Pharmaceutical Commerce - July/August 2017 - 19

Clinical Operations
-80, and 2-8°C operating temperatures.
Another player that has targeted cellular
therapies specifically is Cryoport, which has
offered a tailored LN2 shipping container
for a number of years. The company has
expanded its offerings to include the
SmartPak II condition-monitoring system.
Smartpak starts with a communicationsenabled (Wi-Fi or cellular) datalogger,
which transmits data through the
Cryoportal, a website where Cryoport or its
clients can monitor a shipment. Cryoport
works with a variety of carriers, but also
has arrangements at multiple airports to
replenish LN2 if necessary, with dedicated
depots at Rotterdam, Singapore and Irvine,
CA, its headquarters.
Mark Sawicki, chief commercial officer
at the company, says that a number of
clients are now requesting Cryoport to
collocate a shipping center at their sites; the
service would entail preparing containers
for shipment, packaging the product and
managing the logistics processes to ensure
safe delivery. He also touts the company's
customized shipping containers: "In some
cases, we take a commercial package and
make as many as 50 modifications to it,
providing better locking mechanisms, our
datalogging and condition-monitoring
technology, and other improvements,"
he says.
T h e co m p a ny 's m o s t re ce n t
announcement is CryoStork Next Flight
Out, a branded service specifically for
IVF centers (Cryoport says that as many
as 400 IVF clinics make use of Cryoport
services). CryoStork will handle sperm,
eggs, embryos and reproductive health
tissues, according to the company, with
global delivery.
Another service, about to be
announced, expands Cryoport's offerings
to the 2-8°C refrigerative world. Sawicki
says that it is typical, in applications such
as CAR-T therapy with autologous T-cells
from individual patients, to collect the
T-cells via apheresis, and to ship that blood
component under 2-8°C conditions. The
return trip of the treated cells is performed
cryogenically. "Adding the 2-8°C service
enables us to provide a closed-loop service
to clients," he says. Cryoport has partnered
with Pelican BioThermal to make use of the
latter's Credo line of cold-chain containers,
which feature vacuum insulated panels and
specialized gels as a source of cold.
Pelican BioThermal has developed a
range of phase-change materials (PCMs)
that can be effective in ranges as low as
-40C. There are products, such as vials
with rubber stoppers, that need to be kept
within a lower and upper limit, even in the
subzero range; Pelican's PCM expertise
enables them to meet this need. The
main goal is to sidestep the use of dry ice,
which has limitations in air freight (since
it's regulated as a "dangerous good"). Bill
Mayer, director of research there, also
makes the point that better insulation
(such as the vacuum panels that Pelican
uses) can also make PCMs v iable in

subzero regimes relative to dry ice.
Tricky scheduling
Sawicki and others in the field point
out the extraordinary demands cellular and
related therapies put on traditional pharma
logistics practices. Autologous therapies
(using the patient's own cells) must, of
course, be tracked precisely to and from
the patient; on the other hand, allogeneic
therapies (which includes a number of stem
cell approaches) are a "one to many" process
where one source of cells might treat
multiple patients-but the same tracking
details need to be preserved. Some proposed
cancer treatments require both the patient's
T-cells and biopsied tumor tissue. A further
complication is that the re-infusion of the
cells in the patient is dependent, in part,
on the health and well-being of the patient;
while the extraction and initial processing
might proceed rapidly, once the treated cells

Order & Scheduling

Single Platform

secrets) dimethyl sulfoxide (DMSO), which
has been a common cryopreservation agent
for many years. Many researchers have
"home brew" preservatives with little in the
way of rigorous analysis or consistency-
problems that BioLife is seeking to address
with its products.
"Cryopreservatives minimize damage
from ice cr ystals forming during the
freezing phase; when these cells are
thawed, they have near immediate need
for pH buffering, free radical scavenging
and providing a source of energy for the
cells," explains Mike Rice, CEO of BioLife.
BioLife's products are regulated essentially
as excipients, he says; and because they
have been written into more than 100
clinical protocols they could eventually
become part of formal drug applications.
From that, BioLife expects to generate
revenue as it supplies the preservatives as
essential ingredients.

(and cell proliferation), re-infusion, and all
the logistical steps in between, don't fit any
of these IT platforms. Business managers
looking at eventual commercialization
have realized that the need for monitoring
outcomes of individual patients-and
how that could become an integral part
of a value-based reimbursement for the
therapy-should also be digitized.
TrakCel, which has been operating
since 2012, has coined the term "Cellular
O rc h e s t r a t i o n P l a t f o r m" ( C O P ) t o
characterize this broad foundation. "There
are many stakeholders to bring together
in a cellular therapy project; and some
of those stakeholders follow lab-based
protocols, others, good manufacturing
practices (GMPs), and yet others in healthrelated procedures," notes Martin Lamb,
EVP at the Cardiff, Wales firm. "All of this
has to come together in a tight scheduling






Digital and
configurable GMP

Real-time tracking &

Coordinated resources
management &

Predictable and
automated transport

Automatic triggering of
reimbursement and
time to revenue

Fig. 4. A representation of operational steps whose data is managed by a comprehensive IT system. Adapted from Veniti.

are cryogenically stored, the re-infusion can
be scheduled at an appropriate time.
There is considerable variation in the
sub-zero temperatures called for in clinical
protocols: -40, -60, -79 (the transition
point of dry ice) and -196° all show up in
cellular therapy literature. Much of this
appears to come simply from traditional
lab practices to the preferred, modern
modality-LN2 at -196°C, where nearly
all cellular activity ceases. Most logistics
processes depend on maintaining one
set of standard conditions; the variety
of temperatures involved here is one of
the reasons that specialized life sciences
logistics services are desirable.
"There's considerable debate about
s u i t a b l e t e m p e r a t u r e r a n g e s ," s ay s
Savsu's McCormick. "A big part of this is
the transition from clinical practices to
commercial-level activity," he says.
Cryogenic freezing and thawing are
performed gradually to prevent shocks
to the living cells; but whether slow or
fast, cryogenics usually calls for use of a
cr yopreservative to minimize freezethaw damage. BioLife Solutions is one
company that has taken a proprietary
position on cryopreservation, with two
products, CryoStor (for the -70 to -196°C
regime) and HypoThermosol (for 2-8°C).
The products contain (among other
components, some of which are trade

Rice says that cell viability, a critical
measure of a therapy's potential efficacy,
varies all over the lot in clinical trials being
conducted currently; a rough measure
is that 20-50% of cells lose viability
during freeze-thaw transitions. Using
cryopreservatives like BioLife's can cut that
to below 20%.
BioLife and Savsu formed a joint
venture in 2015, biologistex, to handle
the courier-based or freight-forwarding
operations of their clients. The service
makes use of Savsu's evo Cold Chain 2.0
platform for data collection, monitoring
and quality control.
IT advances
Arguably, the clearest indicat ion
of how different cellular therapies are
shaping up, relative to conventional drug
development, is that there wasn't a readymade IT platform to manage production
and distribution processes. Researchers
are accustomed to working with clinical
trial management systems (CTMS) and
laborator y information management
systems (LIMS); plant managers have used
manufacturing execution systems (MES) or
extensions of enterprise resource planning
(ERP) for years. But the scope of cellular
therapy, involving steps at a healthcare
facility (apheresis or other cell extraction),
advanced genetic manipulation of cells

TrakCel's product is cloud-based, and
while it encompasses a variety of specific
functions (such as data collection during
logistics processes), it is also built with
interfaces to enable data transfer from lab,
manufacturing and other IT systems. For a
client, the company maps out a customized
flowchart of necessary processes, combined
w ith the necessar y interfaces. Some
risk-based contingency planning is also
enabled; for example, a patient might
require preparatory treatments before a
cell-extraction process is carried out;
ensuring that these steps are carried out is
accounted for in the system.
TrakCel looks like it's about to get
some head-to-head competition from a
joint venture between General Electric
Healthcare and the Mayo Clinic, Vineti
(which changed its name from Vitruvian at
the beginning of the year). Like TrakCel's
a p p ro a ch , Vi n e t i a l s o e n co m p a s s e s
healthcare-facility steps, manufacturing
and reimbursement (se e Fig . 4). In
some yet-to-be-determined fashion,
Vineti will also tap into GE's storehouse
of manufacturing knowledge, as well
as resources tied to other parts of GE
Healthcare, and Mayo Clinic's experience
in biomarker development, cell therapy
processes and outcomes.

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