Waivers of In Vivo BE Studies (Biowaivers) INDs, NDAs, and ANDAs: Preapproval

Waivers of In Vivo Bioequivalence Studies (Biowaivers) in INDs, NDAs, and ANDAs: Preapproval.

When the drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to the strength on which BA or BE ( bioequivalence ) testing has been conducted, an in vivo BE demonstration of one or more lower strengths can be waived based on dissolution tests and an in vivo study on the highest strength.(This recommendation modifies a prior policy of allowing biowaivers for only three lower strengths on ANDAs.)

For an NDA, biowaivers of a higher strength will be determined to be appropriate based on
(1) clinical safety and/or efficacy studies including data on the dose and the desirability of the higher strength, (2) linear elimination kinetics over the therapeutic dose range,
(3) the higher strength being proportionally similar to the lower strength, and
(4) the same dissolution procedures being used for both strengths and similar dissolution results obtained.

FDA recommend that a dissolution profile be generated for all strengths. If an appropriate dissolution method has been established , and the dissolution results indicate that  the dissolution characteristics of the product are not dependent on the product strength, then dissolution profiles in one medium are usually sufficient to support waivers of in vivo testing. Otherwise, dissolution data in three media (pH 1.2, 4.5, and 6.8) are recommended. FDA recommend that the f2 test be used to compare profiles from the different strengths of the product. An f2 value greater than or equal to  50 indicates a sufficiently similar
dissolution profile such that further in vivo studies are not needed. For an f2 value greater than or equal to 50, (21 CFR 320.22(d)(2)(ii)). The f2 approach is not suitable for rapidly dissolving drug products (e.g., greater than or equal to  85% dissolved in 15 minutes or less).

For an ANDA.

Conducting an in vivo study on a strength that is not the highest may be appropriate for reasons of safety, subject to approval by the FDA, and provided that the following conditions are met:

* Linear elimination kinetics has been shown over the therapeutic dose range.

* The higher strengths of the test and reference products are proportionally similar to their corresponding lower strength.

* Comparative dissolution testing on the higher strength of the test and reference products is submitted and found to be appropriate.

NDAs and ANDAs:
Postapproval Information on the types of in vitro dissolution and in vivo BE studies for immediate-release drug products approved as either NDAs or ANDAs in the presence of specified postapproval changes are provided in an US FDA’s guideline SUPAC-IR: Immediate Release Solid Oral Dosage Forms Scale-Up and Post-Approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation. For postapproval changes, FDA recommend that the in vitro comparison be made between the prechange and postchange products. In instances where dissolution profile comparisons are suggested, FDA also recommend an f2 test be used. An f2 value greater than or equal to 50 suggests a sufficiently similar dissolution profile and no further in vivo studies are needed. When in vivo BE studies are called for, FDA recommend that the comparison be made for NDAs between the prechange and postchange products, and for ANDAs between the postchange and reference listed drug products.
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