Antibody drug-conjugates (ADCs) involve highly potent cytotoxic payloads and complex, multi-step processes. Because of their complexity, working with an experienced manufacturing partner who develops processes with scale-up in mind, helps to optimise drug-to-antibody ratio (DAR), and provides extensive experience with containment and regulatory requirements can make all the difference in a programme’s success.
Every strong manufacturing campaign starts with robust ADC process development. But even the most robust development programmes can encounter new challenges once the process is translated into a GMP-compliant manufacturing environment, where scale, containment requirements and regulatory expectations introduce greater complexity.
From maintaining consistency in conjugation and controlling payload distribution, to managing potent waste streams and validating analytical methods, clinical manufacturing introduces a range of additional considerations, all of which require careful attention to safety, compliance and efficiency at scale.
In this blog, we discuss the five most important considerations for translating well-developed ADC processes into safe and scalable clinical manufacturing campaigns.
1. Translating development to manufacturing
Why it matters
ADC manufacturing requires a tailored process development approach for every project, as different antibodies, linker payloads and conjugation chemistries all bring varying process considerations.
Key considerations for strong process understanding
- Conducting thorough process risk assessments for every ADC programme to understand critical process parameters (CPPs), proven acceptable ranges (PARs), equipment compatibility and safety considerations
- Reviewing each step of the process to surface potential operational risks, such as scale-dependent constraints
- Selecting a partner that supports both process development and clinical manufacturing to eliminate knowledge gaps and preserve process understanding throughout the programme
- Collaborating with development and analytical teams to understand process intent and potential scale-up challenges
Safely and successfully bringing an ADC process from development to manufacturing necessitates a strong understanding of its unique risks. When teams understand these risks, they can address potential impacts prior to manufacturing and before they impact timelines, costs, or quality.
For example, in fast-tracked ADC programmes, certain process parameters may be transferred into manufacturing without fully established PARs. In these cases, detailed gap assessment and risk analysis, paired with enhanced in-process monitoring, are required to ensure sufficient process control. Additionally, scale-dependent factors like mixing dynamics and thermal mass transfer must be carefully evaluated, as they do not scale linearly and can impact process robustness when handling larger volumes of material.
2. Safety and containment
Why it matters
Though clinical ADC manufacturing involves only small volumes of material, the extreme potency of cytotoxic payloads presents significant risk even at the nanogram level when dealing with low occupational exposure limits (OELs). As a result, safety and containment controls are integral to successful manufacturing.
Key considerations for mitigating exposure risk
- Applying a multi-layer containment model that combines primary containment measures like closed systems and isolators with secondary controls like facility measures and PPE
- Working with in-house toxicology and industrial hygiene teams to develop tailored solutions and ensure ongoing safety
- Operating in closed processing systems
- Implementing flexible film isolators to physically separate operators from materials
- Working under negative pressure with appropriate PPE, including personal respirators, chemical-resistant gowning and gloves, to minimise airborne and contact exposure risk
- Providing comprehensive operator training programmes covering safety protocols and emergency response procedures for handling highly potent compounds
- Supporting contained facility and process design with thorough and well-defined safety and contamination response protocols
Together, these measures ensure an extremely low risk of operator exposure, while ensuring that team members know how to properly respond if potential risks do arise during manufacturing. Establishing a consistent baseline of safety controls across all ADC programmes is equally important. An infrastructure built for high-potency compounds provides the foundation for safe manufacturing, while ongoing reviews as new products are introduced ensure that containment controls remain robust at different levels of potency and process requirements.
3. Compliance and contamination control
Why it matters
As with any drug substance or product, ADC manufacturing must adhere to stringent quality and regulatory expectations. Implementing a thorough Contamination Control Strategy (CCS) is critical for ensuring quality, safety and compliance throughout ADC manufacturing.
Key considerations for compliance and contamination control
- Maintaining documented contamination control strategies aligned with current Good Manufacturing Practice (cGMP) regulations and applicable regional guidelines
- Leveraging single-use systems to avoid cross-contamination between processes
- Evaluating ADC-specific compatibility challenges, such as potential hydrophobic toxin linker interactions with plastic materials
- Thoroughly reviewing vendor-provided validation data with toxicology and industrial hygiene teams to confirm material suitability for each distinct process
A proactive and detailed contamination control strategy is important for safety, quality and compliance.
The development of a CCS for ADC manufacturing requires balancing traditional environmental monitoring systems with the risk of equipment contamination from highly potent compounds. This may include increased reliance on risk assessments, pre-production modelling with surrogate materials and simulation studies to understand potential points of contamination prior to manufacturing.
4. Facility design
Why it matters
In addition to containment requirements, ADC manufacturing comes with unique facility demands that extend beyond those of other drug substance manufacturing, including photosensitivity, waste handling and temperature control, all of which can impact payload and linker stability.
Key considerations for facility design:
- Designing facilities with flexible containment infrastructure, including adaptable isolator systems and closed processing systems, to safely accommodate a range of potency levels
- Accommodating photosensitive products with controlled lighting
- Designing and validating systems for proper temperature control
- Treating waste streams as cytotoxic with integrated liquid waste systems and compliant disposal pathways
- Implementing waste treatment systems that can safely manage high waste volumes from solvent-intensive ADC processes
By building facilities that are made for the specific demands of ADC manufacturing and purpose-built for flexible containment, teams can effectively mitigate operational risk during clinical manufacturing.
As containment is a defining requirement for any ADC manufacturing facility, design decisions are driven by the need to safely support potent compounds without compromising product integrity. Waste handling must be designed to support potent payloads, precise temperature control is important for maintaining conjugation integrity and controlled lighting avoids degradation to cytotoxic payloads and linkers.
5. Flexibility and efficiency
Why it matters
ADC manufacturing requirements vary widely and involve high levels of customisation, but speed and cost control remain pivotal in any programme. This requires organisations to strike the right balance between flexibility and efficiency.
Key considerations for balancing efficiency and flexibility
- Avoiding rigid, standard manufacturing offerings that may force processes to fit predefined approaches, while standardising equipment where appropriate
- Reducing overall costs with strong raw material supplier relationships and integrated development and manufacturing capabilities
- Standardising documentation, materials, and protocols where possible to support efficient manufacturing execution and reporting
When facilities and processes effectively balance standardisation and flexibility, manufacturers can readily adapt to the needs of each distinct ADC programme while still ensuring efficiency and cost-effectiveness.
For example, standardisation can be achieved without limiting process flexibility through the use of templated batch record unit operations like filtration, tangential flow filtration (TFF) cassette installation, buffer preparation and sampling. Similarly, buffer family stability studies in closed systems can support shelf-life risk assessments across programmes, while custom-designed tubing sets aligned with these structured workflows allow for greater adaptability without sacrificing efficiency or consistency.
Ensuring ADC clinical manufacturing success
Successful ADC manufacturing starts with a robust development programme, but it also brings additional operational, safety and compliance considerations that are required to bridge the gap between development and execution.
Facilities that are purpose-built for ADC manufacturing provide a strong foundation, but balancing standardised infrastructure with a flexible and adaptable approach is crucial. Over-standardisation can limit process suitability, while insufficient structure can increase variability and hinder efficiency.
At Sterling, our expertise in process development, analytical methods, and clinical GMP manufacturing gives us a unique perspective on the ADC lifecycle. By viewing the process holistically and working collaboratively across teams, we avoid unanticipated delays, reduce deviation-driven rework and mitigate regulatory risks during clinical manufacturing.
If you’re interested in learning how we can support your ADC programme from development through to clinical manufacturing, speak to an expert.
