Peptide Scale-Up Guide — From Research to Production¶
1. Scale Comparison¶
| Parameter | Research (0.5 L) | Pilot (2 L) | Production (5 L) | Production (20 L) |
|---|---|---|---|---|
| Resin (g) | 5 – 15 | 20 – 60 | 50 – 150 | 200 – 600 |
| Solvent per cycle (mL) | ~150 | ~600 | ~1500 | ~6000 |
| Coupling Time | 30 min | 30 – 45 min | 45 – 60 min | 60 min |
| N₂ flow | 0.5 L/min | 1.0 L/min | 2.0 L/min | 5.0 L/min |
| Cleavage Volume | ~75 mL | ~300 mL | ~750 mL | ~3000 mL |
2. Key Considerations for Scale-Up¶
| Factor | Challenge | Mitigation |
|---|---|---|
| Heat transfer | Larger surface-to-volume ratio changes | Increase coupling time at larger scale |
| Mass transfer | N₂ distribution across larger frit | Optimize N₂ flow, consider mechanical stir |
| Solvent consumption | 10× increase per scale step | Recycle wash solvents where possible |
| Cleavage exotherm | TFA addition generates heat | Add TFA slowly, control temperature |
| Precipitation | Larger ether volumes | Use jacketed precipitation vessel |
3. Process Transfer Protocol¶
- Execute 3 successful runs at research scale
- Execute 1 run at pilot scale (2 L) with same parameters
- Adjust parameters if needed (document changes)
- Execute 3 runs at pilot scale to demonstrate reproducibility
- Transfer to production (5 L or 20 L)