The therapy owner’s perspective is necessarily one of global optimization, rather than localized perfection of automated manufacturing. Viewed in this light, the successful commercial provision of a cell therapy is dependent on the integration of manufacturing, data management and logistics. Having a coordinated, Lean manufacturing and supply ecosystem is critical. As the therapy development progresses, maintaining sufficient visibility of the commercial model allows top-down definition of both the key elements of the ecosystem, and critically, the interfaces between them.
At each stage of the development journey, the therapy owner must understand each element sufficiently to define a hierarchy of needs. This includes the critical aspects of their manufacturing, data management and logistics plans that will support commercial success. Doing so defines the objective for the teams focused on each element.
In considering the transition from therapy development to commercial manufacture, it’s useful to observe that the business model supporting each state is optimized around the needs of that specific state. Commercial manufacturing of a therapy must be Lean. In contrast, research and development requires great flexibility. The significance of the organizational change required to transition between these states should not be underestimated.
The desired end-state is a commercial CGT manufacturing and needle-to-needle supply chain built around Lean principles. Put simply, the Lean philosophy seeks to maximize value creation and minimize waste. Within the orchestration of a complex CGT supply chain, it’s a nontrivial exercise, although three guidelines help visualize the manufacturing facility:
1. Focus on global cost drivers
- Downgrade cleanroom requirements (grade and required area) by closing the process.
- Reduce personnel costs (number and skill-level) through targeted automation including global facility coordination and data management.
2. Target high resource utilization
- Reserve expensive automated equipment for high value-add processes. Use standard solutions for simple process steps (e.g., long-term incubations in simple incubators).
- Ensure process steps on your critical path are robust. The incidence of failure at this point drives the throughput of the entire system.
3. Reduce variability
- Eliminate the art in high-skill steps through automation. Process steps requiring finesse typically have variable outputs and are failure-prone.
- Know and control the drivers of product quality. The cell journey should be as consistent as possible.
The Lean focus of commercial manufacturing generates value through optimization of the dedicated manufacturing resources. In contrast, pre-clinical development places a premium on flexibility and responsiveness. During therapy development, and even into early-stage clinical trials, typical CGT manufacturing processes are predominantly manual, extremely labor intensive and require a high degree of skill. While acceptable at the small-scale, this makes recruitment and training of operators difficult, creates a significant quality control and validation challenge, adds significant cost and ultimately is not scalable.
For Allogeneic therapies, centralized, large-batch manufacturing combined with cryogenic logistics is the default standard. The requirement for close observation of the manufacturing process and strong characterization of the end-product should be expected, given the biological variability of input materials and of response to manufacturing conditions which is common to all CGTs.
Beyond the factory doors we find a further challenge. The delivered frozen product may require a final wash and formulation prior to administration. Depending on the indication, specific methods for administration may be required. In both cases, the success of the therapy is reliant on a skills-based operation that is arguably part of the manufacturing chain. These steps need to be controlled with the same cGMP rigour expected within the manufacturing facility, perhaps through training and certification of clinicians in the final preparation and delivery of your therapy. This is analogous to the market introduction of a new orthopaedic device, where surgeons are trained to appropriately implant and manage the device.
Therapeutic development and commercialization is a balance of resource allocation and risk management. It is crucial to balance giving the right amount of attention to commercial manufacturing against the process development required, funding limitations and clinical trial progress. Key actions are:
- Perform a strategic planning and commercial feasibility study early to build a commercial model/plan for your business detailing a phased implementation of capability. This should include supply chain, manufacturing, regulatory, reimbursement and delivery.
- Close the process to reduce cleanroom classification and facility size and cost.
- Automate the complicated manual and variable process steps to achieve a robust and repeatable manufacturing process.
- Phase in manufacturing solutions progressively as dictated by the commercialization plan to scale to meet escalating production demand.