Abstract

During the production of biologicals from cell cultures, numerous risks of contamination with pathogens, especially viruses, have to be considered. Besides the starting material (cell cultures with endogenous retrovirus-like particles or latent / persistent virus infections (e. g. herpesviruses)) and, potentially, viruses contaminating the genetically modified cell culture during its establishment, as well as virus contamination of the cell culture in fermenters during the production of the biologicals by adventitious viruses have to be considered.

Retroviruses / retrovirus-like particles and potentially adventitious viruses (in a concentration below the detection limit of the assays to release an unprocessed bulk for further manufacturing) have to be inactivated and/or removed in order to obtain a virus safe medicinal product. The methods used to achieve this goal as different chromatography steps to purify and concentrate the desired active substance as well as measures taken during production as solvent/detergent treatment or virus filtration, solely for the inactivation and/or removal of viruses, are described in this article. The capacity of the manufacturing process to inactivate and/or remove a wide range of different viruses is determined in virus validation studies and the virus reduction factors for defined manufacturing steps assessed. The overall reduction factor of the manufacturing process for retroviruses/retrovirus-like particles should be – as outlined in the International Guideline regarding the virus safety of biotechnological products as an example – 6 log₁₀ higher than the virus load in that volume of the unprocessed bulk required for the production of one vial of the medicinal product.