THe BIOWaIVer MONOGraPHS - FIP

Formulation-wise, products designed to be absorbed in the oral cavity (e.g. sublingual
or buccal tablets) are also excluded from the BCS based biowaiver concept since
absorption from such products may occur through the oral mucosa, and so their
intended performance properties do not conform to the conceptual prerequisites of the
BCS based biowaiver.
The definition of ‘high solubility’ refers to the highest dose strength of an immediate
release product, which has to be soluble in 250 ml or less of aqueous media over the pH
range of 1 – 7.5,. Solubility measurements should be performed at 37 °C using a stabilityindicating,
validated method. Further experimental requirements are extensively
outlined and they are basically in line with pharmacopoeial recommendations.
The classification regarding high permeability refers to the extent of absorption in
humans, i.e. high permeability is concluded if the extent of absorption in humans
reaches at least 90 % of an orally administered dose. This conclusion may be based on
either pharmacokinetic studies in humans (e.g. mass balance, or absolute bioavailability
studies) or intestinal permeability methods like e.g. in vivo intestinal perfusion studies
in humans or validated in vitro permeation studies across a monolayer of cultured
epithelial cells.
Comparative in vitro dissolution investigations should ensure that no less than 85 %
of the labelled amount is dissolved within 30 min in each of the required media: 0.1 N
HCl, pH 4.5 and 6.8 buffers. Regarding experimental requirements, reference is made to
the US Pharmacopoeia and the US-FDA guidance for industry on Dissolution Testing of
Immediate Release Solid Oral Dosage Forms (August 1997) 3 . Resulting profiles should
be compared using the similarity factor (f2), unless 85% or more of the labelled amount
dissolves within 15 min from both products. The latter case would allow the conclusion
that the investigated products are similar without requiring any further statistical
calculations.
The US-FDA guidance requires that excipients be employed in usual quantities and
consistent with their intended function, in order to exclude the possibility that
particular excipient-driven effects occur in vivo which may not be detectable by
means of in vitro dissolution experiments. New excipients and/or atypically large
amounts of commonly used excipients require additional information and discussion.
Relative bioavailability studies (i.e. using a simple aqueous solution as a reference)
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