Control of organic impurities in antibiotics

Introduction: the international, as well as Russian Pharmacopoeia criteria for organic impurity assessment are not applicable to medicinal products obtained by fermentation, therefore the setting of limits for product-related impurities in antibiotics is not regulated by any commonly shared rules. The aim of the study was to analyse and summariese pharmacopoeial requirements for and methodological approaches to organic impurities control in active substances and finished products of semisynthetic antibiotics, peptide antibiotics, and antibiotics obtained by fermentation. Material and methods: the authors analysed the requirements for organic impurities control, as established by the leading world pharmacopoeias and the State Pharmacopoeia of the Russian Federation, using the example of three different groups of antibiotics (semisynthetic antibiotics, antibiotics obtained by fermentation, and peptide antibiotics). The study used comparative analysis and content analysis methods. Results: the study demonstrated that the product-related impurity profiles of the analysed active substances and corresponding finished products often differ significantly across the leading pharmacopoeias, either qualitatively or quantitatively, and do not necessarily comply with the EMA Guideline on setting specifications for related impurities in antibiotics. The methodological approaches to product-related impurity control also differ a lot in terms of pharmacopoeial reference standards used, accelerated stability studies, etc. Conclusion: the complex composition of product-related compounds does not always allow for their unambiguous classification as either impurities or active moieties (e.g. in the case of bleomycin). Most Russian Pharmacopoeia antibiotic monographs are harmonised with the European Pharmacopoeia (Ph. Eur.), which is fraught with problems regarding reference standards (RSs) use, since the composition of Ph. Eur. RSs includes both the active substance and several (sometimes up to 8) impurities. The Russian Pharmacopoeia monographs on antibiotics obtained by a process involving the fermentation stage, include the abnormal toxicity test, which seems redundant in comprehensive impurity control, at least for semisynthetic antibiotics.