Cell Therapy, including engineered T-cells, is becoming a more familiar feature in the medical world, especially as a treatment option for patients with late-stage cancer. One of the challenges faced by companies is how to deliver these living therapies rapidly and safely to patients. The importance of manufacturing and supply chain to meet this challenge cannot be underestimated. With autologous cell therapies, in particular, traditional means of scaling manufacturing such as producing larger batches and building drug product inventory do not apply and new ways to meet patient needs must be developed.
Adaptimmune is currently developing and manufacturing autologous cell therapies for clinical trials at numerous sites in North America and Europe for a variety of solid tumor types. With autologous cell therapies, companies must consider the patient journey in a much more integrated way since it is a “make-to-order, one batch, one patient” approach. Essentially, a patient’s white blood cells are collected in a clinical setting and sent to a centralized manufacturing facility where the T-cells are isolated and transduced with viral vectors to express the gene of interest. The cells are then expanded over a period of days, cryopreserved, and returned to the hospital where the cells are thawed and the patient lymphodepleted prior to the infusion of the engineered T-cells. These unique aspects of autologous cell therapy manufacturing must be considered.
Considerations for Manufacturing
The successful manufacturing and supply of an autologous T-cell product is driven by three key parameters:
1) Time for a patient cells to begin manufacturing – At Adaptimmune, this target is seven days from a patient becoming eligible for the treatment to providing a slot for apheresis and cryopreservation of their cells at the manufacturing site. Many activities must be considered to achieve this target: e.g., insurance approval, logistics/travel support, flexible manufacturing scheduling to accommodate both the patient and the treatment center, etc.
2) Time for manufacturing – This is the process turnaround time, which is often referred to as “Vein to Vein” or “Needle to Needle” time. It starts with the apheresis process to collect the patient’s T-cells, includes the cryopreservation of this starting material, subsequent thawing and manufacturing, quality testing and release, shipment to the clinical site, lymphodepletion, and ultimately ends with infusion. Adaptimmune is targeting 30 days of “vein to vein” time (inclusive of 7 day lymphodepletion). Close coordination with the clinical site to schedule the patient treatment, as well as the efficient and effective operational execution of the manufacturing process, contribute to reducing this time.
3) The robustness and success rate of the manufacturing process – Typically, autologous T-cell manufacturers run one batch for each patient. If there is a problem with the batch for any reason (e.g., a product contamination, a facility issue, a batch that fails to meet final specifications, or a supply issue with any material) the entire process may need to be redone. This may be unacceptable to the patient and the company, so the company may choose to invest in redundant manufacturing sites, multiple runs per patient to have a “backup” supply ready, or other strategies that ensure the risk of not supplying a patient is minimized.
A “perfect order,” therefore, would be one where the patient’s cells quickly get into the manufacturing schedule, the turnaround time for manufacturing is fast, and manufacturing of the product is successful. If a company desires a 100% service level, where every patient experiences a perfect order, they may need to invest in very high capacity, multiple manufacturing sites, and make investments in process technology to ensure the process has no manufacturing risk. In this case, the investment required to scale while achieving this very high service level may be unreachable. Aiming for a high, but not perfect, service level may lead to different decisions on where to invest to achieve the goals for each of these three key parameters. As a result, it is important that a company determines the desired service level before defining and implementing a “scale up” strategy.
The manufacturing and supply strategies needed to meet the targeted service level fall into two primary categories. The first is the manufacturing process and execution. Companies will need to consider approaches for the unit operations used in manufacturing to deliver a safe and effective drug product, the quality and analytical systems supporting manufacturing, and investments in automation or electronic manufacturing execution systems.
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Secondly, companies must consider the design of the manufacturing network. This includes capacity decisions both in the long- and short term, locations of the manufacturing facilities based on where there may be demand while factoring in location-associated costs, and if there is distributed versus centralized manufacturing. With the service level defined and the strategies for the two manufacturing categories in place, the challenge of scaling must now be addressed. For growing cell therapy companies, scale is required for two primary reasons:
- “Out” to manage multiple products in multiple clinical trials; and
- “Up” to manage the larger and more geographically diverse patient population of a commercial product.
For each of these scaling challenges, we will examine strategies for both the manufacturing process execution as well as the manufacturing network.
Scaling Out to Manage Multiple Products in Multiple Clinical Trials
Manufacturing Process and Execution
While scaling out to supply multiple products in clinical trials, one approach is to have more manual steps and discrete unit operations. This allows change controls to be more targeted, allowing one aspect to be changed in the process instead of the entire process. For example, it is more efficient and simpler to replace one bioreactor for another instead of changing the overall process. Implementing these changes requires an efficient and effective internal change control process with close coordination between manufacturing, clinical operations, regulatory, and any necessary contract manufacturers (CMOs).
Manufacturing Network
Even with a quick process execution and targeted changes, managing multiple products and processes in a clinical trial setting can be complex, with the use of centralized and internal manufacturing models having big implications. Utilizing a centralized manufacturing model can allow such a complex manufacturing process to be managed all in one facility, which allows for better scheduling efficiency, forecasting, and consistent production. Internal manufacturing can also lend itself to greater flexibility and simplified decision making since there are fewer stakeholders. These key benefits can be critical to a company’s success and are the reasons Adaptimmune has invested heavily in their centralized, internal manufacturing process.
An additional consideration to ensure effective supply of multiple trials is to keep your capacity utilization lower to allow faster response times for patients. For example, in early Phase 1 trials, when there is not a significant amount of data to back the efficacy of the product, the ability to respond when patients are ready is very important in order to overcome any hesitance on trying a new therapy option. Once data shows that the product may have a positive effect, clinical trial sites and investigators may be more flexible to operational challenges of the therapy because they have begun to believe in its potential. Keeping capacity utilization low also affords flexibility for the scheduling of multiple processes and provides enough “slack” in the schedule to effectively manage multiple projects along different timelines.
Early Phase Clinical Trial Design
While not the remit of manufacturing and supply, one additional factor that can impact the ability to scale out across multiple processes and products for early phase trials is the trial design. For instance, when managing trials across our three wholly-owned products, we have learned that smaller trials implemented across a smaller number of clinical sites and in a more limited number of countries, creates strategic relationships with investigators. This helps facilitate rapid iterations and changes, making them easier to manage. It also means less manufacturing capacity required for a broader range of clinical trials, reduced investment in materials, CapEx, personnel, etc. And given that clinical signals of efficacy (or not) often emerge in a limited number of patients, having smaller, more focused trials can speed the “time to insight” from each new trial.
Scaling Up to Manage the Larger and More Geographically Diverse Patient Population of a Commercial Product
Manufacturing Process Execution
Once a company is preparing for a later stage trial, considerations for commercial scale and the need to “lock” the process becomes the priority. Any changes to the process in a potential registration enabling trial will be challenging to implement. The requirement for comparability between processes or manufacturing sites is high for any pharmaceutical company, but even higher for autologous cell therapy companies given the complexity and the “one patient, one batch” reality.
This is where automation comes into its own, including electronic batch records, automated environmental monitoring, laboratory information systems, and software to manage the cell Chain of Custody (CoC) and Chain of Identity (CoI) requirements. We want to close as many open steps as possible to reduce the contamination risks to the product. Applying Lean Sigma principles at this stage is a good way to improve performance while reducing waste, especially as you move into higher patient numbers where reducing costs will be imperative. Unlike large or small molecules where one batch may provide enough drug product for thousands of patients, with autologous cell therapies small improvements in operational effectiveness can have a dramatic impact when doing thousands of individual batches per year.
Within the supply chain it is essential to ensure your supply base can scale up for higher volumes as well as meet commercial GMP quality standards. Much of the supply base in cell therapy is also growing from a research scale and there is high demand for their products and services, all of which make supply chain planning in an emerging therapeutic field very challenging. Adaptimmune has pursued a strategy to build an integrated company so that we can optimize the number of suppliers with whom we need to work to manage volume and quality. One example has been how we have evolved our vector supply chain, starting with material coming from academia during our initial trials, then moving to CMOs, and finally adding our own in-house vector manufacturing capabilities in the UK. Our journey started over two years ago with our first planned commercial launch aimed for 2022 in the US. “One patient, one batch” means hundreds of batch records, thousands of QC release tests, and many other steps, and implementing the scale necessary to meet this demand takes time.
Manufacturing Network
Beyond the process work, it is important to review your network capabilities. This starts with planning for higher volume, determining optimal locations for commercial facilities, and deciding on your target capacity utilization based on your desired service level. We have developed our own model to make sure that we are planning for the appropriate number of manufacturing slots to minimize the time patients must wait to have cells manufactured and re-infused. A higher service level requires potentially lower capacity utilization (meaning a higher capacity for a given forecast). Providing a manufacturing slot requires sufficient equipment, space, and trained staff, and acquiring these assets and capabilities can take a long period of time. Finally, we are reviewing the processes outside of our facility, such as the cryopreservation, for which we are investigating local and regional options to provide more flexibility.
Looking to the future
Beyond the concepts discussed above, there are a number of innovative ways to improve the patient experience while scaling up. These innovations include approaches such as “off -the-shelf” autologous products where, if the therapy is used in second line, drug product manufacturing could continue in parallel with first-line treatment so cells are ready should the patient progress.
Another approach could be “apheresis and hold”. With this model, patients could be tested for specific biomarkers that may put them more genetically at risk for future cancer even before treatment is needed. If there is a future risk of cancer, the patient could go through the apheresis process which could be cryopreserved and held for potential future use. This ensures that if a patient is diagnosed with cancer, the starting material is healthy instead of relying on the cells from someone with cancer.
A few years ago, we began to expand our T-cell research into another type of therapy platform that does not require us to engineer a patient’s own T-cells and thus makes scaling manufacturing less complex. This platform is called allogeneic or “off -the-shelf.” In theory, these allogeneic cell therapies can be administered to any eligible patient, as they are engineered through gene editing to be acceptable to any patient’s immune system. This universal approach would enable drug product inventory to be built in advance, eliminating many of the challenges described above.
The challenges of scaling up cell therapy manufacturing and supply, to manage multiple products in multiple clinical trials as well as larger patient populations, are diverse and complex. However, with forethought and effective execution, these challenges will be overcome and the delivery of these life changing therapies to people with cancer will ultimately become routine.