How Advanced Manufacturing Strategies Can Support Next-Generation Antibody-Drug Conjugate Innovation

Antibody-drug conjugates (ADCs) are attracting increasing attention as a rapidly advancing development in oncology care. The unique combination of monoclonal antibodies and cytotoxic payload in ADCs enables them to deliver cytotoxic agents precisely to targeted cancer cells, killing them or inhibiting replication.

This presents a promising new option for the treatment of cancer, which claims 10 million lives a year and is the second largest cause of death worldwide.¹ By the middle of last year, 19 ADCs had received approval globally,² and potential uses for ADCs are being explored beyond oncology.

These include the targeted delivery of anti-inflammatory drugs and other strategies designed to treat conditions such as rheumatoid arthritis, myasthenia gravis and infectious diseases. As a result, the global ADC market is expected to reach more than $32 billion by 2035, growing at a compound annual growth rate of 9.23%.³

While widespread enthusiasm for ADCs looks set to drive new applications and innovation, drug developers must first demonstrate they can reliably and consistently overcome the challenges of ADC production. ADCs require very high-precision handling due to their unique structural and functional properties. Robust processes are required to demonstrate regulatory compliance and ensure product safety and efficacy.

As a result, any manufacturing strategy must balance the need to optimize and streamline processes with a strong emphasis on precision, quality, and control. This requires a range of innovative approaches, from exploring automation and continuous manufacturing to engaging with expert partners that can integrate processes more seamlessly.

Overcoming the challenges of ADC production

For the pharmaceutical industry to effectively capitalize on the potential of ADCs, it must be able to manage a range of issues inherent in their handling and development. Tackling these issues is a complex process that requires multidisciplinary cooperation and strategies that prioritize quality, safety, and compliance from the outset.

The key issues in ADC manufacturing include:

1. High-potency. ADCs use cytotoxic agents to target specific cancer cells while sparing healthy cells. These payloads are extremely potent and therefore must be handled with the utmost care. This requires the use of facilities that adhere to strict current good manufacturing practice (cGMP) guidelines, as well as containment and environmental controls to ensure worker safety and prevent contamination. This cytotoxicity can also result in a narrow therapeutic window.
2. Variations to the drug-to-antibody ratio (DAR). Any variation in the DAR can affect pharmacokinetics, toxicity, and overall efficacy, and can introduce heterogeneity. This means it is essential to control the exact site of conjugation when the payload is linked to the antibody and to maintain the payload’s structural integrity and stability during conjugation.
3. Optimization of the linker. The linker is an essential component of the ADC as it connects the cytotoxic payload to the monoclonal antibody. This means it must demonstrate several characteristics to be effective. It must demonstrate the requisite stability to deliver the payload efficiently, but must also be able to release it appropriately when the ADC encounters the target cells. It must also ensure that the antibody maintains the highest levels of purity and specificity so that ADC performance is not impacted. As a result, linkers must undergo extensive in vitro and in vivo testing to ensure they are optimized for targeted and effective use.
4. Analytical characterization. The intricate balance among the components of ADCs poses several analytical challenges. These include measuring unconjugated drug concentrations, monitoring and controlling DAR variance, and identifying aggregation and impurities. Traditional analytical methods may not provide the detailed structural information required for reliable ADC development.
5. Effective scale-up. Scaling up ADC production requires manufacturers to significantly increase output without compromising patient safety or treatment efficacy. This results in a multi-step process including production of antibodies, payload synthesis, conjugation and purification, all of which must be strictly optimized to minimize the risk of contamination or inefficiency.
6. Regulatory pressures. Due to the high cytotoxicity of the substances involved, ADCs must be developed in strict cGMP conditions. Regulators also expect detailed data on purity, DAR distribution, immunogenicity, preclinical safety, quality control, and off-target effects.

All of the factors contribute to a complex and challenging development process, in which optimized control and extensive analytics are required to avoid costly knock-on effects. This is why an integrated approach that introduces multidisciplinary expertise and cooperation early is a key element in ensuring quality and safety.

Innovative and integrated approaches in ADC manufacturing

While the challenges of ADC production are daunting, drug developers and contract development and manufacturing organization (CDMO) partners are developing innovative approaches that improve efficiency, reduce costs, and make the analysis of ADC components more reliable and comprehensive. This is a result of increased integration, cooperation, and collaboration by experts at all phases of the development and manufacturing process, enabling the delivery of safe, consistent, and life-changing therapies to patients.

Drug developers may also engage expert CDMO partners to deliver integrated strategies, such as carrying out key steps on the same site. A specialist CDMO can handle stages such as highly potent payload manufacturing and bioconjugation steps in one location, reducing the risk of delays and supply chain issues.

This partner can also provide expertise earlier in the process and across stages, which leads to more effective and frictionless tech transfer. The industry is constantly advancing processes and analytics, with the most pertinent improvements including:

More optimized linker design

Optimization of the linker component is integral in enlarging the therapeutic window, thus improving the efficacy of the drug itself. Linkers are now being designed with bonds that are more resistant to potentially compromising effects while in systemic circulation, such as hydrolysis and enzymatic degradation.

Emerging technologies, such as simulations and computational modeling, can also now predict the stability and release kinetics of linkers. These advancements are designed to minimize off-target toxicity and ensure more controlled release.

Advancements in conjugation

Traditional conjugation methods can lead to increased heterogeneity, affecting the consistency and uniformity of the product and its effects. By developing more site-specific conjugation methods, manufacturers can exert greater control over the drug-to-antibody ratio and direct the payload to more specific locations on the antibody.

This creates ADCs with more consistent characteristics and effects and lowers costs by reducing the risk of batch failures.

Improvements in analytics

In the past, ADCs have been characterized using methods such as ultraviolet-visible spectroscopy, electrophoresis, and fluorescence spectroscopy. These often provided less accurate measurements, lacking the comprehensive information required for consistent manufacturing and to meet advancing regulatory demands.

ADC manufacturers are now employing more advanced methods, including liquid chromatography combined with mass spectrometry. This enables them to measure the ADC's average DAR and DAR distribution, and to calculate the number of molecules conjugated to each antibody by measuring the ADC’s mass and that of its subunits.

Methods such as these can be used to minimize costly recalls, avoid regulatory complications, and demonstrate consistency while maintaining quality.

Automation

Automation is still relatively limited in ADC development, as processes generally take place in smaller reactors of less than 1000 L. However, there are signs that automation could reduce the risk of contamination during manual handling and improve worker safety.

This includes the use of closed-system processing, which can help ensure more reliable sterility and reduce the risk of product loss. Technologies such as automated chromatography, robotic liquid handling, robotic synthesizers, and flow chemistry systems could also play a role in ADC production in future years.

Artificial intelligence (AI)

AI can also be a potentially fruitful technology, allowing researchers to streamline their payload manufacturing, optimize efficiency, and engineer more consistent product output. Algorithms can be used to optimize process parameters and identify impurities, delivering an added layer of discovery and scrutiny.

Continuous manufacturing

The integration of continuous manufacturing techniques could play a key role in making ADC therapies more affordable and available. By adopting integrated, automated processes, this approach can encourage more streamlined, uninterrupted delivery of materials, with higher throughput and lower costs than traditional batch processing methods.

Microfluidics

Recent advances in microfluidics have enabled manufacturers to conjugate antibodies to drugs with greater precision, resulting in a more uniform, consistent product. These developing technologies are enhancing our ability to optimize DAR and manage chemical reactions at a microscopic level.

This has encouraging potential in ADC development because it can improve sustainability in the manufacturing process by reducing reagent use and side reactions.

Enzymatic synthesis

Chemical synthesis often requires harsh solvents and reagents. By contrast, enzymes can drive complex reactions under mild conditions, making them a more environmentally friendly option that can streamline purification.

The use of quality-by-design (QbD)

Maintaining product quality and consistency is an integral part of ADC development. By applying QbD principles, manufacturers can adopt a more systematic approach during development and manufacturing. This introduces several requirements, including the need for target product profiles and critical process parameters, as well as the identification of critical quality attributes.

Looking to the future

The development of new approaches and techniques in ADC development and manufacturing requires all partners to share insights, information and expertise, ideally from the very beginning of a project. ADCs are extremely complex and require high levels of care and precision to deliver the most effective and consistent benefits to patients.

A more integrated approach to manufacturing can help to make that happen, improving the uniformity and quality of ADC batches, reducing failures, contamination and inconsistencies and ensuring cost-efficient and optimized processes from early-stage development to commercial scale-up. CDMOs play a key role in this process.

By sharing critical expertise in fields such as bioconjugation, manufacturing, and regulatory compliance, they can enable drug developers to bring therapies to patients faster. Integrating expertise and manufacturing steps under one roof can also streamline the production process and improve coordination.

They can also help drug developers to integrate innovative new approaches at scale. The pace of innovation in the pharmaceutical industry remains dizzying, with several developments emerging that could shape the future of ADC production.

These include the use of new bioconjugation approaches, such as enzyme-mediated and photochemical methods; bispecific ADCs that can improve targeting by engaging two distinct antigens; and dual-payload ADCs that can deploy two cytotoxic agents to one or multiple targets. We are also seeing the development of more advanced linker technologies and AI-assisted design, which could change the shape of ADC development.

In ADC production, a lack of coherent and strategic process delivery can be costly. By working together, drug developers, researchers and expert CDMOs can safeguard the delivery of ADCs to the patients who need them.

Leveraging integrated strategies can ensure a frictionless tech transfer and the operational discipline to accelerate timelines and reduce the risk of inconsistency or batch failure.

About the Author

Jin Seok Hur, Director of ADC Platform Management, Axplora.

References

1. “Cancer: Key Facts”, World Health Organisation, 2026. https://www.who.int/news-room/fact-sheets/detail/cancer
2. “A quick look at the 19 approved ADC drugs (Updated for 2025)”, ADC Directory, 2025. https://www.adcdirectory.com/news/a-quick-look-at-the-19-approved-adc-drugs-updated-for-2025
3. “Antibody Drug Conjugate market evolution with targeted therapies”, Towards Healthcare, 2026. https://www.towardshealthcare.com/insights/antibody-drug-conjugate-market-sizing