`
`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
`
`hat 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 changesor with
`different strengths, helps assure similarity in
`product performance and signals bioinequiva-
`lence.
`
`Among several methods investigated for dissolu-
`tion profile comparisonf; is the simplest. Moore
`and Flanner proposed a model independent math-
`ematical approach to compare the dissolution
`profile using two factors, f1 and f2 (1 }.
`
`f1 =ll£t=ln l Rt-T't I MEN” R113" 100
`
`f2: 50409 {[l+ilinl2:=1"' ( Rt 5ft)2 1‘35 '100}
`
`where R[ and T1 are the cumulative percentage
`dissolved at each ofthe selected n time points of
`the reference and test product respectively. The
`factor f; is proportional to the average difference
`between the two profiles. where as factorfz 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 f; measures the closeness between the
`two profiles. Because of the natu re of measure-
`ment,f1 was described as difference factor,and f; as
`similarity factor {2). In dissolution profile compar-
`isms, especially to assrrre 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 compar-
`ison has been the focus in Agency guidances.
`When the two profiles are identical, f1: 1 00. An
`average difference of 10% at all measured time
`points results in a f; value of 50. FDA has set a public
`standard of f2 value between 50-1 00 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 f; metric
`is desired,a bootstrap approach to calculate a
`confidence interval can be performed.
`
`- The dissolution measurements of the two prod-
`ucts (test and reference. pre- and post- change.
`two strengths} should be made underthe
`same test conditions'l’he dissolution time
`
`points for both the profiles Should be the
`same, e.g.. for immediate release products 1 5.
`30, 45 and 60 minutes. for extended release
`
`products 1.2, 3, S and 8 hours.
`
`- Because f2 values are sensitive to the number of
`dissolution time points, only one measmement
`should be considered after 85% dissolution of
`the product.
`
`i For products which are rapidly dissolving, i.e.,
`more than 85% in 15 minutes or less,a profile
`comparison is not necessary.
`
`- A f; value of 50 or greater (50-1 00} ensures same-
`ness or equivalence of the two
`curves and. thus. the performance of the
`two products.
`A general question is how large can the differ-
`ence 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 considerationa conservative
`approach is appropriateThe 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:
`
`l. J.W.Moore and H.H.F|anner,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,ln vitro dissolution
`profile comparison - statistics and analysis of the
`similarity factor, f2. Pharm. Res. 1 15:889-896. 1998.
`Dissolution Technologies | August 1999 '5
`
`Amneal 1081
`Amenal v. Endo
`|PR2014-00360
`
`1
`
`