of Dissolution Testing:
Regulatory, Industry and Academic Perspectives
-Role of Dissolution
Testing in Regulating Pharmaceuticals
Vinod P. Shah and Roger L. Williams
Office of Pharmaceutical
- Center for Drug Evaluation
Food and Drug Administration, Rockville, MD
- Dissolution testing over the last
quarter century has emerged as a highly valuable in vitro test
to characterize drug product performance. For the test to be
useful, it should be simple, reliable and reproducible and should
be able to discriminate between different degrees of product
performance. The value of the test is significantly enhanced
when product performance is evaluated as a function of time,
i.e., when the dissolution profile is determined rather than
a single point determination, which is a standard compendial
for batch release.
Dissolution tests are used to assess batch to batch quality,
where the approach forms the basis for specifications (test,
methodology, acceptance criteria) to allow batch release. Dissolution
is also used to: 1) provide process control and quality assurance;
and 2) assess the need for further bioequivalence (BE) studies
relative to minor post-approval changes, where it can function
as a signal of bioinequivalence. In vitro dissolution studies
for all product formulations investigated (including prototype
formulations) are encouraged, particularly if in vivo absorption
characteristics are being defined for the different product formulations.
Such efforts may allow an in vitro/in vivo correlation. When
an in vitro correlation or association is available, the in vitro
test can serve not only as a quality control specification for
the manufacturing process, but also as an indicator of how the
product will perform in vivo. Dissolution guidances developed
by the Agency provide recommendations on the development of dissolution
test methodology, on how to set specifications for dissolution
testing, and the regulatory applications of dissolution testing
(1,2). A recent draft FDA guidance on biowaiver based on the
biopharmaceutics classification system suggests that documentation
of bioequivalence via dissolution studies may be appropriate
for orally administered immediate release drug products which
are highly soluble, highly permeable and rapidly dissolving (3).
A dissolution profile, or at least a two-point determination
should be used to characterize the in vitro performance of an
immediate release drug product. Because a modified release dosage
form is a more complex formulation, three to four dissolution
time points are needed to characterize the product. Dissolution
profile comparison has been extensively used in assessing product
sameness, especially in the presence of certain SUPAC related
post-approval changes. In order to avoid subjective evaluation
of dissolution profile comparison, FDA has adopted a simple method
to compare dissolution profiles, which is termed a similarity
factor, f2 (4).
The art and science of dissolution testing have come a long way
since its inception about 25 years ago. The procedure is well
reliable, and reproducible. Increasingly, in vitro dissolution
testing is relied on to assure product performance. An appropriate
dissolution test procedure is a simple and economical method
that can be utilized effectively in developing countries to assure
acceptable drug product quality.
- 1. Guidance for Industry: Dissolution
Testing of Immediate Release Solid Oral Dosage Form, August 1997.
2. Guidance for Industry: Extended Release Solid Oral Dosage
Forms: Development, Evaluation and Application of In Vitro/In
Vivo Correlations, September 1997.
3. Draft Guidance for Industry: In Vivo Bioavailability and Bioequivalence
Studies for Immediate Release Solid Oral Dosage Forms Containing
Certain Active Drug Ingredients/Active Moieties Based on a Biopharmaceutics
Classification System, January 1999.
4. V P Shah, Y Tsong, P Sathe and J-P Liu. In vitro dissolution
profile comparison-statistics and analysis of the similarity
factor, f2. Pharm. Res. 15: 889-896, 1998.