Journal of Pharmaceutical Sciences xxx (2018) 1-8

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Commentary

FIP Guidelines for Dissolution Testing of Solid Oral Products

Horst Dieter Friedel 1, *, Cynthia K. Brown 2, Amy R. Barker 2, Lucinda F. Buhse 3,
Susanne Keitel 4, Johannes Kraemer 5, John Michael Morris 6, Christos Reppas 7,
David C. Sperry 2, Kumiko Sakai-Kato 8, Mary P. Stickelmeyer 9, Vinod P. Shah 10
1
Bayer Aktiengesellschaft, Corporate Quality, Berlin, Germany
2
Eli Lilly and Company, Product Research and Development, and Global Quality Laboratories, Indianapolis, Indiana 46285
3
U.S. Food and Drug Administration/CDER/OPQ, White Oak, Maryland 10903
4
EDQM, Strasbourg, France
5
PHAST, Homburg, Germany
6
Former Irish Medicines Board, Dublin, Ireland
7
National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, Greece
8
National Institute of Health Sciences, Kawasaki, Kanagawa, Japan
9
Pharmaceutical Consultant, Indianapolis, Indiana
10
Pharmaceutical Consultant, North Potomac, Maryland 20878

a r t i c l e i n f o a b s t r a c t

Article history: Dissolution testing is an important physiochemical test for the development of solid oral dosage forms,
Received 22 June 2018 tablets, and capsules. As a quality control test, the dissolution test is used for assessment of drug product
Revised 3 August 2018 quality and is specified for batch release and regulatory stability studies. In vitro dissolution test results
Accepted 7 August 2018
can often be correlated with the biopharmaceutical behavior of a product.This article provides a sum-
mary of views from major global agencies (Europe, Japan, United States), pharmacopoeias, academia, and
industry. Based on available guidance and literature, this article summarizes highlights for development
Keywords:
automation and validation of a suitable dissolution method, setting appropriate specifications, in vitroein vivo
bioavailability comparison, and how to obtain a biowaiver.
biopharmaceutics classification © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
system (BCS)
dissolution
drug delivery system(s)
formulation
in vitroein vivo correlation(s) (IVIVC)
solid dosage form(s)
surfactant(s)

Introductory Remarks
Dissolution testing is an important physiochemical test for the
development of solid oral dosage forms, tablets, and capsules. As a
quality control test, it is used for assessment of drug product quality
and is specified for batch release and regulatory stability studies.
In vitro dissolution test results can often be correlated with the
biopharmaceutical behavior of a product.
The International Pharmaceutical Federation (FIP) is the global
federation representing 4 million pharmacists and pharmaceutical
scientists worldwide. FIP has previously published Guidelines for
This scientific publication reflects the views of the author(s) and should not be
construed to represent views or policies of U.S. Food and Drug Administration and
Japan Ministry of Health, Labour and Welfare.
* Correspondence to: Horst Dieter Friedel (Telephone: þ49-3046817922).
E-mail address: horst-dieter.friedel@bayer.com (H.D. Friedel).
Dissolution Testing of Solid Oral Products.1,2 The FIP guidelines from
1981 served to provide information to compendial committees
when dissolution methods were being introduced into the
compendia. Compendial harmonization projects between Euro-
pean Pharmacopoeia (Ph. Eur.), United States Pharmacopeia (USP),
and Japanese Pharmacopoeia (JP) were underway, when the FIP
guidelines 1995 were published.
Since 1995, regulatory agencies and pharmacopeial committees
have updated dissolution guidances and general chapters to assure
incorporation of current knowledge, information, and re-
quirements. The FIP in vitro dissolution/drug release focus group
revised the recommendations given in the FIP guideline in 1995
considering the modifications to guidelines for bioavailability,
bioequivalence, and in vitro dissolution. Primary modifications
from the previous guidances include information on harmoniza-
tion, apparatus information, references for the compendial buffer
preparations, and apparatus suitability. The new sections in this

https://doi.org/10.1016/j.xphs.2018.08.007
0022-3549/© 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
2 H.D. Friedel et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-8
guidance inform the reader about the process for dissolution
method development including information about modified for-
mulations and discriminating methods. Specification setting and
biowaiver summaries have also been updated.
This article summarizes the views from agencies (Europe, Japan,
United States), pharmacopoeias, academia, and industry. Evaluating
the information available in literature about dissolution testing and
the experience of the authors, it provides guidance for:
 Development of a suitable dissolution method.
 Validation of the dissolution method and determinative step
(analytical test).
 Setting specifications.
 In vitroeIn vivo comparison.
 Biowaiver.
This article supports pharmaceutical analysts and scientists to
develop suitable dissolution test methods to assess product quality
and in vivo performance.
Concept of Dissolution Testing
In vitro dissolution testing serves as an important tool for char-
acterizing the biopharmaceutical quality of a product at different
stages in its life cycle. Dissolution methodology and its application
evolve along with the drug product throughout the development
process. In early drug development, in vitro dissolution properties
are supportive for choosing between alternative formulation can-
didates for further development and for evaluation of active in-
gredients (drug substances). In vitro dissolution data are supportive
in the evaluation and interpretation of possible risks, especially in
the case of controlled/modified release dosage forms. These include
dose dumping, food effects on bioavailability, and interaction with
other drugs that might influence gastrointestinal (GI) environ-
mental conditions. Biopharmaceutical aspects are as important
over shelf life as they are for batch release after production;
therefore, in vitro dissolution is of high relevance in quality control
and stability testing. Last but not least, in vitro dissolution data are
of great importance when assessing changes in production site,
manufacturing process, or formulation and assist in decisions
concerning the need for conducting supporting bioavailability
studies. None of these purposes can be fulfilled by an in vitro test
system unless it has sufficient reliability. Reliability here means a
system that is experimentally sound, yielding precise, accurate,
repeatable results and with sufficient knowledge of the in vivo
relevance of the dissolution data obtained. Requirements for
dissolution testing have been reviewed in the literature. 1-5 Since in vitro
dissolution is a physical test, defined by convention and is of a
destructive nature, proving reliability requires special attention. It
therefore is within the scope of these guidelines to define suitable
testing equipment and experimental design, to suggest the background
for adequate physical and analytical validation, together with verifi-
cation procedures according to the state of biopharmaceutical science.
The guidelines are primarily dedicated to solid oral products. However,
the general concepts herein may be adapted to in vitro dissolution
testing of drug substances/powders, semisolid oral products, supposi-
tories and, with certain restrictions, to other nonoral products.
Compendial Dissolution Apparatus
The choice of a suitable dissolution apparatus and conditions
should start with evaluation of the compendial apparatus described
in the Ph. Eur., JP, and USP. If these apparatuses and conditions are not
discriminative enough, the next step is to evaluate modifications of
the compendial apparatus. The last recourse is to use noncompendial
apparatus and conditions with an appropriate justification and
demonstration of the discriminatory power of the test.
Basket Apparatus
The basket apparatus can be used for capsules and tablets. The
default basket is 40 mesh but other mesh apertures can be used
with appropriate justification. The basket can be manufactured in
stainless steel, type 316, or other inert material, or it can be gold-
plated (Ph. Eur., JP, USP).
Paddle Apparatus
The paddle apparatus can be used for capsules and tablets. The
paddle can be in 2 pieces (shaft and blades) or it can be constructed
in a single piece. It can be manufactured in stainless steel, type 316,
or other inert material (Ph. Eur., JP, USP).
Reciprocating Cylinder
This assembly consists of a set of cylindrical, flat-bottomed glass
vessels, a set of glass reciprocating cylinders; inert fittings (stainless
steel type 316 or other suitable material) and screens that are made
of suitable inert material that are designed to fit the tops and
bottoms of the reciprocating cylinder. It can be used with capsules
and tablets. As its movement generates more turbulence when
compared to the paddle apparatus, it may be useful for products
containing low-solubility drug substances or substances dispersed
in an oily vehicle. The cylinders are arranged in rows and can
contain dissolution medium with different composition/pH in each
row giving the option of running dissolution profiles in different pH
ranges (EP, USP). This apparatus is not described in JP.
Flow-Through Cell
This assembly consists of a reservoir and a pump for medium, a
flow-through cell, and a water bath that maintains the temperature of
the medium at the appropriate level during the test. It can accom-
modate different sizes and types of cells. There are specific cells for
liquid-filled capsules, granules, powders, etc. The flow rate can be set
to work with very low or very high volumes of dissolution medium.
Because the apparatus can be configured to allow high volumes of the
dissolution medium to reach the dosage form, it can be used with
dosage forms containing poorly soluble drug substances. The
apparatus can be operated in an open-loop mode in which the fresh
medium reaches the sample throughout the entire test, or in a closed-
loop mode, where the dissolution medium is recirculated.
The 2 most commonly used dissolution apparatuses are the
basket and paddle apparatuses. The basket and paddle apparatuses
are simple, robust, and adequately standardized apparatuses that
are used universally and thus are supported by the widest experi-
ence of experimental use. It is because of these advantages that the
paddle and rotating basket apparatuses are recommended in
various guidelines as first choice for the in vitro dissolution testing
of immediate as well as controlled/modified release preparations.
Apparatus Suitability
Different instrument qualification and suitability methods have
been proposed by the pharmacopeias, regulatory bodies, and
standard setting organizations. The FIP focus group recommends
establishing the basket and paddle apparatus suitability by
following the mechanical calibration requirements indicated in
ASTM E2503-07 (Standard Practice for Qualification of Basket and
Paddle Dissolution Apparatus) and referenced in U.S. Food and Drug
 H.D. Friedel et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-8
Administration (FDA) Guidance for Industry: The Use of Mechanical
Calibration of Dissolution Apparatus 1 and 2dCurrent Good
Manufacturing Practice (January 2010)6 and JP general information
(17th edition, March 2016.7 Reference to JP 17th general informa-
tion). If additional system performance information is desired, a
performance verification test using USP Reference Standard tablet
or an established in-house reference product can be conducted. Any
strict requirement on the use of a specific performance verification
test tablet is not recommended at this time.8
Harmonization of the Compendial Chapters
Most of the compendial general chapters on dissolution testing
are harmonized between the Ph. Eur., the JP, and the USP (Ph. Eur.,
2017; JP, 2016; USP, 2016). The International Council for Harmoni-
zation (ICH) recommends that the official pharmacopeial texts, Ph.
Eur. 2.9.3 Dissolution Test for Solid Dosage Forms; JP 6.10 Dissolu-
tion Test; and USP <711 > Dissolution can be used interchangeably
in the ICH regions when using the basket apparatus, the paddle
apparatus, or the flow-through cell. The dissolution test is not
interchangeable under certain circumstances, for example, when
enzymes are used in the media, for dosage forms referred to as
delayed-release, gastro-resistant, or enteric coated nor when ves-
sels greater than 1 L are used. These exemptions are specified in ICH
Q4B Annex 7.9
Method Development
A dissolution test method for quality control purposes should
meet the following criteria:
 It must be robust and reproducible over long time periods.
 It must be easily transferred from laboratory-to-laboratory.
 It must be able to discriminate between batches with respect to
critical process parameters and critical material attributes,
which may have an impact on the in vivo biopharmaceutical (or
bioavailability) behavior. However, the method should not be
overdiscriminating such that minor differences in the
manufacturing process or incoming material, which do not have
a clinically relevant impact on the in vivo behavior, result in test
failure.
Selection of Dissolution Medium
Physicochemical characterization of the active pharmaceutical
ingredient (API) provides the framework for the dissolution test
and its application for formulation development. Solubility data at
37 C in aqueous buffer solutions at different pH values should be
evaluated to be able to select an appropriate dissolution medium
providing sink conditions for the API.
Sink conditions are defined as the volume of medium that is at
least 3 times that required to form a saturated solution of drug
substance. Sink conditions assure that dissolution is not signifi-
cantly limited by solubility characteristics.
In general, an aqueous medium should be used for the disso-
lution test. It is not recommended to attempt to strictly mimic the
physiologic GI environment (e.g., composition of gastric or intes-
tinal fluid) but to choose the testing conditions as far as is
reasonable, based on the physicochemical characteristics of drug
substance, within the range which a drug or dosage form could
experience after oral administration. Dissolution media typically
selected should be in the physiological pH range of 1-7.5. A higher
pH needs to be justified on a case-by-case basis and in general
should not exceed pH 8.
3
For low-pH media, diluted hydrochloric acid (0.1 M or 0.01 M) is
used, whereas at higher pH, buffered solutions (acetate and phos-
phate buffers) are recommended. Although much of the dissolution
compendial methods are harmonized,8 buffer preparations are not
included as harmonized properties. It is recommended to conform
to the buffer preparations that are consistent with requirements for
the country in which the marketing authorization will be held. USP
buffer solutions are defined in the USP reagents section for buffer
solutions. Ph. Eur. instructions for buffer preparations are defined in
Ph. Eur.5.17.1 “Recommendations on Dissolution Testing” and JP
instruction for buffer preparations in 9.41 “Reagents, Test Solu-
tions.” The influence of the ionic strength on the dissolution
behavior should be investigated during method development.
The use of water as the dissolution medium bears the disad-
vantage that test condition details, such as pH and surface tension,
can vary depending on the source of water and may be changed
during the dissolution test itself due to the influence of the drug
products and the (re)absorption of carbon dioxide from air. When
using water as a dissolution medium, purified water is
recommended.
Surfactant
If sink conditions cannot be achieved at any pH in the physio-
logical pH range, surfactants may be added to enhance the solu-
bility of poorly soluble drugs (Biopharmaceutics Classification
System [BCS] classes 2 and 4). For definition of BCS classes, see
chapter VII Biowaiver.
Surfactants can be either anionic, cationic, zwitterionic, or
neutral. Chemically well-defined surfactants, for example, sodium
dodecyl sulfate, should be given preference. Other commonly used
surfactants are polysorbates (Tween 20 or 80), polyoxyethylene 23
lauryl ether (Brij 35) or cetyltrimethyl ammonium bromide.
For an overview of commonly used surfactants and information
on their critical micelle concentration, see USP chapter <1092>.10
The concentration of the surfactant should be the minimum
amount needed to obtain sink conditions and be justified by solu-
bility data at 37 C to maintain the discriminatory power of the
dissolution test method. If different dosages of a drug product are
tested, the same dissolution medium should be used. Thus, the
amount of surfactant added to the dissolution medium should
provide sink condition for the highest dose. The stability of the drug
substance in the chosen dissolution medium must be investigated
at 37 C simulating the dissolution experiment and additionally at
laboratory storage temperature covering the time needed for
quantitation.
Enzymes
Gelatin, in the presence of certain compounds such as aldehydes
and/or when exposed to high humidity and temperature, can cross-
link rendering it insoluble in aqueous solvents. The presence of
cross-linking will alter the in vitro dissolution behavior of gelatin
capsules and gelatin-coated tablets. The capsule will not open and
release its contents into the dissolution medium, or it will open in a
nonuniform way and the dosage form will disintegrate partially or
not disintegrate at all. Consequently, the dissolution results will fail
and/or will have very high variability. This failure may not reflect a
possible failure in vivo.11,12 Where gelatin capsules or gelatin-coated
tablets experience dissolution failure due to the presence of cross-
linking, it is allowed to add proteolytic enzymes to the dissolution
medium. The use of pepsin for the dissolution medium with pH
equal or below 4.0 is recommended, papain or bromelain for the
dissolution medium with pH above 4.0 and below 6.8, and
pancreatin for the dissolution medium with pH equal to or above
4 H.D. Friedel et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-8
6.8. The addition of enzymes into the dissolution medium is not
accepted by the JP.
Delayed-Release Dosage Forms
Dissolution testing of delayed-release dosage forms usually
comprises an acid stage (in 0.1 M HCl) and a buffer stage (in
phosphate buffer pH 6.8). For details, see USP <711> or Ph. Eur. The
JP uses parallel rather than sequential test methodology.
Hydrodynamics
The volume of the dissolution medium should be 500 mL up to
1000 mL for basket and paddle apparatuses with 900 mL being
historically the most common volume used.
For dissolution testing of immediate-release (IR) products most
commonly apparatus 1 (basket) with a stirring rate of 50-100 rpm
or apparatus 2 (paddle) with an agitation speed of 50 or 75 rpm are
used. In case a formulation exhibits “coning” under the paddle, an
increase of the stirring speed from 50 to 75 rpm is typically suffi-
cient to reduce coning and leads to less variable results. Other
agitation rates may be used with justification but should not go
outside the range 25-150 rpm.
Apparatus 4 (flow-through) can be used as an open system with
a fresh solution from the reservoir continuously passing through
the cell where the dosage form is initially accommodated. It is also
possible to operate it as a closed system by recycling a fixed volume
of liquid.13 Two different cells are used for orally administered solid
dosage forms, the large cell (22.6 mm internal diameter) and
the small cell (12 mm internal diameter). Flow rates up to about
16 mL/min can be applied; however, physiologically relevant flow
rates are less than 10 mL/min.14 Various types of filters are available
(e.g., glass-fiber, cellulose-based). The appropriate filter or combi-
nation of filters should be decided with preliminary experiments.
Deaeration
The significance of deaeration should be investigated by
comparing dissolution data in a deaerated and nondeaerated me-
dium. Air bubbles adhering to the dosage unit may alter the
dissolution rate especially for poorly soluble drugs. For dissolution
media containing surfactants, degassing is usually not an option
because of excessive foaming, and the effect of dissolved air on the
dissolution behavior is minimized by the lower surface tension.
Sinkers
Sinkers are often used with apparatus 2 where the dosage form
tends to float (e.g., capsules) or sticks to the vessel wall. Several
sinker types are commercially available. As sinkers can significantly
influence the dissolution behavior of a dosage form, the type of
sinker has to be carefully evaluated and described in the dissolution
procedure. Ph. Eur., JP, and USP recommend the use of wire helix
and a small wire basket. The 3 pharmacopoeias also allow the use of
any validated sinker.
Discriminatory Power
The discriminatory power of the dissolution method should be
investigated simultaneously during formulation and process devel-
opment. The same studies that are used to design the formulation and
the process can be applied to determine method discrimination.
Factors that should be considered when evaluating the disso-
lution procedure include:
 API properties such as particle size and crystal forms.
 Excipient quantity, quality, and grade.
 Manufacturing process parameters such as
 Blending time and rate.
 Granulation conditions.
 Compression force and dwell time.
 Coating conditions (temperature, moisture, and spray rate).
 Stressed samples.
During product development, discriminatory power is desired to
exhibit differences in the in vitro performance of products and/or
batches after changes in composition or manufacturing. In the market-
supply phase, the goal of dissolution testing is to prove similarity of a
freshly manufactured batch to the model, for which bioavailability
data have been generated. However, this requires discriminatory po-
wer of the method with the goal that the dissolution test should be
able to differentiate between drug product batches of different quality
and different in vivo characteristics. On the other hand, a dissolution
method should not be overdiscriminating as explained previously. The
intention of a robust quality control dissolution method is to ensure
consistent in vivo performance of the product.
If discrimination is not observed, then method conditions
should be revisited to try to achieve discrimination. In some cases,
achieving discrimination is not possible. In these cases, adequate
experimental work should nevertheless be done to demonstrate
that discrimination could not be achieved over reasonable ranges of
formulation and process parameters.
In most cases, for solid oral dosage forms, the compendial
method development approaches described previously are suffi-
cient for quality control of the performance of the drug product.
However, in some cases, alternative methods can be justified. In
general, compendial methods should be used, unless they are shown
to be insufficient or unnecessary for the intended purpose. One such
case is outlined in ICH Q6A Decision Tree #7, which states that
disintegration testing can be suitable for control of rapidly dissolving
(RD), high-solubility drug products, where disintegration is the rate-
limiting mechanism.13 Other scenarios may arise on a case-by-case
basis where compendial methods are either unsuitable or imprac-
tical. But, in any scenario, the method design principles listed pre-
viously must be adhered to: robust, reproducible, transferrable, and
able to discriminate. More recently, surrogate dissolution models
based on near-infrared technology have been used to predict in vitro
dissolution and can serve as surrogate for traditional dissolution
testing.15 Typically, in these cases, a conventional dissolution
method is still used throughout development and for other quality
control purposes such as shelf life stability studies.
Validation Parameters
The dissolution procedure has 2 components: the dissolution
step and the determinative step. Before starting with the validation
of the determinative step, the analytical method parameters must
be defined. For the quantification of the dissolved active ingredient,
normally ultraviolet (UV) detection is used and in some cases, it is
necessary to separate the components by high-performance liquid
chromatography (HPLC)/ultra-HPLC. It is essential to select appro-
priate conditions for the analytical method, where there will not be
interferences from other components such as excipients. The vali-
dation of the determinative step is done by following the recom-
mendations in the ICH guidance on analytical validation Q2.16
Specificity
For dissolution testing, the dissolution results must not be
affected by excipients, other drug substances that may be present in
 H.D. Friedel et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-8
the product, and possible degradants. Excipients include coatings,
printing inks, and capsule shells. The specificity evaluation can be
done by spiking a placebo version of the finished product with
known amounts of the drug substance. The interference should not
exceed 2%. If the placebo interference exceeds 2%, modification or
replacement of the method may be necessary. Possible method
modifications include, but are not limited to, selecting an alterna-
tive wavelength, subtraction of the baseline, correction for the
placebo interference, and degradation of the interfering trans-
forming absorbance values (e.g., first derivative).12
Linearity and Range
The linearity should be evaluated using at least 5 concentrations
encompassing the entire dissolution profile. In some cases, it may
be helpful to include the upper limit of uniformity of dose. Linearity
is typically calculated by using an appropriate least squares
regression program. In most cases, a square of the correlation co-
efficient must not be less than 0.98 and the y-intercept must not be
importantly different from zero.12
Accuracy
Accuracy is typically evaluated by preparing multiple samples
containing the active ingredient and any other component present
in the dosage form (e.g., excipients, coating materials, capsule shell,
etc.) in concentration within the linearity range of the method. The
measured recovery is typically 95%-105% of the amount added.
Special procedures may be necessary when evaluating the accuracy
of the acid stage for delayed-release dosage forms.12
Precision
Precision should be evaluated to include spiking of drug substances
into placebo matrix or evaluation of actual formulations to cover the
anticipated concentration range. Repeatability and intermediate pre-
cision should be addressed and reproducibility may be considered.
Robustness
The robustness of a method is a measure of its capacity to remain
unaffected by small but deliberate variations of defined parameters
and provides an indication of its reliability during normal usage.
Acceptance criteria should be established to confirm method
robustness with respect to the defined critical method parameters.
Robustness studies are performed for the quantitation method
(HPLC or UV) and for the dissolution method.
For HPLC quantitation, small deliberate variations, for example,
in pH and composition of the mobile phase, the flow rate, detection
wavelength, and column temperature as well as type of stationary
phase should be studied.
For UV quantitation, small deliberate variations, for example, in
detection wavelength, baseline correction, pH, and ionic strength of
the dissolution medium as well as amount of organic solvent in the
reference solutions should be investigated.
To prove the robustness of the dissolution method, small vari-
ations in pH and surfactant concentration of the dissolution me-
dium, temperature, stirring speed, deaeration, sampling technique,
and tablet placement should be examined.
Validation of Sample Handling
Filtration
Filtration removes undissolved material, including API that may
otherwise interfere with the analytical result or the procedure
5
during the analytical finish. Selection of the proper filter material is
important and should be accomplished, and experimentally justi-
fied, early in the development of the dissolution method. Important
characteristics to consider when choosing a filter material are type,
size, and pore size. In addition, use of the correct filter dimensions
will improve throughput and recovery and reduce clogging. Filter
compatibility should be performed as part of method development.
During method validation, the proposed filter types should be
validated for use to demonstrate appropriate recovery (ensure drug
is not absorbed or adsorbed to the filter).
Automation
When automated equipment is used, a comparison should be
performed between the automated and the manual procedures. This
could be done either by a parallel sampling approach, meaning
manual sampling, is performed out of the same vessels of the
automated equipment or by an independent sampling approach.
Following the independent sampling approach, 2 dissolution runs
(automated and manual) using the same homogenous sample are
conducted. The comparison of independent dissolution experi-
ments is preferred because the influence of the entire automated
equipmentdnot only the sampling procedure itselfdon the disso-
lution results is investigated. To be considered comparable, the re-
sults from these experiments should not differ by more than 5%
depending on the accuracy and precision of the method, at least for
the specified time points, but preferably for all sampling time points.
Justification of Specification
Generally for IR (i.e., non modified formulations), a single or 2-
point acceptance criterion is acceptable to control product quality
where a minimum amount dissolved at the specified time, for
example, “not less than 80% released in 30 min in the chosen
dissolution medium, that is, Q ¼ 75%” where Q is the reference
figure quoted in the harmonized compendial test. Of course in
certain cases for highly potent drugs or those with a narrow ther-
apeutic index, a single-point acceptance criterion may not be
adequate. Further advice on IR products can be obtained in relevant
regulatory guidance from FDA, European Medicines Agency (EMA),
and Ministry of Health, Labour and Welfare (Japan) as well as the
compendia.
For extended-release products, the specifications are naturally
more complex and demanding.
Typically, 3-point acceptance criteria will be included in the
specification:
1. An early time point showing that the drug is not rapidly released
from the formulation and therefore should help to provide
reassurance that rapid release does not occur in vivo after the
dose form has been swallowed (“dose dumping”). Such behavior
would be contrary to the product design and may present a
safety hazard to the patient. A suitable acceptance criterion
might take the form of “not more than 20% (±10%) released after
1 h.”
2. A mid-range time point should be specified with an appropriate
acceptance criterion that supports the intended release char-
acteristics of the drug from the formulation. For example, this
might be along the lines of “not less than 50% and not more than
70% of the nominal dose released after 6 h.” The time here is
chosen to suit the dosage interval proposed and the therapeutic
objective for the product. Range is typically ±10% or other ranges
can be used if justified by clinical data.
3. A final time point is specified showing that drug release from
the formulation is essentially complete and will typically take
6 H.D. Friedel et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-8

the form of “not less than 80% of the drug is released from the
formulation after 8 h.” Again the time point will be chosen and
justified with reference to the intended dosage interval.

Justification of the specifications and in particular the acceptance

criteria will need to be made at the chosen agitation rate and in the
chosen dissolution medium, for simple aqueous dissolution media.
Where surfactants or other substances are added to the dissolution
media, their presence and concentration need to be scientifically
justified based on data generated in the pharmaceutical develop-
ment section of the marketing authorization dossier. In all cases,
justification of specifications should follow relevant regulatory
guidance and most importantly be based on good science.

In VitroeIn Vivo Comparison

An in vitro test for a given drug product serves as the tool for
biopharmaceutical quality, provided that it can distinguish be-
tween “good” and “bad” batches. Good here means “of acceptable
and reproducible in vivo performance” and for oral products “of
acceptable luminal performance.”
With regard to in vitro evaluation of luminal performance of
drug products, that is, to biorelevant in vitro testing,1 a logical hy-
pothesis would be that the closer the in vitro test conditions are to
those in the GI lumen, the better the chances of predicting intra-
luminal dosage form performance. However, depending on the
level and quality of information one is seeking and depending on
certain characteristics of the API, a complete simulation of all as-
pects of luminal conditions may or may not be necessary to eval-
uate drug product performance. In some cases, not only the API
characteristics but also the dosage form characteristics will dictate
the required Level of simulation of luminal conditions.
Figure 1. An overview of the 4 levels of biorelevant media recommended for the
Levels of simulation of luminal conditions have been proposed2
simulation of the luminal environment during development of oral formulations.2
(Fig. 1). Level 0 media are simple aqueous solutions, the pH of
which is adjusted (usually with a buffer) to represent the pH in the
particular location of the GI tract. At this level, the buffer capacity fed state is considered to be the only condition under which the API
may or may not be physiologically relevant, the aim is rather to or the dosage form experiences a highly variable environment
maintain the pH during the course of the experiment. In Level I during its residence in a specific GI region. Therefore, simulation of
media, both the pH and buffer capacity are adjusted to reflect gastric composition in the fed state as a function of time after
physiological values, in fasted and fed state. Bile components are administration is proposed at Level III.2
additionally included in Level II media to reflect the solubilization Composition of media which, depending on the level of simu-
capacity of the luminal fluids, and differences in luminal compo- lation, reflects key luminal characteristics both for the fasted and
sition between the fasted and fed state are addressed. Level III for the fed state has been proposed with dosing conditions similar
media, the most complex compositions, also include proteins, en- to those conditions that are typically applied in bioavailability/
zymes that are usually present in the aqueous phase of luminal bioequivalence studies of oral drug products.2 Such conditions may
contents, and the viscosity effects on drug release. However, pro- differ from those in day-to-day clinical practice. In the latter case,
cesses like adsorption onto particulate matter in the lumen and for example, it may not be worth distinguishing between fasted and
bacterial degradation of dissolved API are not considered in this fed state conditions in the ascending colon, as fed-like conditions
classification. Depending on the location in the GI lumen and are likely to prevail in this region most of the time.
dosing conditions to be simulated, within each Level, the type and
number of media components may be greater or fewer than those
specified in Figure 1. For example, the addition of dietary lipids may Section 1dVerified IVIVC for Regulatory Purposes
be worth considering for Level II simulation of the fed state con-
ditions in the stomach but are not appropriate when simulating Procedures for achieving a verified in vitroein vivo correlation
fasting gastric conditions. Similarly, agents that affect viscosity may (IVIVC) have been described by FDA (for extended-release prod-
be considered for Level III simulation of conditions in the ascending ucts19) and by EMA (for modified-release products20).
colon but have little relevance for Level III simulation of conditions By establishing a meaningful correlation between in vitro
in the fasted upper small intestine. Luminal hydrodynamics are release characteristics and in vivo bioavailability parameters, the
addressed only at the highest Level of simulation (Level III).4 In in vitro dissolution test can serve as a surrogate marker for in vivo
cases where closed in vitro systems are used, it is envisaged that for behavior and thereby confirm consistent therapeutic performance
Level I, Level II, or Level III simulation of conditions in stomach or of batches from routine production.21,22 Although a number of
upper intestine, volumes of about 250 mL and about 500 mL should techniques may be used,21,22 an attempt to develop a level A IVIVC,
be used for fasted state and fed state simulations, respectively.3-5,17 that is, a correlation that represents a point-to-point relationship
In contrast, in the lower intestine, about 200 mL will usually be between in vitro dissolution and the in vivo input rate (e.g., the
appropriate, regardless of dosing conditions.5,18 The stomach in the in vivo dissolution of the drug from the dosage form), is
 H.D. Friedel et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-8
recommended to be developed and be verified by confirming its
predictability.21,22 Both 2-stage approaches (e.g., deconvolution-
based approaches) and 1-stage approaches (e.g., convolution-
based approaches or physiologically based pharmacokinetic
[PBPK] modeling approaches) are acceptable. Adequacy of pre-
dictability could be evaluated using summary parameters (e.g., the
maximum concentration, area under the curve, etc.). Such sum-
mary parameters calculated from the predicted concentration-time
curve are compared with the respective summary parameters for
the observed data. The prediction error (PE), defined as %PE ¼
[(observed valueepredicted value)/observed value]  100, is
calculated for each summary parameter. The absolute value of the
PE for all summary parameters should be less than 15% for each
formulation and the average PE for all formulations included in the
IVIVC developments should be less than 10% for each parameter.
With a verified IVIVC in place, the number of in vivo studies during
product development may be decreased, specifications may be set
more easily, and certain regulatory decisions may be facilitated
(e.g., scale-up and postapproval changes).21,22 However, a level A
IVIVC cannot serve as a basis for claiming bioequivalence between
products from different marketing authorization applicants, based
on in vitro data only.21
Section 2dIVIVC Comparison for Development Purposes
Immediate-Release Products
Biopharmaceutical risk should be initially identified. If the risk is
considered to be low, in vitro dissolution data should be collected
using a compendial dissolution apparatus and media simulating key
luminal characteristics. If biopharmaceutical risk is considered to be
high, the impact of formulation and/or of variation in the process of
formulation on in vivo performance should be evaluated. In such
case, it is likely that an enabling (bio-enhanced) product is used, and
evaluation of its luminal performance should not be strictly related
to intraluminal dissolution but more importantly on its ability to
maintain supersaturated levels intraluminally. In vitro evaluation
could be performed using compendial or noncompendial apparatus,
and testing conditions should reflect the changing of key luminal
characteristics due to the GI transit.21,22 Provided that disposition
and elimination characteristics of the API have been previously
defined, in vitro data could be coupled with PBPK modeling ap-
proaches for generating the plasma profile. Alternatively, in vitro
data may also be directly compared with luminal data in humans.
Modified-Release Products
A procedure similar to that recommended by the regulatory
agencies19-22 could be applied. Specifically:
1. Based on plasma profile after administration of an IR product
and pharmacokinetic-pharmacodynamic relationships and on
absorption modeling, define targeted release rates for the
modified-release product.
2. Develop about 3 batches of the product with different release
rates within the range of targeted release rates in vivo. Confirm
the release rates by performing in vitro dissolution tests. Com-
pendial apparatus are recommended to be used. Exact in vitro
testing conditions could vary with the API and type of modified-
release products under study so that key luminal characteristics
relating to compositions and times of residence in various
regions of the GI lumen are simulated.
3. Perform a clinical study in healthy subjects, for example, single-
dose study in healthy adults with the MR products. Inclusion of
an oral solution or intravenous product will be useful.
7
4. Develop IVIVC. Level A, multiple level C or level B IVIVC21,22
could be considered. Instead of level A correlation, in vitro
data could, alternatively, be coupled with PBPK modeling ap-
proaches for generating the plasma profile.
Biowaiver
The term biowaiver is applied to a regulatory drug approval
process when the dossier (application) is approved based on evi-
dence of equivalence other than in vivo bioequivalence testing data.
A biowaiver can be applied only for IR solid oral dosage forms with
BCS class 1 and class 3 drug substances. It is not applicable to
narrow therapeutic index drugs. Also, it is not applicable to prod-
ucts designed to be absorbed in the oral cavity. A biowaiver is
generally based on a dissolution test and dissolution profile com-
parison, for example, similarity factor f2. Biowaivers can be used
during development, for line extensions, generic drug product ap-
plications, and postapproval changes.
BCS is a scientific framework for classifying drug substances
based on their aqueous solubility and intestinal permeability. BCS
classifies the drug substance into 4 classes based on its solubility
and permeability:
 Class 1: highly soluble/highly permeable (HS/HP).
 Class 2: low solubility/highly permeable (LS/HP).
 Class 3: highly soluble/low permeability (HS/LP).
 Class 4: low solubility/low permeability (LS/LP).
When combined with the dissolution of the drug product, BCS
takes into account 3 major factors that govern the rate and extent of
absorption from IR solid oral dosage forms: dissolution, solubility,
and intestinal permeability.
The dissolution test should be carried out with 12 units by
paddle method or by basket method at pH 1.2, 4.5, and 6.8.
Dissolution is described as very RD (VRD) when 85% of the drug
dissolves in 15 min or less, RD when 85% of the drug dissolves in
30 min, and slowly dissolving when it takes more than 30 min for
85% of the drug to dissolve. Only those products which are VRD
(BCS class 1 and class 3 drug substances) and RD (BCS class 1 drug
substances) are eligible for biowaiver. For biowaiver purpose, the
dissolution profile of the test (multisource) product must always be
compared with the dissolution profile of the reference (compar-
ator) product and must meet the similarity criteria of f2 50. There
is no need for profile comparison if the product is VRD.
Subsequent to the initial publication of FDA's BCS guidance in
2000,23 WHO,24 EMA,25 Health Canada,26 and later FDA draft BCS
guidance in 201527 have been published, which provides biowaiver
for BCS class 1 and class 3 drugs. The guidance documents differ in
definitions and requirements, so that harmonization of BCS
guidelines is desirable. In October 2016, the ICH endorsed the
development of a new multidisciplinary guideline ICH M9 to
address BCS-based biowaivers.
Conclusions
Dissolution testing is the most powerful in vitro test for solid oral
dosage forms to assure product quality and product performance
including drug bioavailability. With the developments in formula-
tion technology and advancing knowledge in dissolution science,
there is an increasing challenge in determining appropriate disso-
lution test methods to meet all objectives: API form and formulation
development, quality control, and change control (life cycle man-
agement). Advances in instrumentation have resulted in develop-
ment of more robust dissolution apparatus. To support the global
marketing and availability of drugs, it is essential that regulatory
8 H.D. Friedel et al. / Journal of Pharmaceutical Sciences xxx (2018) 1-8

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