Practical considerations for establishing GMP manufacturing of cell and gene therapies
Ultimately, two objectives exist for the commercial manufacture of advanced therapy medicinal products (ATMP) and cell and gene therapies (CGT). The first is to deliver an advanced therapeutic benefit to patients, and the second is to capture a return on investment for the manufacturer. Achieving both objectives depends critically on the manufacturing decisions taken throughout the therapy development process.
Advocating a complete consideration of the manufacturing pathway for early stage therapies is naïve. In reality, therapeutic development is a game of resource allocation and risk management. Balancing the combined risks of a non-linear therapy development pathway, funding limitations, clinical trial progress and scarcity of skilled personnel means giving the right amount of attention to commercial manufacturing considerations. Too little attention, paid too late, risks embedding schedule or cost burdens. Conversely, expending too much effort too early could distract from the core therapy development – a pitfall that could conceivably kill the company. How then, can therapy owners appropriately consider manufacturing establishment as they progress their development towards commercialization?
“Balancing the combined risks of a non-linear therapy development pathway, funding limitations, clinical trial progress and scarcity of skilled personnel means giving the right amount of attention to commercial manufacturing considerations.”
Developing a commercial vision for integration of manufacturing, data management and logistics
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.
“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.”
The commercial vision will almost certainly evolve over time. Therefore, continually refining this framework is a two-way conversation where that evolution is guided by the challenges and opportunities emerging in each element, and conversely while the objectives for each element can be tailored to support the evolving vision with a reasonable understanding of the implications.
A complete automated manufacturing and supply chain is not required on emergence from Phase II. Rather, the goal should be a vision of the coordinated ecosystem of manufacturing, data management and logistics that provides the foundation of the commercial therapy.
Transitioning from development to commercial manufacture
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.
“Changes to a cell therapy process after regulatory approval are typically difficult, expensive and time consuming.”
Transitioning from pre-clinical development to commercial manufacturing is a huge challenge, and one that must be pro-actively engaged. Changes to a cell therapy process after regulatory approval are typically difficult, expensive and time consuming. The process used during late-stage clinical trials, regardless of how expensive or difficult it is, will almost certainly be used for commercial production. Using manual processes, the rate at which production can be scaled-up is impeded by the requirement to build and validate cleanrooms, and recruit and train highly-qualified staff—a model that rapidly becomes untenable. The timely consideration of appropriate automation is therefore critical to the commercial evolution of the therapy.
Understanding the cost drivers
Developed ahead of time, an understanding of the cost drivers of therapy production at commercial scale allows the introduction of process changes sufficiently early in the development and clinical trials process to avoid the need for comparability studies.
Ideally, therapy production for Phase III clinical trials should utilize production-prototype equipment and processes. This doesn’t imply complete automation. Rather we advocate for the targeted application of automation to eliminate specific sources of process variability, typically skills-based steps, and to ensure the processes employed are suitable for closed automation without redefining the cell journey.
Establishing this embryonic form of the therapy manufacturing process by Phase III demonstrates the process is mature, automation-friendly and scalable. Manufacturing establishment in parallel with Biologics License Applications (BLA) submission then allows commercial-scale therapy production immediately following regulatory approval—a primary driver of return on investment.
“Developing an understanding of the cost drivers of therapy production at commercial scale allows the introduction of process changes sufficiently early in the development and clinical trials process to avoid the need for comparability studies.”
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.
Autologous therapies, by virtue of their one batch per patient nature and circular logistics, typically require greater consideration of the appropriate manufacturing model. Various degrees of manufacturing localization are possible. More centralized production favors therapies with greater manufacturing complexity and frozen logistics whereas a more decentralized production approach increases the feasibility of fresh logistics, and favors therapies where the manufacturing capability is more easily duplicated.
Cryopreserved product could be considered an aspirational goal in either case, given the significant benefits of logistical and administrative flexibility. Cryopreservation can also reduce tight coupling of the manufacturing process, adding scheduling flexibility to both the in-factory process as well as patient collection and administration. Critically ill patients cannot be expected to attend an apheresis to accommodate a manufacturing cycle. Yet the cryopreservation cycle almost always impacts cell yield and viability, and hence therapeutic potency.
The key advantage of a fresh therapy is the ability to deliver an equivalent potency with reduced process complexity (both manufacturing and administration) and in-process loss (which may allow less invasive collections, smaller expansion targets and reduce product contamination with lysed/apoptotic cells). The manufacturing and logistics cycle in the case of fresh logistics is tight, impacting collection and administration scheduling, and requiring latency (excess capacity) in manufacturing capability to accommodate schedule variation. Ultimately, the fresh versus frozen question will be a trade-off between product robustness, and manufacturing and supply chain cost.
“Ultimately, the fresh versus frozen question will be a trade-off between product robustness, and manufacturing and supply chain cost.”
Near-patient manufacturing is a special case of autologous therapeutics, where the patient material collection, therapy manufacturing, and therapy administration occur within a center of excellence, hospital or clinic. This approach has the potential to shrink the logistics cycle, with attendant advantages in delivery cost and responsiveness to patients. The highly-distributed manufacturing model required lends itself to straightforward manufacturing models (typically no or minimal expansion for example). Indeed, the emergence of simple examples of this type of therapy under practice of medicine regulatory exemption is commonplace, if contentious.
A risk to consider for near-patient manufacturing, is that such approaches may cross the threshold to medical device status as they approach the patient, moving out of the standard cGMP realm. If so, a more stringent development environment is mandated for any manufacturing equipment. Under cGMP, BLA submission is based on the therapeutic product. The manufacturing of that product is of course an important contributor to the BLA dossier (the product is the process), yet the manufacturing equipment’s capability is effectively self-certified through FAT, SAT and IQ, OQ and PQ processes. As a medical device, the equipment itself becomes subject to regulatory approval – either through a PMA or the 510k path. This is an emerging space, and the thresholds and treatment by the regulatory authorities remain to be defined.
Determining manufacturing location – insource versus outsource
For therapy owners, one of the most fundamental commercial decisions is whether to manufacture in-house, or to outsource manufacturing through CMOs or licensed third parties. There are really three reasons to consider outsourcing: capacity, capital preservation and market access. This is driven in each case by the business model the therapy owner is pursuing.
3 reasons to consider outsourcing
1. Capacity: Many groups partner with CMOs to provide capacity for early-stage clinical trials. The investment is offset by the process management expertise brought by the CMO, and additionally, frees up the best developmental internal resources to focus on refining the therapy production process for Phase III and commercial manufacturing.
2. Capital Preservation: The capital preservation rationale becomes clear in the case of intermittent manufacturing requirements. For example, large-scale allogeneic therapy production may require only a handful of batches annually to serve the entire affected population. In that case, in-house manufacturing would see equipment, personnel and expertise languish for much of the year, where a CMO can more effectively redeploy these resources.
3. Market Access: Regional licensing is often used to provide rapid global market access that would otherwise be hard to achieve.
Regardless of the driver, the robustness and cost-effectiveness of the therapy manufactured at a third-party is only as good as the process transferred. Additionally, the third-party, irrespective of capability, is unlikely to share the therapy owner’s cost-reduction incentive. Ultimately, large-scale therapy providers will want their commercial manufacturing in-house as a core competency. Retaining that option, even while outsourcing manufacturing, means the in-house team must maintain a detailed understanding of the nuances of their therapy manufacturing process.
Considering the patient experience in the manufacturing cycle
Despite their extraordinary therapeutic and even curative potential, we must remember that the administration of a CGT likely comes at an unpleasant and difficult time for patients and their families. While they see only a small portion of the orchestration that contributes to providing their therapy, their expectation—which we as an industry should strive to meet—is of crisp, well-managed interactions.
Collection and administration must be as convenient as possible, completed correctly every time, and performed as-scheduled. Supporting the direct patient interaction, failures and breakdowns in the supply chain must be eliminated. No patient should be forced to return for a second collection to compensate for inadequate manufacturing or supply chain robustness.
“As an industry, we must ensure patients have trust in the system bringing them complex therapies.”
Consideration of the patient should extend as far as the therapy manufacturing model. For example, could a more patient-friendly collection approach, perhaps an apheresis replacing a bone-marrow aspiration, be utilized if an alternate therapy manufacturing structure was developed? As therapies are introduced to the market, the uncertainty of market size and adoption speed make manufacturing capacity planning difficult. Ideally, therapy availability scales seamlessly with market size, yet this level of responsiveness is difficult and expensive for manufacturers to provide.
Finally, as an industry, we must ensure patients have trust in the system bringing them complex therapies. While the oversight of federal regulators brings legitimacy, it is ultimately the integrity of the therapy owners, and the coordinated ecosystem of expert partners working to deliver their therapy, that will establish and maintain the reputation of the CGT industry.
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.
White Paper: Commercializing Cell & Gene Therapies
For more action-oriented solutions to cell and gene therapy commercialization, read this white paper we co-authored with market-leading experts from AmerisourceBergen and TrakCel.