After the first oligonucleotide therapeutic was approved in 1998, almost 20 oligonucleotide drugs have reached the market (2). Considering the advancements of manufacturing technologies and increasing demand for large-scale, production of oligonucleotides, new production strategies and novel solutions for existing problems have been developed to increase the efficiency, sustainability, and quality.
In 2016, the development of greener processes for oligonucleotide active pharmaceutical ingredients (APIs) was identified as a key unmet need by the American Chemical Society (ACS) Green Chemistry Institute Pharmaceutical Roundtable (GCIPR). Since then, the implementation of green chemistry and engineering approaches into oligonucleotide manufacturing has increased the sustainability and safety of oligonucleotide products at the molecular level (3). Automation and industry 4.0 approaches are also considered revolutionary with their potential to increase efficiency and productivity, especially in large- production and minimizing human errors.
Another important factor that might limit the yield is the synthesis method. In addition to the widely used solid- phase synthesis method, new technologies have been developed such as enzymatic synthesis using functionalized polymerases and liquid phase synthesis simplifying the steps in the cycles and having the potential of being highly scalable (4).
Manufacturing of longer oligonucleotides is also challenging with the existing methods because the synthesis efficiency and the ratio of full-length oligonucleotides decrease in each cycle. Strategies such as manufacturing longer oligonucleotides by assembling shorter fragments and increasing coupling efficiency in the cycles have been successful. Lastly, finding the proper method to eliminate impurities formed in the synthesis -- such as degradation impurities and structural isomers -- is crucial to increase efficiency and product quality.
With this in mind, this eBook shares some work done by companies and scientists in the field to make oligonucleotide and peptide manufacturing scalable and more efficient.