News | June 1, 1999

AlliedSignal, Amersham Pharmacia Biotech form DNA/RNA Manufacturing Alliance

AlliedSignal Inc. (Morris Township, NJ) and Amersham Pharmacia Biotech (APB; Uppsala, Sweden) have formed an alliance for providing pharmaceutical manufacturers with high-purity reagents and instrumentation for large-scale production of DNA/RNA.

As part of the agreement, AlliedSignal's Burdick & Jackson facility will provide its suite of high-purity synthesis reagents and solvents packaged in large, safe, returnable containers that connect directly to Amersham Pharmacia Biotech's OligoPilot and OligoProcess DNA synthesis system.

APB's OligoPilot bench-scale oligonucleotide synthesizer serves discovery and small-batch manufacturing of oligonucleotides.

"The alliance combines AlliedSignal's high-purity solvent and DNA reagent capability with Amersham Pharmacia Biotech's expertise in synthesis instrumentation and proprietary reagents," said Fred Lynch, general manager of AlliedSignal's Burdick & Jackson facility. "Now, biotechnology companies and pharmaceutical manufacturers can develop and manufacture DNA/RNA-based drugs faster, with greater reliability, convenience and safety than ever before."

OligoProcess, APB's production-grade oligonucleotide manufacturing system. OligoProcess systems employ the same flow-through column technology as OligoPilot, but use industrial grade components that allow operation at scales of 10–1,000 mmol.

According to Peter Ehrenheim, vice president of industrial DNA synthesis at APB, the alliance with AlliedSignal was a natural fit with his company's product and service philosophies. "Together, we are giving our customers what they need—a turnkey oligonucleotide production capability for use in the rapidly growing antisense drug market," said Erenheim.

Flow-Through Design
The flow-through reactor design employed by both OligoPilot and OligoProcess offer several advantages over conventional batch synthesis of oligonucleotides. In the flow-through scheme, the coupling mixture is added to the solid support in a tight reagent zone (shown in blue in the diagram below) which is pushed through the column as a defined reagent band. Reagents at the front of this zone are consumed by the coupling reaction at a continuous rate and are replaced by fresh reagents as the zone moves through the reactor. The amidite concentration and the reaction rate are therefore the same throughout the reaction.

Continuous reagent replacement keeps the reagent concentration constant throughout the reaction zone, and maintains constant high reaction rates throughout the reaction process. This minimizes cycle times and guarantees that the reaction goes to completion, yielding high coupling efficiencies at all synthetic scales.

A batch reactor, on the other hand, does not have a moving reagent zone, so reagents that are consumed are not replaced. The amidite concentration (red zone) thus decreases continuously throughout the coupling reaction. A direct consequence of this drop in concentration is a reduction in the overall reaction rate and increased cycle times. Batch reactors are also not amenable to scale up due to the limited size of the reaction vessel, so increased oligonucleotide output can only be obtained through the use of a larger number of synthesisers.

The flow-through reactor technology of OligoPilot offers significant savings in reagent costs over batch reactor synthesisers. DNA oligomers can be synthesized using only 1.5 molar equivalents of amidite with coupling efficiencies between 98.5 and 99.5%. Batch reactor synthesizers use much larger quatities of reagents and organic solvents than systems designed on flow-through technology. In addition, OligoPilot II generates only about one quarter of the organic waste produced by a batch reactor operating at the same scale, making it environmentally (and user-) friendly.

For more information: Peter Erenheim, Amersham Pharmacia Biotech AB, SE-751 84, Uppsala, Sweden. Tel: +46-1816-5000. Fax: +46-1816-6458.

By Angelo DePalma