Home / Oligonucleotides and Peptides / Drug Substance / Early Phase Development
Early Phase Development
The route in the filing is the route that runs through Phase III, and early-phase development is where it is chosen.
Where early-phase timelines slip
Early-phase timelines rarely slip because the chemistry fails. More often API, formulation, analytical and regulatory work run sequentially or across several partners, each waiting on the last.
At WuXi TIDES, IND-enabling work starts as soon as the preclinical candidate is confirmed, with one CMC plan that connects early development to what the filing will need. The four workstreams run in parallel because they report into the same program.
Route scouting
A sequence that a discovery lab can make is not yet a sequence with a viable process. Route scouting closes that gap, and the route is difficult to change once the IND-enabling campaign has started.
An oligonucleotide example: a biotech brought us a 23-mer siRNA-GalNAc for cardiovascular disease. The incoming process gave a 13% yield at 18% crude purity, and the GalNAc moiety was not commercially available. We made the GalNAc, rebuilt the conjugation chemistry and redeveloped the analytical methods around it. The process now runs at 62% yield and 75% crude purity.
[ Read the case study → ]
A peptide example: a macrocyclic peptide over 30 residues arrived with a route yielding less than one per cent and a building block in short supply. The redesign synthesized main chain and side chain in parallel, cyclized on resin, and completed the API by solid-phase coupling — four times the yield, and an IND filed nine months from the start of the work.
[ Read the case study → ]
Process development
Solid-phase, liquid-phase and ligation-enabled routes are all available, and the choice is made per molecule. For a long or heavily modified sequence, that choice is often the single largest lever on cost of goods.
Development work covers coupling efficiency, resin handling and loading, solvent consumption, throughput and batch-to-batch consistency. Those parameters determine whether a process that works at 100 g works at 10 kg. For established modalities, platform processes, and validated analytical methods for ASO, siRNA, PMO and sgRNA mean development starts from a known position rather than a blank one.
When a modality has no platform, we build one. Phosphorodiamidate morpholino oligomers are difficult to synthesize, so WuXi TIDES developed a high-loading solid-phase PMO process of its own. It runs on customized reactors up to 100 L, with yields above 50% and crude purities around 75%, and delivers final product above 90% purity with endotoxin below 0.045 EU/mg.
Preclinical and IND-enabling manufacturing
For peptide programs, non-GMP scale-up delivers material for candidate confirmation and early formulation work in five to seven weeks.
For oligonucleotides, an IND-enabling CMC package can be ready in seven months, using platform processes and established analytical methods rather than developing both from scratch.
What comes next is handled by the same team
The process developed in early phase is the process that goes into clinical supply, scale-up and validation, with no technology transfer, no second set of analytical methods and no reconciliation of impurity profiles between organizations.
Where the seven months come from
An IND-enabling package in seven months comes from platform processes that start from a known position, analytical methods that already exist, and four workstreams reporting into one program.
Run across separate suppliers, the same work takes longer because each step waits for the one before it.