Safe assessment of contact materials in pharmaceutical products

Project duration: 1 August 2021 to 31 July 2024

The demands placed on pharmaceutical products are very high. They must have a highly specific positive effect without harming health through side effects and interactions. However, a pharmaceutical product is not just the sum of its active ingredients and excipients. Through the production process, in which it comes into contact with the various parts of a production plant, as well as through storage in the final packaging, it is potentially in contact with chemical components that are released from it. This makes it necessary to subject all contact materials to a toxicological assessment during production and storage.

These investigations are carried out as extractables/leachables studies using chemical analyses. The use of bioassays can further improve this toxicological risk assessment. They can reduce the reaction of a complex organism to individual cells (bacteria or human cell lines) and thus characterise substance mixtures without the need to identify the individual substances. With analytically sensitive bioassays, individual substance classes can be excluded, thus not only improving product safety, but also reducing the effort involved in toxicological assessment.

This project "PharmaTox - Application of bioassays in extractables/leachables studies" deals with the endpoint of genotoxicity (DNA damage, mutations, chromosome damage), where particularly low limit values apply due to its serious consequences (tumour development). Existing bioassays are optimised for the assessment of pure substances and therefore show insufficient analytical sensitivity for complex mixtures from extractables/leachables studies. Therefore, assays are to be improved by genetic modifications (cell tinkering) using CRISPR/Cas9 and misexpression so that they detect the lowest possible concentrations. In addition, existing 2D cell culture systems are to be transferred to 3D. Based on the results, a new testing strategy consisting of chemical analysis combined with bioassays will be developed to provide the industry with tools for improved risk analysis in the area of genotoxicity and thus protect consumers from possible negative consequences.

• Integration of bioassays into an improved concept for risk assessment of contact materials of pharmaceutical products inextractables/leachablesstudies
• Establishment of novel eukaryotic genotox assays through genetic modifications
• Development and publication of practical assays for the industry