Recommendations for the development of sterility testing procedures for biological medicinal products based on pharmacopoeial methods

Abstract

INTRODUCTION. The distinctive nature and composition of biological medicinal products present certain challenges for the detection of microbial contamination, which affects the reliability of sterility control results. The main challenges associated with testing biologicals include changes in the appearance and physical properties of culture media or samples, an increased risk of contamination or false-positive results in direct inoculation tests, filtration issues, etc. When drafting product specification files and analytical method validation reports in dossiers for biologicals, manufacturers need adequate, reproducible, and pharmacopoeia-based sterility testing procedures for specific medicinal products, including live and inactivated, viral and bacterial, single- and multi-component vaccines, bacteriophages and interferons, sera and immunoglobulins. These challenges can be addressed through providing recommendations for developing analytical procedures based on compendial methods of direct inoculation and membrane filtration.AIM. This study aimed to offer key recommendations for the development of sterility testing procedures for biologicals based on pharmacopoeial methods.DISCUSSION. This article presents a retrospective analysis of the results of reviewing regulatory documentation for biological medicinal products submitted to the testing centre of the Scientific Centre for Expert Evaluation of Medicinal Products in 2021–2023. Having considered major issues with the analytical procedures described in the Sterility section of regulatory submissions, the authors offer the following recommendations for addressing these issues. The authors advise against using low-pH Sabouraud culture media to test blood products by direct inoculation. Biologicals containing mercury preservatives should be tested using a thioglycollate medium at two temperature settings. When testing various biologicals, analysts should refrain from plugging vials with cotton gauze. Instead, they should pour culture media into glass vials with rubber stoppers and crimps. Biologicals in large primary packaging (≥10 mL) should be tested by membrane filtration. Membrane filtration tests for biologicals should use solvents and rinsing agents selected in validation studies. It is also recommended to set the maximum volume of a biological medicinal product that can be filtered through a membrane filter. A reduction in the filtration speed is recommended to minimise foaming when testing blood products.CONCLUSION. The recommendations presented in this article can guide the development of sterility testing procedures for inclusion in the relevant section of regulatory submissions for biologicals. Manufacturers, control laboratories, and regulatory authorities may implement these recommendations to harmonise their approach to sterility testing of biologicals.