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50 Pharmaceutical Technology ® The Real Message Behind Commercial mRNA Products April eBook 2023 PharmTech.com PAULISTA - STOCK.ADOBE.COM O ligonucleotide drug substances general- ly are unstable at room temperature, and some are also degraded in the presence of certain enzymes. That is why, in part, they are formulated using special delivery solutions such as lipid nanoparticles (LNPs). (These delivery technologies also facilitate entry of nucleotide APIs into target cells.) Degradation can occur via loss of terminal nucleotides or certain functional groups, oxidation, and other mechanisms. Oligonucleotide–oligonucleotide inter- actions that can occur at higher concentrations are an added concern. These instability issues must be man- aged throughout the entire manufacturing process. The challenges are particularly great for messenger RNA (mRNA), which can be degraded by enzymes found commonly in the environment, temperature, a nd due to t he overa l l shea r sen sit iv it y of t he long-chained molecule. Variety of oligonucleotide drug substances The landscape of nucleotide-based therapeutics is based on more than half a century of research and develop- ment in these modalities, according to Julian Mochayedi, strategic marketing manager for mRNA solutions with MilliporeSigma, the Life Science business of Merck KGaA, Darmstadt, Germany. This knowledge translates to the clinic and beyond, with several approved thera- peutic products on the market. The different types of nucleotide-based therapeutics can be broadly classified by the type of nucleic acid, Mochayedi continues, such as those with DNA or RNA as a basis. Alternatively, they can be differentiated by their functional design, which determines the mode of action. "One can cite DNA-based adeno-associated virus (AAV) vectors for gene delivery, antisense oligo- nucleotides (ASOs), small-interfering RNAs (siRNAs) for gene expression disruption, and most recently, mRNA to Managing mRNA Instability During Formulation, Manufacturing, and Shipment Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology ® . Unique solutions are required to protect inherently unstable messenger RNA.