Roles 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 Science,
Center for Drug Evaluation and Research
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 established,
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.