Chimeric antigen receptor T-cell (CAR-T) therapy has become one of the most significant advances in cancer treatment in decades. The process works by collecting a patient’s T cells, genetically engineering them to recognize and attack cancer cells and then reinfusing them into the body. Since the first regulatory approval in 2017, CAR-T therapies have reached markets worldwide — seven are approved in the U.S., with additional approvals in China, India and Europe, bringing the global total to 11 commercially available products, and growing. The global CAR-T market is projected to grow significantly over the next decade, with more than 2,300 clinical trials registered in the U.S. alone, and expanding into solid tumors and autoimmune diseases.
The growth of CAR-T represents a fundamental shift in how the pharmaceutical industry manufactures therapies. Traditional small-molecule drug production involves creating large batches that are shipped worldwide. CAR-T and the broader cell and gene therapy (CGT) field are challenging this model to address issues related to the high cost of production, scale and distribution. Because most approved CAR-T therapies are made from an individual patient’s cells, each manufacturing run produces a treatment for a single person. Production may occur at the point of care (POC), using a decentralized model in which the product is manufactured within or near the facility where the patient will be treated, rather than at centralized pharmaceutical production sites.
Whether a POC approach or centralized manufacturing is chosen, critical attributes must be addressed to maintain product quality and safety while improving operational workflow and supply chain dynamics. And speed and logistics become even more critical in CGT manufacturing: Patients are often critically ill during the weeks it takes to manufacture their therapy, with some facing disease progression while waiting for treatment.
All of this changes the demands on manufacturing infrastructure, and meeting these challenges starts with a critical foundational element: water quality.
Why water quality matters so much in cell therapy
Water for injection (WFI) is used throughout CAR-T manufacturing for media preparation, buffer and reagent dilution, and as process water in aseptic processes. Because many cell therapies – especially during the Investigational New Drug (IND) phase – rely on small scale production, the infrastructure and validation costs of generating WFI internally can be prohibitive. As a result, these manufacturers frequently rely on certified, packaged WFI rather than large water systems. Regardless of the WFI source, because CAR-T products are infused directly into patients’ bloodstreams, often immunocompromised, any contamination during manufacturing can have serious consequences. With a complex manufacturing process already subject to numerous variabilities at each step, manufacturers need water purity to be a constant, not another variable that could compromise critical quality attributes.
Endotoxins are a primary concern. Because cell therapies have such short shelf lives, the therapy may be administered before final sterility or bioburden results are available. This makes highly consistent endotoxin testing carry even more weight as a critical gateway for indicating contamination. Endotoxin molecules are potent enough to trigger dangerous immune responses, even at low levels, and are notoriously difficult to remove once they enter a production environment. Regulatory agencies, including the FDA and European Pharmacopoeia, set the pyrogenic threshold at 5 endotoxin units (EU) per kilogram of body weight per hour for injectable products. WFI must meet a pharmacopeial limit of 0.25 EU/mL. CAR-T manufacturers must validate their endotoxin testing methods for each specific product, since the complex biological matrices involved can interfere with standard assays.
The water quality requirements extend beyond endotoxins. Total organic carbon (TOC), conductivity and bioburden must all be monitored throughout the production process. During the R&D phase, when cells are isolated and modified, ultrapure water is also needed — a challenge Veolia addresses across the life sciences industries.
The push for faster, more reliable monitoring
The shift toward continuous manufacturing and process analytical technology (PAT) in biopharma is putting pressure on traditional water quality testing methods. While transitioning to real-time testing (RTT) of TOC and conductivity is vital for facilities with large water systems, smaller scale production will shift the pressure to the lab. Even in the lab, pressure to meet increasing production demands means analytical solutions and technologies must evolve to improve operational efficiency, lean out processes and reduce risk. Conventional endotoxin assays can take upward of an hour to set up and require well-trained technicians to carefully prepare samples, standards and controls. These methods are prone to operator-to-operator variability and do not align well with modern data integrity requirements.
For CAR-T manufacturers operating under tight timelines, this approach creates bottlenecks. Many facilities conditionally release materials into production while awaiting lab results, accepting the risk that a failed test could result in scrapping an entire patient-specific therapy batch worth well over $100,000. Whether a facility is moving toward real-time quality control for a water system or relying on lab instruments for efficiency gains, testing instruments need to deliver results faster, with less manual intervention and with data systems that satisfy regulatory scrutiny.
Workforce dynamics add another layer of complexity. The cell and gene therapy field faces a well-documented shortage of qualified manufacturing staff, and high turnover means manufacturers need instruments that are intuitive enough for new operators to learn quickly without compromising accuracy or compliance.
How Veolia’s Sievers technology helps
Veolia’s analytical instruments are used throughout biopharma manufacturing to monitor water quality for TOC and endotoxins. With analytical and labwater solutions designed to support CGT manufacturing, Veolia is committed to meeting the evolving demands of the industry. For CAR-T and cell therapy manufacturers facing the challenges described above, Veolia’s Sievers Eclipse bacterial endotoxins testing (BET) platform and real-time TOC support offer meaningful improvements over traditional methods.
The Eclipse platform uses microfluidic technology to automate kinetic chromogenic assays, reducing assay setup time by up to 85% — from roughly an hour to about nine minutes for a 21-sample run. Furthermore, because cell and gene therapies are extraordinarily expensive to produce, manufacturers are sensitive to the sample volumes required for quality assays. The Eclipse platform's microfluidic technology allows for a reduced sample volume per test, while simultaneously reducing the use of Limulus amebocyte lysate (LAL) reagent by up to 90%. LAL is derived from the blood of horseshoe crabs, and reducing its use addresses growing sustainability goals in the pharmaceutical industry while maintaining the sensitivity and specificity that regulators require.
The platform meets all requirements of the harmonized global pharmacopeia — USP <85>, EP 2.6.14, JP 4.01 and ChP 1143 — and its customizable software complies with 21 CFR Part 11 and ALCOA+ data integrity guidelines.
The simplified workflow also helps address workforce challenges. Because the Eclipse automates standard curves and positive product controls through pre-loaded microplates, it reduces the number of pipetting steps and minimizes operator-to-operator variability, making it easier for new team members to run reliable tests without extensive training.
Keeping pace with what comes next
As CAR-T therapies expand and more manufacturers enter the field, the demands on water quality infrastructure will continue to grow. Emerging trends like allogeneic (off-the-shelf) therapies, in vivo CAR-T production and automated smart manufacturing promise to increase production volumes and push quality control requirements even further. Manufacturers that establish highly consistent and reliable testing platforms early – often during the IND phase – will mitigate quality risks and be better positioned to scale with the market.
In a high-risk space where therapies are extraordinarily expensive and sample volumes are critical, Sievers instruments deliver the consistency CGT manufacturers need to maintain patient safety and keep pace with the speed of modern cell therapy.
Contact our experts to learn how our water quality monitoring solutions can support your manufacturing operations.
Tags
Author | Brittany Gleason
Global Marketing Director, Analytical Solutions, Veolia Water Tech
