THe BIOWaIVer MONOGraPHS - FIP

is often difficult to pinpoint whether an absolute bioavailability of less than 85%
reflects less than “high” permeability or whether the drug substances is in fact highly
permeable and the low bioavailability is solely due to first pass effects. Further, there
are quite a few drug substances that cannot be administered intravenously (or have
not been) due to unwanted reactions upon injection or to inability to formulate a
parenteral version of the drug substance. In all these cases, it can be difficult to decide
between a Class III and a Class I drug substance. In the USA this is crucial, since at the
time of this writing, Class III drug substances are still excluded from biowaiving. In
Europe, and in countries following the WHO guidances, the permeability is not so
crucial, since both Class I and III drug substances can be considered for biowaivers.
However, as the requirements to be satisfied for a biowaiver based approval are far
more stringent for Class III drug substances, the classification is still quite important for
the sponsor of the application. Also with respect to the permeability, there needs to be
harmonization among the various regulatory authorities concerning the cutoff value
for high permeability. Currently the cutoff is made at a fraction absorbed of 0.9 in the
USA but at 0.85 in other jurisdictions. In the future, we will need to address a common
standard cutoff value and also determine which value of fraction absorbed would be
appropriate.
Third, based on current evidence, there seems to be little risk associated with applying
the biowaiver to NSAIDs that are weak acids with adequate solubility at pH 6.8 and
above. To date Biowaiver Monographs have been published for ibuprofen, diclofenac
salts and ketoprofen. There is a large body of evidence in the literature which suggests
that multisource products containing these drug substances tend to be bioequivalent.
When lack of bioequivalence occurs, it is usually the C max rather than the AUC which
falls out of the limits for the confidence interval. In other words, it is the rate rather than
the extent of absorption which can be a problem. On the one hand, a change in rate
of absorption might be critical if a rapid onset of action is required, but on the other
hand, these drugs can all be taken with or without food, which itself has a significant
influence on the rate of emptying into the intestine and hence on the rate of absorption
of drug substances belonging to this group. So it is not clear that a small change in the
rate of absorption is clinically important. Mostly the BCS biowaiver dissolution tests
can detect differences of this nature, though recent results from the Alvarez group
show that this might not always be the case if the f2 statistic is applied to determine
similarity of the dissolution profiles 6 . One suggestion might be to scale the data to
100% release from the reference formulation before applying the f2 statistic (since f2
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