20 BioPharm International
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Manufacturing and Facilities eBook 2023 www.biopharminternational.com
Facilities:
OligOnucleOtides
• The material use is proportional to chain length.
• The yield of full-length product drops off signifi-
cantly as the number of couplings increase due to
intrinsic inefficiency per coupling.
• Longer molecules occupy more column volume re-
sulting in lower column loading per unit volume to
accommodate the larger molecules attached to the
support material. That results in increased rinse
solvent demands per gm of product produced.
The combination of all these factors has a multipli-
cative effect on raw material use. For example, to syn-
thesize the same amount of drug substance, a 100-mer
synthesis can use 60 times more solvent than a 20-mer
synthesis (Figure 4). The following is a typical lon-
ger-chain scheme:
• Increased solid support loading for synthesis col-
umns
• 24/7 production
• Significant increase in required raw material sup-
plies and waste collection (Figure 5).
Code implications
Production of longer-chain oligos tend to have similar
facility infrastructure impact to those of production at
larger scales, but those required changes arrive more
quickly in the scale-up trajectory due to the inefficiency
of synthesis.
Summary
The f lammable solvent storage and usage implicit in
a SPOS-based approach means facility design com-
plexity and magnitude of facility cost become tan-
gible factors much earlier in the clinical life cycle
than would be true for a different therapeutic mo-
dality such as a monoclonal antibody. For the larg-
est therapeutic scales relevant in today's industr y,
the required facilities are more closely related to
traditiona l industria l chem ica l faci lities t han to
Figure 3: Typical increase in raw material and waste collection
Figure 4: Acetonitrile used per mmol of synthesized full-length
FIGURE 4. Acetonitrile used per
mmol of synthesized full-length
product (FLP).
FIGURE 5. Impact of molecule length on raw material and waste collection.
