Allison Hoffman, global product manager, Cell Therapy Technologies, Terumo BCT, discusses how automation is leading the way to optimising autologous manufacturing in the C> sector.
Key insights:
- To reach more patients cost-effectively, the industry needs better methods for scale-out and the ability to run parallel batches that can be processed with fewer labour hours and other resources.
- Automated data acquisition and reporting allows careful monitoring and recording of what the system is doing and serves to optimise the process as operators acquire and analyse more of the data generated.
- Each autologous manufacturing line is specific to each patient, it requires parallel processing of multiple patient lots simultaneously which can hinder developing economies of scale in production.
As the autologous cell and gene therapy industry continues to grow, it must face the challenge of creating products that are safe and effective, but also affordable to both patients and payers. Currently, the prices for approved autologous products ($0.4–$2 million) are restricting access for many patients.
Furthermore, there is a large gap between the expected and actual selling price of autologous therapies approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). For example, in 2018 Novartis announced that its genetically modified autologous immunocellular therapy, Kymriah, would cost $475,000 per treatment.
Why are autologous therapies so expensive? An International Society of Cell Therapy (ISCT) subcommittee posted survey results that showed labour and materials to be an estimated average of 61% of the total cost of goods (COGs). In terms of “rate limiting” manufacturing constraints that might substantially contribute to increased costs, ISCT respondents cited “lack of automation” and “manpower” ahead of regulatory concerns, materials and testing.
Time to jettison the risk and cost of manual operations
Although pharma has learned to refine and control the manual processes associated with autologous therapeutics, these methods — however accurate and well-controlled for compliance — may not be efficient enough to offset associated labour costs and the potential for human error. On top of this is the demand for more accurate data for compliance and quality assurance, especially relative to a commercial therapeutic offering.
Manual processes, especially those involved in delivering autologous therapies, can introduce variables that are hard to identify, let alone control with efficiency and accuracy as processes scale up and out. These issues can potentially cause poor quality outcomes. When quality is compromised, the resulting interruptions to the therapeutic value chain can cause frustrating delays in delivering finished products where they’re needed most, to the patient.
To reach more patients cost-effectively, the industry needs better methods for scale-out and the ability to run parallel batches that can be processed with fewer labour hours and other resources. One viable approach is to automate processes and the data acquisition behind them.
Automated data is key to quality and efficient compliance
Although the regulatory demands on regenerative medicine are the same for manual and automated processes, controlling the variability of biological materials and proving process robustness and quality outcomes can raise the COGs during production. The reason for such a high degree of control is simple: the failure of a product lot can potentially be life-threatening to the patient waiting for treatment.
This extra burden of quality assurance and control creates additional regulatory requirements and current Good Manufacturing Practices (cGMP) imperatives — for example, a separate batch record and lot release for each patient. Because an autologous manufacturing line is dedicated to each patient, it also requires parallel processing of multiple patient lots simultaneously, which can drastically hinder developing economies of scale in production.
Automated solutions at the forefront of process development
Terumo Blood and Cell Technologies was one of the first equipment vendors to offer an automated closed fill and finish device. The company’s fill and finish system provides cryoprotectant mixing and aliquots products into single-use bags. Other single-use bag or vial-based solutions for the fill and finish step from other suppliers also exist. These automated closed-loop systems integrate data monitoring and other information technologies to gather information regarding a broad range of functions.
That gathered data is available to the system, which allows it to check for potential red flags during processing. A timely alert prompting an operator intervention can often make the difference between a batch that is releasable and one that is not. Regardless, any issues or variations are captured in a report available digitally to both operators and regulators.
All product runs acquire data that identifies initial targets as well as those during production, such as volume, timing and temperature. When the system can offer data on actual volume in process, though, an operator can know in real time how exactly it is performing.
Data integrity is key to compliance and quality
Issues stemming from poorly organised data and error-prone systems can greatly affect quality and compliance risk if not addressed and corrected systematically. Fortunately, efficiently acquiring meaningful, accurate data at each step and leveraging it intelligently is now much more accessible with the advent of digitally controlled automated autologous cell processing systems.
Automated data acquisition and reporting becomes very useful in automating autologous therapy processing in a cGMP setting. The capability not only allows more careful monitoring and recording of what the system is doing but also serves to optimise the process as operators acquire and analyse more of the data generated. A facility operator can set targets in the application, prompting an alert if this system is, for example, a predefined percentage away from delivering a desired volume.
Because these applications are hosted on the user's network, each device communicates to that central digital clearing house its configuration data and vice-versa. That means operators can push configurations from a central location down to the device, and the device automatically reports data back to the application at the end of the procedure. That allows an autologous therapy developer to capture manufacturing and process data while controlling and monitoring systems and users across the data networks of often geographically dispersed locations.
The facility of the future
Data automation facilitates cGMP compliance and product quality by giving users access to accurate, high-fidelity data that is extremely useful for optimising processes and operations. Automated autologous processes with digitally enabled systems offer a straighter path to compliance and COGs control.
Eventually, the path from the bench to the clinic will require automation, if only to meet cGMP process criteria and manage costs. Automating and closing these processes will likely proceed incrementally, with early adopters concentrating on the unit operations that are the most labour-intensive and expensive. Ultimately, the future of autologous manufacturing is a fully automated factory complete with electronic documentation and manufacturing execution systems that deliver process data and actionable information to improve quality, compliance and patient access.