Antibody-drug conjugates (ADCs) are an advanced cancer therapy designed to precisely target and deliver cytotoxic agents directly to cancer cells. However, this approach introduces significant challenges in manufacturing, particularly in safely handling highly potent cytotoxic payloads.
As the number of ADC candidates rises and regulatory safety standards become more stringent, the complexities of ADC manufacturing remain a significant hurdle, demanding advanced solutions to overcome technical and operational challenges.
Challenges in ADC Manufacturing
The production of ADCs is a complex process that involves several meticulous steps, such as conjugating monoclonal antibodies with cytotoxic agents and linkers. This process requires exceptional precision and control, especially when the Occupational Exposure Limits (OELs) for these substances fall below 30 ng/m³. The stability of ADCs is critically dependent on both the antibody and the linker-toxin components, each presenting its own unique challenges. Integrating these components into a final product adds an additional layer of complexity.
If the linker-toxin is unstable, the ADC may degrade, releasing toxic substances prematurely, which can diminish therapeutic efficacy and pose significant safety concerns for patients. To mitigate this risk, ADCs can be lyophilized (freeze-dried) from early stages of development. Cytotoxins, being highly potent and complex, require careful handling and production within high-containment facilities. Given their potency, only minute quantities are needed, which necessitates specialized techniques that are often impractical for large-scale drug manufacturing.
Production typically involves multiple steps that may be distributed across various manufacturing facilities. Each stage—ranging from antibody production and linker-toxin synthesis to their conjugation and final drug formulation—might be handled by different companies. This adds complexity and requires meticulous coordination and specialized testing to confirm that the ADC is safe, effective, and manufactured consistently.1
Embrace the Future: It’s Happening Now
As the ADC market continues to grow—with over 300 ADC candidates in development globally—new applications will play an increasingly vital role in enhancing patient outcomes for years to come. However, this progress must be approached with caution. The industry is rapidly evolving, adopting more efficient and safer production methods to protect both operators and the environment from exposure. Among these advancements, the integration of single-use isolators stands out as a transformative innovation.
The need for robust containment systems has never been more critical. Traditional rigid isolators, while effective, pose several challenges, including time-consuming cleaning processes, high capital costs, and the risk of cross-contamination between production batches. Single-use or flexible isolators, also known as containment systems, have emerged as a highly viable alternative to traditional rigid isolators in ADC manufacturing. These systems offer several key benefits that address the unique challenges of ADC production.
High Containment
One of the primary concerns with single-use isolators has been their containment performance compared to traditional rigid isolators. However, advancements in materials, manufacturing processes, and the incorporation of pressure-decay integrity release tests have demonstrated that single-use isolators can achieve containment levels as low as 10 ng/m³ throughout the entire lifecycle of ADC-payload handling, from weighing and dispensing to transfer and disposal.
Equipped with sensors and a PLC-based control system, they automatically adjust internal pressure to maintain necessary negative pressure, ensuring containment even during power failures or breaches. Continuous liner welding simplifies material removal while maintaining containment performance. Integrating a pre-welded hose line port with a single-use tube assembly ensures a fully contained, single-use solution, effectively managing high-potency ADC payloads and preventing particle migration at transfer points.
Process Simplification
Single-use isolators adapt easily to existing facilities and various ADC production scales, enabling rapid scale-up, scale-down, and scale-out. This flexibility is crucial for pharmaceutical companies and CDMOs to expedite molecule development. They also eliminate the need for complex cleaning and validation, reducing cross-contamination risk and downtime.
With integrated automatic control systems, single-use isolators manage airflow, temperature, humidity, and pressure differentials in GMP chambers. ILC Dover’s isolators, for example, use the Atmospheric Control Module (ACM) for precise negative pressure control and can accommodate oxygen-sensitive or explosive materials. These isolators can be easily modified for new ADC processes and operator ergonomics.
After use, single-use isolators collapse safely via fan exhaust, fitting into incineration bins, streamlining disposal and reducing risks and costs compared to liquid waste from cleaning rigid isolators.
Economic Benefits
ILC Dover conducted a cost analysis comparing cumulative expenses for a CDMO using single-use versus rigid isolators for multi-product ADC cytotoxic operations. Single-use isolators require a minor initial investment, with costs mainly linked to the number of products handled annually, including minimal maintenance and training expenses.
Rigid isolators, however, demand significant upfront capital. With ongoing multi-product projects, costly validated cleaning processes are required to meet regulatory standards and prevent cross-contamination, leading to higher cumulative costs over time. These costs, including residual toxin assays, QC tests, and downtime for cleaning, increase with the number of products handled.
The high cytotoxicity of ADC payloads also requires ultra-low cleaning limits, potentially adding further costs. Additionally, single-use isolators offer greater flexibility and ease of adaptation for capacity expansion compared to rigid isolators.
Sustainability
Single-use isolators optimize resource usage by eliminating the need for extensive water, cleaning reagents, and energy typically required for cleaning rigid isolators. This significantly reduces the demand for natural resources, making the production process more sustainable. For instance, cleaning a contaminated rigid isolator can consume 100–200 liters of water, which is then disposed of in a plastic waste bag—costs and environmental impacts that are completely avoided with single-use isolators.
Incorporating Single-Use Isolators into ADC Manufacturing
ILC Dover addresses the unique challenges of ADC production with customized, single-use solutions. The SoloADC™ Disposable Containment System provides unmatched containment, flexibility, and cost-efficiency. Whether managing multiple production stages across different facilities or adapting to evolving demands, SoloADC™ offers the versatility and high-performance containment required.
We offer comprehensive support from concept to delivery, working closely with pharmaceutical companies to ensure systems and components align perfectly with ADC workflow requirements. Our services include validation, integration, and training, enabling companies to focus on their core competencies while enhancing safety, efficiency, and consistency in ADC production.
Don’t let the complexities of ADC manufacturing hold you back. Contact us today to learn how SoloADC™ can be tailored to your needs and take your ADC manufacturing to the next level. We offer a 5-day turnaround on custom drawings to bring your vision to life.
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