A recent webinar highlights challenges to this new treatment.
By Mark Crawford
Dhananjay Jere, senior principal scientist with Lonza Drug Product Services, and Zhimei Du, director and chemistry, manufacturing, and controls (CMC) lead for Merck, presented the webinar Chimeric Antigen Receptor T-Cell Therapy (CART): Process, Analytical, and Cryopreservation Challenges on December 12, 2019, which discussed the development and manufacturing challenges regarding chimeric antigen receptor T-cell therapy. This presentation was followed by an overview on the broader challenges of manufacturing cell therapy products (CTPs) such as CAR-T and other advanced therapy medicinal products (ATMPs).
Medical researchers continue to investigate how to use the body’s own defense mechanisms to defeat diseases through cell therapy. Cell therapy has been studied for decades and demonstrated several early successes, especially chimeric antigen receptor T-cell therapy (CAR-T), where genetically engineered T-cells are used to treat cancer patients. Major milestones occurred in 1989 (first generation CAR T-cell construction process described) and in 2009 (second generation CAR-T cells persisting in the body after reimplantation). Kymriah, which fights lymphoblastic leukemia using the body's own T cells, became the first Food and Drug Administration (FDA)-approved cell and gene therapy in the U.S. in 2017.
Manufacturing CTPs is a complex, multi-step process, especially the requirement to maintain the stability of these delicate cells in cryopreserved formulations. Other challenges include process development and scale-up approaches, challenges in analytics, and how to determine the most suitable cryopreservation formulations.
Common Features of Cell and Gene Therapies
For many patients, cell and gene therapies represent “last chance” therapies, especially for serious diseases such as cancer. These therapies are, however, difficult to manufacture and offer many challenges, such as variable in vitro processes (both autologous cells and allogenic cells), cellular differentiation, immunological memory, genetic variation, environmental factors, gene-environment interactions, and a host of physiological factors. The system must also manage a dynamic cell population during the manufacturing process and after administration, during which time variations in predictability and efficacy can occur.
Many of these manufacturing techniques are adapted from academic research settings. They tend to be complex in design with many steps, which create more quality variability and higher manufacturing costs (raw materials, labor, scale out versus scale up).
The basic process platform was developed from haematopoietic stem cell transplantation (HSCT) research in the 1960s. The system requires complex and highly manual manipulations and process schemes, as well as numerous process components and reagents. Perhaps the biggest challenge is maintaining a robust cell population, which is highly sensitive to manufacturing process conditions.
These complexities and quality issues translate into high costs of operation (low-volume production, high capital expenditures, high cost and variability of raw materials, in-process and release testing, and complicated distribution, transportation, and logistics).
Semi-automation or complete automation can greatly streamline the manufacturing of cell and gene therapies, with higher quality and repeatability, as well as greater ease in scaling up. Automation is key to defining processing variables and control strategies, especially over material quality control and collection yield, establishing standard operating procedures, and establishing a risk-based decision-making process.
Challenges of ATMP Manufacturing
Improving the efficiency of ATMP manufacturing is best accomplished by shifting from a labor-intensive, academic production setting to a rapid, robust, consistent, and low-cost manufacturing system.
The sensitive nature of the cellular components creates special challenges for CMC leaders. Factors that impact the quality of autologous and allogenic cellular therapy manufacturing include isolation, processing, maintenance, quality control measures, and release, as well as administration, especially thawing and dose preparation.
Parenteral drug product quality expectations by the ICH/USP/EU include:
- Sterility
- Established container closure system (CCS)
- Assured CCS
- Formulation and approved excipients
- Meticulously controlled endotoxins and cellular byproducts (HCP)
- Intrinsic and extrinsic particulate matter
- GMP-compliant and robust quality-control analytics (CQAs)
- Defined and controlled CQAs
- Controlled processes
- Risk mitigation and controlled strategies
- In-use stability, safety, and handling procedure
Challenges for current state-of-art manual manufacturing process for CTP cell-therapy products include:
- Batch/slot process with multiple handling steps
- Expensive process
- One batch per patient
- High risk of contamination (for example, particles)
- High batch-to-batch variability
- Sterility and aseptic processing at risk
- Sub-optimal use of resources
CTP quality controls face challenges such as complexity of analytical methods, rapid release due to short life of CTPs, and large number of batches for release. Other challenges exist for sterility of CTPs—for example, is sterile filtration or terminal sterilization most compatible with frozen storage and container closure integrity (CCI) of frozen product? Test method suitability also comes into play, such as rapid sterility assessment and CCI for the frozen product—any loss in CCI is a breach of sterility and hence a safety risk. Dye-based testing for CCI also may not be suitable for all products with frozen storage.
Yet another concern is the monitoring visible and subvisible particles for parenteral dosage forms. Filtration is not an option for CTPs; particle contaminants in CTPs will be undetected and administered to patient. Differentiation of cells, and unwanted particle contaminants, are extremely difficult to discern and special detection methods may be necessary. Cryopreservation is another major challenge for CTPs and DMSO is still the cryopreservant of choice, even though it is toxic and requires post-manufacturing procedures in clinics (thawing, DMSO elimination).
Automation Boosts Efficiency, Reduces Costs
For the manufacturing of cell and gene therapies such as CAR-T and other ATMPs or human cellular- and tissue-derived products, semiautomated or fully automated manufacturing can eliminate much of the variance observed in many of the steps. Automated manufacturing:
- Increases efficiency of process
- Reduces number of handling steps
- Optimizes resources, labor, media, and consumables
- Reduces number of interventions
- Improves process robustness
- Allows multiple batch processing in parallel
An example of automation is the Lonza Cocoon Platform, a closed system for automating cell therapy manufacturing that can manage numerous clinical programs and/or manufacturing at a commercial scale. With a minimal footprint of about one square meter of space, the platform manages cell expansion via continuous monitoring and management of temperature, pH, CO2, and DO, along with in-process sampling. Internalized media and reagent storage is achieved via a cold chamber.
Moving Forward
Regulations for CTPs continue to evolve. Safety of course is the top concern. Assurance of sterility and CCI of frozen product is a top priority. Particulate contaminants in cell-based ATMPs must also be monitored, as well as cryopreservants, methods, and alternatives to frozen liquid CTP.
Automation can assist the manufacturing of cell therapy products end to end, including the key operations of isolation, activation, transduction, expansion, and harvest. Manufacturing is fully enclosed with minimal touchpoints. Monitoring and control of temperature and gases, pH, and DO, as well as information logging and control with electronic batch records for full product traceability, are managed in real time. Automation also provides the flexibility to move from preclinical scale to full-scale commercial manufacturing.
“Closed system for automation cell therapy manufacturing can improve quality and affordability of cell-based ATMPs,” says Jere. “This includes collection and preparation, selection, activation, transduction, expansion, formulation, and patient administration for cell therapy products.”
Watch
This webinar is available to AAPS members.
Mark Crawford is a science and technology freelance writer based in Corrales, NM.