Masterarbeit

Discussion of regulatory requirements for DNA starting material used for the manufacture of mRNA and gene therapy medicinal products ***

Dr. Pawel Masiewicz (2025)

Summary

Language: English  

The purpose and general interest of this master’s thesis is to evaluate the currently applicable and emerging regulatory requirements for the DNA used as starting material for the manufacture of Gene Therapy Medicinal Products (GTMPs)/Cell and Gene Therapies (CGTs) and mRNA-based vaccines. 

Due to its genetic stability and the capability of encoding specific genes, plasmid DNA has already been established in the pharmaceutical industry for use as an active substance for the manufacture of viral and non-viral vector-based GTMPs as well as DNA vaccines.  However, due to its molecular features and possibility to exist in different topological forms, linearized plasmid DNA can also be applied as a starting material for the manufacture of GTMPs/CGTs and mRNA vaccines. Development and global authorization of COVID-19 mRNA vaccines has underscored the need for common quality standards for mRNA-based products across Europe, United States and beyond. 

In this master’s thesis, the current regulatory landscape in the EU, US and the WHO applicable to DNA starting material has been presented with a focus on quality requirements. These have been subsequently discussed with the newly emerging quality standards from the European and United States Pharmacopeia as well as guidelines related to Good Manufacturing Practice (GMP) from different authorities. The purpose of the discussion and comparison is to provide meaningful guidance to the manufacturers of linear DNA template starting material (i.e. derived either from plasmid DNA or enzymatically synthesized) for GTMPs/CGTs and mRNA-based active substances on the regulatory expectations regarding its quality and stability. In the first place, quality requirements outlined in the EU, US and the WHO are described, however, additional country-specific provisions from the Rest of World markets are presented, as applicable. Due to the biological nature of plasmid DNA and linear DNA template starting material the importance of extensive product characterization, manufacturing process controls and analytical testing strategy as well as comparability exercise when introducing changes are underlined. Detailed discussion of all these aspects throughout this master’s thesis is aimed at helping developers and manufacturers of mRNA and gene therapy products to establish appropriate control strategy for DNA starting material, considered acceptable by the relevant regulatory authorities when submitting clinical trial or marketing authorization application.     

Pages: 77

Annexes: 2, Pages: 14