Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Implementing the Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents (EMEA/CHMP/SWP/4446/2000) ***

Dr. Ulrich Reichert (Abschlußjahr: 2009)

Language: English

Due to the apparent significant impact of impurities on pharmaceutical safety and quality there are regulatory recommendations on impurities in pharmaceutical substances. The guidelines of the International Conference on Harmonisation (ICH) are presumed to be the most important ones. However, metallic impurities are not addressed in sufficient detail in the current ICH Q3X guidelines. The development of the European "Guideline on Specification Limits for Residues of Metal Catalysts or Metal Reagents" intends to fill this gap. The final version of this guideline has been issued by the EMEA after about 10 years of consultation and came into effect on the 1st of September, 2008. For existing marketed drug products a time limit of five years is set for the implementation, if not feasible earlier.

The scope of the EMEA guideline covers metals that are likely to be present due to deliberate addition during the manufacturing process. Maximum acceptable concentration limits for the residues of metal catalysts or metal reagents that may be present in pharmaceutical substances or in drug products are recommended. The applicant for the Marketing Authorisation Application has to compile correct information on this matter. In many cases it will not be sufficient to consider only the last manufacturing step to assess the metals which are "likely to be present". Preceding steps of production and starting materials should also be considered. A metal used as a catalyst or reagent in the manufacturing process is assumed as "likely to be present" unless it is demonstrated to be removed consistently. Requirements on metal analysis and reporting levels are discussed.

A questionnaire for manufacturers and suppliers is presented to obtain information on metal residues in purchased pharmaceutical substances. Besides an audit of the manufacturer, this has been demonstrated to be a suitable tool to obtain the necessary information. The completed questionnaires of more than 100 substances are evaluated with regard to completeness, plausibility and way of providing the information. Moreover, an appropriate option is discussed on how to include information on metal residues in the certificate of analysis of a substance to be in line with the criteria of the guideline.

The development of the EMEA guideline beginning with the first draft up to the currently valid version is reviewed and the current developments in this area are summarised. The guideline is discussed in connection with the existing regulatory framework on impurity control. An overview of the general concepts relating to impurities and their fundamental origins in pharmaceutical substances is provided whereby the existing guidelines are considered particularly to their relation to metallic impurities.

"Metal Impurities" has become one of the "Hot Topics" on the USP website after the USP published a concept for revision of the general test on heavy metals. The proposed USP approach is compared with that of the finalised EMEA guideline and an outlook for future developments is discussed.

Pages: 48