By Sanjin Zvonic, PhD, Director, Technology & Business Development
So how can a cell therapy developer use this knowledge to develop with commercialization in mind? Start by determining whether your cell therapy will be delivered by a direct or multi-step process – the two main types of delivery.
Based on our experience and understanding of CTP delivery, Progenitor Cell Therapy coined the term direct delivery for CTPs formulated and QC-released at the time of manufacture into the final formulation without requiring additional clinical site processing prior to patient administration.
With direct delivery, the cell product is released fresh from the manufacturing site in a validated shipper. It is received by the qualified clinical staff per SOP and kept in the shipper until administration. Processing or long-term storage at the clinical site are not required for direct delivery products. Qualified clinical staff will then transfer the product to the administration device and administer the product.
Understanding the steps of direct delivery is the first step. The second step is to carefully detail the resource requirements for each step of the process. For example, for shipping, a manufacturing site with quality assurance and shipping resources, and, for administration, qualified clinical staff, established SOPS, and ongoing training and qualification.
Since the direct delivery method seems so simple you may wonder “what’s the catch?” Although the direct delivery method streamlines the delivery process, it comes at a cost upstream. The operational cost of CTP manufacturing, being driven on a per-patient basis, can never truly reach the commercial-level economy of scale seen in products manufactured in bulk or on a campaign basis. Additionally, this manufacturing paradigm is not suitable for acute/emergency indications, and requires a suitable CTP stability profile to support long-distance shipping if the product is not manufactured at the clinical site. Furthermore, to ensure late-Phase and commercial-scale geographic/market coverage, manufacturing may need to be transitioned to multiple regional centers, or point-of-care facilities, thus significantly increasing the cost/resource demand needed to maintain product safety, quality and consistency.
Alternately, the multi-step delivery process is by nature more complicated. Multi-step delivery CTPs requires additional clinical-site processing, QC and logistics before patient administration. The released product is shipped from the manufacturing site in a validated shipper, received by the clinical site’s qualified staff, and either transferred to the clinical site or to intermediate storage facility until administration. Prior to administration, frozen products must be thawed before being further cultured and/or manipulated at the clinical site. The manipulated product must be formulated before administration by the clinical staff.
Clearly, the multi-step delivery process creates significant risks and resource requirements downstream, which increase almost linearly with the addition of each new clinical site. The sites may need intermediate storage, processing, and formulation capacity, equipment and facilities. However, the multi-step delivery process offers significant upstream advantages. It allows for the flexibility and efficiency of CTP manufacturing on a campaign basis. Also, if the product can be frozen and/or is stable enough to be stored at the clinical site in intermediate storage, patient scheduling will not affect manufacturing. Thus the product is more suitable for acute/emergency indications and “off-the-shelf” use by allowing the clinical site to create inventory. Importantly, it also allows for the use of final formulations with shorter stability.