Identifying Histamine Impurity in Biological Products: Prospective Transition from in vivo to in vitro Methods

INTRODUCTION. Drug impurities lowering blood pressure can cause side effects in patients. These impurities include histamine and other depressor substances. The current General pharmacopoeial monograph “Test for Histamine” of the State Pharmacopoeia of the Russian Federation presents a quantification method of histamine impurity based on histamine interaction with H1 receptors of the guinea pig intestine. However, 3R concept (Replacement, Reduction, Refinement) introduced as an international standard and decision of leading pharmacopoeias to exclude in vivo histamine tests makes it necessary to develop in vitro methods for quantification of histamine impurity.

AIM. This study aimed to select an advanced in vitro method for quantification of histamine impurity as an alternative to in vivo tests.

DISCUSSION. Strategy of European Pharmacopoeia aimed at abandoning biological tests for histamine drug impurities was analysed. Scientific literature has shown the most common physicochemical and immunochemical methods for quantification of histamine impurity. The authors systematised test methods using high-performance liquid chromatography (HPLC). Indirect competitive heterogenous enzyme-linked immunosorbent assay (ELISA) was shown feasible for histamine quantification in the biological drugs. Choice between HPLC and ELISA was based the matrix of a test substance.

CONCLUSIONS. HPLC and ELISA are promising quantification methods of histamine impurity in biological products. In vitro methods are developed according to the composition, structure, and matrix properties of a test substance. Heterogeneous matrices, such as heparins, profit from HPLC, while ELISA is recommended for peptides and proteins, for example aprotinin.

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