Dissolution Profile Comparison Using
Similarity Factor, f2
Vinod P. Shah, Yi Tsong, Pradeep Sathe and Roger L. Williams
Office of Pharmaceutical Science, Center for Drug Evaluation and Research
Food and Drug Administration, Rockville, MD

What is a dissolution profile comparison and what is its impact?

In recent years, FDA has placed more emphasis on a dissolution profile comparison in the area of post-approval changes and biowaivers. Under appropriate test conditions, a dissolution profile can characterize the product more precisely than a single point dissolution test. A dissolution profile comparison between pre-change and post-change products for SUPAC related changes, or with different strengths, helps assure similarity in product performance and signals bioinequivalence.

Among several methods investigated for dissolution profile comparison, f2 is the simplest. Moore and Flanner proposed a model independent mathematical approach to compare the dissolution profile using two factors, f1 and f2 (1).

where Rt and Tt are the cumulative percentage dissolved at each of the selected n time points of the reference and test product respectively. The factor f1 is proportional to the average difference between the two profiles, where as factor f2 is inversely proportional to the average squared difference between the two profiles, with emphasis on the larger difference among all the time-points. The factor f2 measures the closeness between the two profiles. Because of the nature of measurement, f1 was described as difference factor, and f2 as similarity factor (2). In dissolution profile comparisons, especially to assure similarity in product performance, regulatory interest is in knowing how similar the two curves are, and to have a measure which is more sensitive to large differences at any particular time point. For this reason, the f2 comparison has been the focus in Agency guidances.

When the two profiles are identical, f2=100. An average difference of 10% at all measured time points results in a f2 value of 50. FDA has set a public standard of f2 value between 50-100 to indicate similarity between two dissolution profiles.
For a dissolution profile comparison:

· At least 12 units should be used for each profile determination. Mean dissolution values can be used to estimate the similarity factor, f2. To use mean data, the % coefficient of variation at the earlier point should not be more than 20% and at other time points should not be more than 10%.
· For circumstances where wide variability is observed, or a statistical evaluation of f2 metric is desired, a bootstrap approach to calculate a confidence interval can be performed.
· The dissolution measurements of the two products (test and reference, pre- and post- change, two strengths) should be made under the same test conditions. The dissolution time points for both the profiles should be the same, e.g., for immediate release products 15, 30, 45 and 60 minutes, for extended release products 1, 2, 3, 5 and 8 hours.
· Because f2 values are sensitive to the number of dissolution time points, only one measurement should be considered after 85% dissolution of the product.
· For products which are rapidly dissolving, i.e., more than 85% in 15 minutes or less, a profile comparison is not necessary.
· A f2 value of 50 or greater (50-100) ensures sameness or equivalence of the two
curves and, thus, the performance of the
two products.

A general question is how large can the difference between the mean dissolution profiles be before the difference is likely to impact on in vivo performance. From a public health point of view, and as a regulatory consideration, a conservative approach is appropriate. The f2 comparison metric with a value of 50 or greater is a conservative, but a reliable estimate to assure product sameness and product performance.

References:
1. J.W.Moore and H.H.Flanner, Mathematical Comparison of curves with an emphasis on in vitro dissolution profiles. Pharm. Tech. 20(6), : 64-74, 1996.

2. V.P.Shah, Y.Tsong and P.Sathe, In vitro dissolution profile comparison - statistics and analysis of the similarity factor, f2. Pharm. Res. 15: 889-896, 1998.