ADCs: When Bioprocessing Becomes Toxic

While several antibody drug conjugates (ADCs) have achieved success in clinical trials and received FDA approval, issues such as off-target effects, resistance mechanisms, and manufacturing complexities persist. Despite their positive impact on patient health, some bioconjugate compositions still fail to deliver satisfactory results in clinical trials.  

The challenges of manufacturing ADCs are many – from the high costs and inherent weaknesses in chemical structures during bioconjugation that make it difficult to deliver safe and effective products, to fluid and cold chain managements, we need to ask: what can be done to address such challenges for ADCs?  

Perhaps the most daunting challenge is the leap from laboratory-scale production to commercial manufacturing. This transition is a true balancing act in maintaining product quality and safety while dramatically increasing production volumes. The key to success in this area is in embracing modular and flexible manufacturing systems. By designing production facilities with scalability in mind, ADC developers can more easily adapt to changing requirements and streamline the path to commercialization. Modular systems enable increased scale-up and scale-out, as well as batch size, depending on the product and at which step of the manufacturing process it is applied (i.e. bioprocessing of a commercialized mAb for global commercialization or genetic engineering and banking of mammalian cells for cell line development).  

Single-use technologies can play a critical role by offering unparalleled flexibility and reducing the complexity of scale-up operations. However, investment in the development of robust analytical methods and GMP-compliant process controls to ensure consistent product quality across all production scales is a must.  

Single-use technology also plays a role in other aspects of ADC production. For example, consider the toxicity of ADCs through unconjugated cytotoxin. While this potency is what makes them so effective against cancer cells, it also poses a serious safety risk to staff involved in their production. Operators must be protected from exposure to these highly toxic compounds. Closed systems and automation can help.

By implementing fully contained fluid pathways and minimizing manual handling, we can dramatically reduce the risk of operator exposure, reduce errors due to human intervention, and standardize liquid transfer processes. The ADC solution must remain homogeneous and stable throughout the dispensing process into single-use bioprocess containers to ensure consistent efficacy and safety across all filled bags. Single-use technologies can minimize product loss and contamination risks, as well as improve safety.

Another common challenge with ADCs is protein aggregation during freezing and thawing. This issue isn't unique to ADCs, but it takes on a whole new level of importance when dealing with such potent and expensive molecules. Uncontrolled freezing can wreak havoc on protein stability, leading to aggregation and potentially compromising the safety and efficacy of products. It's not enough to simply hope for the best – you need precise control over the freezing process. Controlled rate freezing technologies carefully manage the freezing rate according to freezing protocols and implement optimized cooling performance. This can significantly reduce the risk of aggregation and maintain the critical quality attributes of ADCs.

These are just a few examples of how the right technological approaches can assist with the manufacture of ADCs. By prioritizing operator safety, protein stability, and scalable manufacturing processes, manufacturers and CDMOs can enhance ADC production through shared knowledge and pushed limits.  

Perhaps the most daunting challenge is the leap from laboratory-scale production to commercial manufacturing. This transition is a true balancing act in maintaining product quality and safety while dramatically increasing production volumes. The key to success in this area is in embracing modular and flexible manufacturing systems. By designing production facilities with scalability in mind, ADC developers can more easily adapt to changing requirements and streamline the path to commercialization. Modular systems enable increased scale-up and scale-out, as well as batch size, depending on the product and at which step of the manufacturing process it is applied (i.e. bioprocessing of a commercialized mAb for global commercialization or genetic engineering and banking of mammalian cells for cell line development).  

Single-use technologies can play a critical role by offering unparalleled flexibility and reducing the complexity of scale-up operations. However, investment in the development of robust analytical methods and GMP-compliant process controls to ensure consistent product quality across all production scales is a must.