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During the DIA International Workshop “Impurities and Degradation Products—Biological Qualification, Process Capability, and Analytical Control,” the EU Committee for Human Medicinal Products draft guideline on genotoxic impurities was presented. About half of the attendees expressed their support for the use of the threshold of toxicological concern concept as a pragmatic solution. The Food and Drug Administration guidance is under development. The process of qualification of impurities starts with identification. For genotoxic impurities, identification should start with an evaluation of the starting materials and the routes of synthesis to compile a list of impurities that can reasonably be expected to be present in the drug substance. Among this list, the search for alerting structures and classification of impurities as highly toxic can be facilitated by use of structure activity relationship databases. Relevant impurities that were identified as potentially genotoxic should be tested as isolated impurities because these impurities are usually present below the detection level of the genotoxicity assay when the drug substance is used in the assay. Knowledge of the impurity and its source is also the basis for a reduction of these compounds to the lowest possible level that can be achieved with reasonable effort. Trace analytical methods are usually required to monitor process optimization activities. Avoiding a hazardous impurity or a reduction of its levels may require a substantial effort and time in process chemistry or formulation development. The allowance of higher limits for short-term exposure is therefore seen as a pragmatic way to define reasonable effort, especially for batches used in the early clinical development. This remains an important issue that should be further addressed.

To facilitate management of the technical and regulatory Chemistry Manufacturing and Controls (CMC) issues within core dossiers, companies have turned to a range of organizational structures and procedures to manage the input most effectively. The objectives of this survey were to identify how companies have organized to provide regulatory strategy for the CMC sections of dossiers and to assess how, on a global basis, CMC documentation is created and reviewed. Seventeen of the top 30 United States- and European-based pharmaceutical companies participated in the survey.

A DIA workshop was held in Noordwijk, The Netherlands on October 24-25, 1994 on the subject of managing the global chemical/pharmaceutical documentation. Speakers and chairpersons were drawn from both the major regulatory authorities and the pharmaceutical industry. The objective of the workshop was to review the content and the format of the chemical/pharmaceutical documentation (CMC section) of the dossier filed in support of an application for a marketing authorization in Europe, the United States, Canada, Australia, or Japan. The aim of the workshop was to provide an overview of how to develop and maintain an international core dossier that the authorities find user friendly.The proposal which follows divides the CMC file into two major sections: drug substance and drug product. Each major section of the CMC file is divided into two parts: regulatory (manufacturing and control) and scientific. This division would enable the file to be split after approval to provide an official regulatory file which c...

This paper provides a summary of recommendations from discussions held in Paris, France from April 26–29, 1992 on regulatory requirements for chiral drugs.