used in this guideline are defined below. They may have different meanings in
The rate and extent to which the active moiety is absorbed from a pharmaceutical dosage form and
becomes available at the site(s) of action. In the majority of cases reliable measurements of drug
concentrations at the site(s) of action are not possible. The substance in general circulation, however, is
considered to be in equilibrium with the substance at the site(s) of action. Bioavailability can be
therefore defined as the rate and extent to which the active pharmaceutical ingredient or active
moiety is absorbed from a pharmaceutical dosage form and becomes available in the general
circulation. It is assumed by PK-PD theory that in the same subject an essentially similar plasma
concentration time course will result in an essentially similar concentration time course at the site(s)
Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or
pharmaceutical alternatives and their bioavialbility in terms of peak (Cmax and Tmax) and total
exposure (AUC) after administration of the same molar dose under the same conditions are similar to
such a degree that their effects can be expected to be essentially the same. Bioequivalence focuses on
the equivalence of release of the active pharmaceutical ingredient from the pharmaceutical product
and its subsequent absorption into the systemic circulation.
Biopharmaceutics Classification System (BCS)
BCS is a scientific framework for classifying active pharmaceutical ingredients based upon their
aqueous solubility and intestinal permeability. When combined with the dissolution of the
pharmaceutical product, the BCS takes into account three major factors that govern the rate and extent
of drug absorption (exposure) from immediate release oral solid dosage forms: dissolution, solubility,
and intestinal permeability.
The term biowaiver is applied to a regulatory drug approval process when the dossier (application) is
approved based on evidence of equivalence other than in vivo bioequivalence test.
Comparator product is a pharmaceutical product with which the new multisource product is intended
to be interchangeable in clinical practice. The comparator product will normally be the innovator
product for which efficacy, safety and quality has been established. The selection of the comparator
product is usually made at the national level by the drug regulatory authority. A national drug
regulatory authority has in principle options which are described in section 6.5.2.
The finished formulation of a pharmaceutical product, e.g. tablet, capsule, suspension, solution for
In vivo and/or in vitro testing requirements for multisource pharmaceutical product approval and
Equivalence test is a test that determines the equivalence between the multisource product and the
comparator product using in vivo and/or in vitro approaches.
Fixed-dose combination (FDC)
A combination of two or more active pharmaceutical ingredients in a fixed ratio of doses.
This term is used generically to mean a particular combination of active pharmaceutical
ingredients irrespective of the formulation or brand. It may be administered as single entity
products given concurrently or as a finished pharmaceutical product.
Fixed-dose combination finished pharmaceutical product (FDC-FPP)
A finished pharmaceutical product that contains two or more active pharmaceutical ingredients.
A “generic product” is a multisource pharmaceutical product which is intended to be interchangeable
with the comparator product. It is usually manufactured without a licence from the innovator
company and marketed after the expiry of patent or other exclusivity rights.
[Note from the WHO Secretariat:
WHO's Legal Department has commented that the use of the word "usually" in the
definition of generic product is not favoured. Please comment.]
Innovator pharmaceutical product
Generally, the innovator pharmaceutical product is that which was first authorized for marketing, on
the basis of documentation of quality, safety and efficacy.
Interchangeable pharmaceutical product
An interchangeable pharmaceutical product is one which is therapeutically equivalent to a
comparator product and can be interchanged in clinical practice.
In vitro equivalence test
In vitro equivalence test is a dissolution test that includes dissolution profiles comparison between the
multisource product and the comparator product in three media: pH1.2 HCl, pH 4.5 and pH 6.8.
In vitro quality control dissolution test
Dissolution test procedure identified in the pharmacopoeia, generally a one time point dissolution test
for immediate release products and three or more time points dissolution test for modified release
Multisource pharmaceutical products
Multisource pharmaceutical products are intended to be pharmaceutically equivalent or
pharmaceutical alternatives that are bioequivalent and hence are therapeutically equivalent and
Products are parmaceutical alternative (s) if they contain the same molar amount of the same active
pharmaceutical moiety(s) but differ in dosage form (e.g. tablets versus capsules), and/or chemical
form (e.g. different salts, different esters). Pharmaceutical alternatives deliver the same active moiety
by the same route of administration but are otherwise not pharmaceutically equivalent. They may or
may not be bioequivalent or therapeutically equivalent with the comparator product.
Products are pharmaceutical equivalents if they contain the same molar amount of the same active
pharmaceutical ingredient(s) in the same dosage form that meet the same or comparable standards
and are intended to be administered by the same route. However, pharmaceutical equivalence does
not necessarily imply bioequivalence and therapeutic equivalence, as differences in the excipients
and/or the manufacturing process can lead to differences in product performance.
Two pharmaceutical products are considered to be therapeutically equivalent if they are
pharmaceutically equivalent or pharmaceutical alternatives and after administration in the same
molar dose, their effects, with respect to both efficacy and safety, will be essentially the same when
administered to patients by the same route under the conditions specified in the labelling. This can be
demonstrated by appropriate bioequivalence studies such as pharmacokinetic, pharmacodynamic,
clinical or in vitro studies.