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OCTOBER 2014
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
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-
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.
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
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.
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/
iii.
iv.
v.
vi.
vii.
viii.
2.
3.
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.
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.
JURISDICTION OR
ORGANIZATION
ESTABLISH
HIGH
pH RANGE
SOLUBILITY OF
Canada
Highest dose
(draft guidance)
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
HIGHLY
OPTIMAL
PERMEABLE
PADDLE SPEED
in vivo
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
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
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
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
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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