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Peptide and Oligonucleotide Formulation and Manufacturing Technologies
The dosage-form technologies behind peptide and oligonucleotide drug products, available from feasibility through commercial supply.
The dosage form is an early decision
A peptide or oligonucleotide will usually end up as a lyophilized vial or a solution in a prefilled syringe. The choice determines the stability program, the fill format, the cold chain and how the product is administered, and changing it after Phase II means new stability data and a bridging study.
The screening that informs that choice is best done while the API process is still being developed, and the platforms below are available from that point.
Sterile fill-finish
Almost every peptide and oligonucleotide drug product is an injectable. Five aseptic filling lines with fully enclosed isolation systems and automated filling, at a combined capacity of more than 100 million units a year, produce more than 270 sterile batches annually.
Filling into vials, prefilled syringes and cartridges. Dosage forms cover solution, emulsion, suspension, lyophilized powder and liposome. Single-use technologies and robotic operation keep changeover between programs short, so small clinical batches can be run on the same lines.
For potent molecules, a dedicated line at Wuxi City runs at an occupational exposure limit of 10 ng/m³, with two 20 m² lyophilizers, filling up to 200 units a minute for 25 million units a year. For conjugates carrying cytotoxic or radionuclide payloads, that line is what allows the program to stay on one site from first-in-human to launch.
Lyophilization
Most peptide and oligonucleotide injectables are lyophilized, because few reach a two-year shelf life in solution.
Tray lyophilizers run from 0.5 m² to 20 m² of shelf area, with two 20 m² units on the high-potency line. That range matters because a cycle developed on a half-square-meter tray transfers to twenty square meters only through the intermediate scales, all of which are available on the platform.
Cycle development runs on the same equipment types used for commercial manufacture, so a cycle developed for clinical supply transfers to commercial scale without being redeveloped.
Lipid and nano formulation
For systemically delivered oligonucleotides that are not GalNAc-conjugated, lipid nanoparticles are usually the delivery system.
Supply of the lipids is the constraint. Ionizable and PEGylated lipids are specialist chemistry with a short supplier list and long lead times, and an LNP program dependent on a single external source carries a supply risk. We synthesize both in-house.
The LNP platform runs end to end: lipid discovery, formulation and process development, analytical development, and GMP clinical and commercial manufacture, with different assembly structures achieved through formulation and process control. Programs scale from R&D through to GMP without changing platform.
Liposomal and other nanoparticle formulations are supported on the same aseptic lines.
Oral solids
For oral peptide programs, the tableting and encapsulation capacity already exists and is validated: tablets, capsules, powders, granules, liquid in bottle, liquid-filled hard capsules and softgels, on a platform that has supported more than 1,000 drugs from preclinical to commercial across sites at Shanghai Waigaoqiao and Wuxi City in China, Couvet in Switzerland and San Diego in the United States.
For an oral peptide program the constraint is the formulation science, and that work is described here.
Spray-dried dispersion
An oral peptide that needs a solid dispersion to reach useful exposure has a narrow set of options, because peptides generally do not tolerate the thermal processing routes, which leaves spray drying.
The spray drying platform runs more than 460 batches a year, from 50 mg at laboratory scale through to 100 kg and beyond at commercial scale, on PSD-1, SD-2, PSD-3 and PSD-4 dryers. One program scaled from PSD-1 to PSD-3 in three months and delivered 1,400 kg of spray-dried intermediate for a Phase III trial.
What the dosage form decides
The choice between a lyophilized vial and a solution in a prefilled syringe determines the stability program, the cold chain, the fill format and how the product is administered. Made early, it is a screening exercise; revisited after Phase II, it is a bridging study.