ADC manufacturing: Conjugation

Development

Initial development of ADC candidates includes the following elements:

• The antibody, which can be a mAb, a bispecific antibody (BsAb), an antigen binding fragment (Fab), or another format.
• A variety of linkers to help maintain stability of the ADC, offer the desired release kinetics, and prevent payload loss, following administration to the patient.
• Different classes of payload that could include small molecules, protein toxins, biologically active peptides, enzymes, and radionuclides.
• Multiple ADC solubilizers, needed to achieve a high drug-antibody ratio (DAR), a wider therapeutic index, and improved drug efficacy.

An efficient conjugation step and generation of multiple ADC candidates is essential to meet development timelines and identify the preferred options for advancing into preclinical and clinical development.

From the earliest stages of development, ADC production should be designed with scalability in mind. Choosing appropriate technologies and equipment that enable easy scaling from bench to large scale will facilitate the transition to clinical- and commercial-scale GMP production. Similarly, containment should be primary focus from the start, as the highly cytotoxic HPAPIs need to be contained to protect operators and the production environment from potential contamination.

Manufacturing

Throughout ADC development and manufacturing, single-use technologies can be used to enhance process flexibility and eliminate the risk of cross-contamination. However, before implementation, it is crucial to confirm that any single-use technology is chemically compatible with the organic solvents used in ADC conjugation. The risk to the ADC from extractables and leachables (E&L) must be considered as they can alter safety, identity, strength, quality, and purity of the drug product. A data-driven, risk-based approach is recommended to support E&L risk assessment efforts and regulatory compliance.

Additional considerations during ADC manufacturing and large-scale conjugation include:

• Ensure robust supply and reliable lead times for raw materials, including the mAb and linker-payload to maintain business continuity and preventing process disruptions.
• Increase the likelihood of successful conjugation by using strong, leak proof containers.
• Improve conjugation efficiency and process robustness through consistent mixing, monitoring and control of key process parameters including temperature and pH.
• Consider ergonomics in containment strategy and equipment selection to enable precise and safe addition of reagents while minimizing drip formation that could compromise the mAb and ADC quality.

Explore our solutions designed to address the challenges of ADC conjugation throughout development and manufacturing:

• High-quality chemicals, essential raw materials and excipients for manufacturing and formulation such as buffers, pH adjusters, solvents, surfactants, and stabilizers. More than 350 chemicals are supported by extensive documentation through our Emprove® Program, accelerating your risk assessment. 

• Single-use technologies including Mobius® ADC Reactor and single-use equipment and consumables for TFF, chromatography and aseptic processing to meet different downstream demands in both small- and large-scale processes.  

• Real-time monitoring and control solutions, sampling systems, and advanced automation and analytics software, which take process control to a new level.  

• Comprehensive contract manufacturing services for mAbs, payloads, linkers, linker-payload intermediates, bioconjugation, and ADC product characterization to accelerate development and manufacturing timelines.  

Request Information