Profile Comparison

Among several methods investigated for dissolution profile comparison, the fz factor is the simplest and widely applicable (1). Moore and Flanner (10) proposed a model inde- 

Dissolution Profile Comparison Model Independent Analysis Similarity Factor 

Average Difference Between Reference and Test Curves 

A value of 50 or greater (50-100) ensures sameness or equivalence of the two curves and, thus, the performance of 

---

Profile comparison of temperature, velocity, major species (CH, Oj, CO, COj, and HjO), and minor species (H, O, and OH) at the extinction state using different outer-flow conditions, for counterflow twin-stoichiometric methane/air flames. For clarity, the symbols do not represent the actual grid distribution employed in the calculation. 

P. M. Sathe, Y. Tsong, V. Shah. In vitro dissolution profile comparison Statistics and analysis, model dependent approach. Pharm. Res. 1996, 13, 1799-1803. 

Figure 36. Solid fraction profile comparisons for Tidd PFBC and cold model based on simplified scaling laws. (From Glicksman and Farrell, 1995.)...

The theories applied to dissolution have stood the test of time. Basic understanding of these theories and their application are essential for the design and development of sound dissolution methodologies as well as for deriving complementary statistical and mathematical techniques for unbiased dissolution profile comparison (3). 

The BCS also predicts the possibility of obtaining an in vitro/in vivo correlation. Justification of a biowaiver is based on a combination of the BCS classification of the drug substance and a drug product dissolution profile comparison. In all these instances, an anchor with a bioavailable product is established. Specifically, to obtain a biowaiver for an IR generic product ... 

Figure 4 Dissolution profile comparison model independent analysis.

For drug products dissolving 85% or greater in 15 min or less, a profile comparison is not necessary. 

Shah VP, Tsong Y, Sathe P, Liu JP. In vitro dissolution profile comparison—statistics and analysis of the similarity factor, f2. Pharm Res 1998 15 889-896. 

Freitag G. Guidelines on dissolution profile comparison. Drug Inf J 2001 35 865-874. 

Sathe P, Tsong Y, Shah VP. In vitro dissolution profile comparison and IVIVR, carbamazepine case. In Young D, Devane JG, Butler J, eds. In Vitro-in Vivo Correlations. New York Plenum Press, 1997 31-42. 

SUPAC Dissolution Profile Comparison Supporting Post-approval Changes... 

Key operating parameters that may change (or be optimized) throughout a product s development and approval cycle are dissolution sampling time points and dissolution limits or specifications by which the dissolution results should be evaluated. The results generated from the dissolution test need to be evaluated and interpreted based on the intended purpose of the test. If the test is used for batch-to-batch control, the results should be evaluated in regard to the established limits or specification value. If the test is being utilized as a characterization test (i.e., biopharmaceutical evaluations, formulation development studies, etc.) the results are usually evaluated by profile comparisons. 

If the development formulation were considered a pilot batch, then increasing batch size from 10 kg to 1100 kg using equipment of the same design and operating principles (see later) would be considered a Level 2 change. Additional tests recommended include stability (three months accelerated stability and longterm stability data on one batch) and multipoint dissolution profile comparison in the application or compendial medium (Case B). 

A high degree of sensitivity of in vitro dissolution tests to formulation differences raises questions about the appropriate acceptance criteria—how similar should two in vitro dissolution profiles be to be considered similar The SUPAC-IR introduced to the regulatory decision-making process a metric referred to as f2 [43] for profile comparison. Application of this criterion to the examples cited in this report (e.g., piroxicam formulations) would have resulted in a recommendation for the in vivo bioequivalence study. 

Design of the Rate (Profile) Comparison Study The typical in vitro release... 

Two dissolution profiles are considered similar when the f2 value is 50. To allow the use of mean data, the coefficient of variation should not be more than 20% at the earlier time points (e.g., 10 minutes), and should not be more than 10% at other time points. Note that when both test and reference products dissolve 85% or more of the label amount of the drug in < 15 minutes using all three dissolution media recommended above, the profile comparison with an f2 test is unnecessary. 

---