12/27
(or strength in the planned bioequivalence study) and the strength(s) for which a waiver is considered.
In order to assess linearity, the applicant should consider all data available in the public domain with
regard to the dose proportionality and review the data critically. Assessment of linearity will consider
whether differences in dose-adjusted AUC meet a criterion of ± 25%.
If bioequivalence has been demonstrated at the strength(s) that are most sensitive to detect a potential
difference between products, in vivo bioequivalence studies for the other strength(s) can be waived.
General biowaiver criteria
The following general requirements must be met where a waiver for additional strength(s) is claimed:
a) the pharmaceutical products are manufactured by the same manufacturing process,
b) the qualitative composition of the different strengths is the same,
c) the composition of the strengths are quantitatively proportional, i.e. the ratio between the
amount of each excipient to the amount of active substance(s) is the same for all strengths (for
immediate release products coating components, capsule shell, colour agents and flavours are
not required to follow this rule),
If there is some deviation from quantitatively proportional composition, condition c is still
considered fulfilled if condition i) and ii) or i) and iii) below apply to the strength used in the
bioequivalence study and the strength(s) for which a waiver is considered
i. the amount of the active substance(s) is less than 5 % of the tablet core weight, the
weight of the capsule content
ii. the amounts of the different core excipients or capsule content are the same for the
concerned strengths and only the amount of active substance is changed
iii. the amount of a filler is changed to account for the change in amount of active
substance. The amounts of other core excipients or capsule content should be the
same for the concerned strengths
d) appropriate in vitro dissolution data should confirm the adequacy of waiving additional in vivo
bioequivalence testing (see section 4.2).
Linear pharmacokinetics
For products where all the above conditions a) to d) are fulfilled, it is sufficient to establish
bioequivalence with only one strength.
The bioequivalence study should in general be conducted at the highest strength. For products with
linear pharmacokinetics and where the drug substance is highly soluble (see Appendix III), selection
of a lower strength than the highest is also acceptable. Selection of a lower strength may also be
justified if the highest strength cannot be administered to healthy volunteers for safety/tolerability
reasons. Further, if problems of sensitivity of the analytical method preclude sufficiently precise
plasma concentration measurements after single dose administration of the highest strength, a higher
dose may be selected (preferably using multiple tablets of the highest strength). The selected dose may
be higher than the highest therapeutic dose provided that this single dose is well tolerated in healthy
volunteers and that there are no absorption or solubility limitations at this dose.
Non-linear pharmacokinetics
For drugs with non-linear pharmacokinetics characterised by a more than proportional increase in
AUC with increasing dose over the therapeutic dose range, the bioequivalence study should in general
be conducted at the highest strength. As for drugs with linear pharmacokinetics a lower strength may
be justified if the highest strength cannot be administered to healthy volunteers for safety/tolerability
reasons. Likewise a higher dose may be used in case of sensitivity problems of the analytical method
in line with the recommendations given for products with linear pharmacokinetics above.
For drugs with a less than proportional increase in AUC with increasing dose over the therapeutic dose
range, bioequivalence should in most cases be established both at the highest strength and at the
lowest strength (or a strength in the linear range), i.e. in this situation two bioequivalence studies are
needed. If the non-linearity is not caused by limited solubility but is due to e.g. saturation of uptake
transporters and provided that conditions a) to d) above are fulfilled and the test and reference
products do not contain any excipients that may affect gastrointestinal motility or transport proteins, it
is sufficient to demonstrate bioequivalence at the lowest strength (or a strength in the linear range).