the generic applicant’s responsibility to define the
impurity profile (if any), provide impurity levels,
their characterization and biological qualification
according to current guidelines. However, the pre-
sence of a toxic impurity, or an impurity endowed
with a particular biological activity, and which
is not present in the reference product, will make
the latter’s dossier an inappropriate reference.
Toxicity of impurities should be discussed in the
nonclinical overview, with cross-references to the
quality overview.
Whenever an active substance is the subject of a
pharmacopoeia monograph, suitability of the
monograph for the substance must be controlled.
On request of the active substance manufacturer
the European Pharmacopoeia issues Certificates of
Suitability (CEP), which replace the information of
the corresponding sections and allow reference to
the pharmacopoeia monograph. Any technical
characteristics not covered by the certificates
must be supplied as additional information.
Drug product
A generic product should comply with the follow-
ing characteristics:
Same qualitative–quantitative composition of
the active ingredient as the reference product.
Known excipients of established use.
Same pharmaceutical form. Oral solid pharma-
ceutical forms of immediate release, such as
tablets and capsules, are regarded as the same
dosage form.
Bioequivalence with the reference product.
The note for guidance CPMP/EWP/QWP/1041/98
on investigation of bioavailability and bioequiva-
lence sets the criteria for showing pharmacokinetic
equivalence and thus permits waiver of extensive
clinical trials for demonstration of efficacy.
Two products are considered bioequivalent
when the drug substance, in the same molar con-
centration, is absorbed at the same rate and extent.
Authorization of a generic product is essentially
based on demonstration of identical bioavailability
that is defined as the rate and extent at which an
active ingredient is absorbed and becomes avail-
able at the site of action.
In the great majority of cases, medicines are
intended for a systemic therapeutic activity. There-
fore, being difficult or impossible to measure the
quantity of active substance at the site of action, it
is accepted that equivalence of levels in the sys-
temic circulation, or other biological fluids, are
accepted as surrogates of therapeutic equivalence.
For the typical generic application, a bioequiva-
lence study against a reference product in a cross-
over, single and/or multiple dose design in healthy
volunteers (or patients wherever appropriate) is
used to demonstrate bioequivalence. The CPMP
‘Note for Guidance on Investigation of Bioavail-
ability and Bioequivalence’ provides details on
design and conduct of studies, statistical and ana-
lytical aspects, selection of subjects and conditions
for study standardization. The number of subjects
to be included depends on many factors, such as the
variability of the primary characteristic to be
assessed, the predetermined significance level
and the required power. In any case, not less than
12 subjects should be used. Clinical therapeutic
bioequivalence must always be documented for
oral modified release and transdermal dosage
forms.
Rarely, waivers from human bioequivalence can
be granted, although these are only under the most
straightforward situations imaginable. The com-
monest case is that of a generic, intravenous (IV),
aqueous solution containing the same active drug
at the same concentration. The same concept can
be extended to intramuscular (IM) and subcuta-
neous injectables, when the test and reference pro-
ducts consist of the same type of solution with the
same or comparable excipients. This does not
extend to topical products, however, when a bioe-
quivalence study must always be carried out if a
systemic action is expected.
Different problems are encountered for approval
of ‘copies’ of biotechnologically derived products.
The issue is of practical relevance as the patent of
many biological products has or is going to expire.
Biotechnology derived products may represent a34.10 GENERIC MEDICINAL PRODUCTS 467