Multisource drug products need to conform to the same standards of quality, efficacy and safety required of 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, including - most evidently - parenteral formulations of highly water soluble compounds, interchangeability is adequately assured by implementation of Good Manufacturing Practices 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 product manufactured by biotechnology, the concept of interchangeability raises complex considerations that are not addressed in this document, and these products are consequently excluded from consideration. 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 such assessment should be included in the documentation 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. Based on these suggestions, WHO convened three consultations during 1993 and 1994 in Geneva which have led to formulation of the present guideline. Participants at the consultations included representatives of drug regulatory authorities, academia, and the pharmaceutical industry including the generic industry.

The objective of this guideline 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 of WHO’s Tuberculosis Programme and the International Union against Tuberculosis and Lung Disease. Inter alia, this states 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”. The message is that fixed dosage combinations containing rifampicin must 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 within WHO’s Model List of Essential Drugs. WHO will assist small regulatory authorities, for whom this guideline is 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 interchangeability of multisource products within an international as well as a national context by proposing the establishment of international reference materials as comparators for bioequivalence testing.

This guideline refers to the marketing of pharmaceutical products that are intended to be therapeutically equivalent and thus interchangeable but produced by different manufacturers. The WHO Guideline should be interpreted and applied without prejudice to obligations incurred through existing international agreement on trade-related aspects of intellectual property rights (Marrakesh Agreement Establishing the World Trade Organization, Annex 1C, Article 39).