An equivalence approach has been and continues to be recommended for BE comparisons. The recommended approach relies on (1) a criterion to allow the comparison, (2) a confidence interval for the criterion, and (3) a BE limit. Log-transformation of exposure measures before statistical analysis is recommended. BE studies are performed as single-dose, crossover studies. To compare measures in these studies, data have been analyzed using an average BE criterion.
FDA recommends continued use of an average BE criterion to compare BA measures for replicate and nonreplicate BE studies of both immediate- and modified-release products.
For oral solutions, elixirs, syrups, tinctures, or other solubilized forms, in vivo BA and/or BE can be waived (21 CFR 320.22(b)(3)(i)). Generally, in vivo BE studies are waived for solutions on the assumption that release of the drug substance from the drug product is self-evident and that the solutions do not contain any excipient that significantly affects drug absorption (21 CFR 320.22(b)(3)(iii)). However, there are certain excipients, such as sorbitol or mannitol, that can reduce the bioavailability of drugs with low intestinal permeability in amounts sometimes used in oral liquid dosage forms.
FDA recommend that BA and BE for a suspension generally be established for immediate-release solid oral dosage forms, and both in vivo and in vitro studies are recommended.
C. Immediate-Release Products: Capsules and Tablets
1. General Recommendations
For product quality BA and BE studies, FDA recommend that where the focus is on release of the drug substance from the drug product into the systemic circulation, a single-dose, fasting study be performed. FDA also recommend that in vivo BE studies be accompanied
DOCUMENTATION OF BA AND BE
An in vivo study is generally recommended for all solid oral dosage forms approved after 1962 and for bioproblem drug products approved before 1962. Waiver of in vivo studies for different strengths of a drug product can be granted under § 320.22(d)(2) when (1) the drug product is in the same dosage form, but in a different strength; (2) this different strength is proportionally similar in its active and inactive ingredients to the strength of the product for which the same manufacturer has conducted an appropriate in vivo study; and (3) the new strength meets an appropriate in vitro dissolution test, it is defined proportionally similar in the following ways:
*All active and inactive ingredients are in exactly the same proportion between different strengths (e.g., a tablet of 50-mg strength has all the inactive ingredients, exactly half that of a tablet of 100-mg strength, and twice that of a tablet of 25-mg strength).
*Active and inactive ingredients are not in exactly the same proportion between different strengths as stated above, but the ratios of inactive ingredients to total weight of the dosage form are within the limits defined by the SUPAC-IR and SUPAC-MR up to and including Level II.
* For high potency drug substances, where the amount of the active drug substance in the dosage form is relatively low, the total weight of the dosage form remains nearly the same for all strengths (within + 10 % of the total weight of the strength on which a biostudy was performed), the same inactive ingredients are used for all strengths, and the change in any strength is obtained by altering the amount of the active ingredients and one or more of the inactive ingredients. The changes in the inactive ingredients are within the limits defined by the SUPAC-IR and SUPAC-MR up to and including Level II. Exceptions to the above definitions may be possible, if adequate justification is provided.
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