THe BIOWaIVer MONOGraPHS - FIP

Last but not least, there were three APIs which failed to meet solubility criteria at
low pH but which easily met the criterion at pH 6.8 and above. These were the three
weakly acid anti-inflammatory drugs, diclofenac, ibuprofen and ketoprofen. As
these APIs all have wide therapeutic indices and their dissolution is rapid at higher
pHs, it was considered to be an acceptable risk to allow them to be biowaivered.
Almost all published pharmacokinetic studies with formulations of these APIs show
bioequivalence in AUC for the test and reference products. Occasionally the C max is
slightly out of the confidence interval for bioequivalence, and it is still not clear whether
this can be detected with BCS conform dissolution testing 6,7 . However, since labeling
indicates that these APIs can be taken with or without food, and since C max is lower and
occurs at a later time when the products are given with food, it seems highly unlikely
that a small discrepancy in C max would have any ramifications for therapy in clinical
practice. This argumentation underscores recommendations of the WHO guidance,
which allows APIs with such characteristics to be eligible for the biowaiver.
From the foregoing discussion it is obvious that there is more to biowaiving than just
the BCS classification of the drug substance and that there is no “one-size-fits-all”
approach to biowaiving. Instead, the approach of weighing up the risks and benefits for
each individual drug substance has proven to be the more useful approach over the 32
compounds assessed to date.
Nevertheless it is interesting to consider the results for the 32 drug substances to date
in the context of the BCS classification.
BCS Class I
Altogether 14 APIs in the dataset can be reasonably assigned to BCS Class I. These
are acetylsalicylic acid, amitriptyline, chloroquine, doxycycline, levofloxacin,
metronidazole, prednisolone, prednisone, primaquine, propranolol, quinidine, quinine,
stavudine and verapamil. Of these, 12 were recommended for biowaivers and only two
drugs, both with NTI status, were excluded from biowaiving.
Acetylsalicylic acid, doxycycline hyclate, propranolol hydrochloride, primaquine
phosphate, and stavudine are highly soluble and highly permeable and BCS Class
I, with no reports in the literature suggesting an impact of specific excipients on
bioequivalence and which possess a wide therapeutic index. In general, as long as the
excipients in the test product have already been used in products approved in ICH and
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