When equivalence studies are not necessary
In the following circumstances, multisource pharmaceutical products are
considered to be equivalent without the need for further documentation:
(a) when the pharmaceutical product is to be administered parenterally
(e.g. intravenously, subcutaneously or intramuscularly) as an
aqueous solution containing the same API in the same molar
concentration as the comparator product and the same or similar
excipients in comparable concentrations to those in the comparator
product. Certain excipients (e.g. buffer, preservative and antioxidant)
may be different provided it can be shown that the change(s) in
these excipients would not affect the safety and/or efficacy of the
pharmaceutical product. The same principles are applicable for
parenteral oily solutions but, in this case, the use of the same oily
vehicle is essential. Similarly, for micellar solutions, solutions
containing complexing agents or solutions containing co solvents of
the same qualitative and quantitative composition of the functional
excipients are necessary in order to waive equivalence studies and
the change of other excipients should be critically reviewed;
(b) when pharmaceutically equivalent products are solutions for oral
use (e.g. syrups, elixirs and tinctures), contain the API in the same
molar concentration as the comparator product, contain the same
functional excipients in similar concentrations (if the API is BCS
Class I) and the same excipients in similar concentrations (for APIs
from other BCS classes);
(c) when pharmaceutically equivalent products are in the form of
powders for reconstitution as an aqueous solution and the resultant
solution meets either criterion (a) or criterion (b) above;
(d) when pharmaceutically equivalent products are gases;
(e) when pharmaceutically equivalent products are otic or ophthalmic
products prepared as aqueous solutions and contain the same
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191
API(s) in the same molar concentration and the same excipients in
similar concentrations. Certain excipients (e.g. preservative, buffer,
substance to adjust tonicity or thickening agent) may be different
provided their use is not expected to affect bioavailability, safety
and/or efficacy of the product;
(f) when pharmaceutically equivalent products are topical products
prepared as aqueous solutions and contain the same API(s) in
the same molar concentration and the same excipients in similar
concentrations (note that a waiver would not apply to other
topical dosage forms like gels, emulsions or suspensions, but
might be applicable to oily solutions if the vehicle composition is
sufficiently similar);
(g) when pharmaceutically equivalent products are aqueous solutions
for nebulization or nasal drops, intended to be administered
with essentially the same device, contain the same API(s) in the
same concentration and contain the same excipients in similar
concentrations (note that this waiver does not apply to other
dosage forms like suspensions for nebulization, nasal drops where
the API is in suspension, nasal sprays in solution or suspension,
dry powder inhalers or pressurized metered dose inhalers in
solution or suspensions). The pharmaceutical product may include
different excipients provided their use is not expected to affect
bioavailability, safety and/or efficacy of the product.
For situations (b), (c), (e), (f) and (g) above it is incumbent upon the applicant to
demonstrate that the excipients in the pharmaceutically equivalent product are
the same and that they are in concentrations similar to those in the comparator
product or, where applicable (i.e. (a), (e) and (g)), that their use is not expected
to affect the bioavailability, safety and/or efficacy of the product. In the event that
the applicant cannot provide this information and the NRA does not have access
to the relevant data, it is incumbent upon the applicant to perform appropriate
studies to demonstrate that differences in excipients or devices do not affect
product performance.
When equivalence studies are necessary
and types of study required
Except for the cases discussed in section 4, these guidelines recommend that
documentation of equivalence with the comparator product be required by
registration authorities for a multisource pharmaceutical product. Studies must
be carried out using the product intended for marketing (see also section 7.3).
192WHO Technical Report Series, No. 1003, 2017
WHO Expert Committee on Specifications for Pharmaceutical Preparations Fifty-first report
5.1 In vivo studies
For certain APIs and dosage forms, in vivo documentation of equivalence,
through either a pharmacokinetic comparative bioavailability (bioequivalence)
study, a comparative pharmacodynamic study or a comparative clinical trial,
is regarded as especially important. In vivo documentation of equivalence is
necessary when there is a risk that possible differences in bioavailability may
result in therapeutic inequivalence (2). Examples are listed below:
(a) oral, immediate-release pharmaceutical products with systemic
action, except for the conditions outlined in section 10;
(b) non-oral, non-parenteral pharmaceutical products designed to act
systemically (such as transdermal patches, suppositories, nicotine
chewing gum, testosterone gel and skin inserted contraceptives);
(c) modified-release pharmaceutical products designed to act
systemically, except for the conditions outlined in section 10;
(d) fixed-dose combination (FDC) products with systemic action,
where at least one of the APIs requires an in vivo study (3);
(e) non-solution pharmaceutical products, which are for nonsystemic use (e.g. for oral, nasal, ocular, dermal, rectal or vaginal
application) and are intended to act without systemic absorption.
In the case of non-solution pharmaceutical products for non-systemic use, the
equivalence is established through, e.g. comparative clinical or pharmacodynamic
studies, local availability studies and/or in vitro studies. In certain cases,
measurement of the concentration of the API may still be required for safety
reasons, i.e. in order to assess unintended systemic absorption.
5.2 In vitro studies
For certain APIs and dosage forms, in vitro documentation of equivalence may
be appropriate. In vitro approaches for systemically acting oral products are
discussed in section 10.
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