CMC: Regulatory overview for Oligonucleotide drug substances


ML_Consult, Cincinnati, USA


CMC (Chemistry, Manufacturing and Control) for oligonucleotide therapeutics is a vast topic. There are no clear guidelines for all the aspects of CMC for those products yet. This paper will propose a view on the regulatory approach that teams developing such product could follow. I’ll provide some reference to also guide you regarding the pure synthetic aspect of the process. This paper is the author’s view based on his experience.


CMC (Chemistry, Manufacturing and Control) for oligonucleotide therapeutics, synthesized on solid phase synthesis and purified by column chromatography – so the most usual way at the moment - is an unusual situation compared to small molecules and even to synthetic peptide due to the relative short experience.


The first investigational new drug (IND) application for an oligonucleotide type of NCE drug was filed in 1992, and since the first IND filing for a 20-mer DNA phosphoro- thioate antisense oligonucleotide, ISIS 2105, administered locally to genital warts for the treatment of human papilloma virus (HPV), a lot has been done. In 1998, Vitravene®  (fomivirsen sodium, ISIS 2922, also from the company then named ISIS, now known as IONIS) became the first oligonucleotide drug to receive market approval in the US and Europe for the treatment of CMV retinitis. Vitravene is an antisense molecule that blocks translation of viral mRNA by binding to a coding segment of a key CMV gene.  We now have 15 approved synthetic oligo ...