FDA bioavailability waiver

Poor aqueous solubility, a compound-related factor rather than an assay-related factor, has a major effect by introducing noise into absorption screening and thus has an effect on making computational model building very difficult. It must be stressed that the compound solubility factor virtually never appears as an explicit consideration in the published permeability literature. Compoufid sets are published that are used to validate in vitro cell-based absorption assays. Validation usually means obtaining an acceptable correlation between human fraction absorbed data and in vitro permeability data. The absorption data always include the experimentally well-controlled but compound number-limited human fraction-absorbed data that are used to define absorption ranges in the FDA bioavailability waiver guidelines. This limited compound set is then supplemented... 

The method requires a compound in the low milligrams and works best for very insoluble compounds, which also are the most difficult to quantitate by other methods. The method is relatively slow, since for best results the titration rate is greatly slowed as the precipitation point is reached. The compound is solubilized at the beginning of the assay, either by pH dissolution of solid or by dissolution of a concentrated DMSO stock solution in aqueous media of appropriate pH. As a result there is no control as to which polymorphic form of the compound corresponds to the solubility product. The method is likely to be particularly useful in the solubility classification of compounds according to the FDA bioavailability waiver system because of the extensive validation of the method, its reproducibility, and its particular applicabifity to compounds with the poorest solubility. 

Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms based on a biopharmaceutics classification system. Center for Drug Evaluation and Research, Food and Drug Administration, issued 8/2000, posted 8/31/2000. http //www.fda.gov/cder/guidance/ index, htm... 

FDA Guidance for Industry Waiver of in vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Containing Certain Active Moieties/ Active Ingredients Based on a Biopharmaceutics Classification System, CDER-GUID 2062dft.wpd Draft, Jan. 1999. 

Food and Drug Administration (FDA). Guidance for Industry. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-release Solid Dosage Forms Based on a Biopharmaceutics Classification System. RockviUe, MD FDA, 2000. 

FDA 2000 Guidance for industry Waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms based on Biopharmaceutics Classifiaction System, Rockville, MD. 

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