LIFE SCIENCE I TECHNICAL BULLETIN

OCTOBER 2014

COMPARATIVE DISSOLUTION PROFILE

A QUALITY CONTROL TOOL AND BEYOND
AUTHORS: SETHU RAGUPATHY, BUSINESS MANGER, SGS LIFE SCIENCE SERVICES (SINGAPORE),

SUNIL S POTDAR , FORMULATION DEVELOPMENT MANGER, SGS LIFE SCIENCE SERVICES (LINCOLNSHIRE, IL, USA)

Solid, oral-dosage tablets and capsules are the most effective and efficient means of treatment available in the
pharmaceutical industry. The drug, taken orally, dissolves in the gastrointestinal fluids and becomes bioavailable as it
is absorbed into systemic circulation. Routine in vivo measurement of the active pharmaceutical ingredient (API) in
blood and urine is not possible in practice. Measurement methods are inherently error prone due to matrix complications. Therefore, in vitro methods to measure the dissolution rate of the API from the solid oral form are officially
recognized by regulatory agencies as an important consideration when formulating solid-oral-dosage forms.
Dissolution tests are established valuable
quality-control tools to monitor batch-tobatch consistency. They are also useful in
providing pharmaceutical product quality
information following post-approval
changes to the product such as changes
in formulation, changes to the manufacturing process or the site of manufacture, and in process scale-up. In addition,
dissolution data can be used in support
of a biowaiver for lower strengths of
such dosage forms where solid-oraldosage forms have been proportionally
formulated in different strengths. As
long as an acceptable bioequivalence
study has been carried out on one of
the strengthsusually the highest
strengthand the API release rate is
linearly proportional to the concentration,
a bio waiver is preferable.
Adequate release of the API from the
dosage form is critical to API absorption. Dissolution and solubility of the API
under physiological conditions, and its
permeability through the membranes of
the gastrointestinal tract, are important
physiochemical factors. Due to the critical nature of these factors, dissolution
of a pharmaceutical product in vitro is

relevant, in certain instances, in anticipating the in vivo characteristics or results.

During the development of a pharmaceutical product, dissolution testing is
used as a tool to identify formulation
factors that influence and may have a
significant effect on the bioavailability of
the API. After composition and manufacturing processes are defined, dissolution
testing is used in the quality control of
scale-up and of production batches. This
ensures both batch-to-batch consistency
and that the dissolution profiles remain
similar to those of pivotal clinical-trial
batches. Furthermore, dissolution testing
can be used to support the bioavailability
of a new pharmaceutical product, the
bioequivalence of an essentially equal
product, or other product variations. It
gauges quality assurance and bioequivalence.

1. Quality assurance is used

To establish specifications for

quality control on formulated
product and API test batches
used in bioavailability and bioequivalence studies as well as
pivotal clinical studies.
To demonstrate consistency in

product manufacturing.
To benchmark against reference
products used in bioavailability
and bioequivalence studies and
pivotal clinical studies.

2. Bioequivalence is used

To demonstrate similarity
between the different product formulations of an active
substance (including variations
and new, essentially similar
products) and the reference
medicinal product.
As another measure, to collect
information on batch-to-batch
consistency of the products
(test and reference) to be used
as a basis for the selection of
appropriate batches for the in
vivo study.

BIOPHARMACEUTICAL
CLASSIFICATION SYSTEM AND
SPECIAL CASES
The biopharmaceutical classification system (BCS) is an important classification
used for waiver of in vivo bioavailability
and bioequivalency decisions by regula-

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tory agencies. This classification system
is based on the aqueous solubility and
intestinal permeability of the API. The
system classifies API into four classes:
Class 1: High Solubility
High Permeability
Class 2: Low Solubility
High Permeability
Class 3: High Solubility
Low Permeability
Class 4: Low Solubility
Low Permeability
This system takes into account dissolution of drug product, its solubility, and
API permeability. A BCS based biowaiver
can be requested for rapidly dissolving
immediate-release (IR) tables containing
class 1 API with few additional considerations, such as dissolution profile and
original dosage form.
If an active substance is considered
highly soluble and if the dosage form
rapidly dissolves at physiological pH, it
is reasonable to expect that it will not
cause any bioavailability problems. In
those situations, a bioequivalence study
may be waived based on the case history and similarity of dissolution profiles.
It is essential to evaluate country-specific
regulatory guidelines for proposal of a
biowaiver program.
If an active substance is considered to
have a low solubility and a high permeability, the rate limiting step for absorption
may be dosage form dissolution. This is
also the case when one or more of the
excipients are controlling the release and
subsequent dissolution step of the active
substance. In those cases a variety of
test conditions is recommended, and
adequate sampling should be performed
to characterize the dissolution profile
completely (eg, at 10, 15, 20, 30, 45, and
60 minute time interval analysis).
For poorly water soluble drug products,
dissolution testing at more than one time
point, and preferably a dissolution profile,
is recommended for quality control
purposes. Alternatively, the use of the
United States Pharmacopeia (USP) apparatus 4 (Flow-Through Method) should be
considered for the development of dissolution specifications for such products.

2
If a monograph for a fixed-dose combination is not included in the USP or British
Pharmacopoeia (BP), the monographs
for the individual components should be
used to set the dissolution requirements
for each, or an alternate dissolution
method should be developed.

a.

COMPARISON OF
DISSOLUTION PROFILES REQUIREMENTS

b.

Dissolution of test and reference products should be performed in USP Apparatus I at 100 rpm or Apparatus II at 50 rpm
using 900 mL of the following dissolution
media:

c.

Acidic media such as 0.1 N HCl

or simulated Gastric Fluid USP
without enzymes
pH 4.5 Acetate Buffer
pH 6.8 Phosphate Buffer or
simulated Intestinal Fluid USP
without enzyme

batch at time t.
A specific procedure to determine
difference and similarity factor is as
follows:
Determine the dissolution profile of
two products (i.e., of the test and
reference products [using 12 units
each]) following a validated dissolution method
For f2 calculations, a minimum of
three time points (excluding point
zero) must be used, and only one
measurement after 85% dissolution
of both products may be included
For curves to be considered similar,
f2 values should be greater than 50
(50 to 100) to ensure sameness or
equivalence of the two curves and,
thus, of the performance of the test
and reference products

Two scenarios for comparing the profiles

obtained from multipoint dissolution are
operative:

This model-independent method is

most suitable for dissolution profile
comparisons when three to four or more
dissolution time points are available. The
following recommendations should also
be considered:

1.

i.

2.

If both the test and reference product show more than 85% dissolution within 15 minutes, the profiles
are considered similar (no calculations required). If not,
Calculate the f2 value. If f2 50, the
profiles are regarded as similar and
no further in vivo studies are necessary. Note that only one measurement should be considered after
85% dissolution of both products
has occurred and excluding point
zero. A minimum of 12 dosage
units of the drug product should be
evaluated.
The similarity factor (f2) is a logarithmic reciprocal square root transformation of the sum of squared
errors, and is a measurement of the
similarity in the percentage (%) dissolution between the two curves.

f2 = 50 log {[1+ (1/n)t=1n (Rt - Tt)2]-0.5

100}
3.

Where n is the number of time

points, Rt is the dissolution value of
the reference batch at time t, and Tt
is the dissolution value of the test

The dissolution measurements

of the test and reference batches
should be made under exactly the
same conditions. The dissolution
time points for both profiles should
be the same (eg, 10, 15, 20, 30, 45,
60 minutes). For rapidly dissolving
products (profiles reaching 85%
at 30 minutes) the minimum time
points are 10, 15, 20 and 30 minutes
ii. Only one measurement should be
considered after 85% dissolution of
both products has occurred
iii. To allow use of mean data, the percent coefficient of variation (CV) 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%

REPORTING OF COMPARATIVE
DISSOLUTION PROFILE STUDY
Documentation of a comparative dissolution profile shall be prepared and include
at minimum, the:
i.
ii.

Purpose of study
Product / batch information; e.g.,
Batch number, manufacturing/

LIFE SCIENCE I TECHNICAL BULLETIN

expiry date, packaging
Certificates of Analysis (COAs)
and batch size for test batches
Dissolution conditions and method
Validated analytical method
Results (% API dissolved)
Tabulated data
Graph representation
Similarity determination /
calculation
Discussion / Conclusion
Date of analyses and date of report
A GMP compliance declaration by
the laboratory. This includes the
availability of validation records of
test methods and procedures and
records of equipment maintenance
and instrument calibration

iii.
iv.
v.

vi.
vii.
viii.

WHEN CAN YOU REQUEST A

BIOWAIVER?
A biowaiver can be requested in the
following cases:
1.

Proportionally formulated products of the same API

Manufactured by the same
manufacturer at the same
manufacturing site
An appropriate bioequivalence
study has been performed on
at least one of the strengths
of the formulation (usually
the highest strength unless a
lower strength is chosen for
reasons of safety). Dissolution
profiles generated for the test

2.

3.

and other strength multisource

products (i.e., lower and higher
strengths) should be compared
for each of the specified media
When sink conditions do not
exist in one or more media, the
profiles of the higher and lower
strengths may not be similar
in those media due to saturation. In this case, supporting
data may be generated with
the local innovator or reference
product of the same strength

Immediate release tablets

For different strengths of a multisource formulation, if the dissolution profiles in the three dissolution
media specified above are similar.
Extended release tablets
When the drug product
is in the same dosage form, but
in a different strength, and
is proportionally similar in its
active and inactive ingredients,
and
has the same drug release
mechanism.

In all of the cases, the dissolution profile

should be comparable and show that
similarity factors met the criteria of f2
50 in the three specified dissolution
media.

The biowaiver program may not be applicable if there are significant changes in
excipients, or if the product is a prodrug,
and in cases such as Narrow Therapeutic
Index range drugs and products designed
to be absorbed in the oral cavity.
However, the biowaiver depends on the
approval of the respective countries
regulatory departments (Table 1). In
every case, the submission of additional
supporting documents helps to ensure
full consideration.

WHAT DOES SGS PROVIDE?

SGS provides the following to assist in
the submission of a biowaiver:

Study Protocol
Systematic method development and the validation
package for dissolution profile
generation
Study report F1, F2 computation, graph comparisons between the innovator (reference
product) and test product
The broadest network of contract analytical laboratories with
facilities in the US, Canada,
Belgium, France, Germany,
India, China, Taiwan, Thailand,
and Singapore
Global Quality System
A list of SGS FDA-inspected
labs

REFERENCES
1.

2.
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. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research
(CDER), August 2000.
Moore, J.W. and Flanner, H.H. (1996). Mathematical Comparison of Dissolution Profiles. Pharm. Technol. 20 (6):64-74.
Guidance for Industry: Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations. U.S. Department of
Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), September 1997.

TABLE 1: EXAMPLE SIMILARITIES AND DIFFERENCES TO BIOWAIVER CRITERIA

BASIC CRITERIA FOR ESTABLISHING

THAT DRUG SUBSTANCE IS
HIGHLY SOLUBLE

JURISDICTION OR
ORGANIZATION

ESTABLISH
HIGH
pH RANGE
SOLUBILITY OF

Canada
Highest dose
(draft guidance)

BASIC CRITERIA FOR ESTABLISHING THAT DRUG SUBSTANCE

SHOWS HIGH INTESTINAL PERMEABILITY

ARE in vivo
NUMBER OF
PERMEABILITY
pH VALUES TO TEST
STUDIES
ACCEPTABLE

ARE in vitro
PERMEABILITY
STUDIES
ACCEPTABLE

ARE in vivo OR in
vitro INTESTINAL
PERMEATION
STUDIES
ACCEPTABLE

ARE LITERATURE
DATA
ACCEPTABLE

BASIC CRITERIA FOR ESTABLISHING THAT

PRODUCT IS RAPIDLY DISSOLVING OR
VERY RAPIDLY DISSOLVING
CLASS I SHOULD BE AT LEAST RAPIDLY DISSOLVING
CLASS III SHOULD BE VERY RAPIDLY DISSOLVING

HIGHLY
OPTIMAL
PERMEABLE
PADDLE SPEED
in vivo

RESTRICTIONS ON HOW EXCIPIENTS CAN VARY

FROM TEST TO REFERENCE PRODUCT

OPTIMAL
BASKET
SPEED

CRITERIA FOR
RAPID
DISSOLUTION

CRITERIA FOR
VERY RAPID
DISSOLUTION

CLASS I

CLASS III

1.2-6.8

At least 3, to
encompass pKa
region

Yes

No, perhaps as
supportive

No

Yes, if
acceptable
design

85%

Should be
50

Should be
100

>85% in
30 min

>85% in
15 min

Recommend Q1 same. Q2 very

similar, but test and reference
excipients may differ

Should be Q1 same.
Q2 very similar

EMA

Highest dose

1.2-6.8

At least 3, to
encompass pKa
region

Yes

No; perhaps as
supportive

No

Yes, if
acceptable
design

85%

Usually 50

Usually
100

85% in
30 min

>85% in
15 min

Recommend Q1 same. Q2 very

similar, but test and reference
excipients may differ

Should be Q1 same.
Q2 very similar

USA

Highest
Strength

1-7.5

Depends on
ionization profile;
should encompass
pKa region

Yes

Yes

Yes

No; perhaps as
supportive

90%

Should be
50

Should
be 50

85% in
30 min

Not defined

Use well-established excipients

in usual amounts

Does not grant

biowaivers for class III

1-6.8

At least 3, to
encompass pKa
region

Yes

No; perhaps as
supportive

Not
specified

85%

Not
specified

Not
specified

85% in
30 min

>85% in
15 min

Excipients that might affect bioavailability should be qualitatively

and quantitatively the same in
the test product and the
reference product.

Does not grant

biowaivers for class III

ASEAN
Member
Countries

Highest dose

Not specified

This table is an expansion of Table IX in International Guidelines for Bioequivalence of Systemically Available Orally Administered Generic Drug Products: A Survey of Similarities and
Differences found at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787230/

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