Current approaches to the control of process-related impurities in antibiotics

INTRODUCTION. Antibiotic active substances have a distinct class of organic impurities other than related substances or organic solvents, namely, process-related impurities, such as N,N-dimethylaniline and 2-ethylhexanoic acid and its derivatives. These compounds are used as reagents in the production process, and national and international pharmacopoeias require that their residual levels should be controlled.

AIM. This study aimed to justify the requirements for the control of process-related impurities in antibiotic active substances.

MATERIALS AND METHODS. The study analysed general chapters and individual monographs on antibiotic active substances of the State Pharmacopoeia of the Russian Federation and international pharmacopoeias, including the European Pharmacopoeia (Ph. Eur.), the United States Pharmacopeia (USP), and The International Pharmacopoeia (Ph. Int.). The study also analysed registration dossiers for local and imported antibiotic active substances listed in the Russian State Register of Medicines. The study used comparative and content analysis methods.

RESULTS. The Ph. Eur. requires that 2-ethylhexanoic acid should be controlled in antibiotic active substances, such as semisynthetic and fermentation-derived antibiotics. In contrast, the USP does not include this quality attribute in individual monographs. The Ph. Eur. and USP individual monographs on semisynthetic antibiotics require manufacturers to control residual levels of N,N-dimethylaniline. This is probably due to the high toxicity of N,N-dimethylaniline. The relevant requirements of the State Pharmacopoeia of the Russian Federation are harmonised with those of the Ph. Eur. According to the analysis of registration dossiers, manufacturers replace 2-ethylhexanoic acid and N,N-dimethylaniline with less toxic reagents and, if necessary, control the residual levels of these alternative reagents in accordance with the general requirements for residual organic solvents.

CONCLUSIONS. Current technological processes can produce antibiotic active substances without the use of 2-ethylhexanoic acid and N,N-dimethylaniline. Therefore, the concept of process-related impurity control in active substances should be based on risk assessment. Furthermore, the relevant general chapters should require testing for 2-ethylhexanoic acid and N,N-dimethylaniline only if these compounds are used in the production process.

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