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Late Phase Development
Scale up in steps, on the same platform, with the analytical methods already filed.
What changes after Phase I
The chemistry usually does not change. The process now has to make more material, more often, at a cost a commercial model can carry, while the impurity profile becomes something a regulator asks about in writing.
Most late-phase problems in peptide and oligonucleotide programs are one of three things: a purification step whose cost grows faster than the batch size, an impurity that only appears above a certain scale, or a technology transfer that introduced both.
Clinical API manufacturing
More than 20 solid-phase peptide synthesis production lines, with vessels from 10 liters to 5,000 liters. Thirty oligonucleotide manufacturing lines, including four large-scale Oligo Process systems at Changzhou.
The vessel range matters more than the total volume. A campaign that jumps from a 50 L pilot straight to 3,000 L carries risk that one moving through the sizes between them does not. The intermediate scales are on the same site, running the same analytical methods, which keeps scale-up an engineering question.
Process optimization
For both peptides and oligonucleotides, purification is where late-phase economics are decided. Batch preparative chromatography consumes solvent in proportion to the material it fails to recover, and at clinical scale that becomes the dominant line in the cost of goods.
Continuous flow chromatography recovers the fractions that batch chromatography discards, which raises yield and cuts solvent at the same time. Alongside it we run ion-exchange, reverse-phase, hydrophobic interaction and membrane-enabled purification, chosen per molecule.
On the synthesis side, process options are introduced selectively as scale increases: enzymatic ligation, PN bond formation, precipitation, stirred-bed processing, thin-film evaporation. Each is applied where it improves yield or impurity profile.
Scale-up
For long or heavily modified sequences, hybrid solid-phase and liquid-phase approaches often scale better than either alone. Both are available at WuXi TIDES, and the choice is made per molecule.
Scale-up work runs against the same platform processes used in early phase, so the impurity profile the regulator has already seen is the one that continues.
Analytical work at late phase
At late phase, analytical method capability determines whether an impurity question can be answered with data. For peptides that means in-house amino acid analysis and enantiomeric purity assessment to quantify D-isomer content, peptide mapping for identity, and LC-MS/MS sequence confirmation for linear, branched and multi-cyclic peptides.
Where higher resolution is needed, multi-dimensional LC-MS supports detailed impurity separation and identification. For programs heading toward a BLA, Bio-ID and bio-assay method transfer, qualification and validation continue from the methods already in use.
The analytical laboratories sit alongside API process development, in the same building, so method troubleshooting during a campaign does not wait on a shipment.
Scaling in steps
A campaign moving from a 50 L pilot to 3,000 L in one step carries risk that a process moving through the intermediate scales does not. More than twenty production lines from 10 L to 5,000 L is what makes scale-up an engineering exercise.