while developing procedures to ensure consistent quality.
BY RONNDA L. BARTEL
Over the past five years, there has been a jump in the
number of cell therapy products commercially distributed
by companies in the U.S., with eight cell
therapy products receiving approval since 2009. Once such
therapies are approved for the market, however, biopharmaceutical
companies face new challenges as they develop the
infrastructure to scale up the manufacture of larger quantities
of cell products while maintaining high standards of
quality control.
Companies advancing cell therapies at smaller scales
already face multiple challenges in executing the safe, reliable,
and consistent manufacture of a cell-based product. Crosscontamination
due to the mixing of cell samples, as well as
cell damage inflicted during freezing or other procedures, can
jeopardize the purity and efficiency of the process. Improper
labeling and record keeping could lead to a loss of patient
identity in the development of autologous treatments, which
use patient-derived cells. To reduce these risks, researchers
often use closed-system technology, in which the cells are not
exposed to the environment from the time they are put into
the system until they are delivered to the patient. This enables
large quantities of cells to be cultured at the same time; minimizes
cell manipulation to reduce the chance of contamination;
and automates the work as much as possible to curtail
human error and variability.
At Durham, North Carolina–based Argos Therapeutics,
for example, scientists have designed an automated manufacturing
process using functionally closed disposables to
meet their autologous-cell processing needs while ensuring
consistency and the ability to meet the demands of large
markets. The system involves three separate stand-alone
units that isolate and amplify RNA from a patient’s disease
sample; program dendritic cells to target disease antigens;
and perform various cellular and plasma processing steps
to generate the product. In contrast, traditional cell therapy
processes include many labor-intensive and nonintegrated
steps—including centrifugation, incubation, media addition,
cell selection, and cell washing—which require highly
skilled operators. Argos’s automated system can be rapidly
scaled up to handle large patient numbers, allowing the
company to carry out production at higher throughput levels
and with a lower overall cost of materials.
Single-use disposable bioreactors are commonly used
in a closed system to protect cell products while they are
being expanded. Using automated processes can help minimize
the risk of operator error while also ensuring sterility,
increasing productivity, and enhancing consistency of cell
batches. Robotic handling of cells in a sterile environment
has also been shown to reduce the level of particulates and
contaminants found in manually cultured cells.
Use of advanced tracking technologies can be applied to
bioreactors to further safeguard cells against a break in the
chain of identity of a patient sample, particularly when used
for autologous cells. At Aastrom Biosciences, we designed
and implemented software called Autolotrack, which automatically
assigns a lot number to each patient’s cell sample
and creates a production schedule that can be edited by the
team. This software organizes and tracks data about each
bioreactor during every phase of the production process,
and all instruments used in manufacturing automatically
feed back into the system, so that the production team can
easily see how far a cell sample has advanced in the manufacturing
process.
Preparing cells for patients
Typically, cells harvested from culture are not suitable for
direct patient administration. The cells must be processed
to remove serum and other culture reagents and to achieve
a product volume suitable for therapeutic delivery. These
steps can be time-consuming and can significantly increase
the risk of error, contamination, and excessive holding
times, as well as the potential for cell loss and decreased
viability. Autologous cell therapies pose additional challenges
for large-scale production because individual doses
must be produced for each patient.
One common step in traditional approaches to cell harvesting
is the washing away of residual culture reagents.
Bioreactors that both drain away culture medium and rinse
cells to remove residues before they are harvested eliminate
two cell-transfer steps and lead to lower rates of cell damage
and loss. Perfusion bioreactors, which continuously replace
the culture media and remove waste products, can similarly
enable cells to be harvested and purified quickly, reducing
the time dedicated to processing.
The examples listed above are just a sampling of the range
of advanced capabilities in computerization, automation, and
process integration now available to help companies drive
down costs and increase production volume and quality of
cell therapies. The application of technologies to reduce the
number of manufacturing steps or streamline overall production
should be considered at all phases of research, but especially
as a company advances to late-stage clinical trials and
prepares for commercialization. Success requires continually
identifying and assessing viable advances in technology
that can be applied to any phase of cell therapy production
and incorporating such advances at the earliest opportunity to
improve performance and reduce risk.
Ronnda L. Bartel is the chief scientific officer at Aastrom
Biosciences, a Michigan-based biotechnology company focused
on patient-specific cell therapy applications.
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