COLD CHAINQUALIFICATIONFIVE QUESTIONSYOU MUST ASK
WHEN SHIPPINGBIOLOGICS

Introduction

3

Five questions you must ask

3

Can you achieve end-to-end cold chain visibility?

4

Has that biological therapy been handled properly?

6What is that pre-qualified shipper pre-qualified for?

9

What about temperature monitoring?

11

How does your shipping system stack up
over the entire transit process?

12

Additional resources

15

About us152

Introduction“Cold Chain” refers to theundisrupted series of logisticalactivities (packaging, shipping,storage, distribution, handling) for
products that must be maintained
within a given temperature
range. And as those of us in thebiopharmaceutical industry know
well, maintaining cold chain is criticalto the integrity of biologically derived
therapeutic products.
The Centers for Disease Control and Prevention(CDC) has estimated that $300 million worth ofvaccines alone are destroyed each year due toimproper storage and distribution; the numbers
for other bio-therapeutics are unknown. The scary
aspect of that figure is that this includes only
the product that was known or suspected to becompromised. Think of the health care implications
for administering adulterated medications topatients! The consequences can go well beyond
economic losses. Failure at some point in the cold
chain can potentially have dire consequences.
Most of us in the biopharmaceutical industry would
agree that patient safety and regulatory complianceare the key drivers within cold chain logisticalsystems. Organizations recognize the growing
need for control of the entire cold chain. The everchanging global scenario requires highly efficient
processes as a backbone to accommodate thegrowing needs of organizations.

Five questions
you must ask$300 million
vaccines destroyed

Improper storage& distribution

1

Can you achieve
end-to-end cold
chain visibility?

2

Has that biologicaltherapy beenhandled properly?

3What is that
pre-qualified shipper
pre-qualified for?

4

What abouttemperaturemonitoring?

5

How does yourshipping system stack
up over the entire
transit process?
3Can you achieve end-to-end cold chain visibility?
The advent of global commerce has made the distance between
countries appear smaller due to the successful amalgamation ofscience, process and technologies but the physical separation between
geographical entities remains. This is where the enhanced focus onprocess, end-to-end cold chain visibility and efficient traceability
systems come into play.
The good news is that cold chain-related technologies are evolving.
Tracking systems, temperature monitoring devices, courier capabilities,
and regulations are all changing to accommodate both the increasing
numbers of bio-therapeutic products moving through the supply chain
and the increasingly stringent criteria for temperature compliance.
How can manufacturers provide end-to-end cold chain visibility
and thus satisfy both patient safety and regulatory requirements?

4Can you achieve end-to-end cold chain visibility? (Continued)
The Fisher Clinical Services team helps ourcustomers answer this question with “solutionoriented engineering.” We qualify the entire shipping
process at a temperature range from X°C to Y°C,
for Z hours along the transit lanes. Solution-orientedengineering begins with the components usedwithin the cold chain and extends through theentire shipping/transit lane. An assessment of thematerials, suppliers, shipping lanes and methods
are part of our process mapping.

Manufacturing/bioproduction

The goal is to develop cost effective solutions
that are end-user friendly and also ensure
performance, established through documented
testing. We recognize that cold chains are complex
and we work toward reducing this complexity
for our clients by incorporating compliancewith cold chain requirements into the testing
protocols, pack-outs, shipping instructions, quality
agreements, and training that we provide.

Clinic site/
patient

Cold chain
management
Biobanks/
cold storage

In short, end-to-end cold chain visibility is achievedby meshing together the technologies and carriercapabilities currently available in the market bymapping them to the supply chain components.
Shipper Qualification

7.50

2.50

Global transportation & distribution

0.00

18:36:00

Temperature ˚C

5.50

Transit Time
03:24:00

12:12:00

21:00:00

05:48:00

14:36:00

5

Has that biological therapy been handled properly?
The Biologically derived
therapies have varying
temperature requirements,
ranging from cryogenic,
ultra-low, frozen,
and refrigerated.
Maintaining refrigerated
temperatures may be
the most challenging.

smaller in magnitude than losses
from temperatures that are toocold. However, exposure to freezing
temperatures rapidly diminishes
the potency of most vaccines, andaccording to the CDC1, the potencyof a dose of vaccine can be reduced
even though there are no visible
signs of freezing. For this reason,
maintenance of correct temperatureof vaccines is especially critical,
as well as challenging, be it duringstorage or distribution.

The majority of vaccines require
storage and distribution underrefrigeration (2°C to 8°C), andexposure to both warmer andcolder temperatures may affecttheir potency. The negative effectsof warming above 8°C are usuallymore gradual, predictable, andBiologics that must be kept frozen,
whether at around -20°C or -80°C,
are typically shipped in dry ice, andthese shippers and pack-outs arewell defined in the industry. The more
recent challenge is the shipping anddistribution of cell- based therapies
at cryogenic temperatures (<-150°C)
in liquid nitrogen.

2°C to 8°C-20°C to -80°C-150°C to -196°C

1. Galazka, A.; Milstien, J. & Zaffran, M. (1998). Thermostability of Vaccines. World Health Organization, Global
Programme for Vaccines and Immunization, Geneva, Switzerland: Publication No. WHO/GPV/98.07.

6

Has that biological therapy been handled properly? (Continued)
The most challenging issue in thedistribution of cold chain materials
is the clinical site. For instance, anassessment of 721 primary care
physician offices showed that an
estimated 17 to 37 percent of thestaff members responsible formanaging the vaccine had exposed
their vaccine inventory to improperconditions2,3, including refrigeratorsthat were set too warm or too cold,
placing vaccine in the refrigerator
door, placing food in the same unit,
leaving inventory on a table duringgroup vaccination events, andreturning unused doses tothe refrigerator.

“Patient cell therapy administration” at clinic/hospital-196˚CManaging cell-based therapies at theclinical site is especially challenging,as these products must often bethawed and administered using a
specific protocol, and clinical site
staff must be trained in handling theshipper as well as the therapy.

2. Gazmararian, J.A.; Oster, N.V.; & Green, D.C. et al.
(2002). Vaccine stor- age practices in primary care
physician offices. American Journal of Pre- ventiveMedicine, 23(4):246–53.
3. Bell, K.N.; Hogue, C.J.; Manning, C. & Kendal, A.P.
(2001). Risk factors for improper vaccine storage
and handling in private provider offices. Pedi- atrics
1:107:E100.

Biologic manufacturer / biologic management facility
7

Has that biological therapy been handled properly? (Continued)
The Fisher Clinical Services team has
years of experience in qualifying thesedry shippers and is also working insideclinical sites to provide the training,infrastructure, and implement bestpractices in handling bio-therapeutics
all the way to a patient’s bedside.
Ensuring the correct handling of
biological therapies and creating a fullytransparent distribution system means
extending the cold chain not to theclinical site door, but to the patient.

Exposure
to ambient
temperature

Vaccinemanufactured
packaged, must
be maintainedat 2˚C-8˚C

Stored inrefrigerator
at packaging
facility

Transferred
to a shipping
container fortransport

Summer temps
90˚C, Wintertemps, -5˚C

Tarmac temp -5˚C, to90oC, Cruising altitude
temps 0F to -20˚C

Loaded onto atruck, 0-? hours

Loaded onto
plane, 0-? hours

Summer temps
90˚C, Wintertemps, -5˚CTransferred
to a container
for transport

Loaded onto
a truck

Stored inrefrigerator
at packaging
facility

Transferred toa refrigerator
at a wholesaler
distribution
center

Unloaded
to a truck

Loaded onto
a truck

Transferredfrom transport
container toclinical siterefrigerator(unvalidated?)

Removed fromclinical siterefrigerator
and moved tovaccination
location

Summer temps
90˚C, Wintertemps, -5˚CTransferredfrom transport
container toretail distribution
centerrefrigerator

Put into a
container fortransport

Time limit between removingfrom refrigeration andadministration to patient

Unused vaccine
returned torefrigerator?

Vaccine waits
on tray/cart until
administered

8What is that pre-qualified shipper pre-qualified for?
The cold chain distribution process is an extension of
the good manufacturing practice (GMP) environmentthat all drugs and biological products are required
to adhere, and is enforced by the Food and Drug
Administration (FDA) and other similar regulatory
bodies in the US and overseas.
Most manufacturers and distributors of vaccine andother biological therapeutics turn to pre-qualifiedshippers, and there are many choices available.
We do not manufacture shippers, but we test andqualify shippers and pack-outs for our clients, andthese units do not always perform as specified.
There are a number of reasons why shippers may
not perform to the manufacturer’s specification, andbefore purchasing a pre-qualified shipper, you needto investigate how the testing was conducted.

For instance, shippers can fail because of:•Inadequate stressing: The environmental stressing profile standards
typically employed to qualify these shippers come from ISTA (International Safe Transit Association), which are not representative of mosttransit conditions and should only be used as a starting point for more
rigorous and true-to-life temperature simulations.

•Issues with pre-qualification: We have found instances where thetesting profile selected helped to ensure a successful run, either throughlack of temperature extremes or prolonging the duration of complianceby alternating the heat and cold stress to keep the package within thetargeted temperature range.

•Orientation was not maintained: Shippers can fail because they wereturned on their side, in spite of signage to keep the item right side up.
Pre- qualification should include orientation testing in order to demonstrate
the shipper’s ability to maintain temperature regardless of the orientation.

•Damage: Shippers must be strong enough to ensure the security of thepayload under worst-case handling conditions. Pre-qualification testingshould capture drop-testing and related cold chain applicable stresses.

•Variations in Payload: Compare the payload tested as part of theshipper qualification and relate it to your own payload requirements. The
introduction of previously untested sizes or amounts of payload can alterperformance, and pre-qualification should include variations in the numberof units and the overall volume of the contents.

9What is that pre-qualified shipper pre-qualified for? (Continued)
Be sure to thoroughly review the qualification report. Since there could besome bias in the in-house testing of a product line, you want to be sure thatthe testing was sound, rigorous, and comprehensive in scope and quality.
Ask the vendor to supply you with a certificate of conformance.
In addition to providing a high degree of patient safety, a well- qualified
shipper and pack-out leads to cost savings by eliminating the ongoing resupply of adulterated material, and expediting FDA approval of BMLA, IND,and NDA submissions.

If shipping costs are of a concern then you may want to perform a costanalysis to determine whether a pre-qualified shipper with a tare weightof 36 lbs, for instance, is sufficient or overkill for your needs. We typicallydesign and qualify packaging configurations at half that weight including theproduct payload. We can qualify shippers and pack-outs that will allow more
economical distribution modes, such as shipping ground or two-day rather
than overnight.

Shipper qualification
Develop protocol
for rigorous testingand qualification:
Assess productspecifications andclient shipping/
distribution needs

Select Shipper,
refrigerant
and packing
components andpack-out design,
data logger
probe placement• Min/max payload• Drop testing• Worst-casethermal conditions

Testing performed
according toapproved protocol

Final report to client• Vibration testing• Send to client for
approval

10What about temperature monitoring?
The common adage that proper
temperature monitoring is the key
to accurate cold chain management
is true in this context, but notnecessarily all encompassing.
The need for real time data andzuse of multiple temperature
gathering platforms has created
its own challenges. Most of theentities in the supply chain are
working toward simpler, moremanageable ways of determining
temperature compliance.

Even with a qualified package, on-board dataloggers should be employed to provide time/
temperature information during transit. It is nearly
impossible to test for and protect against allcontingencies, like extended shipping delays
and handling. However, data loggers have theirlimitations. Loggers capture a single location inside
the shipper and cannot account for the entire cavity
temperature. If the pack-out was not done properly,
the difference between the temperature readingat the location of the probe and temperatures
elsewhere in the cavity can be upwards of 7°C.
As mentioned above, temperature monitoring isevolving. Dry shippers have temperature monitors
built into the lid, while for vaccine, bulky dataloggers are being replaced by thermo-chromic
labels in short Vaccine Vial Monitors (VVM).
These provide an instant answer to the ultimate
question of whether or not an individual dose wasmaintained at the correct temperature at all times.

Temperature ˚C-120

DRY SHIPPER TEMPERATURE LOG

-140

-160

-180

-200
00:00
23SEP

12:00

00:00
24SEP

12:00

00:00

12:00

25SEP

Temperature of dry shipper with cell therapeutics-001 from Maryland, USA to UK

00:00
26SEP

12:00

00:00
27 SEP

12:00

00:00

12:00

28 SEP

Transit Time11

How does your shipping system stack up
over the entire transit process?
Due diligence in cold chain means
not simply using a qualified shipper,
but qualifying the shipper to perform
within the conditions of the entire
shipping process, whether overnight
to the Midwest, or four days to theFar East.
Commissioning a transit study to qualify yourshipping system will lower costs in a number ofways. These include dramatically reducing lossof material and the repetitive testing of suspectmaterial. A transit study will allow you to identify
when a more expensive shipper combined with aless expensive transport option, such as two-day
ground vs. overnight, is more cost effective than aless expensive shipper, combined with occasionaluse of a specialized courier service (such as
FedEx White Glove service).
Choosing the right shipping system begins with:

2-Day ground vs overnight

1. Begin with a thoroughshipping lane analysis

1. a thorough shipping lane analysis,
2. determining critical control points, and3. performing a transit study—testing the shipper
and configuration to the highest degree ofperformance during transit.

3. Perform atransit study

Shippingsystem

2. Determine criticalcontrol points

12How does your shipping system stack up over the entire transit process? (Continued)
What does shipping lane analysis entail? This iswhere we identify critical elements such as thepackage carriers operating within the shipping
route and the environmental/ temperature trends
affecting the geographical locations along theroute. Critical control points include but are
not limited to the shipper, coolant, pack-out,size of your payload, the stability and allowabletemperature range of the materials, and storage
and handling requirements.
Once the shipping lane analysis is completed,and critical control points identified, we designa transit study. When performing a transit study
for a biologic, we devise multiple pack-out
configurations and test them to see which best
meets your needs with regard to performance andcost. For instance, we test a payload of a single
dose up to, for example, 100 doses so that theend solution will perform reliably regardless of thenumber of doses placed in the shipper.

Shipping lane
analysis

critical
control points
identified

critical
control points
identified

critical
control points
identified

critical
control points
identified
Sample caption

Transit study

13How does your shipping system stack up over the entire transit process? (Continued)
The transit study is performed in triplicate
with mock material to verify how the validated
configuration works in live conditions, byshipping to sites deemed worst case in terms ofenvironment (e.g., Minneapolis, Minnesota for cold
and Tucson, Arizona, for heat). Transit studies test
for temperature, relative your distribution center
humidity, CO2 exposure, preferred couriers andcourier transport methods, minimum and maximum
payloads, distribution center conditions, recipient
capabilities, and any other applicable variables.
We deliver qualified pack-outs and can provide
materials for training across all your distribution
centers, so that your process is standardized for ahigher degree of product integrity throughout theentire cold chain.
If you have asked and answered these fivequestions, and are using a rigorously designed
and qualified shipping system, then the data will
provide an objective affirmation that you performed
due diligence and significantly advanced thecommercial success of your product.

A transit study tests for...
• Temperature• Relative humidity• CO2 exposure• Preferred couriers / courier transport methods• Minimum and maximum payloads• Distribution center conditions• Recipient capabilities• Any other applicable variableYour
distribution
centerYour
distribution
centerYour
distribution
center14

Additional resources
As a worldwide provider of ultra cold chain management of biologics and cell therapeutics, we can assist
companies looking to validate cold storage equipment, qualify pack-outs and shippers, and conduct cold
chain transit studies.

Pack-out and shipper qualification

Cold storage equipment validation

Lane qualification and transit studies15

+1 919 226 3200 • thermofisher.com/patheon • pharmaservices@thermofisher.com© 2021 Thermo Fisher Scientific Inc. All rights reserved.
Published 09/21