RegMedNet: CAR-T Therapy Release Testing and Quality Control

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As CAR-T (chimeric antigen T-cell) therapy advances, the immunotherapy could soon become key to various clinical cancer care applications. That said, manufacturers and regulatory bodies must overcome challenges surrounding manufacturing, release testing, and quality control before the therapy can achieve optimal patient solutions. Overcoming these challenges could enable the broad utilization and eventual commercialization of CAR-T therapy.

Researchers who need to keep up to date with the development of CAR-T therapy can follow RegMedNet, a community site that publishes features on the latest advances in the global regenerative medicine community. CAR-T therapy's recent developments are hot discussion points, and RegMedNet is sharing a wealth of content into release testing and quality control as the therapy evolves.

Quality Control in CAR-T Therapy Manufacturing

It's difficult to develop effective technologies and cost-effective clinical manufacturing platforms that support CAR-T therapy's later clinical trial phases and commercialization. This is because the quality of CAR-T cell products is not only subject to donor-to-donor variation but also to the manufacturing environment and the quality and availability of reagents and ancillary raw materials. Therefore, manufacturers must consider various requirements, logistics, and platforms to ingrain quality in each stage of the manufacturing process.

To comply with Current Good Manufacturing Practices (CGMPs), CAR-T therapy manufacturers must equip their facilities with:

  • Technologies like air handlers and 24/7 alarm monitoring systems
  • Environmental monitoring equipment like viable and nonviable particle counters
  • Manufacturing process equipment like cell washers and bioreactors
  • Analytical equipment like automatic cell counters and flow cytometers.

Manufacturers must properly maintain this equipment, support the manufacturing process, operate a highly skilled workforce with extensive knowledge of GMP manufacturing, and perform adequate quality control testing.

Quality Control of the Manufacturing Platform

A cellular therapy needs a controlled, reproducible, robust manufacturing platform to reach its potential. Such a platform should integrate the readiness of the:

  • Facilities, utilities, equipment qualification, and environmental monitoring plan
  • Raw materials selection
  • Standard operation methods and batch production-controlled records
  • In-method and end-of-method sampling plans
  • Trained manufacturing personnel
  • Quality control and analytical assays.

Manufacturers should test these elements individually, but the qualification process makes it possible to identify challenges that manufacturers haven't anticipated during the evaluation and qualification of each component. Manufacturers can also collect data throughout the manufacturing process to gain a better understanding of process challenges and inconsistencies in process-to-process product quality.

Quality Control of Ancillary Components

CAR-T cell manufacturing requires several ancillary components, including culture medium, one-time-use disposables, reagents for genetic modification, cytokines, formulation medium, and cryopreservation reagents. Raw materials and components utilized in clinical manufacturing must be qualified or approved for human use. Plus, manufacturers must hold a certificate of analysis from qualified vendors, and this certificate must meet acceptance criteria and be reviewed for each lot.

Raw materials must undergo routine testing by the quality control laboratory to ensure product integrity. Manufacturers should also establish backup vendors for critical materials to reduce the risk of supply chain disruption. Meanwhile, viral vectors require separate release tests because of their own complex biological materials.

CAR-T Therapy Release Tests

CAR-T therapies are inherently variable because of differences in sampled patient cell populations and their responses to processing. As the CAR-T production process is complicated - it requires a high level of operator skill and complex biological materials - regulators now require researchers to perform several release tests on each single lot during clinical assessments of CAR-T therapies. These tests analyze identity, purity, safety, and potency and are essential as CAR-T therapies can have significant side effects (like cytokine release syndrome), despite being effective in certain patient populations.

CAR-T Therapy Costs and Timescales

The cost of CAR-T therapies is high: While Yescarta costs $373,000 per patient, Kymriah costs $475,000. However, the affordability equation will shift as more therapies gain approval for bigger patient populations. Overall therapy costs depend on the costs of quality control testing, release testing, and in-process control testing. Combination therapies, like the use of CAR-Ts with checkpoint inhibitors, may also affect the cost pressure on production.

Release testing directly impacts the timeframes (and, in turn, the costs) required for CAR-T therapy manufacture and release for delivery to the patient. This testing can add 100% to the time required for the therapy from apheresis to formulation. Some manufacturers aim to reduce manufacturing timeframes but need to minimize the release testing timescale to do so. Future technologies may make this possible.

Scaling Up CAR-T Therapies

As autologous cell-based therapies are personalized, they pose various manufacturing challenges when it comes to scaling up. For example, scaling up patient-specific CAR-T cell manufacturing requires manufacturers to accommodate several independent productions in parallel. But current CAR-T cell-manufacturing platforms are labor-intensive, and issues surrounding quality control and single-lot release make manufacturing processes even more complicated and costly.

Meanwhile, many academic centers are sponsoring CAR-T therapy trials, but the industry is now seeing a shift toward commercial production. Pharmaceutical and biotechnology companies are only just breaking into the adoptive cell therapy arena. However, new partnerships between industry and academic centers should enable process transfer and improvement, opening doors to development and commercialization prospects. This progress should accelerate the development of manufacturing platforms, which should enable manufacturers to scale up production and meet the inevitable rising demand when therapies are approved for clinical use.

Some organizations are considering decentralized models for CAR-T production. Such models would provide the ability to scale up without individual players investing in large, centralized production facilities. A decentralized model would require organizations to service large geographic regions, and samples would need low-temperature shipping. That said, moving production to multiple satellite locations could trigger major manufacturing and quality control challenges. Many manufacturers and equipment suppliers are developing automation equipment for centralized and decentralized facilities. This equipment should enable more sophisticated in-line testing, which should minimize the requirement for sampling and manual transfer to off-line testing.

Evolving Testing Needs

As new therapies gain market approval and the regulatory framework evolves, the ways that manufacturers can produce and test CAR-T therapies will change. For example, new therapies will shift the requirements for quality control testing, perhaps because of different antigen targets beyond CD19, the use of precisely selected T cell populations beyond CD3+, and/or different methods of transduction.

Because of this differentiation, regulators are working with manufacturers to agree on quality control testing measures for individual therapies. Regulators are also developing wide-ranging guidance on the release tests required during each phase of clinical trials and in commercial production. Regulators will adapt this regulatory framework as manufacturers collect more information on the safety and efficacy of their CAR-T therapies.

Meanwhile, testing technologies will also advance, which should make testing faster and more cost-effective over time. For example, molecular biology-based methods may replace culture-based sterility tests and lessen the burden of culture-based potency analysis. And new cell identification tests based on flow cytometry principles could streamline in-process control testing.

The Future of CAR-T Therapy

As technologies for clinical CAR-T cell manufacturing emerge and evolve, regulators and manufacturers must develop and optimize quality control testing procedures, all while improving efficiency and lowering costs. Scalability and reduced costs should be possible through the simplification of workflows, improved price robustness, and the employment of automated closed systems. On top of this, the participation of (and collaboration among) stakeholders will pave the way for CAR-T therapy's commercialization.

Learn more about RegMedNet and CAR-T therapy.

About RegMedNet and Future Science Group

RegMedNet is a community website that provides critical overviews of new treatments as they become mainstream medicines. The site serves an ever-growing, multidisciplinary community of professionals who work or study in the fast-moving regenerative medicine sector. Users can watch, read, and listen to content that explores the development, trialing, manufacture, regulation, and commercialization of cell therapies on the site.

RegMedNet is one of the progressive publisher Future Science Group's sites, and its sister journal Regenerative Medicine, is one of the group's 34 peer-reviewed journals. Regenerative Medicine publishes high-quality papers and reviews that explore an array of approaches to regenerative medicine, like cell and gene therapies, biologics, biomaterials, tissue engineering, and small molecule drugs.

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