In order to obtain a marketing authorisation for a drug product the applicant has to show evidence of efficacy, safety and quality of the drug product. To assure this, appropriate documentation on the active substance including the manufacturing of the active substance has to be submitted to the competent authority. This can be done by including the documentation on the active substance into the registration file of the drug product or in cases where the active substance manufacturer is not identical with the applicant for the drug product by using the Drug Master File procedure.

The regulations concerning the manufacturing of active substances have undergone and still are undergoing various changes:

ICH Q7A, released for adoption in November 2000, introduced good manufacturing practice, up to then only known for the manufacturing of drug products, for the manufacturing of active substances. This guideline has been adopted in the ICH regions Europe, USA and Japan, as well as in numerous other countries.

ICH M4, released for adoption in November 2000, introduced the common technical document. Although the CTD harmonises the structure of the registration dossier in the ICH regions, the differences in the requirements of the documentation remain.

Whereas in most ROW countries and in Japan no particular requirements are defined for the manufacturing of active substances, the European Union and the USA both have defined their requirements for the active substance manufacturing. In both cases the relevant guidelines are currently under revision.

The main European guideline on manufacturing of active substances, the CPMP/QWP/130/96, underwent long history as draft, was revised in 2001 in order to comply with the common technical document and released again as a draft. The main US guideline on manufacturing of active substances, the "Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances" of 1987 is also currently under revision in order to comply with the current requirements of the common technical document.

Both guidelines are heavily discussed with the pharmaceutical industry. Particularly the definition of active substance starting material is discussed as the starting material determines the point from which the manufacturing process is described in the registration file. The discrepancies arise on one hand from the fact that the pharmaceutical industry is interested in defining the starting material as late as possible in the manufacturing process and on the other hand from the divergent definitions of the starting material for GMP in the ICH Q7A and the starting material for registration purposes as defined in the regulatory guidelines.

Another intensely discussed issue is the description of manufacturing steps prior to the starting material. The European draft guideline was published with such a suggestion and in the United States it has been required by some FDA assessors although not being written in any guideline.

These two issues together with others are still discussed during the revision process of the above mentioned guidelines.

The variation guidelines in the European Union and in the United States as well are under revision or not yet published: In the European Union the Commissions Regulations 541/95 and 542/95 describe the examination of variations to marketing authorisations granted by the mutual recognition procedure and centralized procedure. Both are under revision and have been published as draft in 2002, but due to the strong concerns received by the pharmaceutical industry are to be reissued completely. In the United States guidance on changes in drug substance manufacturing up to the step of the final intermediate is given in BACPAC I. Changes to the final intermediate and manufacturing changes after the final intermediate are to be addressed by BACPAC II which is not drafted yet.

As a summary, the manufacturing of active substances is currently subjected to various modifications and changes in regulations.

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