51 TWENTYFOURSEVENBIOPHARMA Issue 3 / October 2025 AXPLORA component must show exceptional purity, specificity, and stability, as imperfections can compromise the ADC’s performance. Scaling up ADC production for clinical trials and commercialization introduces new logistical and manufacturing difficulties. The multi-step process, which includes antibody production, payload synthesis, conjugation, and purification, requires careful process development and optimization. Strict quality control measures are essential to ensure the final product’s consistency and purity, requiring the development of robust analytical methods to characterize the complex ADC structure. The risk of contamination and impurities means that rigorous manufacturing practices and advanced purification techniques are needed. Additionally, there are major regulatory and safety considerations around ADCs because of their potent payloads and intricate structures. Demonstrating their safety and efficacy requires comprehensive preclinical and clinical studies, addressing potential toxicities and off-target effects. The need for continuous monitoring and risk mitigation strategies throughout the development and manufacturing process shows how important a robust quality management system is. The journey from payload synthesis to a clinically viable ADC is complex, requiring a multidisciplinary approach and constant focus on quality and safety. Ensuring efficient and cost-effective ADC manufacturing Overcoming the complex challenges in ADC payload production and bioconjugation requires an approach focused on precise engineering and efficient production. Innovative strategies and technological advancements have been streamlining ADC production, with a focus on addressing challenges and delivering therapies to patients efficiently and cost-effectively. These include: Advanced conjugation technologies Site-specific conjugation allows precise control over the DAR, resulting in more homogeneous ADCs with predictable pharmacokinetics and efficacy. By directing the payload attachment to specific locations on the antibody, this technology ensures a more uniform product, without the heterogeneity of traditional conjugation methods. This precision minimizes variability, reducing the risk of batch failures and lowering production costs. As a result, each ADC molecule exhibits a similar potency. Optimized linker design Developing linkers with optimal stability in circulation and controlled release at the target site matters greatly. Linkers are designed with chemical bonds resistant to hydrolysis or enzymatic degradation in the systemic circulation. This prevents premature payload release and reduces off-target effects. Computational modeling and simulations can be used to predict linker stability and release kinetics. This optimization enhances the therapeutic window, minimizing off-target toxicities and improving patient outcomes. Enhanced analytical technique Advanced analytical methods help thoroughly characterize ADCs. For example, liquid chromatography coupled with mass spectrometry can accurately determine the average DAR and DAR distribution of the ADC. By measuring the mass of the intact ADC or its subunits, researchers can work out the number of molecules conjugated to each antibody. Chromatography can be useful for separating ADC species based on their hydrophobicity, which correlates with the number of conjugated drug molecules. Using these and other methods helps protect product quality and consistency, reducing the risk of costly recalls or regulatory issues. Before these techniques were widely used, ADC characterization relied on less precise methods such as UV-Vis or fluorescence spectroscopy, or electrophoresis, among others. Those traditional methods often gave only average values or indirect measurements, without the detailed structural information. Quality by design (QbD) Adopting QbD principles throughout the development and manufacturing process ensures that critical quality attributes are identified and controlled. QbD represents a systematic and proactive approach to achieving consistent product quality, using target product profiles (TPPs), identifying critical quality attributes (CQAs) and critical process parameters (CPPs), and proactively assessing risk. This approach minimizes process variability and enhances product quality. Future strategies to streamline the ADC payload manufacturing process A range of technological advancements and specific strategies aim to simplify complex synthetic routes, reduce waste, and consistently produce high-quality payloads. Although automation and closed systems are widely adopted in large-scale pharmaceutical manufacturing, their use in ADC production remains limited due to the relatively small reactor sizes typically employed (often below 1,000 L). Nevertheless, emerging technologies such as robotic synthesizers, automated
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