THe BIOWaIVer MONOGraPHS - FIP

Similar to the US-FDA guidance, therapeutic aspects are addressed first, i.e. the
drug substance in question should not have a narrow therapeutic index (NTI). This
recommendation is meant to serve as an initial risk assessment since as of this writing
it has not been proven that the BCS based biowaiver is eligible even when narrowed
acceptance limits (i.e. 90 – 111%) for AUC and/or C max are required in vivo.
Solid oral formulations other than immediate release products are excluded from
the biowaiver approach but it is specifically mentioned that it could be used for
orodispersible formulations provided it can be shown that the drug is not absorbed
across the oral mucosa.
Another particularity of the revised EMA guideline refers to the EU directive (2001/83/
EC, Article 10(2)(b) allowing a generic to contain different salts, esters, ethers, isomers,
mixtures of isomers, complexes or derivatives of an active substance. Appendix 3
therefore clarifies that this general definition of the ‘same active substance’ can not be
applied for a generic applying the BCS based biowaiver concept. Instead, only different
salts, both of which are shown to be BCS Class I drug substances, are considered
acceptable. All of the other variations on the active substance mentioned above do
not qualify for the biowaivers since potential bioavailability differences would not be
detectable by means of investigations relevant for the BCS based biowaiver concept.
Class boundaries and formulation-related requirements have been modified and
specified as follows:
The criterion for high solubility refers now to the highest single dose (rather than the
highest dose strength), and a physiological pH range between pH 1 – 6.8. It is expected
that not only usual three media are used (pH 1.2, 4.5, and 6.8) but that solubility should
also be investigated at the pKa, if applicable.
It is interesting to note that the European guidance particularly requires information
on absorption rather than demonstration of high permeability. According to section
III.2 the extent of absorption should reach at least 85 % in order to classify for high
permeability. This interpretation of the permeability approach is in line with a paper
published by Benet et al. 7 where the ‘ambiguous’ definition of high permeability
has been criticised. In contrast to US-FDA and WHO requirements, absorption
characteristics can only be substantiated by means of human data, i.e., cell culture
investigations could be supportive but are not considered valid as stand-alone
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