Monomer and Ligand — GMP Manufacture

The building block as a supply risk

A modified amidite with one supplier, a six-month lead time and no Drug Master File is a single point of failure in a CMC package, and it usually becomes visible when a regulator asks where the regulatory starting material came from and what controls it.

Making the monomer where the oligonucleotide is made removes the dependency, the shipping and the second set of specifications. It also means the impurity profile of the building block and the impurity profile of the API are understood by the same people.

Nucleoside and phosphoramidite chemistry

More than 1,000 amidite molecules customized for client programs, made in plants dedicated to amidite production, with more than 500 amidite catalog products readily available.

Modifications run across the whole molecule:

Sample molecules include RNAi amidite (2′-F, OMe, MOE, OTBS), LNA amidite, TNA amidite, Vpm-POM, DNA C(Bz) amidite, PACE amidite, thio-amidite and PMO monomer.

Drug Master Files

At NDA, the Drug Master File is what matters. More than 40 catalog amidites are available at commercial scale with Drug Master Files already filed — DNA, 2′-MOE, 2′-OMe, 2′-F, LNA and PMO monomers among them.

Without a DMF, an amidite used as a regulatory starting material has to be documented in the sponsor’s own filing. With one, it is cited by reference number.

Impurity control

Behind the DMFs sits an impurity control strategy. More than 1,000 amidite impurities were synthesized deliberately, characterized and assessed for their effect on oligonucleotide API quality, which is what allows a specification to be justified.

GalNAc

N-acetylgalactosamine is an amino sugar derivative of galactose, and conjugation with GalNAc is an efficient way to raise siRNA accumulation in the target organ and help cellular uptake.

We have made more than 100 types of GalNAc molecule: mono-, tri- and tetra-GalNAc, GalNAc amidite, GalNAc PFP ester, GalNAc azide and GalNAc-PEG conjugates among them. With more than 100 GalNAc building blocks and CPG and polystyrene conjugate resins behind it, the platform supports GalNAc-oligonucleotide programs from discovery onward.

Batch scales run from milligrams to more than 50 kilograms, from discovery through to commercial launch.

Where GalNAc synthesis goes wrong, and what we changed

GalNAc is synthetically awkward because most of the intermediates are oily or foamy solids. The synthesis then needs many column and prep-HPLC purification steps, which makes scale-up difficult and yields low. The analytical work is equally awkward: low UV response, a complex impurity profile and poor stability.

We developed convergent routes through telescoping processes with no column purification steps, so that the isolated intermediates are stable solids rather than oils. Precipitation and spray drying reduce the need for columns and prep-HPLC. Our analytical teams identified a large number of GalNAc-related impurities to support method development and release testing.

Chelators for radionuclide work

For radionuclide programs the chelator is the critical building block. DOTA and NOTA chelation is available on both peptide and oligonucleotide sequences, made in the same place as the sequence itself.

Oligonucleotide Conjugate →

Removing a dependency

For more than 40 of our amidites the Drug Master File is already filed, so the building block is cited by reference number rather than documented in the sponsor’s own submission.

For everything else, the monomer or the ligand is made on the same site as the molecule it goes into, by the people who hold both impurity profiles.