PHARMACEUTICALS controlled raw material specifications and production process parameters. This approach enables end-to-end optimisation of all relevant purity attributes and ensures compliance with stringent pharmaceutical quality standards.
CABB has developed and continuously refined a proprietary catalyst and process technology for the production of DCA and its key intermediates, ensuring consistent compliance with the strict purity requirements of the oligonucleotide industry.
The finished product, DeTrityl * Ultrapure, is characterised by extremely low levels of chloral
Study design
DCA reagents from three different suppliers were evaluated in a blinded study. Five independent syntheses at 1 mmol-scale were performed for each DCA group, resulting in a total of 15 syntheses. Apart from the DCA reagent, all synthesis and deprotection parameters, as well as analytical procedures, were kept constant throughout the study.
A 20-mer DNA / MOE gapmer oligonucleotide( 5--MOE [ mCGmUGA ]- DNA [ AGmCGAAGTGG ]- MOE [ AGAmCG ]-3’), known as Bepirovirsen, was synthesised using standard solid-phase phosphoramidite chemistry at a synthesis scale of 1 mmol and a Knauer OligoScaler machine. Synthesis was performed on controlled-pore glass( CPG) support( 500 Å pore size, loaded with 93 µ mol g-1 universal linker).
All syntheses were carried out under identical conditions to minimise experimental variability. All reagents used throughout the study originated from the same production batches. Deblocking solution, amidite and sulfurisation solutions were prepared in bulk for each hydrate, glyoxylic acid, formaldehyde, and free chloride. This is a direct consequence of CABB’ s proprietary catalyst and process technology, which inherently avoids the formation of these impurities, rather than relying on additional purification of a compromised feedstock.
The highly demanding nature of DCA necessitates specialised handling by experienced and welltrained personnel. Its properties pose significant challenges in storage, handling, packaging and transportation, requiring rigorous operational controls to ensure consistent quality and supply reliability.
study-group immediately before use to reduce batch-to-batch variation.
Capping, amidite coupling and sulfurisation were performed using standard methods with set volumes, concentrations and flow rates. These steps were kept identical throughout all syntheses. Detritylation was performed using 3.0 ± 0.1 %( w / w) DCA. The completion of each detritylation step was monitored in real time by UV detection using a threshold signal recorded at 380 nm.
Flow rate during deblocking was maintained under standard operating conditions, whereas contact time and reagent consumption were automatically adjusted according to the UV threshold. The required DCA volume for each deblocking step was recorded as an experimental variable.
Crude oligonucleotide products were analysed with regards to product purity and identification of related substances by LC / MS( Thermo Vanquish UPLC / Orbitrap), while quantification was performed by UV detection at 254 nm( Implen Nanophotometer).
* DeTrityl Ultrapure is a registered trademark of CABB
To mitigate geopolitical and supply risks while meeting growing demand from new oligonucleotide drug products, CABB operates two manufacturing sites in Germany and Switzerland. Reliable supply to CDMOs requires full ownership of the multistep manufacturing process. From raw material through intermediates to DeTrityl Ultrapure, all critical steps are performed under one quality system, ensuring full traceability, process understanding and audit-ready transparency. That cannot be achieved by purifying externally sourced DCA.
Controlled synthesis study
In a recent study conducted by XNA Pharma Germany, multiple DCA grades from China and India were evaluated, and their performance in a 1 mmol-scale synthesis of Bepirovirsen was compared with DeTrityl Ultrapure.
The DCA reagents from different suppliers were compared in a blinded study comprising five independent 1 mmol syntheses / batch, using Bepirovirsen as a model oligonucleotide and keeping all other synthesis, deprotection, and analytical conditions constant. Detritylation efficiency was monitored by UV detection and DCA consumption, while crude product purity, identity, related substances and yield were evaluated by LC / MS and UV spectroscopy( see box).
As a first step, the impurity profile of the crude oligonucleotide product produced with the different DCA grades was assessed in an LC / MS analysis, which revealed distinct differences in purity levels. DeTrityl Ultrapure consistently showed lower levels of critical related substances, such as N-1, N-2 and depurination products, which are difficult to remove during downstream processing and can adversely affect overall yield, purity, and cost( Figure 1).
This perspective is consistent with the total impurity profile of the crude oligonucleotide product. DeTrityl Ultrapure shows best-in-
SEP / OCT 2026 SPECCHEMONLINE. COM
23