PEPTIDES
Maximize yield, reduce solvent, eliminate re-chromatography — no purity–yield trade-off.
MCSGP is the twin-column preparative HPLC process proven at commercial scale by Bachem on Bivalirudin.
Across 4 PPQ runs: 99.2% Purity | −96% In-process controls | Multi-day GMP campaigns | +9% Yield gain
Source: Eisenhuth & Müller-Späth, Processes 2025 (Bachem Bivalirudin PPQ campaign, Open Access)
Peptide demand is surging — driven by GLP-1 agonists, oncology peptides, and a pipeline of 150+ candidates in clinical trials. Purification by reversed-phase HPLC is the critical bottleneck.
Peptide purification becomes particularly challenging when the target must be separated from closely related impurities with similar chromatographic behavior, making selectivity, recovery and fraction collection critical to the purification strategy.
Conventional batch chromatography forces a painful trade-off: high purity or high yield — not both. Achieving target purity requires a narrow center-cut, discarding valuable product in side-fractions. Recovering that product means costly re-chromatography — with all the associated solvent consumption, QC testing, and campaign delays.
For high-volume APIs like semaglutide and tirzepatide, this inefficiency is unsustainable.
MCSGP (Multi-column Countercurrent Solvent Gradient Purification) eliminates the purity-yield trade-off in peptide chromatography. Two identical columns continuously recycle impure side-fractions — recovering peptide product that batch processes discard. It uses the same RP and IEX resins and solvents as your existing batch peptide method.
AutoPeak® dynamic process control monitors peptide elution profiles in real-time via UV and conductivity, automatically adjusting collection windows to maintain consistent output quality — enabling robust, unattended 24/7 peptide purification.
Same chemistry. Better results. MCSGP works with the RP-C18, C8, C4, IEX, and mixed-mode stationary phases and mobile phases already used in your peptide batch process — your existing resin and solvent conditions are the starting point for MCSGP development. No change to your chromatographic chemistry is needed.
Established RP, IEX, or mixed-mode processes are a good starting point for developing, evaluating and implementing MCSGP. Choosing an appropriate peptide purification method depends on the impurity profile, required purity and recovery, chromatographic selectivity, and intended production scale. Process factors such as solvent consumption, robustness, and compatibility with existing stationary phases also become increasingly important as purification moves from development to manufacturing, and this applies equally to batch chromatography and MCSGP.
| Consideration | Why it matters for peptide purification |
|---|---|
| Impurity profile | Determines how much chromatographic selectivity is required and is influenced by many factors including the complexity of the peptide synthesis |
| Stationary phase | Choosing the right stationary phase and eluent combination is a key goal in process development and crucial for achieving target purity. Well optimized stationary phase / eluent combinations benefits both batch and continuous (MCSGP) purification processes |
| Purity and yield target | A narrow batch collection windows can improve purity at the expense of recovery, often an essential tradeoff in batch mode chromatography. MCSGP greatly reduced this compromise and increasing process yields |
| Production scale | Method performance must remain consistent when moving from process development to manufacturing – MCSGP is both scalable and helps unlock access to larger scale production per system compared to batch chromatography |
| Solvent consumption | Becomes increasingly important at preparative and commercial scale due to large volume of hazardous waste generated – MCSGP typically reduces this, enabling greener processes |
| Process robustness | Feed variability and retention-time drift can affect consistent fraction collection – AutoPeak control enhances process robustness allowing MCSGP to counteract these effects |
+10–50%
Yield Increase
30-75% ↓
Solvent Reduction
80% ↓
Campaign Time
Zero
Re-chromatography Runs
75–95% ↓
Fewer IPC Analyses
50% ↓
Lyophilization Volume
| Parameter | Batch Peptide Chromatography | MCSGP with AutoPeak® |
|---|---|---|
| Purity-Yield Trade-off | Inherent — narrow cuts sacrifice yield | Eliminated — high purity AND yield simultaneously |
| Product Yield | 50–80% | 80–99% (+10–50% absolute) |
| Re-chromatography | Required for side-fractions | Eliminated — internal recycling |
| Solvent Consumption | High | Up to 75% reduction |
| IPC/QC Burden | Testing every side-fraction, every batch | 75–95% fewer analyses |
| Campaign Duration | Days per batch | Up to 80% shorter (continuous 24/7) |
| Process Control | Manual monitoring | Automated (AutoPeak® UV-based PAT) |
| Robustness | Sensitive to drift and feed variability | AutoPeak® dynamically compensates |
| Operator Requirement | Requires supervision | Designed for unsupervised operation |
| Sustainability (PMI) | High waste and solvent intensity | Significantly improved PMI |
| Stationary Phase / Eluents | Standard RP / IEX | Same — no change required |
Long-chain peptides (30–39 aa) with complex impurity profiles. MCSGP enables high-yield RP-HPLC purification at the multi-hundred-kg scale demanded by the GLP-1 market — with up to 75% less solvent and proportional upstream synthesis savings.
MCSGP consistently outperforms optimized batch processes for peptides in the 10–30 aa range. Published data on glucagon showed +23% yield at identical purity, with a straightforward one-day method transfer from batch.
Some peptide purification methods benefit from combining orthogonal chromatographic steps when a single separation does not provide sufficient selectivity. ChromaCon supports automated multi-step workflows such as RP + IEX or RP + RP using 2D chromatography, while MCSGP can be applied to the throughput-limiting purification step.
ICH-required peptide impurity characterization typically takes weeks of repetitive analytical runs. N-Rich automated on-column enrichment isolates milligram quantities of target peptide impurities up to 80× faster.
Ready to Upgrade Your Peptide Purification Process?
This application note presents a systematic approach for optimization of MCSGP with regards to the performance parameters Yield, Productivity and Eluent Consumption, and gives recommendations on the priority of the parameters.
This application note provides a simple step-bystep flowchart template to guide the development of batch gradient conditions that result in optimal input data for the MCSGP wizard.
First publication presenting a Process Characterization and Process Performance Qualification approach for regulatory-compliant Process Validation of MCSGP, demonstrated for Bivalirudin purification.
Bachem white paper about “Reducing Solvent Consumption for Large-Scale Peptide API Manufacturing” using MCSGP
Bachem webinar about the “Continuous Chromatography of Peptides” using MCSGP
