Lonza

Kathleen Zohorsky

Kathleen Zohorsky is a Process Development Scientist at Lonza, specializing in personalized medicine and process commercialization. With a background in Biomedical Engineering and a MESc from Western University, she is currently part of the Cocoon Process Development team, focusing on advancing innovative biopharmaceutical solutions.

Rahul Purohit is a Senior Scientist in Personalized Medicine at Lonza, specializing in CAR T cell therapy process development using Lentivirus and CRISPR-based gene editing. With extensive expertise in protein biochemistry, structural characterization, and enzymology, he has contributed to advancements in molecular biology, protein purification, and therapeutic innovations.

Tamara J. Laskowski, PhD, is the Global Head of Clinical & Process Development for Personalized Medicine at Lonza. With over 18 years of experience in immuno-oncology, cell and gene therapy, and drug discovery, she is a strategic leader known for her technical expertise and business acumen.

Through this article, Zohorsky et al. highlights the need for smart bioprocessing to optimize and automate cell therapy manufacturing to lower costs while increasing efficiency and throughput.

Novel therapy modalities carry great potential for the treatment of life-threatening conditions such as cancer and autoimmune diseases. While antibodies and small molecules have been widely used, cell therapies are a fast-developing modality with strong clinical success demonstrated over the last decade. CAR-T cell therapy has gained significant attraction, with six CAR-T cell products approved by the FDA for the treatment of hematological malignancies since 2017. Currently, there are nearly 3000 unique cell therapy products undergoing various stages of clinical development . Despite remarkable progress, the ability to bring novel cell and gene therapies to patients continues to be challenging. Scaling out the production of patient-specific therapies to meet commercial demands can lead to an unsustainable increase in cost, labor, and logistic complexities under current manufacturing paradigms.  Therefore, smart bioprocessing enables therapy developers to optimize and automate the manufacturing process to lower overall costs while increasing efficiency and throughput.

The impact of reagent selection: Balancing material cost, performance, and scalability when designing and optimizing a manufacturing process is critical to improving process efficiency. Cell therapies require unique process design decisions such as cell selection, activation, and gene editing, which can impact the final drug product. Moreover, viral vectors are often employed when manufacturing cell therapies and represent a substantial contributor to the cost of these products. Strategies to improve these critical steps by selecting appropriate reagents and materials can improve efficiency and reduce costs. Transduction enhancers offer the opportunity to boost transduction efficiency while reducing the quantity of viral vector required per manufacture. The use of serum-free media formulations may also help to improve transduction efficiency and, additionally, eliminate the need for pre-screening of human serum, thereby reducing time, labor, and costs associated with qualification and validation efforts.

Other important raw materials for cell therapy manufacturing include activating reagents and cytokines. GMP-grade activating reagents, both in soluble form and bead-conjugated, should be tailored to the process and adapted for the vessel size and input cell number. With informed data-driven decisions and by investigating cell activation profiles, therapy developers can refine culture conditions to increase process efficiency and robustness. Expansion kinetics are also dependent on cytokine concentration and the selected cytokine (e.g., IL-2, IL-7, IL-15, IL-21), which can impact memory and exhaustion phenotypes of the final drug product. Altogether, appropriately selected raw materials and reagent optimization may significantly impact cost in a manufacturing process.

Process Automation: Cell therapy manufacturing processes are highly complex and labor-intensive. Often, these processes rely upon manual operations at various steps during production, increasing the risk of product variability, process errors, and contamination and posing challenges to scalability.  

A rapid influx of new cell therapy products has outpaced progress in automation development. The adoption of automation technologies early in process development is crucial to streamlining manufacturing for large-scale clinical translation. Platform scale and dose requirements are key factors when making automation decisions. Modular and end-to-end automation platforms are available with varying levels of manual intervention. While the adoption of an end-to-end automation platform is an attractive approach, broad applicability and the degree of flexibility for process modifications are important considerations when selecting the appropriate platform. Alternatively, modular systems that combine various automation platforms to cover multiple unit operations also offer flexibility and may enable a wider range of processes. The challenges with modular approaches include the requirement for properly trained personnel on all instrumentation, increased GMP space requirements, and the establishment of robust connectivity across instruments. Employing robotics systems and digital connectivity between the different modules are some developments that can help alleviate challenges. Integrated robotics systems that can handle multiple modular units in the process workflow can further decrease the need for operator time.

As the complex manufacturing of cell therapies evolves, partnerships between technology providers and drug developers may enable new opportunities for tailoring cell therapy process development to address specific user requirements.  Ultimately, determining the level of automation required for a given process and whether the selected manufacturing platform suits the process requirements will be required to ensure success.

“Opportunities to innovate on bioprocessing and manufacturing may offer valuable strategies to enable robust scalability, decrease costs, reduce labor requirements, and increase patient accessibility to these therapies, thus supporting a stronger path to clinical development and commercial readiness.”

Process duration: Reducing vein-to-vein time has become a focus in the industry as a way to bring therapies to patients faster. Cell therapy products can take 3-5 weeks for manufacturing and quality assessment before release.  To mitigate this issue, therapy manufacturers are exploring rapid quality control methodologies and shortened manufacturing protocols.  For example, the U.S. FDA recently approved a shorter production time for Yescarta^®, which led to a reduction in median turnaround time from 16 to 14 days from collection of patient cells to final product release. Various short or next-day therapies are in development and promise to further reduce the vein-to-vein time, increase reliability, and simplify the process to increase the number of doses produced a year. Therapy developers should also evaluate requirements for the release of rapid products. Because these products may be different from their longer-manufacture counterparts, there is a need to improve current assays or develop new analytical methods to assess the critical quality attributes of these products. Additionally, considerations regarding viral vector residuals and stability of vector copy number (VCN) may necessitate appropriate assays and quality controls.

Expanding patient accessibility: Currently, a centralized manufacturing approach is used for FDA-approved therapies in which patient material is shipped to the manufacturing site where production will take place, and then the final drug product is shipped back to the clinical center for patient administration. Decentralized manufacturing is an alternate solution that has garnered significant interest and has also received regulatory guidance. Major benefits to this approach include the proximity to the patient, which decreases/eliminates complex shipping logistics, potentially helping to deliver therapies to patients in a shorter time. Decentralized manufacturing requires standardization of process controls and central hubs that oversee operations across multiple manufacturing/treatment sites. Ensuring robust and reproducible process execution to minimize variability in manufacturing across sites is critical to support the expansion of decentralized programs.

Undoubtedly, there are still challenges that must be overcome to ensure the full potential of cell and gene therapies is realized. Opportunities to innovate on bioprocessing and manufacturing may offer valuable strategies to enable robust scalability, decrease costs, reduce labor requirements, and increase patient accessibility to these therapies, thus supporting a stronger path to clinical development and commercial readiness.