There are some instances where the FDA hasВ stated that bio-waivers are not appropriate, i.e., narrow therapeutic range drugs such as warfarin sodium and products designed for absorption in the oral cavity 6. For BCS class 3 products, the drug substance needs to be highly soluble and rapidly dissolve, and the test product formulation is required to be quantitatively and qualitatively similar to the reference product. To support a bio-waiver, the drug substance must be shown to be both highly soluble and permeable (BCS class 1) and it must be rapidlydissolving, i.e., в‰Ґ 85% of the analyte must dissolve in в‰¤ 15 minutes under the defined conditions and the excipients present in the drug product must not impact on the permeability and subsequent rate of absorption of the drug. Similarly, when the gastrointestinal tract transit times are rapid it is not always necessary to perform in vivo bioavailability or bioequivalence studies for BCS class 1 and 3 drugs 6. Where the in vivo dissolution of an immediate-release product is very fast with respect to gastric emptying, and the drug solubility is high, then drug absorption is typically not affected by dissolution rate. Some immediate-release products can be classified as having very rapid dissolution and in some instances the BCS classification can be used as a justification for a subsequent bio-waiver.

The objectives of the guidance was twofold: to provide a strategy to identify those clinical bioequivalence tests which may not be required and secondly, to recommend where dissolution testing can be used to replace bioequivalence testing, advising on methods for solubility, dissolution and permeability to aid in this classification. Highly soluble compounds are categorised as BCS class 1 (highly permeable) or BCS class 3 (poorly permeable) and poorly soluble compounds are classified as BCS class 2 (highly permeable) or BCS class 4 (poorly permeable). BCS classifies compounds into four categories based on their solubility and permeability characteristics. A recent United States Food and Drug Administration (FDA) guidance 6 describes how sponsors can apply for waivers in lieu of in vivo bioavailability and bioequivalence testing based on a combination of the biopharmaceutics classification system (BCS) and in vitro dissolution testing.

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