Additional Considerations

When requesting a BCS-based waiver for in vivo BA/BE studies for IR solid oral dosage forms, applicants should note that the following factors can affect their request or the documentation of their request.

Excipients can sometimes affect the rate and extent of drug absorption. In general, using excipients that are currently in FDA-approved IR solid oral dosage forms will not affect the rate or extent of absorption of a highly soluble and highly permeable drug substance that is formulated in a rapidly dissolving IR product. To support a biowaiver request, the quantity of excipients in the IR drug product should be consistent with the intended function (e.g., lubricant). When new excipients or atypically large amounts of commonly used excipients are included in an IR solid dosage form, additional information documenting the absence of an impact on BA of the drug may be requested by the agency. Such information can be provided with a relative BA study using a simple aqueous solution as the reference product. Large quantities of certain excipients, such as surfactants (e.g., polysorbate 80) and sweeteners (e.g., mannitol or sorbitol) may be problematic, and the sponsors are encouraged to contact the review division when this is a factor.

Permeability of prodrugs will depend on the mechanism and (anatomical) site of conversion to the drug substance. When the prodrug-to-drug conversion is shown to occur predominantly after intestinal membrane permeation, the permeability of the prodrug should be measured. When this conversion occurs prior to intestinal permeation, the permeability of the drug should be determined. Dissolution and pH-solubility data on both the prodrug and drug can be relevant. The sponsors may wish to consult with appropriate review staff before applying the BCS approach to IR products containing prodrugs.

Exceptions

The BCS-based biowaivers are not applicable for the following. Narrow Therapeutic Range Drugs

The narrow therapeutic range drug products are defined as those containing certain drug substances that are subject to therapeutic drug concentration or pharmacodynamic monitoring, and/or where product labeling indicates a narrow therapeutic range designation. Examples

Excipients

Prodrugs include digoxin, lithium, phenytoin, theophylline, and warfarin. Because not all drugs subject to therapeutic drug concentration or pharmacodynamic monitoring are narrow therapeutic range drugs, the sponsors should contact the appropriate review division to determine whether a drug should be considered to have a narrow therapeutic range.

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