Masterarbeit

Current Quality Requirements for mRNA-based Drug Substances

Melike Uzun (2023)

Summary
Language: English
Messenger ribonucleic acid (mRNA) is a naturally occurring, endogenous carrier molecule encoding for proteins, and crucial to the central dogma in molecular biology. mRNA has been explored as a drug substance (DS) for decades, and can be computationally designed (e.g., codon optimized) to be multivalent and encode for multiple different disease targets. The disease targets that can be managed with mRNA-based medicines include not only prophylactic vaccines against infectious diseases, but much more for example RNA-based vaccines against non-infectious diseases such as cancer immunotherapy. There are three different modalities that utilize mRNA: mRNA-based vaccines, mRNA-based therapeutics, and mRNA-based cell therapy. In mRNA-based therapeutics, mRNA encode therapeutic proteins, or protein replacement therapy, particularly for disease targets that were previously undruggable by supplying intracellular and transmembrane proteins.  In cell therapy, mRNA is usually transfected into cells ex-vivo and then delivered back in-vivo e.g., T-cell therapy against disease targets including cancer, or cardiovascular diseases. The scope of this work covers mRNA-based therapeutics and vaccines.
Because mRNA is coding, mRNA-based DS are regulated as biological medicines, and categorized into three modalities: mRNA-based vaccines, mRNA-based therapeutics and mRNA-based cell therapies. There are also non-coding RNA moieties, which are classified as chemical substances. Non-coding RNAs such as RNA interference (RNAi) have regulatory function, e.g., up- or downregulating protein expression. Typically, mRNA is manufactured via in vitro transcription (IVT) based on a plasmid DNA, which is linearized and serves as the template in IVT. The scope of this work is on IVT mRNA drug substances.
This thesis aims to answer the question what the quality attributes, and analytical procedures are that can be used to ensure mRNA-DS quality, based on the current regulatory landscape specific to mRNA-based medicines. The goal of this thesis is to identify and summarize the quality attributes, and analytical procedures in conjunction with the attempt to provide a high-level synopsis for CMC Module 3 information for mRNA-DS. In this regard, this thesis provides an overview of the regulatory landscape specific for mRNA-based medicines and identifies specifically applicable guidelines  for mRNA-DS quality. Based on the specifically applicable quality guidelines for mRNA-DS then quality attributes, and analytical procedures for mRNA-DS are identified, summarized, and presented herein in conjunction with a high-level synopsis of CMC Module 3. Next is a discussion on findings and challenges that were observed upon the identification of quality attributes and analytical procedures for mRNA-DS, particularly  regarding integrity and purity. At the conclusion a sound judgement can be made that quality attributes, and analytical procedures that were initially developed for mRNA-based vaccines are equally applicable to mRNA-based therapeutics as well. Finally, an outlook is provided on the need for specifically applicable guidelines to ensure mRNA-DS quality and the emergence of mRNA-medicines beyond vaccines against infectious diseases into mRNA-based vaccines against non-infectious diseases such as cancer immunotherapy, and mRNA-based therapeutics for protein replacement therapies.
Pages: 71