Scaling complexity in ADC payload – linker purification
Dr Mattia Stucchi of Olon, shares a statistical approach to the development of purification processes for payloadlinkers
As antibody – drug conjugates( ADCs) continue to mature as a therapeutic modality, the chemical complexity of payloads and linkers is increasing in parallel. Many of these highly potent, structurally dense small molecules pose significant challenges during early development, particularly at the purification stage, where limited material availability, instability and stringent impurity control requirements converge.
Olon supports ADC programmes at this critical interface between chemical complexity and industrial feasibility. Building on decades of experience in high-potency chemistry and chromatographic purification, the company has developed and applied a structured, statisticallydriven approach to chromatographic development that enables rapid decision-making while maintaining robustness for scale-up and GMP translation.
In this context, chromatographic purification often becomes unavoidable. Whilst crystallisation and other non-chromatographic techniques remain preferable whenever feasible, the reality of early-stage ADC development is that structurally similar impurities and unstable intermediates frequently limit alternatives. The key industrial question is therefore not whether chromatography should be used but how it can be developed rapidly, predictably and with confidence.
From an industrial perspective, chromatographic purification is not a simple analytical exercise. At production scale, it represents a multi- variate, non-linear system influenced by stationary phase chemistry, mobile-phase composition, gradient structure, temperature, loading and solubility behaviour of crude material. Traditional trial-and-error approaches struggle to cope with this complexity, often resulting in extended development timelines and fragile operating windows.
Industrial challenge of chromatographic purification
Payload – linker production typically comprises multiple synthetic transformations interspersed with purification, concentration and isolation steps. These molecules frequently display poor solubility, chemical instability and a strong tendency to generate closely related impurities. Under these conditions, purification methods originating from medicinal chemistry are rarely suitable for scale‐up, with excessively long
gradients, low loading factors and limited robustness.
Addressing these challenges requires a development strategy that balances speed with statistical confidence. Rather than relying on incremental adjustments, Olon applies a structured workflow designed to rapidly map the relevant chemical space and identify robust operating regions suited to industrial execution.
The chromatographic development strategy begins with rapid qualitative screening using analytical HPLC. This step is designed to quickly eliminate unfavourable stationary- and mobile-phase combinations, while identifying systems that provide meaningful selectivity and practical solubility behaviour. The objective is informed narrowing of options within a compressed timeframe.
In a representative early-stage payload – linker programme developed for one key customer, this screening
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