Pharmaceutical Commerce - July/August 2017 - 18

Clinical Operations
Pharma's cold chain is going below zero
Cellular and genetic therapies drive a 'new paradigm' for logistics
By Pharmaceutical Commerce Staff

There is true excitement in the rapid
pace of advances in cellular and genetic
therapies-Kite Pharma, for example, one
of the leaders in developing this science, has
gone from concept to Phase III trials in 27
months, and an FDA approval is possible
this year for one of its products. Dozens
of other companies are pursuing targets in
immuno-oncology, autoimmune disorders
and a variety of rare diseases. Still with the
wind at their back are a variety of stem cell
therapies that continue to advance.
While all of this is generating high
enthusiasm in R&D circles, logistics service
providers are scrambling to revise their
processes to meet the new demands of these
therapies. A "new paradigm" is evolving, in
the words of Bruce McCormick, president
of Savsu, a logistics equipment and
services provider, replacing what he calls
"cold chain 1.0," the traditional practices
associated with shipping refrigerated
(2-8°C) products.
This new paradigm is driven by two
radical changes:
* The preva lence of cr yogenic
temperatures to ship and store living
cells
* The need to make cell collection
(often from individual patients) part
of the drug-approval process, which
in turn taxes parts of the healthcare
system-hospitals, blood collection
networks, infusion centers-with
GMP responsibilities that are new to
them.
A third factor-not unique to subzero
pharma logistics, but arguably more
consequential-is that there is no turning
back once a frozen cell or biospecimen
h a s i m prop er ly t h awe d . A p oi n t of
reference: in April, Arctic ice cores stored
at the University of Alberta thawed due to
a freezer malfunction, ruining some part
of the specimens representing millions
of dollars of work and constituting an

invaluable record of climatic history. More
to the point: in 2012, 150 autopsied brains
of autism patients stored at a Harvard
biorepository thawed and were ruined; the
director called the collection "priceless."
Potentially, a process upset like these at
any point in cells going to or from patients
undergoing cellular therapy could be a last
chance at life.
"A reliable cell therapy development
strategy is imperative to ensuring [the
industry's] biopharmaceutical products,
therapeutic materials and patient biological
samples remain viable from the point of
collection to the final clinical site delivery,"
reads a statement from Fisher BioServices,
one of a number of service organizations
preparing for the new technology.

Fig. 1. Cell processing at Lonza. Credit: Lonza

It's not industry vendors alone who are
paying attention to the growing challenges.
In Europe, the European Medicines Agency
is struggling to develop a tailored regulatory
system for what it calls "advanced therapy
medicinal products" (ATMPs). There is
pushback from the PIC/S organization, a
non-governmental body focused on GMP
policies and practices; it sees problems in a
potential "loss of harmonization" between
the conventional GMP policies it follows,
and new ATMP regulatory scheme.
A research-oriented EU project is
CARAT-Chimeric Antigen Receptors
(CARs) for Advanced Therapies, which

Fig. 3. Logistics-specific elements of the NCMC roadmap,
and their developmental timelines. Credit: NCMC
18 Visit our website at www.PharmaceuticalCommerce.com July | August 2017

kicked off in January 2016 with a goal
of integrating "novel cell manufacturing
tools and enabling technologies into a new,
comprehensive platform that will facilitate
the safe, automated and cost-efficient
manufacture" of CAR-T cells. The project
has €6 million in EU funding, will last
until 2020, and is being project-managed
by Miltenyi Biotec (Bergisch Gladbach,
Germany).
In the US, besides ongoing efforts at FDA
Office of Cellular, Tissue and Gene Therapy
within the Center for Biologics Evaluation
and Research, a collaboration between the
Georgia Institute of Technology and the
Georgia Research Alliance, with support
from the National Institute of Standards
and Technology (NIST) has established a
National Cell Manufacturing Consortium
(NCMC). NCMC, in turn, has published
"A Technology Roadmap to 2025," to define
manufacturing and supply chain needs.
(Fig. 3) NCMC has a distinctly American
slant: "The cell manufacturing community
can facilitate the advancement and market
penetration of next-generation cell-based
medical products, and support the longterm growth and global competitiveness of
the US cell manufacturing industry."
In a like manner, the UK government,
through its Innovate UK program, has
supported the creation of a center of
excellence, the Cell and Gene Therapy
Catapult. Interestingly, it is headquartered
inside a London, England hospital; there
is also a manufacturing center currently
under construction in Stevenage, just north
of London. Its vision "is for the UK to be a
global leader in the development, delivery
and commercialization of cell and gene
therapy." In March, Fisher BioServices
announced that it would locate units
of its CryoHub setup there. CryoHub is
a combination of storage and logistics
handling systems, modularized so that it
can be expanded from clinical through to
commercial operations.
Meanwhile, the field is getting another
momentum boost from a handful of IT
vendors, such as the UK's TrakCel and a
GE-Mayo Clinic partnership, Vineti, both
of whom are offering IT platforms not only
to manage logistics processes, but also the
internal manufacturing steps (customized
to manufacturer requirements), and even
the reimbursement and patient follow-up
steps desirable for commercial viability of
the technology.
In the freezer
Cryogenic (technically, under -180°C;
we'll use "subzero" to cover the entire range)
processing is not new to pharma research
labs and some healthcare processes:
Biorepositories have been using liquid
nitrogen (LN2, at -179°C) for decades,
and there are various low-temperature

Fig. 2. The evo DV line of revamped
LN2 containers. Credit: Savsu

refrigeration processes and equipment for
subzero storage and shipping. Companies
like Fisher BioServices, Chart Industries,
Taylor-Wharton (now part of Worthington
Industries) and Brooks Instrument,
have been providing dewars (generally, a
metal, double-walled container), freezers
and related equipment for many years,
used in biobanks, at in-vitro fertilization
clinics and in research labs. (There is also
a substantial industry around cryogenic
air separation, liquefied natural gas, and
cryogenic application in aerospace and
electronics). Thermo Scientific, Panasonic
and others sell mechanical refrigerator/
freezers, which can reach temperatures as
low as -86°C. When products or research
materials need to be transported, a dewar
containing liquid nitrogen or dry ice is
customary.
Those dewars present two problems
for routine, commercial-scale distribution
of cellular therapy products: they can be
big and bulky (the transportable units are
generally more than 50 lbs.); and they are
prone to tipping over, which can cause LN2
vapor to leak out more rapidly, cutting into
the stable temperature range of the device.
Savsu, which has been providing reusable
containers for 2-8°C shipping for years,
is addressing both of these concerns with
the just-introduced "evo DV" line (Fig. 2),
which has redesigned dewars equipped
with what it calls a Smart Cap top (to make
the device relatively immune to tipping
complications), and in a range of sizes
that are manageable. "If you think about
a cellular therapy provided to a patient
at a hospital, you need to consider where
and how the drug is going to be warmed
prior to administration," notes Savsu's
McCormick. "If it's at bedside, you'd need
a forklift to deliver a conventional dewar
and that's not going to happen."
Another logistics problem with
conventional dewars is that it takes upwards
of 24 hours to load them with LN2 and
stabilize the container's temperature. The
DV device is said to cut this to less than an
hour. The unit can be specified for -196,


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