18 BioPharm International
®
Manufacturing and Facilities eBook 2023 www.biopharminternational.com
Facilities:
OligOnucleOtides
Production at larger batch sizes
Production r uns t hat generate sign if icant quan-
tities of drug substance for clinical trials or com-
mercia l sca le of t herapeut ics genera l ly requ i re
l a r g e , f i x e d e q u i p m e n t , s t o r a g e t a n k f a r m s ,
c e n t r a l u t i l i t y s y s t e m s , a n d c l e a n - i n - p l a c e
(C I P) s y s tem s. T he f ol low i ng i s a t y pic a l l a rge
batch size scheme:
• Synthesis scales to accommodate clinical and
commercial-scale production (approximately
300 mmol to >1 mol), which typically requires
full-scale, custom production equipment.
• Increased solvent required for the process and for
rinsing/CIP of equipment in a production envi-
ronment.
• 24/7 production.
• Increase in required raw material supplies and
waste collection.
Code implications
For large-sca le batch sy nt hesis, t he inventor y of
f lammable liquids and solutions is likely to lead to
tank farms, solution delivery, and production areas
exceeding the MAQs. Those areas must be designated
as H-occupancies.
In some cases, large-scale production may require
handling some ignitable liquids and solutions at pres-
sures >15 psig. This demands H-2 compliance if the
inventory at pressure exceeds the more restrictive
MAQ limits that result from the >15 psig limit, even
when the ignitables are used in a closed vessel.
Production of longer chain oligos
Synthesis of longer chain molecules (e.g., sgRNA and
tRNA) increases the amounts of hazardous material
used during production and generated waste. This
occurs due to three factors:
Figure 1: Hazard classification of chemicals typically used in oligo production.
Figure 2: Base Case: Typical raw material and waste collection scheme.
FIGURE 2. Base Case: Typical raw material and waste collection scheme.
FIGURE 3. Typical increase in raw material and waste collection due
to increased throughput.
