Operations: Gateway to Success in Cell and Gene Therapies

April 2, 2019

Life sciences therapies are moving away from a one-size-fits-all approach to a targeted approach using a patient's own genetic information and immune system to treat previously incurable diseases.

Fifteen years after completion of the Human Genome Project, the next revolution has begun in Life Sciences where therapies are moving away from a one-size-fits-all, trial-and-error approach to a targeted approach that uses a patient’s own genetic information and immune system to treat previously incurable diseases. Precise and patient specific treatments like cancer vaccines and CAR-T cell therapies are among the most important scientific developments to advance human health in the last decade.

Cell and gene therapies have the potential to cure previously untreatable diseases, and fundamentally alter the trajectory of many other diseases. The FDA anticipates that by 2025, they will be approving 10 to 20 cell and gene therapy products a year based on an assessment of the current pipeline and the clinical success rates of these products.1

The first two autologous CAR-T therapies from Novartis and Gilead, which have been available commercially for over a year now, are the most complex to execute operationally. Autologous therapy uses the patient’s own cells in the end product, as compared to an allogeneic therapy, which uses cells from a donor. Autologous CAR-T therapy exemplifies the operational challenges and opportunities in precision cell and gene therapies. 

 

Instead of using off-the-shelf drugs, the revolutionary autologous CAR-T process requires that white blood cells be taken from a patient, shipped to a manufacturing facility in a temperature controlled or cryopreserved state, reengineered, and then shipped back in a cryopreserved state for infusion to the same patient.

While many industries are grappling with consumer demands for mass customization, autologous CAR-T represents the ultimate challenge in personalization–processing a batch of one for each patient while maintaining chains of custody and identity. While the therapeutic benefits have been proven, operations’ functions such as supply chain, manufacturing, and quality have to deliver flawless execution every time. Simultaneously, they have to automate processes, significantly reduce cost, and increase capacity to make the therapy widely accessible and affordable.

 

Operational challenges

Traditional pharmaceutical manufacturing consists of batch production of large quantities of drugs. Inventory at every step of transcontinental supply chains buffer against variability in demand and execution. In most cases, it takes well over a year from the time of starting manufacturing of drug substance to time of consumption by patients.

(Figure 2)3 

 

In contrast, for CAR-T, the needle-to-needle time, i.e. the time it takes from the collection of white blood cells to infusion of re-engineered T-cells, is around three weeks.

(Figure 3)3 

 

The execution complexity is exponentially greater because of the speed, reliability, traceability, and temperature-controlled transport required for the efficacy and safety of the treatment. It also takes an enormous amount of coordination across multiple stakeholders in the healthcare ecosystem, including patients, healthcare providers, manufacturing, suppliers, and payors before, during, and after the therapy.

 

Unlike traditional pharmaceutical manufacturing, which is based on forecast driven large batch manufacturing, CAR-T is truly demand driven manufacturing. For autologous CAR-T, each patient’s sample is processed as a single batch in a manufacturing setting, which is more lab-like than a highly automated industrial operation. Processes are labor intensive and use very expensive materials for processing and testing. Because of regulatory approvals being fast-tracked, the manufacturing facilities have been built quickly to ensure early launches. Further cost reductions through automation and reducing cycle time are still underway.

Hundreds of materials are used in the manufacturing process and as part of quality testing. Many of the newly developed materials are sole- or single-sourced. In addition, since some of the CAR-T programs started in non-cGMP environments, e.g. academia, standards at some of the key suppliers have to be upgraded before the therapies can be commercialized.

In contrast to conventional biopharma where production occurs in industrial cell cultures and variability can be controlled by better operations and process control, in CAR-T the product comprises the specific patient’s living cell itself, which creates intrinsic variability in the process-which is hard to remove, or even reduce.

To be commercially successful, cell therapies must retain their viability and potency, and this requires protection from exposure to adverse temperatures. In addition, given the nature of autologous therapy, it is important to maintain the chain of identity and custody at all times while respecting patient privacy.

Currently approved treatments list for $373,000 to $475,000 per patient in the US.2 Dramatically lowering costs is critical to make these revolutionary therapies more affordable and prescribed as earlier lines of treatment. In addition to cost reduction that will result from smart innovation and refinements in process engineering and manufacturing technology, enhanced affordability will also require digital orchestration of the complex supply chain for CAR-T.

 

Navigating these challenges

Fast-track approvals have resulted in manufacturers rushing to commercial launch before optimizing all of the materials and manufacturing possibilities. The hundreds of patients who have been treated successfully have proven the power of this therapy. Now, the natural evolution in the life cycle of this nascent therapy is to focus on reliability, costs, and capacity increases.

 

Optimization of the manufacturing process and supply base

The highest priority now is to develop the next generation of closed manufacturing systems that reduce the need for manual handling and can assure the required sterility and efficacy of the finished product. Modular, aseptic, closed manufacturing platforms are being built, where the batch of one is moved through a series of integrated steps, each dedicated for a specific part of the process. Larger CAR-T companies are collaborating with leading edge equipment suppliers and engineering teams on these systems. Incorporating IoT sensors for process control and in/on/at line quality control will ensure the ability to stabilize the manufacturing process.

With a stable process and a modular automated manufacturing system, it may become feasible to operate in less stringent environments without compromising safe and effective manufacturing. Since there is no possibility to scale up through larger batch sizes in an autologous therapy, capacity increase can be achieved by scaling out, i.e. creating new processing facilities in different geographies. Creating modular manufacturing systems that can operate in less stringent environments could make it easier to create manufacturing sites outside an industrial setting, such as in university hospitals. This will not only help to reduce costs but will make the therapy more accessible.

Companies should institute clear policies, processes, and practices to ensure that suppliers chosen for development programs are thoroughly vetted for GMP capabilities, financial strength, and capacity availability. Establishing multiple sources, material qualification, and ensuring GMP capabilities of vendors are extremely important tasks to accomplish. The CAR-T industry should also consider training academia and startups to plan for continuous upgrades of cGMP capabilities during the development programs. This will make it easier and faster to commercialize future therapies at lower risk.

 

Tailor made information systems for autologous CAR-T therapy

CAR-T and other forms of cell and gene therapy will bring about a dramatic change in the planning, operations, and execution mindset. The ability to link demand planning, scheduling, and manufacturing execution is not merely a value enhancer, but is a core pre-requisite for CAR-T.

As CAR-T therapies move to significant scale, smooth execution and planning of pre- and post-treatment activities will require full visibility of end-to-end available capacity and status of patients entering therapy. Demand and supply management will be more akin to airline flight operations rather than a push type of manufacturing system.

Within the plant, there are significant opportunities to continuously track and speed up the manufacturing process. Leveraging proven technologies like IoT sensors, automatic process control and MES systems designed specifically for cell and gene therapy will enable continual improvement of manufacturing execution as well as compilation and submission of regulatory documents. Applying advanced analytic tools such as machine learning and neural networks to the complex processes for CAR-T will help to detect otherwise unnoticeable patterns in manufacturing deviations and prevent their recurrence.

 

Operations impact should be a key consideration in R&D decisions

Changing materials, processes, or suppliers engaged in GMP controlled steps is extremely costly and time consuming. During the R&D stage, decisions related to materials, equipment, and suppliers should be made very deliberately with cross-functional input. While speed is of the essence during development, longer-term implications on cost, risk, and ability to scale up should also be key considerations in decision making.

Futurists envision CAR-T drugs to be manufactured at the point-of-care. This will be realized only when CAR-T manufacturing is robust and automated, and when appropriate regulatory authorizations are in place. R&D has a key role to make this vision a reality.

There are ongoing attempts to develop allogeneic CAR-T products. Collecting white blood cells from healthy donors and producing batch sizes of multiple doses will significantly reduce costs and supply chain complexity. This could make allogeneic CAR-T an earlier line of treatment.

 

Collaborate to compete

Given that cell and gene therapies are in their infancy, no single company has the wherewithal to upgrade and improve the capabilities and performance of the entire ecosystem. Collectively, the industry should collaborate in areas which are not competitive threats. For example, it would be beneficial to focus on creating standards for suppliers and apheresis center qualification, processes, and systems. Organizations where the industry can continue to collaborate are center-of-excellence-focused organizations like the Bio Supply Management Alliance and the UK’s Cell & Gene Therapy Catapult. These organizations have created the opportunity for those working on CAR-T to come together and share their successes and failures for the community to learn from and move forward quickly.

 

Executive management relies on strong operations leadership

Given the novelty of CAR-T, the exposure of operations professionals to its complexities has been limited. The required skillset and profile of a CAR-T operations manager are different from that of their traditional biopharmaceutical industry counterpart. Instead of complexity arising from large numbers of SKUs and multiple distribution points, CAR-T operations managers will be working in a demand-centric and just-in-time environment where agility and speed will be the main competitive drivers. The delivery of CAR-T products requires coordination between supply chain, manufacturing, quality, patient, and physician. Scheduling occurs in a more fluid manner and often in parallel. Success in cell and gene therapy will require professionals with a deep understanding of the processes and unit operations involved in execution coupled with a good breadth of knowledge of technology, supply chain, and business modeling. Executive management will have to find, enable, and inculcate such talent.

Next generation supply chain processes, technology, and training are imperative to achieve the benefits from breakthroughs in the field of cell and gene therapy. These therapies have the potential to significantly improve the quality of life for millions of patients. Success depends on our ability to combine cutting-edge supply chain knowledge with innovations in manufacturing, clinical, and regulatory affairs. This requires that multiple stakeholders in the ecosystem embrace significant change. Leaders of such change efforts will have to create a compelling vision for their organization, its suppliers, and its customers. This vision should combine business value with the moral and social imperative of succeeding in this endeavor.

 

References

1. FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on New Policies to Advance Development of Safe and Effective Cell and Gene Therapies.”

2. Schultz and Mackall, “Driving CAR T Cell Translation Forward.”

3. Adapted from: Tim Moore, “Pioneering the Development of the Supply Chain for Immuno-therapy Drugs: The Brave New World,” Presentation at BSMA 2017

 

About the Authors

Shankar Suryanarayanan is a global operations consultant specializing in the life science industry and digital transformations and can be reached at sshankar@alum.mit.edu.   

Devendra Mishra is co-founder and executive director of the Bio Supply Management Alliance (BSMA).

Alyssa Palmer is a consultant at the Plaster Group and can reached at alyssap@plastergroup.com.

Prashant Yadav is a lecturer at Harvard Medical School and Strategy Leader-Supply Chain at the Bill & Melinda Gates Foundation, and can be reached at Prashant_Yadav@hms.harvard.edu.