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Tuesday, January 12, 2021

For which products bioequivalence is required or not required

 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 

Annex 6

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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