APR September/October 2020 - 130

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BIOPHARMACEUTICAL PROCESSING

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Scaling Autologous T-Cell Therapy Manufacturing
John Lunger
Chief Patient Supply Officer
Adaptimmune

Cell Therapy, including engineered T-cells, is becoming a more
familiar feature in the medical world, especially as a treatment option
for patients with late-stage cancer. One of the challenges faced by
companies is how to deliver these living therapies rapidly and safely
to patients. The importance of manufacturing and supply chain to
meet this challenge cannot be underestimated. With autologous cell
therapies, in particular, traditional means of scaling manufacturing
such as producing larger batches and building drug product inventory
do not apply and new ways to meet patient needs must be developed.
Adaptimmune is currently developing and manufacturing autologous
cell therapies for clinical trials at numerous sites in North America
and Europe for a variety of solid tumor types. With autologous
cell therapies, companies must consider the patient journey in a
much more integrated way since it is a "make-to-order, one batch,
one patient" approach. Essentially, a patient's white blood cells are
collected in a clinical setting and sent to a centralized manufacturing
facility where the T-cells are isolated and transduced with viral vectors
to express the gene of interest. The cells are then expanded over a
period of days, cryopreserved, and returned to the hospital where the
cells are thawed and the patient lymphodepleted prior to the infusion
of the engineered T-cells. These unique aspects of autologous cell
therapy manufacturing must be considered.

Considerations for Manufacturing
The successful manufacturing and supply of an autologous T-cell
product is driven by three key parameters:
1) Time for a patient cells to begin manufacturing - At Adaptimmune,
this target is seven days from a patient becoming eligible for the
treatment to providing a slot for apheresis and cryopreservation
of their cells at the manufacturing site. Many activities must be
considered to achieve this target: e.g., insurance approval, logistics/
travel support, flexible manufacturing scheduling to accommodate
both the patient and the treatment center, etc.

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2) Time for manufacturing - This is the process turnaround time,
which is often referred to as "Vein to Vein" or "Needle to Needle" time.
It starts with the apheresis process to collect the patient's T-cells,
includes the cryopreservation of this starting material, subsequent
thawing and manufacturing, quality testing and release, shipment to
the clinical site, lymphodepletion, and ultimately ends with infusion.
Adaptimmune is targeting 30 days of "vein to vein" time (inclusive of
7 day lymphodepletion). Close coordination with the clinical site to
schedule the patient treatment, as well as the efficient and effective
operational execution of the manufacturing process, contribute to
reducing this time.
3) The robustness and success rate of the manufacturing process
- Typically, autologous T-cell manufacturers run one batch for each
patient. If there is a problem with the batch for any reason (e.g., a
product contamination, a facility issue, a batch that fails to meet final
specifications, or a supply issue with any material) the entire process
may need to be redone. This may be unacceptable to the patient and
the company, so the company may choose to invest in redundant
manufacturing sites, multiple runs per patient to have a "backup"
supply ready, or other strategies that ensure the risk of not supplying
a patient is minimized.
A "perfect order," therefore, would be one where the patient's cells
quickly get into the manufacturing schedule, the turnaround time
for manufacturing is fast, and manufacturing of the product is
successful. If a company desires a 100% service level, where every
patient experiences a perfect order, they may need to invest in very
high capacity, multiple manufacturing sites, and make investments
in process technology to ensure the process has no manufacturing
risk. In this case, the investment required to scale while achieving this
very high service level may be unreachable. Aiming for a high, but not
perfect, service level may lead to different decisions on where to invest
to achieve the goals for each of these three key parameters. As a result,
it is important that a company determines the desired service level
before defining and implementing a "scale up" strategy.
The manufacturing and supply strategies needed to meet the
targeted service level fall into two primary categories. The first is

| September/October 2020

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APR September/October 2020

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