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With a renewed and growing interest in therapeutic oligonucleotides across the pharmaceutical industry, pressure is increasing on drug developers to take more seriously the sustainability ramifications of this modality. With 12 oligonucleotide drugs reaching the market to date and hundreds more in clinical trials and preclinical development, the current state of the art in oligonucleotide production poses a waste and cost burden to manufacturers. Legacy technologies make use of large volumes of hazardous reagents and solvents, as well as energy-intensive processes in synthesis, purification, and isolation. In 2016, the American Chemical Society (ACS) Green Chemistry Institute Pharmaceutical Roundtable (GCIPR) identified the development of greener processes for oligonucleotide Active Pharmaceutical Ingredients (APIs) as a critical unmet need. As a result, the Roundtable formed a focus team with the remit of identifying green chemistry and engineering improvements that would make oligonucleotide production more sustainable. In this Perspective, we summarize the present challenges in oligonucleotide synthesis, purification, and isolation; highlight potential solutions; and encourage synergies between academia; contract research, development and manufacturing organizations; and the pharmaceutical industry. A critical part of our assessment includes Process Mass Intensity (PMI) data from multiple companies to provide preliminary baseline metrics for current oligonucleotide manufacturing processes.

The feasibility of using simulated moving bed technology (SMB) for chiral separation on cellulose triacetate is demonstrated on the preparative scale: 1 kg of a chiral epoxide has been separated. On comparing SMB technology w i t h conventional liquid chromatography it turns out that the main advantage of SMB lies in the signhcant reduction of mobile phase consumption. The process design for SMB is made theoretically and the predictions are c o h e d by our pilot study. o 1993 Wiley-Liss, Inc.KEY WORDS: simulated moving bed technology, chiral separation, cellulose triacetate, preparative scale liquid chromatography, racemic epoxide raphy. Using cellulose triacetate (CTA) as the stationary phase and methanol as eluent, baseline separation of the enantiomers can be achieved in a reasonable time. To overcome the problem of solvent recovery when scaling up into the kilogram range, simulated moving bed (SMB) technology offers an attractive alternative to conventional liquid chromatography (LC).The original SMB process was patented by UOP in the early 1960~,'-~ and has since been used in the petroleum industry, mainly for p-xylene production and in the sugar industry for fructose purification. In these applications, the separations are relatively easy-with selectivity factors of about 2 or higher-and therefore large particle size sorbents (500-1000 pm) and concomitantly low chromatographic efficiencies have proved adequate. However, in the fine chemical or pharmaceutical industries, production rates are lower (the ton range) and the separations are more demanding, and some the solid phase and the eluent which move in opposite directions. Feed, containing components A and B, is injected in the middle of the column. Provided that the affinities of A and B for the solid are different (B being more retained than A), appropriate choice of the solid and liquid flow rates will split the feed into two fractions. The less retained component (A) goes up in the direction of the fluid, and is collected in the raffinate stream, whereas B moves in the drection of the solid, and is collected in the extract stream. Countercurrent systems are attractive because they are usually more efficient than batch processes. Simulated Moving Bed ChromatographyThe simulated moving bed pilot plant (Licosep plant at Separex, Champigneulles, France) can deal w i t h systems having from 4 to 24 columns. In order to separate our epoxide enantiomers, 10 and 12 column configurations were investigated. Packing of Columns for SMB UnitThe COlumnS were superformance columns (Merck) of 2.6 cm i.d. and 11 cm length, packed with 25-40 pm cellulose effort has yet to be made to extend SMB technokgy to these applications. Enantioseparations have recently been performed by SMB on a small scale, involving ligand exchange with large particle size sorbents7 or adsorption on small, high efficiency phases.The aim of this work is to study the applicability of SMB technology for separation of the above mentioned oxide on a CTA sorbent, and to ep-SMB with an opti-

Oligonucleotide drugs show promise to treat diseases afflicting millions of people. To address the need to manufacture large quantities of oligonucleotide therapeutics, the novel convergent liquid-phase synthesis has been developed for an 18-mer oligonucleotide drug candidate. Fragments containing tetra- and pentamers were synthesized and assembled into the 18-mer without column chromatography, which had a similar impurity profile to material made by standard solid-phase oligonucleotide synthesis. Two of the fragments have been synthesized at ∼3 kg/batch sizes and four additional tetra- and pentamer fragments were synthesized at >300-g scale, and a 34-mer was assembled from the fragments. Critical impurities are controlled in the fragment syntheses to provide oligonucleotides of purities suitable for clinical use after applying standard full-length product purification process. Impurity control in the assembly steps demonstrated the potential to eliminate chromatography of full-length oligonucleotides, which should enhance scalability and reduce the environmental impact of the process. The convergent assembly and telescoping of reactions made the long synthesis (>60 reactions) practical by reducing production time, material loss, and chances for impurity generation.

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