Whitepaper. Small Molecule Vs Cell Therapy Clinical Trial Supply Chain. Martin Lamb, Executive Vice President for Sales and Marketing

Transcription

1 Small Molecule Vs Cell Therapy Clinical Trial Supply Chain Page 1 Whitepaper Small Molecule Vs Cell Therapy Clinical Trial Supply Chain Martin Lamb, Executive Vice President for Sales and Marketing

2 Small Molecule Vs Cell Therapy Clinical Trial Supply Chain Page 2 Introduction After more than 20 years working in the well-established clinical supply chain for small and large molecule products, my first year working in cell therapies has been something of an eye-opener. While there are parallels with the supply chain I am familiar with, I am quickly finding challenges unique to this emerging class of therapy. Cell Therapy 101 The FDA defines cell therapy as treatment through which living cells are introduced into a patient s body to illicit a therapeutic effect. Cell therapies fall under two broad categories: Figure 1: Current Scale of, and Investment in, the Regenerative Medicine Industry: Autologous cell therapies are produced from cells extracted from the patient themselves. A sample of the patient s cells are removed, modified ex Vivo, expanded and infused into the same patient. This is about as personalised as medicine gets, with a 1:1 donor/recipient relationship in which it is critical to ensure that modified and expanded cellular material is infused back into the original donor. Allogeneic cell therapies allow cells removed from a single donor to be used to treat multiple patients. While universal allogeneic cell therapies have a supply chain similar to that of traditional medicines, human leukocyte antigen (HLA)-matched allogeneic cell therapy supply chains can add some complexity. Although cell therapies have been in existence for decades, recent advances in the development of these exciting, potentially curative, therapies have led to renewed interest from major pharma and investors alike.

3 Small Molecule Vs Cell Therapy Clinical Trial Supply Chain Page 3 Cell Therapy 101 (cont.) An increasing number of cell therapies are reaching the market (Examples: EMA approval of GSK s Strimvelis in 2016, FDA approval of Novartis s Kymriah in August 2017, and Kite s Yescarta in October 2017) or entering late-stage development. With this comes the prospect of wider access to these new medicines as patient numbers grow, more treatment centres are required, potentially supplied by a wider network of manufacturing sites. This, in turn, leads to a more complex supply chain as unlike traditional small molecule and biologic therapies, mass production of and pre-stocking of autologous cell therapies is not an option. For the purposes of this article, I will focus on autologous cell therapies and how their clinical supply chain poses challenges different from those I ve experienced with more established therapies.

4 Small Molecule Vs Cell Therapy Clinical Trial Supply Chain Page 4 Where does the GMP supply chain begin and end? For traditional small molecule and biologic therapies, GMP processes cover the entire process from raw materials, API, manufacturing, packaging and distribution. However, where does GMP start for cell therapies, in which starting material is not manufactured but is collected from a patient in a clinic or apheresis centre? The current view is that GMP begins when starting material is received at a manufacturing site. However, cell therapies are living therapies and as such any deviation in handling can impact upon cell viability and the eventual efficacy of the therapy itself. While tests performed on starting materials upon receipt at manufacturing sites can help eliminate bad cells, steps should be taken to ensure that variability at the collection site is limited to minimise the risk of this happening. After all, repeating apheresis is undesirable, and in cases where cell therapy is a treatment of last resort this may not be possible. Similarly, since autologous therapies need to be infused into the same patient starting material was collected from, cell collection processes need to include tracking systems that will maintain the donor-material link throughout its supply chain a problem that does not exist for small- and large-molecule therapies. While cell collection may remain outside of GMP, controlled, traceable and consistent processes remain essential. Figure 2: Supply Cycle for Manufacture of CAR-T Cell Therapy CAR-T Manufacture

5 Small Molecule Vs Cell Therapy Clinical Trial Supply Chain Page 5 Where does the GMP supply chain begin and end? (cont.) Following manufacture, testing and release of the finished cellular product, it needs to be transported back to the clinical site for infusion back to the original donor. Again, where does the manufacturer s responsibility end? When product is received at site when it becomes the responsibility of the clinician and is governed by GCP regulations as with more established treatments? Not so in the case of cell therapies: Treatment may need to be infused or transferred to specific storage conditions within a specific time limit from receipt. Receipt at site does not necessarily mean the product has been received by the appropriate person. Additional processing may need to be conducted following receipt. For example, the finished product may have been cryogenically frozen upon completion of manufacture. Prior to infusion back to the patient, material needs to be thawed. Once again, this should follow prescribed processes to maintain consistent, high quality and safe product. Recent EU Draft Guidance for the manufacture of Advanced Therapeutic Medicinal Products (which includes cell therapies) included enhanced requirements for traceability of starting material as it enters the supply. In addition, the Guidance document includes a clear indication that the EU Regulators at least consider the manufacturer s responsibility to end only when the product is infused. ii Make-to-Stock vs Make-to-Order In my past experience, while certain parts of the clinical supply chain could be executed on demand (for example, final labelling and distribution to clinical sites), manufactured product could be produced in advance and either stored in bulk or in primary packs until clinical trial plans were finalised. This was possible because product was not patientspecific, and also because products typically had long shelf lives, or at least could be formulated to maximise storage time. Contrast this with autologous cell therapies, which are produced on a patient-by-patient basis. While allogeneic therapies can be stored for use across wide patient populations, the autologous production process is totally on-demand. Also, during clinical development many therapies rely on fresh material that must be collected, transported, expanded, transported and infused within a short period of time. As therapies advance through development, supply chains may be improved to include cryopreservation steps to provide some flexibility in scheduling downstream activities, (see below) this does not alter the fact that autologous supply chains are totally demand-led, making up-front planning and economies-of-scale difficult to achieve.

6 Small Molecule Vs Cell Therapy Clinical Trial Supply Chain Page 6 Scheduling Challenges Any manufacturing process requires scheduling in order to maximise asset utilisation and keep costs to a minimum, while still maintaining sufficient inventory in the supply chain to meet forecast or real demand. In a traditional pharma setting, while clinical demand drives production, scheduling is generally driven by factors within the walls of the manufacturing site material availability, trained headcount, machine/room capacity, testing schedule. Again, autologous therapies take this complexity to a new level beyond what is happening in the manufacturing site. In addition to manufacturing constraints (materials, equipment, clean rooms, laboratory capacity, trained staff), it is also necessary to consider capacities required for upstream and downstream activities. For example, if a patient is scheduled for apheresis on a particular day is there capacity at the manufacturing facility to process starting material? Even if this is possible, does the clinic have the ability to treat the patient with fresh finished product on the day it becomes available? If patient conditioning (e.g. in the CAR-T supply chain above patients require leukodepletion before they can be treated) is required before infusion, how does the clinic know when to start this in order to complete this process before the final cellular drug product arrives? While cryopreservation can add some flexibility for downstream scheduling in that material can be frozen if clinical capacity is not immediately available following manufacture, scheduling of activities across stakeholders is especially challenging for autologous cellular products. Centralised vs Decentralised Manufacturing The clinical supply chain for traditional pharmaceuticals is often based on a centralised model for manufacture and packaging, although storage and distribution to clinical sites has become increasingly decentralised as clinical trials increase their geographic footprint. This is possible because, as explained above, products have long shelf lives and can be produced ahead of time based on forecast demand. How does this work for autologous cell therapies, especially those involving fresh materials? Producing finished product at a single site, providing sufficient capacity is available, can support a domestic clinical trial. However, what happens when a development programme extends into other territories in far-flung corners of the world? Can a single site receive, manufacture and return material in an appropriate timeframe? How easy are the logistics around this? As a result, while there are exceptions, we typically see a less centralised approach to cell therapy manufacturing involving multiple CMOs or multi-site global CMOs. Not surprisingly, proliferation of CMOs and clinical sites as product development advances or therapies commercialise can increase the risk of product variability, which I will discuss in more detail below.

7 Small Molecule Vs Cell Therapy Clinical Trial Supply Chain Page 7 Variability Small- and large-molecule therapies are, particularly in later development, produced at large scale using validated processes on often proven, automated equipment. Input materials are quality-checked before use, helping minimise risk to the quality of the finished product. Finally, as mentioned previously, products are generally produced using a centralised manufacturing facility, further eliminating inconsistency from processes. As a result, products are produced through reproducible processes so batch-to-batch variability should be limited. Cell therapies, especially during early development, are often produced using manual processes executed by highly skilled scientists. While this may work during early development, recruitment of sufficient patients to support late stage pivotal trials could require a rapid expansion of the supply chain to incorporate additional clinics, apheresis sites and decentralised manufacturing facilities. As the number of parties involved in the supply chain increases, how do we maintain a consistent process that, in turn, minimises the risk of variable product quality and safety? Even when processes are manual, it should be possible to reduce process variability to help minimise the risk of inconsistent product quality. My own company, TrakCel, has developed a Cell Orchestration Platform (COP). This was originally developed to help ensure traceability of cell therapies from the original donor, through the supply chain, and back to the original donor. However, the system also includes project and process specific workflows that must be followed, and signed off at each stage, to ensure these are performed consistently at all facilities in the supply chain clinics, apheresis centre, couriers, manufacturing sites. At the end of the day, it is unlikely we will ever be able to fully eliminate variability from the cell therapy supply chain. We are working with a living therapy, and variability is to be expected. However, by controlling the parts of the supply chain where we influence the process, the risk of variability can be greatly reduced. Automation of processing steps can help eliminate inter-operator variability, consistently control environmental conditions (sterility, temperature, ph, processing time), which in turn can reduce reliance on a limited pool of skilled operators and Centres of Excellence while at the same time minimising variability as a result of processing inconsistencies. Areas where automated equipment has been developed include manufacturing iii and point-of-care thawing equipment.

8 Small Molecule Vs Cell Therapy Clinical Trial Supply Chain Page 8 Conclusion Commercialisation of Autologous Therapies All of the above comparisons are based on the clinical development supply chain. However, the supply chains of autologous cell therapies remain complex even after they reach the market. As suggested by the details above, autologous cell therapy production is the most personalised of all manufacturing processes. Even when a product is commercialised, there is no economy of scale. The need to track donor material back to the correct patient does not go away. The risk of process variability, if anything, increases as more and more patients, clinical sites, apheresis sites, manufacturers, logistics providers and equipment chains become involved in the supply chain. Finally, as license approval and in many cases payment models are based on patient followup over many years and continued satisfactory clinical outcomes, consistent data capture remains a critical component of cell therapy management. COP systems, like TrakCel, can help cell therapy developers maintain this control over their supply chain beyond clinical development. The need for such systems is best summed up by the FDA s assessment of the challenges facing Provenge, the first autologous cell therapy product to be granted market approval. i i i i i i The major challenge in manufacturing this product is not in the manufacturing protocol Logistics is perhaps the more challenging aspect of producing this product due to the short shelf life of both the incoming apheresis units and the final product. Given the tight manufacturing schedule, short process time limitations, overlapping production schedules, QC testing, and complex shipping situations. It will be difficult to generate this product at high throughput without substantial attention paid to coordinating and orchestrating these events. iv advtherapies/2016_06_pc/2016_06_draft_guideline.pdf i v cellulargenetherapyproducts/approvedproducts/ucm pdf UK Office: 11 Raleigh Walk, Waterfront 2000, Cardiff, Wales, CF10 4LN +44 (0) US Office: 1200 US Highway 22 Suite 2000 Bridgewater, NJ