Bio-waivers: Accepting dissolution results in lieu of bio-(availability/equivalence) assessments

Bio-waiver is a term used for establishing and accepting quality of a pharmaceutical product (tablet and capsule) based on in vitro drug dissolution testing without corresponding bioavailability/bioequivalence data.

The scientific rationale behind this practice is that, in general, the bioavailability of a drug product depends on its release and solution formation (dissolution) characteristics. This, in vivo (physiological) dissolution is monitored or simulated in vitro by a dissolution test. Therefore, an assumption made here is that the in vitro dissolution test will appropriately and accurately reflect in vivo dissolution in humans and thus the bioavailability/bioequivalence characteristics of the products. This linkage is commonly referred to an in vitro-in vivo (co)relationship or IVIVC. Therefore, a pre-requisite for bio-waiver practices is a well established IVIVC.

It is, however, generally well recognized and documented in the literature that current practices of dissolution testing do not relate well to in vivo outcomes or often lack IVIVC. Therefore, presently, a bio-waiver should be considered as a scientifically weak case.

There are, however, guidances available for considering bio-waivers in certain, very specific, cases.  For example, bio-waivers are considered for products having drugs with high aqueous solubilities and absorbabilities from the GI tract in humans. In addition, the products should show fast dissolution. The underlying thought is that if drugs are highly soluble and absorbable, and the products show fast and complete in vitro dissolution (usually in less than 30 minutes), then the products are not expected to pose any potential problems in vivo, and thus they may be considered for bio-waivers. Therefore, it may be assumed that current practices of bio-waivers are based on faith rather their scientific merits.

In short, for an appropriate and scientifically valid bio-waiver inference, one has to establish IVIVC, with evidence that the techniques and methodologies (dissolution apparatus, medium and associated experimental conditions) employed are indeed capable of providing physiologically relevant results.

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