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«WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS: GUIDELINES ON REGISTRATION REQUIREMENTS TO ...»

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Equivalence test 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.

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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.

Generic product 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 products.

Multisource pharmaceutical products Multisource pharmaceutical products are intended to be pharmaceutically equivalent or pharmaceutical alternatives that are bioequivalent and hence are therapeutically equivalent and interchangeable.

Pharmaceutical alternatives 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.

Pharmaceutical equivalence 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.

Working document QAS/04.093/Rev.4 page 8 Therapeutic equivalence 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.

3. DOCUMENTATION OF EQUIVALENCE FOR MARKETING AUTHORIZATION

Multisource pharmaceutical products must be shown, either directly or indirectly, to be therapeutically equivalent to the comparator product in order to be considered interchangeable.

Suitable test methods to assess equivalence are:

(a) comparative pharmacokinetic studies in humans, in which the active pharmaceutical ingredient and/or its metabolite(s) are measured as a function of time in an accessible biological fluid such as blood, plasma, serum or urine to obtain pharmacokinetic measures, such as AUC and Cmax that are reflective of the systemic exposure;

(b) comparative pharmacodynamic studies in humans;

(c) comparative clinical trials; and (d) comparative in vitro tests.

Applicability of each of these four modalities is discussed in subsequent sections of this guideline.

Detailed information is provided to conduct an assessment of equivalence studies using pharmacokinetic measurements and in vitro methods, which are currently the most often used methods to document equivalence for most orally administered pharmaceutical products for systemic exposure.

Acceptance of any test procedure in the documentation of equivalence between two pharmaceutical products by a drug regulatory authority depends on many factors, including characteristics of the active pharmaceutical ingredient and the pharmaceutical product. Where an active pharmaceutical ingredient produces meaningful concentrations in an accessible biological fluid such as plasma, comparative pharmacokinetic studies can be performed. Where appropriate in vitro testing and BCS based biowaivers for immediate release pharmaceutical products can assure equivalence between the multisource product and the comparator product (see sections 5 and 9), in vitro studies may be sufficient. Where an active pharmaceutical ingredient does not produce measurable concentrations in an accessible biological fluid, comparative pharmacodynamic studies are a further alternative to document equivalence. Comparative clinical trials may also be used to document equivalence. In certain cases when it is not possible to determine the pharmacokinetic profile or to find suitable pharmacodynamic endpoints, comparative clinical trials can be considered appropriate.





Criteria that indicate when equivalence studies are necessary are discussed in the following two sections of the guideline.

4. WHEN EQUIVALENCE STUDIES ARE NOT NECESSARY

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(a) When the pharmaceutical product is to be administered as an aqueous intravenous solution containing the same active pharmaceutical ingredient in the same molar concentration as the comparator product. Bioequivalence testing is also not required when pharmaceutically equivalent products are to be administered by other parenteral routes (e.g. intramuscular, subcutaneous) as aqueous solutions and contain the same active pharmaceutical ingredient(s) in the same molar concentration and the same or similar excipients in comparable concentrations as in the comparator product. Certain excipients (e.g. buffer, preservative, 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;

(b) When pharmaceutically equivalent products are solutions for oral use (including syrups, elixirs, tinctures or other soluble forms but not suspensions), contain the active pharmaceutical ingredient in the same molar concentration as comparator product, and contain essentially the same excipients in comparable concentrations. Excipient(s) known to affect gastrointestinal (GI) transit, GI permeability and hence absorption or stability of the active pharmaceutical ingredient in the GI tract should be critically reviewed;

(c) When pharmaceutically equivalent products are powders for reconstitution as a solution and the 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 active pharmaceutical ingredient(s) in the same molar concentration and essentially the same excipients in comparable concentrations. Certain excipients (e.g. preservative, buffer, substance to adjust tonicity or thickening agent) may be different provided use of these excipients is not expected to affect safety and/or efficacy of the product;

(f) When pharmaceutically equivalent products are topical products prepared as aqueous solutions and contain the same active pharmaceutical ingredient(s) in the same molar concentration and essentially the same excipients in comparable concentrations;

(g) When pharmaceutically equivalent products are aqueous solutions for nebulizer inhalation products or nasal sprays, intended to be administered with essentially the same device, and contain the same active pharmaceutical ingredient(s) in the same concentration and essentially the same excipients in comparable concentrations. The pharmaceutical product may include different excipients provided their use is not expected to affect safety and/or efficacy of the product.

For elements (b), (c), (e), (f) and (g) above, it is incumbent upon the applicant to demonstrate that the excipients in the pharmaceutically equivalent product are essentially the same and in comparable concentrations as those in the comparator product. In the event that this information about the comparator product cannot be provided by the applicant and the drug regulatory authority does not have access to these data, it is incumbent upon the applicant to perform appropriate studies to demonstrate that differences in excipients or devices do not affect product performance.

Working document QAS/04.093/Rev.4 page 10

5. WHEN IN VIVO EQUIVALENCE STUDIES ARE NECESSARY AND TYPES OF

STUDIES REQUIRED

Except for the cases illustrated in Section 4 this guideline recommends that documentation of equivalence with the comparator product be requested by registration authorities for a multisource pharmaceutical product. Studies must be carried out using the product intended for marketing (see also Section 6.5).

5.1 In vivo studies

For certain medicines and dosage forms, in vivo documentation of equivalence, through either a pharmacokinetic bioequivalence study, a comparative pharmacodynamic study, or a comparative clinical trial, is regarded as especially important. In vivo documentation of equivalence is needed when there is a risk that possible differences in bioavailability may result in therapeutic inequivalence (3). Examples are listed below.

(a) Oral immediate release pharmaceutical products with systemic action when one or more of

the following criteria apply:

• critical use medicines;

• narrow therapeutic range (efficacy/safety margins); steep dose-response curve;

• documented evidence for bioavailability problems or bio-inequivalence related to the active pharmaceutical ingredient or APIs of similar chemical structure or formulations (unrelated to dissolution problems);

• there is scientific evidence to suggest that either the polymorphs of API, the excipients or the pharmaceutical processes used in manufacturing could affect the bioequivalence.

(b) Non-oral and non-parenteral pharmaceutical products designed to act by systemic absorption (such as transdermal patches, suppositories, nicotine chewing gum, testosterone gel and skin-inserted contraceptives, etc.).

Modified release pharmaceutical products designed to act by systemic absorption.1 (c) (d) Fixed combination products with systemic action, where at least one of the active pharmaceutical ingredients requires an in vivo study. (Ref WHO, FDC guide, TRS 929, Annex 5).

(e) Non-solution pharmaceutical products, which are for non-systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc., application) and are intended to act without systemic absorption. In these cases, the equivalence is established through, e.g. comparative clinical or pharmacodynamic, dermatopharmacokinetic studies and/or in vitro studies. In certain cases, active pharmaceutical ingredient concentration measurement can be still required for safety reasons in order to assess unintended systemic absorption.

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5.2 In vitro studies For certain medicines and dosage forms, in vitro documentation of equivalence may be appropriate.

These studies are addressed in section 9.

6. BIOEQUIVALENCE STUDIES IN HUMANS



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