ADC Manufacturing's Biggest CMC Challenges And Ways To Approach Them

By Purbasa Patnaik, Exelixis

Antibody drug conjugates (ADCs) have emerged as a revolutionary class of cancer therapeutics, combining the precision of monoclonal antibodies (mAbs) with the potency of cytotoxic agents. Unlike traditional chemotherapy, which lacks specificity and harms healthy cells, ADCs target tumor antigens with high precision, improving efficacy while reducing systemic toxicity. However, despite their promise, ADCs pose unique challenges in formulation, drug product (DP) manufacturing, and supply chain logistics that must be addressed to unlock their full potential.

Since the first ADC approval in 2000, the landscape has evolved with 15 approved ADCs and hundreds more in development. However, the very attributes that make ADCs effective – the complex structure composed of an antibody, cytotoxic payload, and linker – also create significant challenges in their development and production. ADCs exhibit lower conformational and colloidal stability compared to their parent antibodies, largely due to the hydrophobic nature of the payload. ADC manufacturing involves several sub-stages, namely, mAb production, linker-payload production, conjugation, drug substance manufacturing, DP manufacturing, and fill/finish, adding to its complexity and creating multiple points of introducing stress on the final ADC drug product. In particular, the conjugation step, which leverages the functional groups of mAbs, alters the antibody’s higher-order structure, leading to instabilities such as aggregation, solubility challenges, and thermal instability. These issues not only compromise the manufacturability, potency, and shelf life of ADCs but also increase the risk of immunogenicity for patients.

Navigating Key Development And Manufacturing Challenges

Formulation development challenges

Key instabilities in ADC formulation development include aggregation, solubility challenges, and thermal stability concerns. Aggregation, driven by the hydrophobic nature of ADC payloads, can compromise mAb stability, shorten shelf life, reduce potency, and increase immunogenicity risks. To mitigate this, formulation strategies include incorporating free amino acids such as cysteine, serine, or tyrosine, which have been shown to suppress aggregation. Additionally, using lower ionic strength buffers can help reduce aggregation, particularly for ADCs with a higher drug-antibody ratio (DAR). Lowering mAb concentrations is another effective approach, as ADCs’ high selectivity and efficacy eliminate the need for high concentrations, reducing aggregation risks associated with hydrophobic payloads.

Solubility issues present another significant challenge, arising from the conjugation process, which disrupts the hydrophobic-hydrophilic balance. This imbalance can lead to precipitation, increased aggregation, and manufacturability concerns. To counteract this, hydrophilic linkers can be used to balance the hydrophobic payload. Further solubility enhancements can be achieved by modulating ionic strength, adjusting pH, and incorporating excipients like arginine and cysteine.

Thermal instability is another critical concern, as conjugation reduces the melting temperature (Tₘ) of the CH2 transition in the mAb, making ADCs more susceptible to degradation at elevated temperatures. This degradation negatively impacts drug potency and shelf life. To enhance thermal stability, lyophilization is a widely adopted strategy that improves long-term stability and preserves drug integrity.

Beyond these targeted strategies, increasing polysorbate concentrations can further mitigate the effects of hydrophobicity and overall interfacial stress, contributing to a more stable and manufacturable ADC formulation. Addressing these formulation challenges is essential to ensuring ADCs remain safe, effective, and scalable for clinical and commercial applications.

Ensuring safe and efficient drug product manufacturing

ADC manufacturing presents significant safety risks due to the highly potent cytotoxic payloads, necessitating strict containment strategies. Automated filling systems with isolators, auto-loading lyophilizers, and automated vial washing post-crimping help minimize operator exposure and maintain safety. Additionally, proper waste management and facility engineering controls are essential to prevent cross-contamination and environmental hazards. ADC manufacturing demands specialized equipment and advanced engineering controls to ensure safety, given the highly potent nature of ADC payloads. However, not all CDMOs are equipped to meet these stringent safety and operational requirements. It is essential to collaborate with specialized CDMOs that have the necessary systems and expertise in place for ADC manufacturing. These facilities are uniquely equipped to handle the complexities of ADC production, ensuring safety and compliance. However, it is important to note that the inclusion of such specialized equipment and engineering controls significantly adds to the overall manufacturing cost, making careful selection of a capable CDMO even more critical.

ADC payloads often contain photosensitive functional groups that, when exposed to light, can lead to drug and/or protein degradation, posing a significant challenge during manufacturing. During the fill-finish process, ADCs are particularly vulnerable to light exposure, necessitating additional protective measures. These may include performing operations in a darkroom or using light-protective foil overwrap. Amber vials are also commonly employed to shield the product from light; however, their use can make visual inspection more difficult. To address that, automated visual inspection during filling can be utilized, and following USP <790> supplemental inspection can ensure product quality. Additionally, some specialized CDMOs offer visible particle analysis kits, providing a robust solution to overcome visual inspection limitations while maintaining the integrity of photosensitive ADCs.

Impact on compatibility and clinical in-use stability studies

Phase I clinical doses for ADCs are typically low, necessitating significant dilution of the drug product, which introduces several challenges. These include difficulties in analyzing critical quality attributes (CQAs) and an increased risk of surface adsorption. Dilution also reduces the concentration of stabilizing excipients, particularly surfactants, which can lead to aggregation and particle formation. Additionally, the hydrophobicity of ADC payloads can exacerbate surface adsorption. To address these challenges, it is essential to determine the highest dilution levels that can be reliably reproduced in clinical settings and identify a suitable diluent. Dosing solutions should be tested under various conditions for 24 to 48 hours to evaluate their use period. Incorporating light exposure studies during clinical in-use testing is also crucial to ensure the stability and efficacy of diluted ADC formulations.

Addressing compatibility challenges with closed system transfer devices

ADCs are considered hazardous drugs under USP <800>, necessitating the use of closed system transfer devices (CSTDs) for dose preparation. CSTDs from different manufacturers exhibit significant variations in size, design, material of construction, fluid path geometry, and lubricants. These differences hinder the interchangeable use of CSTDs, creating challenges for consistent drug delivery. Additionally, incompatibility with CSTDs can result in visible and subvisible particles, such as silicone oil leaching, which may compromise product quality and patient safety. Another concern is the significant increase in holdup volumes, which can impact dose delivery and reduce treatment efficacy.

To address these issues, it is critical to screen CSTDs with the drug product during representative in-use studies early in development. This ensures that CSTDs listed in the pharmacy manual have been thoroughly assessed before clinical use. Collaboration with clinical sites and clinical operations teams is essential to align on the selection and use of CSTDs. Furthermore, CSTD manufacturers should disclose all materials of contact and potential leachables, taking steps to limit materials that could adversely affect the drug product or patient safety. These proactive measures ensure compatibility and maintain the integrity of the drug product during clinical administration.

Supply chain complexities and strategic planning

The manufacturing of ADCs is significantly more complex than that of monoclonal antibodies due to the need for producing multiple components and coordinating logistics across various stages. Each intermediate often requires specialized skills, sometimes involving up to five different CDMOs, necessitating meticulous planning and timeline management. Any delay in one stage can disrupt the entire timeline, as rescheduling manufacturing slots is difficult. Some CDMOs offer comprehensive, multi-service capabilities under a single quality system, increasing flexibility, reducing shipping costs, and enabling streamlined forward processing with minimal testing. Organizations must carefully evaluate CDMO capabilities, weighing the benefits of "one-stop-shop" providers against specialized service providers for individual needs. Transferring projects early to a commercial supplier can mitigate the need for later tech transfers, saving time and resources. To ensure success, it is essential to choose partners with strong technical expertise, manufacturing proficiency, and the ability to collaborate flexibly within tight timelines and budgets. Organizations must also weigh the trade-offs between in-house production and outsourcing, considering factors such as capability, cost, and flexibility.

Unlocking The Potential Of ADCs

ADCs represent a paradigm shift in cancer treatment, but their complexity demands a strategic approach to formulation, manufacturing, and supply chain management. By leveraging innovative formulation techniques, ensuring stringent safety measures, and optimizing supply chain coordination, the industry can navigate these hurdles and bring transformative ADC therapies to patients worldwide.

About The Author:

Purbasa Patnaik is an associate director at Exelixis, specializing in biologics formulation and drug product development and manufacturing. With extensive experience in biologics development, she currently focuses on ADC formulation, development, and manufacturing. Previously, at NGM Bio and Harpoon Therapeutics, she played a pivotal role in advancing ophthalmic and oncological biologics. Her career spans roles at Cook Pharmica (Catalent), Bayer, and Eli Lilly. She earned her master’s degree in biotechnology from Northwestern University, where she pioneered microRNA-based sensors for novel cancer diagnostics.