1.

What are the principles of in vitro dissolution tests for immediate release
solid oral dosage forms such as tablets & capsules?

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.

What is the basis for the similarity factor criterion?

2.

3.

Define similarity factor.

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.

What is a model independent approach?

A simple model independent approach uses a difference factor (f1)
and a similarity factor (f2) to compare dissolution profiles. 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:

4.

What are the limitations of the similarity factor?

The similarity factor f2 (where 0 f2 100 and f2 50% implies
dissolution profiles are similar) is a function of mean differences
and does not take into account the differences in dissolution within
the test and reference batches. Hence, careful interpretation is
warranted when f2 is used as a similarity factor when the variances
of the profiles are very different.
One of the major drawbacks identified was finding the sampling
distribution of the statistics. This statistic has complicated
properties and deriving the distribution of the statistic is not
mathematically tractable. Shah et al. (1998) proposed a bootstrap
method to calculate a confidence interval for the f2 factor. Because
f2 is sensitive to the measurements obtained after either the test
or reference batch has dissolved more than 85%, Shah et al.
(1998) recommended a limit of one sampling time point after 85%
dissolution. A recent article, discussing the aspects of the
dissolution profile testing problem, by Eaton et al. (2003) also
raised some issues concerning the use of the f2 statistic.
As a result its sampling error can not be analytically quantified, and
its expectation and variance require numerical integration. In
addition, a value of f2 between 50 and 100 computed from a
sample of 24 dosage units does not guarantee dissolution
similarity in a population of millions of dosage units because of
sampling error. Thus the similarity factor is based on convenience,
although it does measure the similarity of two dissolution profiles
and is easy to perform. The proposed critical value 50 was based
on reviewers practical understanding of similarity of two true
profiles. However, f2 as an estimate does not have the desirable
properties often expected in statistical science.
What are the objectives of comparative dissolution profiling?
For accepting product sameness under SUPAC-related changes.
To waive bioequivalence requirements for lower strengths of a
dosage form.
To support waivers for other bioequivalence requirements.
Define an immediate release dosage form.

where n is the number of time points, Rt is the dissolution value of

the reference (prechange) batch at time t, and Tt is the dissolution
value of the test (postchange) batch at time t.
Most suitable for dissolution profile comparison when three to four
or more dissolution time points are available
Other recommendations
o 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.
o Only one measurement should be considered after 85%
dissolution of both the products.
o 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%.
o The mean dissolution values for Rt can be derived either
from (1) last prechange (reference) batch or (2) last two or
more consecutively manufactured prechange batches.

What are the uses of f2?

Dissolution profiles may be considered similar by virtue 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.

What is multi-point dissolution testing?

10.

How many dosage units of a drug product should be evaluated to support a

biowaiver request?

11.

A minimum of 12 dosage units of a drug product should be

evaluated to support a biowaiver request. Samples should be
collected at a sufficient number of intervals to characterize the
dissolution profile of the drug product (e.g., 10, 15, 20, and 30
minutes).
How many time points should be used for similarity profile comparison?
In the FDA guideline for industry, the procedure allows the use of
mean data and recommends that the Relative Standard Deviation
(RSD) at an earlier time point (for example 5 or 10 minutes) not be
more than 20%, and at other time points not more than 10%. In
instances where the RSD within a batch is more than 15%, the
guideline suggests using a multivariate model-independent
procedure, but no references are given for these situations.

12.

13.

When are dissolution properties of two products regarded similar?

- 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.
What are the usual reasons for the failure to meet f2?

14.

What may be done in case the profiles fail to meet f2?

15.

How are comparative dissolution data reported?