In Vitro Release Approaches Lower Strength

Usually only one strength of a topical dermatological drug product is available although sometimes two or rarely, three strengths may be marketed. When multiple strengths are available, a standard practice is to create lower strengths by altering the percentage of active ingredients without otherwise changing the formulation or its manufacturing process. Topical dermatological drug products usually contain relatively small amounts of the active drug substance, usually < 5% and frequently < 1%. In this setting, changes in the active ingredient may have little impact on the overall formulation.

Safety and efficacy should be documented for all strengths of topical drug products in the NDA submissions. Using some of the approaches suggested in this guidance, BA may also be documented for the highest strength. For lower strengths, where documentation of BA is considered important, this guidance suggests that in vitro release may be performed. Similarly, for an ANDA, when BE has been documented for the highest strength, in vitro release may also be used to waive in vivo studies to assess BE between these lower strengths and the corresponding strengths of the RLD. If this approach suggests bioinequivalence, further studies may be important.

To support the BE of lower strengths in an ANDA, the following conditions are important.

■ Formulations of the two strengths should differ only in the concentration of the active ingredient and equivalent amount of the diluent.

■ No differences should exist in manufacturing process and equipment between the two strengths.

■ For an ANDA, the RLD should be marketed at both higher and lower strengths.

■ For an ANDA, the higher strength of the test product should be BE to the higher strength of RLD.

In vitro drug release rate studies should be measured under the same test conditions for all strengths of both the test and the RLD products. The in vitro release rate should be compared between (i) the RLD at both the higher (RHS) and lower strengths (RLS); and (ii) the test (generic) products at both higher (THS) and lower strengths (TLS). Using the in vitro release rate, the following ratios and comparisons should be made:

Release rate of RHS/Release rate of RLS ~ Release rate of THS/Release rate of TLS

The ratio of the release rates of the two strengths of the test products should be about the same as the ratio of the release rate of reference products, that is:

Release rate of RHS X Release rate of TLS

Release rate of RLS X Release rate of THS

Using appropriate statistical methods, the standard BE interval (80-120) for a lower strength comparison of test and reference products should be used.

After approval, a sponsor may wish to develop an intermediate strength of a topical dermatological drug product when two strengths have been approved and are in the marketplace. In this case, the in vitro release rate of the intermediate strength should fall between the in vitro release rates of the upper and lower strengths. Modifications of the approach described in this section of the guidance can thus be applied, providing all strengths differ only in the amount of active ingredient and do not differ in manufacturing processes and equipment.

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