Dr Youchu Wang , head of API early phase development at WuXi STA , shares an example of the application of flow chemistry in a high potency target
Empowering highly potent peptide drug conjugate scale-up with flow chemistry
Dr Youchu Wang , head of API early phase development at WuXi STA , shares an example of the application of flow chemistry in a high potency target
In the last few years , we have seen increasing interest in and utilisation of continuous processing for the development of novel pharmaceuticals , with the chief reason being its greater manufacturing efficiency and lower overall footprint . Continuous processing has also opened Pandora ’ s box in helping overcome many scale-up issues that are unsolvable in conventional batch production set-ups .
In this article we will look specifically at the development challenge faced when moving a peptide-drug conjugate ( PDC ) from pre-clinical ( gram-scale ) to phase I ( kg-scale ). New modality conjugations with HPAPIs and peptides – particularly for oncology targets – are now an increasingly large part of the discovery pipeline . Consequently , we will see many innovations and CDMOs looking to technologies like continuous manufacturing to meet the unique challenges of scale-up .
Experimental
Recently we worked with a biotech that was developing a new oncology drug and needed a new solution for the API manufacturing of a PDC , including a highly potent cytotoxin .
The PDC can be successfully synthesised at gram scale , but impurities emerged when it was scaled up to the kg level .
In order to achieve the assembly between the toxin-linker and peptide , the client chose the TBTU coupling reagent . In discoveryscale synthesis ( 25g scale ), this assembly scheme worked well , with a ~ 70 % step yield . However , problems emerged during the process scale-up . The step yield dropped significantly and impurities started to appear .
Our team identified that the problem was caused by the
Figure 1 - Toxin-linker & peptide conjugation via TBTU coupling ( top ); activated ester degradation due to an intracellular nucleophilic attack at high concentration or long reaction time ( bottom )
20 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981