Guest Column | April 10, 2019

The Unique Demands of Cell and Gene Therapy Supply Chains

By Erin Harris, editor-in-chief

gene_therapy_dna_istock

Innovations in the cell and gene sector continue to advance development of safe and effective therapies. But can the cell and gene therapy sector’s exceptionally complex supply chains keep up with the rapid rate of progress? I conferred with three of the field’s most valuable luminaries representing both academia and industry — Dr. Bruce Levine, Barbara and Edward Netter professor in Cancer Gene Therapy at the University of Pennsylvania; Simon Ellison, ISCT (International Society of Cell & Gene Therapy) Commercialization Committee; and Ryan Bartock, head of supply chain and network strategy at Spark Therapeutics — to determine how CMOs can and should successfully manage cell and gene therapy supply chains.

WHAT ARE THE UNIQUE DEMANDS OF CELL AND GENE THERAPIES’ SUPPLY CHAINS?

LEVINE: A large proportion of our reagents, materials, and equipment is single source. Therefore, when there is a disruption in the supply, it can have a catastrophic effect on the ability to manufacture the therapy. With the growth of the field over the past few years, there are beginning to be more options for alternatives. Still, these alternatives must be validated and demonstrated to be comparable to the primary materials in use.

ELLISON: Traditional pharmaceutical supply chains differ between clinical and commercial scale. Advanced therapies have essentially the same time- and temperature- sensitive supply chain throughout their lifetime. In addition, this is the first time that the patient has been part of the supply chain, either making a donation and/or receiving a live therapy.

This puts pressure on the supply chain and means that companies must take a logistics by design (LbD) approach and create logistics platforms that can connect therapies to patients at both clinical and commercial scale. LbD is an evolution of the quality by design concepts used within process development. It gives developers and CDMOs a toolkit to build, test, and optimize their logistics platforms alongside their manufacturing, clinical, assay, etc. platforms. This codevelopment ensures that therapies are connected to patients through clinical trials and are ready for commercial distribution post pivotal trials.

BARTOCK: With the success of LUXTURNA and other high-profile product candidates coming to both the clinic and commercial market, there is no question that the field of gene therapy is growing rapidly. These novel products bring the potential for one-time, durable treatments to patients, but also come with their own unique set of challenges:

  1. Accelerated regulatory pathways are becoming the norm rather than the exception. This generally requires commercially viable supply chains to be in place at the inception of a combined Phase 1/2 program. If changes to the manufacturing processes, analytical methods, and/or supply sites are required later in the life cycle, this can add complexity when scaling supply chains to support growth in the product or portfolio.
  2. Most gene therapy companies start small, often emerging from academic and other collaborations. As a result, supply chains often have a high degree of reliance on CMOs along with single- sourced novel materials, reagents, and analytical vendors. This introduces both complexity and risk to supply performance and security.
  3. Viral-vector development and manufacturing are critical to the gene therapy supply chain, and competition for capacity and starting materials to produce them is increasing. While conventional controls like inventory and capacity buffers can be employed to reduce risk, this comes with an associated cost that will only increase as lead times extend and capacity becomes more constrained.
  4. Because we’re bringing a novel medicine to the patient, often in a setting that requires either infusion or a surgical procedure, demand will remain volatile and capacity planning can be impacted by:

a. patient enrollment, screening failures, treatment cancellations/rescheduling

b. broad differences in demand across therapy areas (i.e., rare disease vs. more prevalent targets)

c. uncertainty in uptake rates as supply extends across global geographies.

WHAT ADVICE DO YOU HAVE FOR PHARMA/BIO EXECUTIVES AND CMOs TO SUCCESSFULLY MANAGE THE UNIQUE DEMANDS OF THE SUPPLY CHAINS?

LEVINE: First, know your suppliers and establish the relationships that will serve well in the event of a disruption. Secondly, engage in horizon scanning for new technologies and suppliers for alternative materials. Thirdly, as an academic institution, we have established relationships with peer institutions that may be able to lend a material in short supply in an emergency supply situation.

ELLISON: Logistics could be a critical manufacturing step. In a paper published in Cytotherapy (“CAR-T Cell Therapy Manufacturing: Modelling the Effect of Offshore Production on Aggregate Cost of Goods”) it is shown that the cost of logistics on a per-dose basis is like that for staffing and facility costs. It must also be noted that a failure in a logistics movement has the same impact as a failure in the manufacturing process. This understanding drives a mindset around “how do I connect therapies to patients?”

Advanced therapies are moving from first-in-human studies to commercial launch in around five years. This means that senior executives need to develop a vision, or target logistics profile, of what their logistics platform will look like at commercial scale, while still in early clinical trials. This enables them to take a risk-based approach to developing their logistics platform. This approach enables the identification and ranking of critical logistics attributes that can be addressed as they progress through the clinical development process, providing them a functioning logistics platform as they come out of their pivotal trials.

BARTOCK: I have three key suggestions:

  1. Start early — begin planning for predictable, consistent performance often before proof of concept. Get connected with the clinical and commercial organizations to understand the target product profile and begin developing a life cycle strategy for products and the emerging portfolio. This will take months, there will be gaps in understanding, but the sooner you get a sense for what must be true for a product to succeed clinically and commercially, the better you can diagnose if the current supply chain is fit-for-purpose and how it will need to scale.

Use supply chain maps and risk assessments to understand the capacity and reliability of your supply base. Because of the small and often academic origin of most gene therapy companies, most of the risk is likely to be concentrated among your raw material, vector manufacturing, and analytical supply base. Look across capacity, performance, business continuity, and redundancy. This will help you prioritize the areas of highest risk and assess where to form strategic partnerships and/or look for additional and alternative sources of supply.

Effective S&OP processes also need to be established to ensure capacity matches clinical and commercial demand. At Spark Therapeutics, we start the process with tactical reviews where demand-and-supply scenarios are focused across a near-term window of several months and gradually build up to a multiyear master demand- and-supply planning window. This ensures that sites can focus their schedules in the near term and leadership can stay aligned on available capacity, budget/workforce planning and capital investments, and emerging risks across the short and long term.

  1. Don’t linger in the weeds — A strategic operating model is just as important as tactical management. Establishing a set of sourcing, allocation, and network design principles provides a basis for making strategic decisions for the supply chain. Supply chain leaders can check recommendations against these for alignment or to understand where trade-offs are made. Some examples of principles include:
  • first intent sites of supply (materials, drug substance, drug product and analytical testing)
  • network design (what will be made internally/externally and capacity utilization targets to guide investment)
  • risk management (principles around inventory, dual and second sourcing).

Involve senior leadership across R&D, process development, manufacturing, technical operations, and commercial in an annual strategic operating cycle where:

  • The roles of analytical labs and supply sites are clearly defined for the network and revisited;
  • Emerging products are allocated across those sites proactively based on process/platform fit and technology strategy;
  • Clinical and commercial demand within the zero-to-five-year planning horizon are aligned with network capacity;
  • Constraints are identified and aligned with investment and sourcing strategies;
  • Product strategy is reviewed in concert with network and technology strategies and translated to supply sites (both internal and external) to inform on priorities and objectives over the next business cycle.
  1. Be an integrator and an innovator. Supply chain functions exist to make connections between development, technical, manufacturing, and commercial functions. Identify their challenges and work together to solve them.

Supply chain leaders should encourage their internal technical organizations and CMOs to establish standard process platforms, with associated scale-down models and systems to capture the data from process experimentation and batch manufacturing. These standard platforms can be mapped to therapeutic categories, volumetric demand, or phases in a product’s life cycle. This is key for any organization since the reduced lead time for technology transfer coupled with a better understanding of process and analytical robustness will enable you to navigate accelerated regulatory pathways and stay agile as the technology landscape for viral vectors and other platforms continue to evolve.

Opportunities for supply chain leaders to contribute to disruptive solutions aren’t just limited to our own internal organizations.

The national discussion in the U.S. around healthcare is slowly starting to turn away from volume and intensity of care and toward health outcomes. For those leaders in the gene therapy and biopharma industries who take the leap to learn more about how to balance commitment to patient access alongside budgetary concerns of public and private payers, supply chain leaders will need to be prepared to design novel distribution and order-to-cash models in response.

WHAT DO PHARMA AND BIO EXECUTIVES AS WELL AS CMOs NEED TO UNDERSTAND WHEN IT COMES TO STREAMLINING THE SUPPLY CHAINS?

ELLISON: Decisions made early in the development process can impact a therapy’s ability to commercialize. For example, if the donation or therapy is shipped “fresh,” this is expected to give a better cell viability; however, it creates a shelf-life issue. In other words, the shipping window is constrained by the duration that the cells remain active, etc. A constrained shelf life means that the therapy can only be collected/distributed within a certain catchment around individual manufacturing sites, and therefore, the developer will need multiple sites if it is to serve a global patient population.

Having a fresh product is a perfectly viable commercial strategy, but the therapy developer needs to understand the impact early in the development cycle and either budget for process development to create a cryopreserved supply chain, or the cost and complexity of having multiple CDMOs and/or manufacturing sites. All this drives cost, as well as regulatory and manufacturing equivalence issues. Streamlining the supply chain is reliant on an LbD approach and planning with the future in mind.

BARTOCK: While gene therapy clearly presents its fair share of challenges, it also provides several exciting opportunities for supply chain leaders and CMOs to be catalysts for change inside and outside of our organizations. We’ll succeed by staying true to the fundamentals, being integrators, innovators, and building partnerships that keep a clear focus on the patient at the end of our supply chains.

RYAN BARTOCK, head of supply chain and network strategy at Spark Therapeutics

SIMON ELLISON, ISCT (International Society of Cell & Gene Therapy) Commercialization Committee

DR. BRUCE LEVINE, Barbara and Edward Netter professor in Cancer Gene Therapy at the University of Pennsylvania