Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1
(1997; 248 pages) [French] View the PDF document
Table of Contents
Open this folder and view contentsIntroduction
Open this folder and view contents1. National drug regulation
Close this folder2. Product assessment and registration
View the documentGuidelines for the assessment of herbal medicines1,2
Open this folder and view contentsStability of drug dosage forms1
Open this folder and view contentsGuidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms1
Close this folderMultisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability1
View the documentIntroduction
View the documentGlossary
Open this folder and view contentsPart One. Regulatory assessment of interchangeable multisource pharmaceutical products
Open this folder and view contentsPart Two. Equivalence studies needed for marketing authorization
Open this folder and view contentsPart Three. Tests for equivalence
View the documentPart Four. In vitro dissolution tests in product development and quality control
View the documentPart Five. Clinically important variations in bioavailability leading to non-approval of the product
View the documentPart Six. Studies needed to support new post-marketing manufacturing conditions
View the documentPart Seven. Choice of reference product
View the documentAuthors
View the documentReferences
View the documentAppendix 1. Examples of national requirements for in vivo equivalence studies for drugs included in the WHO Model List of Essential Drugs (Canada, Germany and the USA, December 1994)
View the documentAppendix 2. Explanation of symbols used in the design of bioequivalence studies in humans, and commonly used pharmacokinetic abbreviations
View the documentAppendix 3. Technical aspects of bioequivalence statistics
Open this folder and view contents3. Distribution
Open this folder and view contents4. The international pharmacopoeia and related activities
Open this folder and view contents5. Basic tests
Open this folder and view contents6. Laboratory services
Open this folder and view contents7. International trade in pharmaceuticals
Open this folder and view contents8. Counterfeit products
Open this folder and view contents9. Training
View the documentSelected WHO publications of related interest
View the documentBack cover


Multisource (generic) drug products must satisfy the same standards of quality, efficacy and safety as those applicable to the originator’s product. In addition, reasonable assurance must be provided that they are, as intended, clinically interchangeable with nominally equivalent market products.

With some classes of product, obviously including parenteral formulations of highly water-soluble compounds, interchangeability is adequately assured by the implementation of good manufacturing practices (GMP) and evidence of conformity with relevant pharmacopoeial specifications. For other classes of product, including many biologicals, such as vaccines, animal sera, products derived from human blood and plasma, and products manufactured by biotechnology, the concept of interchangeability raises complex considerations that are not addressed here, and these products will consequently not be considered. However, for most nominally equivalent pharmaceutical products (including most solid oral dosage forms), a demonstration of therapeutic equivalence can and should be carried out, and should be included in the documentation submitted with the application for marketing authorization.

During the International Conference of Drug Regulatory Authorities (ICDRA) held in Ottawa, Canada, in 1991 and again in The Hague, The Netherlands, in 1994, regulatory officials supported the proposal that WHO should develop global standards and requirements for the regulatory assessment, marketing authorization and quality control of interchangeable multisource (generic) pharmaceutical products. On the basis of these suggestions, WHO convened three consultations during 1993 and 1994 in Geneva which led to the formulation of the present guidelines. Participants at the consultations included representatives of drug regulatory authorities, the universities, and the pharmaceutical industry, including the generic industry.

The objective of these guidelines is not only to provide technical guidance to national drug regulatory authorities and to drug manufacturers on how such assurance can be provided, but also to create an awareness that in some instances failure to assure interchangeability can prejudice the health and safety of patients. This danger has recently been highlighted in a joint statement by the WHO Tuberculosis Programme and the International Union against Tuberculosis and Lung Disease. This states, inter alia, that “studies of fixed-dose combinations containing rifampicin have shown that in some of the preparations the rifampicin was poorly absorbed or not absorbed at all”. Fixed-dosage combinations containing rifampicin must therefore be “demonstrably bioavailable”.

Highly developed national drug regulatory authorities now routinely require evidence of bioavailability for a very large majority of solid oral dosage forms, including those contained in the WHO Model List of Essential Drugs. WHO will assist small regulatory authorities, for whom these guidelines are primarily intended, in determining relevant policies and priorities - in relation to both locally manufactured and imported products - by compiling and maintaining a list of preparations that are known to have given rise to incidents indicative of clinical inequivalence. It will also work to promote a technical basis for assuring the interchangeability of multisource products within both an international and a national context by proposing the establishment of international reference materials as comparators for bioequivalence testing.

These guidelines apply to the marketing of pharmaceutical products intended to be therapeutically equivalent and thus interchangeable (generics) but produced by different manufacturers. They should be interpreted and applied without prejudice to the obligations incurred through existing international agreements on trade-related aspects of intellectual property rights (1).

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