in vitro
`specifications for generic products should be established based on a dissolution profile. For new
`drug applications, as well as generic drug applications, the dissolution specifications should be
`based on acceptable clinical, bioavailability, and/or bioequivalence batches.
`
`Once the specifications are established in an NDA, the dissolution specifications for batch-to(cid:173)
`batch quality assurance are published in the United States Pharmacopeia (USP) as compendia!
`standards, which become the official specifications for all subsequent IR products with the same
`active ingredients. In general, these compendia! dissolution standards are single-point dissolution
`tests, not profiles.
`
`III.
`
`BIOPHARMACEUTICS CLASSIFICATION SYSTEM
`
`Based on drug solubility and permeability, the following Biopharmaceutics Classification System
`(BCS) is recommended in the literature (Amidon 1995):
`
`Case 1:
`Case 2:
`Case 3:
`Case 4:
`
`High Solubility - High Permeability Drugs
`Low Solubility - High Permeability Drugs
`High Solubility - Low Permeability Drugs
`Low Solubility - Low Permeability Drugs
`
`This classification can be used as a basis for setting in vitro dissolution specifications and can also
`provide a basis for predicting the likelihood of achieving a successful in vivo-in vitro correlation
`(IVIVC). The solubility of a drug is determined by dissolving the highest unit dose of the drug in
`250 mL of buffer adjusted between pH 1.0 and 8.0. A drug substance is considered highly soluble
`when the dose/solubility volume of solution are less than or equal to 250 mL. High-permeability
`drugs are generally those with an extent of absorption that is greater than 90% in the absence of
`
`2
`
`

`

`documented instability in the gastrointestinal tract or those whose permeability has been
`determined experimentally. The BCS suggests that for high solubility, high permeability (case 1)
`drugs and in some instances for high solubility, low permeability (case 3) drugs, 85% dissolution
`in O.lN HCl in 15 minutes can ensure that the bioavailability of the drug is not limited by
`dissolution. In these cases, the rate limiting step for drug absorption is gastric emptying.
`
`The mean TSO% gastric residence (emptying) time is 15-20 minutes under fasting conditions.
`Based on this information, a conservative conclusion is that a drug product undergoing 85%
`dissolution in 15 minutes under mild dissolution test conditions in O.IN HCl behaves like a
`solution and generally should not have any bioavailability problems. If the dissolution is slower
`than gastric emptying, a dissolution profile with multiple time points in multimedia is
`recommended.
`
`In the case oflow solubility/high permeability drugs (case 2), drug dissolution may be the rate
`limiting step for drug absorption and an IVIVC may be expected. A dissolution profile in multiple
`media is recommended for drug products in this category. In the case of high solubility/low
`permeability drugs (case 3), permeability is the rate controlling step and a limited IVIVC may be
`possible, depending on the relative rates of dissolution and intestinal transit. Drugs in case 4 (i.e.,
`low solubility/low permeability drugs) present significant problems for oral drug delivery.
`
`IV.
`
`SETTING DISSOLUTION SPECIFICATIONS
`
`In vitro dissolution specifications are established to ensure batch-to-batch consistency and to
`signal potential problems with in vivo bioavailability. For ND As, the dissolution specifications
`should be based on acceptable clinical, pivotal bioavailability, and/or bioequivalence batches. For
`ANDAs/AADAs, the dissolution specifications should be based on the performance of acceptable
`bioequivalence batches of the drug product. The NDA dissolution specifications should be based
`on experience gained during the drug development process and the in vitro performance of
`appropriate test batches. In the case of a generic drug product, the dissolution specifications are
`generally the same as the reference listed drug (RLD). The specifications are confirmed by testing
`the dissolution performance of the generic drug product from an acceptable bioequivalence study.
`If the dissolution of the generic product is substantially different compared to that of the reference
`listed drug and the in vivo data remain acceptable, a different dissolution specification for the
`generic product may be set. Once a dissolution specification is set, the drug product should
`comply with that specification throughout its shelf life.
`
`The International Conference on Harmonisation (ICH) QlA guideline (Stability Testing of New
`Drug Substances and Drug Products) has recommended that for an NDA, three batches (two
`pilot and one smaller scale) be placed into stability testing. These batches also may be used to set
`dissolution specifications when a suitable bioequivalence relationship exists between these batches
`and both the pivotal clinical trial batch and the drug product intended for the market.
`
`3
`
`

`

`Three catagories of dissolution test specifications for immediate release drug products are
`described in the guidance.
`
`•
`
`Single-point specifications
`
`As a routine quality control test. (For highly soluble and rapidly dissolving drug
`products.)
`
`•
`
`Two-point specifications
`
`I.
`
`For characterizing the quality of the drug product.
`
`As a routine quality control test for certain types of drug products ( e.g., slow
`2.
`dissolving or poorly water soluble drug product like carbamazepine).
`
`•
`
`Dissolution profile comparison
`
`I.
`
`2.
`
`3.
`
`For accepting product sameness under SUP AC-related changes.
`
`To waive bioequivalence requirements for lower strengths of a dosage form.
`
`To support waivers for other bioequivalence requirements.
`
`In the future, a two-time point approach may be useful, both to characterize a drug product and
`to serve as quality control specification.
`
`A.
`
`Approaches for Setting Dissolution Specifications for a New Chemical Entity
`
`Dissolution methodology and specifications developed by a sponsor are presented in the
`biopharmaceutics section (21 CFR 320.24(b)(5)), and the chemistry, manufacturing, and
`controls section (21 CFR 314.SO(d)(l )(ii)(a)) of an NDA. The dissolution characteristics
`of the drug product should be developed based on consideration of the pH solubility
`profile and pKa of the drug substance. The drug permeability or octanol/water pattition
`coefficient measurement may be useful in selecting the dissolution methodology and
`specifications. The dissolution specifications are established in consultation with
`biopharmaceutics and CMC review staff in the Office of Pharmaceutical Science (OPS).
`For ND As, the specifications should be based on the dissolution characteristics of batches
`used in pivotal clinical trials and/or in confirmatory bioavailability studies. If the
`formulation intended for marketing differs significantly from the drug product used in
`pivotal clinical trials, dissolution and bioequivalence testing between the two formulations
`are recommended.
`
`4
`
`

`

`Dissolution testing should be carried out under mild test conditions, basket method at
`50/100 rpm or paddle method at 50/75 rpm, at 15-minute intervals, to generate a
`dissolution profile. For rapidly dissolving products, generation of an adequate profile
`sampling at 5- or I 0-minute intervals may be necessary. For highly soluble and rapidly
`dissolving drug products (BCS classes I and 3), a single-point dissolution test
`specification ofNLT 85% (Q=80%) in 60 minutes or less is sufficient as a routine quality
`control test for batch-to-batch uniformity. For slowly dissolving or poorly water soluble
`drugs (BCS class 2), a two-point dissolution specification, one at 15 minutes to include a
`dissolution range (a dissolution window) and the other at a later point (30, 45, or 60
`minutes) to ensure 85% dissolution, is recommended to characterize the quality of the
`product. The product is expected to comply with dissolution specifications throughout its
`shelf life. If the dissolution characteristics of the drug product change with time, whether
`or not the specifications should be altered will depend on demonstrating bioequivalence of
`the changed product to the original biobatch or pivotal batch. To ensure continuous
`batch-to-batch equivalence of the product after scale-up and postapproval changes in the
`marketplace, dissolution profiles should remain comparable to those of the approved
`biobatch or pivotal clinical trial batch(es).
`
`B.
`
`Approaches for Setting Dissolution Specifications for Generic Products
`
`The approaches for setting dissolution specifications for generic products fall into three
`categories, depending on whether an official compendia! test for the drug product exists
`and on the nature of the dissolution test employed for the reference listed drug. All
`approved new drug products should meet current USP dissolution test requirements, if
`they exist. The three categories are:
`
`I.
`
`USP Drug Product Dissolution Test Available
`
`In this instance, the quality control dissolution test is the test described in the USP.
`The Division of Bioequivalence, Office of Generic Drugs, also recommends taking
`a dissolution profile at 15-minute intervals or less using the USP method for test
`and reference products (12 units each). The Division ofBioequivalence may also
`recommend submitting additional dissolution data when scientifically justified.
`Examples of this include (I) cases in which USP does not specify a dissolution test
`for all active drug substances of a combination product and (2) cases in which USP
`specifies use of disintegration apparatus.
`
`USP Drug Product Dissolution Test Not Available; Dissolution Test for
`2.
`Reference Listed NDA Drug Product Publicly Available
`
`In this instance, a dissolution profile at 15-minute intervals of test and reference
`products (12 units each) using the method approved for the reference listed
`product is recommended. The Division ofBioequivalence may also request
`
`5
`
`

`

`submission of additional dissolution testing data as a condition of approval, when
`scientifically justified.
`
`USP Drug Product Dissolution Test Not Available; Dissolution Test for
`3.
`Reference Listed NDA Drug Product Not Publicly Available
`
`In this instance, comparative dissolution testing using test and reference products
`under a variety of test conditions is recommended. The test conditions may
`include different dissolution media (pH I to 6.8), addition of surfactant, and use of
`apparatus I and 2 with varying agitation. In all cases, profiles should be generated
`as previously recommended. The dissolution specifications are set based on the
`available bioequivalence and other data.
`
`C.
`
`Special Cases
`
`I.
`
`Two-Point Dissolution Test
`
`For poorly water soluble drug products ( e.g., carbamazapine ), dissolution testing
`at more than one time point for routine quality control is recommended to ensure
`in vivo product performance. Alternatively, a dissolution profile may be used for
`purposes of quality control.
`
`2.
`
`Two-Tiered Dissolution Test
`
`To more accurately reflect the physiologic conditions of the gastrointestinal tract,
`two-tiered dissolution testing in simulated gastric fluid (SGF) with and without
`pepsin or simulated intestinal fluid (SIF) with and without pancreatin may be
`employed to assess batch-to-batch product quality provided the bioequivalence is
`maintained.
`
`Recent examples involving soft and hard gelatin capsules show a decrease in the
`dissolution profile over time either in SGF or in SIF without enzymes. This has
`been attributed to pellicle formation. When the dissolution of aged or slower
`releasing capsules was carried out in the presence of an enzyme (pepsin in SGF or
`pancreatin in SIF), a significant increase in the dissolution was observed. In this
`setting, multiple dissolution media may be necessary to adequately assess product
`quality.
`
`D.
`
`Mapping or Response Surface Methodology
`
`Mapping is defined as a process for determining the relationship between critical
`manufacturing variables (CMV) and a response surface derived from an in vitro
`dissolution profile and an in vivo bioavailability data set. The CMV include changes in the
`
`6
`
`

`

`formulation, process, equipment, materials, and methods for the drug product that can
`significantly affect in vitro dissolution (Skelly 1990, Shah 1992). The goal is to develop
`product specifications that will ensure bioequivalence of future batches prepared within
`the limits of acceptable dissolution specifications. Several experimental designs are
`available to study the influence of CMV on product performance. One approach to study
`and evaluate the mapping process includes(!) prepare two or more dosage formulations
`using CMV to study their in vitro dissolution characteristics; (2) test the products with
`fastest and slowest dissolution characteristics along with the standard or the to be
`marketed dosage form in small groups (e.g., n2: 12) of human subjects; and (3) determine
`the bioavailability of the products and in vitro-in vivo relationship. The products with
`extreme dissolution characteristics are also referred to as side batches (Siewett 1995). If
`the products with the extreme range of dissolution characteristics are found to be
`bioequivalent to the standard or the to be marketed dosage form, future batches with
`dissolution characteristics between these ranges should be equivalent to one another. This
`approach can be viewed as verifying the limits of the dissolution specifications. Product
`dissolution specifications established using a mapping approach will provide maximum
`likelihood of ensuring stable quality and product performance. Depending on the number
`of products evaluated, the mapping study can provide information on in vitro-in vivo
`correlations and/or a rank order relationship between in vivo and in vitro data.
`
`E.
`
`In Vivo-In Vitro Correlations
`
`For highly water soluble (BCS classes 1 and 3) immediate release products using currently
`available excipients and manufacturing technology, an IVIVC may not be possible. For
`poorly water soluble products, BCS class 2, an IVIVC may be possible.
`
`The value of dissolution as a quality control tool for predicting in vivo performance of a
`drug product is significantly enhanced if an in vitro-in vivo relationship (correlation or
`association) is established. The in vitro test serves as a tool to distinguish between
`acceptable and unacceptable drug products. Acceptable products are bioequivalent, in
`terms of in vivo performance, whereas unacceptable products are not. To achieve an in
`vitro-in vivo correlation, at least three batches that differ in the in vivo as well as the in
`vitro performance should be available. If the batches show differences in in vivo
`performance, then in vitro test conditions can be modified to correspond with the in vivo
`data to achieve an in vitro-in vivo correlation. If no difference is found in the in vivo
`performance of the batches and if the in vitro performance is different, it may be possible
`to modify test conditions to achieve the same dissolution performance of the batches
`studied in vivo. Very often, the in vitro dissolution test is found to be more sensitive and
`discriminating than the in vivo test. From a quality assurance point of view, a more
`discriminative dissolution method is preferred, because the test will indicate possible
`changes in the quality of the product before in vivo performance is affected.
`
`7
`
`

`

`F.
`
`Validation and Verification of Specifications
`
`Confirmation by in vivo studies may be needed for validation of an in vitro system. In this
`situation, the same formulation should be used but nonformulation CMV should be varied.
`Two batches with different in vitro profiles should be prepared (mapping approach).
`These products should then be tested in vivo. If the two products show different in vivo
`characteristics, then the system is validated. In contrast, if there is no difference in the in
`vivo performance, the results can be interpreted as verifying the dissolution specification
`limits as discussed under mapping. Thus, either validation or verification of dissolution
`specifications should be confirmed.
`
`V.
`
`DISSOLUTION PROFILE COMPARISONS
`
`Until recently, single-point dissolution tests and specifications have been employed in evaluating
`scale-up and postapproval changes, such as (l) scale-up, (2) manufacturing site changes, (3)
`component and composition changes, and ( 4) equipment and process changes. A changed
`product may also be a lower strength of a previously approved drug product. In the presence of
`certain minor changes, the single-point dissolution test may be adequate to ensure unchanged
`product quality and performance. For more major changes, a dissolution profile comparison
`performed under identical conditions for the product before and after the change(s) is
`recommended (see SUP AC-IR). Dissolution profiles may be considered similar by vittue of (1)
`overall profile similarity and (2) similarity at every dissolution sample time point. The dissolution
`profile comparison may be carried out using model independent or model dependent methods.
`
`A.
`
`Model Independent Approach Using a Similarity Factor
`
`A simple model independent approach uses a difference factor (f1) and a similarity factor
`(f2) to compare dissolution profiles (Moore 1996). The difference factor (f1) calculates the
`percent(%) difference between the two curves at each time point and is a measurement of
`the relative error between the two curves:
`
`where n is the number of time points, R. is the dissolution value of the reference
`(prechange) batch at time t, and T, is the dissolution value of the test (postchange) batch
`at time t.
`
`The similarity factor (f2) is a logarithmic reciprocal square root transformation of the sum
`of squared error and is a measurement of the similarity in the percent(%) dissolution
`between the two curves.
`
`J; = 50 • log {[1+(1/n)L~t" ( R. · T, )2 l 0
`
`' • 100}
`
`8
`
`

`

`A specific procedure to determine difference and similarity factors is as follows:
`
`1.
`Determine the dissolution profile of two products (12 units each) of the
`test (postchange) and reference (prechange) products.
`
`Using the mean dissolution values from both curves at each time interval,
`2.
`calculate the difference factor (f1) and similarity factor (f2) using the above
`equations.
`
`For curves to be considered similar, f1 values should be close to 0, and f2
`3.
`values should be close to I 00, Generally, f1 values up to 15 (0-15) and f2 values
`greater than 50 (50-100) ensure sameness or equivalence of the two curves and,
`thus, of the performance of the test (postchange) and reference (prechange)
`products.
`
`This model independent method is most suitable for dissolution profile comparison
`when three to four or more dissolution time points are available. As further
`suggestions for the general approach, the following recommendations should also
`be considered:
`
`•
`
`•
`
`•
`
`•
`
`The dissolution measurements of the test and reference batches should be
`made under exactly the same conditions. The dissolution time points for
`both the profiles should be the same (e.g., 15, 30, 45, 60 minutes). The
`reference batch used should be the most recently manufactured prechange
`product.
`
`Only one measurement should be considered after 85% dissolution of both
`the products.
`
`To allow use of mean data, the percent coefficient of variation at the earlier
`time points (e.g., 15 minutes) should not be more than 20%, and at other
`time points should not be more than 10%.
`
`The mean dissolution values for R, can be derived either from (1) last
`prechange (reference) batch or (2) last two or more consecutively
`manufactured prechange batches.
`
`B.
`
`Model Independent Multivariate Confidence Region Procedure
`
`In instances where within batch variation is more than 15% CV, a multivariate model
`independent procedure is more suitable for dissolution profile comparison. The following
`steps are suggested:
`
`9
`
`

`

`Determine the similarity limits in terms of multivariate statistical distance
`I.
`(MSD) based on interbatch differences in dissolution from reference
`(standard approved) batches.
`
`2.
`
`Estimate the MSD between the test and reference mean dissolutions.
`
`Estimate 90% confidence interval of true MSD between test and reference
`3.
`batches.
`
`Compare the upper limit of the confidence interval with the similarity limit.
`4.
`The test batch is considered similar to the reference batch if the upper limit of the
`confidence interval is less than or equal to the similarity limit.
`
`C. Model Dependent Approaches
`
`Several mathematical models have been described in the literature to fit dissolution
`profiles. To allow application of these models to comparison of dissolution profiles, the
`following procedures are suggested:
`
`Select the most appropriate model for the dissolution profiles from the
`I .
`standard, prechange, approved batches. A model with no more than three
`parameters (such as linear, quadratic, logistic, probit, and Weibull models) is
`recommended.
`
`Using data for the profile generated for each unit, fit the data to the most
`2.
`appropriate model.
`
`A similarity region is set based on variation of parameters of the fitted
`3.
`model for test units (e.g., capsules or tablets) from the standard approved batches.
`
`Calculate the MSD in model parameters between test and reference
`4.
`batches.
`
`Estimate the 90% confidence region of the true difference between the two
`5.
`batches.
`
`Compare the limits of the confidence region with the similarity region. If
`6.
`the confidence region is within the limits of the similarity region, the test batch is
`considered to have a similar dissolution profile to the reference batch.
`
`10
`
`

`

`VI.
`
`DISSOLUTION AND SUPAC-IR
`
`The SUP AC-IR guidance defines the levels of changes, recommended tests, and filing
`documentation to ensure product quality and performance of reference (prechange product) with
`postapproval changes in (I) components and composition, (2) site of manufacturing, (3) the scale
`of manufacturing, and ( 4) process and equipment changes in the manufacturing of immediate
`release products (FDA 1995). Depending on the level of change and the biopharmaceutics
`classification system of the active drug substance, the SUPAC-IR guidance recommends different
`levels of in vitro dissolution test and/or in vivo bioequivalence studies. Tests vary depending on
`therapeutic range and solubility and permeability factors of the drug substance. For formulation
`changes beyond those listed in the guidance, additional dissolution profile determinations in
`several media are recommended. For manufacturing site changes, scale-up equipment changes,
`and minor process changes, only dissolution testing should be sufficient to ensure unchanged
`product quality and performance. The SUP AC-IR guidance recommends dissolution profile
`comparisons for approving different levels of changes and documenting product sameness
`between the test (postchange) and reference (prechange) product. It recommends dissolution
`profile comparisons using a model independent approach and the similarity factor (f2).
`
`VII. BIOW AIVERS
`
`In addition to routine quality control tests, comparative dissolution tests have been used to waive
`bioequivalence requirements (biowaivers) for lower strengths of a dosage form. For biowaivers, a
`dissolution profile should be generated and evaluated using one of the methods described under
`Section Vin this guidance, "Dissolution Profile Comparisons." Biowaivers are generally provided
`for multiple strengths after approval of a bioequivalence study performed on one strength, using
`the following criteria:
`
`For multiple strengths of!R products with linear kinetics, the bioequivalence study may be
`performed at the highest strength and waivers of in vivo studies may be granted on lower
`strengths, based on an adequate dissolution test, provided the lower strengths are proportionately
`similar in composition (21 CFR 320.22(d)(2)). Similar may also be interpreted to mean that the
`different strengths of the products are within the scope of changes permitted under the category
`"Components and Composition," discussed in the SUP AC-IR guidance. In all cases, the approval
`of additional strengths is based on dissolution profile comparisons between these additional
`strengths and the strength of the batch used in the pivotal bioequivalence study.
`
`11
`
`

`

`Appendix A
`Dissolution Testing Conditions
`
`Apparatus
`
`The most commonly employed dissolution test methods are (I) the basket method (Apparatus 1)
`and (2) the paddle method (Apparatus 2) (Shah 1989). The basket and the paddle methods are
`simple, robust, well standardized, and used worldwide. These methods are flexible enough to
`allow dissolution testing for a variety of drug products. For this reason, the official in vitro
`dissolution methods described in U.S. Pharmacopeia (USP), Apparatus 1 and Apparatus 2 should
`be used unless shown to be unsatisfactory. The in vitro dissolution procedures, such as the
`reciprocating cylinder (Apparatus 3) and a flow-through cell system (Apparatus 4) described in
`the USP, may be considered if needed. These methodologies or other alternatives/modifications
`should be considered on the basis of their proven superiority for a particular product. Because of
`the diversity .of biological and formulation variables and the evolving nature of understanding in
`this area, different experimental modifications may need to be carried out to obtain a suitable in
`vivo correlation with in vitro release data. Dissolution methodologies and apparatus described in
`the USP can generally be used either with manual sampling or with automated procedures.
`
`Dissolution Medium
`
`Dissolution testing should be carried out under physiological conditions, if possible. This allows
`interpretation of dissolution data with regard to in vivo performance of the product. However,
`strict adherence to the gastrointestinal environment need not be used in routine dissolution
`testing. The testing conditions should be based on physicochemical characteristics of the drug
`substance and the environmental conditions the dosage form might be exposed to after oral
`administration.
`
`The volume of the dissolution medium is generally 500, 900, or 1000 mL. Sink conditions are
`desirable but not mandatory. An aqueous medium with pH range 1.2 to 6.8 (ionic strength of
`buffers the same as in USP) should be used. To simulate intestinal