Overcoming Manufacturing, Regulatory and Distribution Challenges


Recent approvals of CAR-T immuno-oncology therapies present a market opportunity estimated to grow nearly 50 percent annually over the next decade, exceeding $8.5 billion globally by 2028 (1). Taking advantage means scaling up CAR-T production to industrial levels. This presents several highly technical and interrelated manufacturing, regulatory and distribution challenges.

Partnering with a clinical research organization experienced in immuno-oncology, such as ICON, can provide the manufacturing and distribution, and regulatory expertise sponsors will need to succeed. Here, we outline some significant challenges of scaling up CAR-T, and potential solutions.


Challenge: Viral vectors 

Selection and consistent production of safe and effective viral vectors is an essential first step for successful CAR-T manufacture. As the mechanism by which genes are inserted into T cells extracted from patients, viral vectors not only need to be effective and efficient, but also need to be safe over the long term. Industrial manufacture will also require vectors that can be reliably produced in much larger volume than for research and clinical trials.

Because it is a new field of therapeutic manufacture, many production and quality improvement processes required for large-scale CAR-T production will have to be developed. These include production processes capable of generating consistent quality improvement processes for validating vector batches and end products delivered to patients, and long-term outcomes reporting.

Solution: Developing or contracting for expertise in testing and developing viral vectors, and developing process and quality controls to ensure consistent quality using novel bioreactor culture systems will be critical for success.

Challenge: Cell collection

Ensuring consistent, predictable cell collection across diverse clinical therapy sites. Because the starting material for CAR-T therapy is T cells harvested from the individual to be treated, variability is unavoidable. Such variability may be compounded by variations in cell collection, a manual step dependent on individual operator skills, and institution-level procedures and processes.

Reducing the risk this variability may pose to product quality, yield and efficacy requires standardisation of blood collection, apheresis and cell preparation and storage processes based on existing institutional best practices. Developing a universally applicable collection template from the experiences and best practices of individual institutions will require significant development and validation.

Solution: Expertise in clinical process development, validation and improvement are needed to establish uniform cell collection processes that can minimise starting material variability.

Challenge: Ensuring consistent quality and improving quality across diverse therapeutic sites with variable starting materials

In addition to validated standardised cell collection processes, rigorous training and ongoing oversite and quality testing will be required to ensure such processes are properly implemented, adhered to and improved over time; and that the quality and efficacy of end products is maintained.

Solution: Expertise developing and harmonising quality assurance standards and practices across global markets, and advanced reference lab capabilities will be required.

Regulatory compliance

Challenge: Lack of regulatory standards and harmonisation

As a new technology, regulatory standards for manufacturing CAR-T therapies are at best a work in progress and subject to considerable subjective interpretation by regulators. As most CAR-T trials, to date, have been conducted in North America, the problem may be particularly pronounced in the European Union and Asia-Pacific countries, where regulators have little experience considering the unique challenges CAR-T presents for assessing the adequacy of manufacturing processes.

Prominent among these is the variability of starting materials noted above, which is likely to influence variation in final products far more than differences in manufacturing processes. Therefore, manufacturing assessments will have to be based more on well-defined critical process parameters at each step.

The case for approval, based on such standards, will have to be made on a country-by-country basis, and will require educating and working with regulators.

Solution: Essential capabilities include expertise in identifying, designing and validating critical process controls and parameters, and experience working early in product development cycles with regulators in Europe and Asia.

Challenge: Complying with evolving European and Asian standards for use of genetically modified products.

The European Medicines Agency is currently revising its guidelines on the use of genetically modified cells in medicinal products to specifically include CAR-T products with the goal of harmonising regulatory practices throughout Europe.

However, the outcome remains uncertain, and sponsors should prepare by maintaining inspection documentation of reagent origins, compositions, traceabilities, and certifications that are in use.

In addition, the Alliance for Regenerative Medicine has urged regulators to harmonise genetically modified organism standards, which vary by country and create a significant burden for conducting gene therapy trials and obtaining regulatory approval. Asian standards are similarly in development.

Solution: Working toward international harmonisation efforts is critical to create a favourable long-term approval and market environment for CAR-T and other gene therapies.


Challenge: Ensuring the identity, chain of custody and proper handling of cell source material.

The individualised nature of CAR-T therapy and the fragility of cells harvested from patients create unique distribution challenges. Ensuring samples are packaged, kept at proper temperatures and quickly shipped is just the beginning.

The identity of the patient donor of each sample must be verified and documented at every step – from collection to shipping to the manufacturing facility – throughout the cell genetic altering and expansion process. The samples can then be shipped back to the treatment facility and infused into the patient.

Managing distribution within the shelf life of unprocessed materials and processed products in the face of uncertainties of shipping schedules, patient availability, and manufacturing capacity scheduling on a global scale will be necessary for successfully delivering CAR-T therapy on an industrial scale.

Solution: Expertise managing biomaterial shipping logistics and large-scale sample processing, and workflow development and management across multiple sites will be essential.


Scaling up CAR-T therapy from an institutional to a commercial scale will require identifying and addressing multiple novel manufacturing, regulatory and distribution challenges. Significant experience and expertise in all three areas will be required.

As a leader in immuno-oncology, ICON has conducted approximately 100 clinical trials encompassing immune system-enhancing technologies, and more than 350 total oncology trials ranging from early research to post-market surveillance involving about 13,000 patients. ICON has the clinical and process engineering skills essential for developing, manufacturing and distributing the next generation of immuno-therapies


(1) Abhijit, R. Global CAR T Cell Therapy Market to Reach US$ 8.5 Billion by 2028.

(2)Aabhijit, R. Global CAR T Cell Therapy Market, By Targeted Antigen. Coherent Market Insights, Feb 2017. 

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