A request for a waiver of in vivo BA/BE studies based on the BCS is not appropriate for dosage forms intended for absorption in the oral cavity (e.g., sublingual or buccal tablets).
REGULATORY ASPECTS INDs/NDAs
Evidence demonstrating in vivo BA or information to permit the FDA to waive this evidence must be included in the NDAs [21 CFR 320.21(a)]. A specific objective is to establish in vivo performance of the dosage form used in the clinical studies that provided primary evidence of efficacy and safety. The sponsor may wish to determine the relative BA of an IR solid oral dosage form by comparison with an oral solution, suspension, or intravenous injection [21 CFR 320.25 (d)(2) and 320.25 (d)(3)]. The BA of the clinical trial dosage form should be optimized during the IND period.
Once the in vivo BA of a formulation is established during the IND period, waivers of subsequent in vivo BE studies, following major changes in components, composition, and/or method of manufacture (e.g., similar to SUPAC-IR Level 3 changes) may be possible using the BCS. The BCS-based biowaivers are applicable to the to-be-marketed formulation when changes in components, composition, and/or method of manufacture occur to the clinical trial formulation, as long as the dosage forms have rapid and similar in vitro dissolution profiles. This approach is useful only when the drug substance is highly soluble and highly permeable (BCS Class 1), and the formulations pre- and post-change are pharmaceutical equivalents [under the definition at 21 CFR 320.1 (c)]. The BCS-based biowaivers are intended only for BE studies. They do not apply to food effect BA studies or other pharmacokinetic studies.
The BCS-based biowaivers can be requested for rapidly dissolving IR test products containing highly soluble and highly permeable drug substances, provided that the reference listed drug product is also rapidly dissolving and the test product exhibits similar dissolution profiles to the reference listed drug product (see "The Biopharmaceutics Classification System" and "Method of Classification"). This approach is useful when the test and reference dosage forms are pharmaceutical equivalents. The choice of dissolution apparatus (USP Apparatus I or II) should be the same as that established for the reference listed drug product.
The BCS-based biowaivers can be requested for significant post-approval changes (e.g., Level 3 changes in components and composition) to a rapidly dissolving IR product containing a highly soluble, highly permeable drug substance, provided that dissolution remains rapid for the post-change product and both the pre- and post-change products exhibit similar dissolution profiles (see "The Biopharmaceutics Classification System" and "Method of Classification"). This approach is useful only when the drug products pre- and post-change are pharmaceutical equivalents.
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