THe BIOWaIVer MONOGraPHS - FIP

quinine I-II Dose-related
toxicity at
concentrations
not
far above
therapeutic
levels
No Solubility at highest dose
strength (300mg) passes
D:S criteria at pH 6.8 but not
pH 7.5. Dissolution is poor
at pH 6.8 from marketed
products.
ranitidine III few Yes “rapid dissolution” and
similarity between test and
reference is recommended
as the pre-requisite.
rifampicin II Many
reports of
failure to
meet BE
No Poorly soluble API, unexplained
lack of bioequivalence
among products
common
stavudine I few Yes Dissolution requirements
per Guidances for Class I
verapamil *I/II few YEs *Meets solubility criteria
at pH 6.8 but not pH 7.5 (not
biowaivable according to
FDA).
Where applicable, dissolution
requirements per
Guidances for Class I
Of the Biowaiver Monographs published to date, most have recommended a biowaiverbased
approval after a significant post-approval change or for approval of a generic
version. This is largely because most of the APIs considered to date have been highly
soluble over the BCS pH range and have a wide therapeutic index.
For seven of the 32 APIs considered to date, it was deemed inappropriate to recommend
a biowaiver. In the case of ciprofloxacin, furosemide, mefloquine and rifampicin,
the solubility of the drug substance was simply far too low at pH values typical of
the small intestine to consider applying the biowaiver. Additionally for furosemide
and rifampicin, there had been many reports of formulations failing bioequivalence
studies published in the literature and moreover, these failures could often not be
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