This document discusses the importance of maintaining proper cold chain management for pharmaceutical products, especially clinical trial materials. It covers definitions of active and passive cold chain systems, requirements for validation of cold chain processes, challenges in global clinical trials, and the roles of service providers and regulations. Proper cold chain is crucial for ensuring product quality and safety.

1. Dr. Marlene Llópiz Avilés
CEO
Investigación Farmacológica y
Biofarmacéutica, S.A.P.I. de C.V.
IFaB

2.  Cold Chain – Definition
 Importance of Cold Chain
 Logistics and Management
 Validation
 Cold Chain Challenges
 Impact of Cold Chain Failure on Clinical Trial Material
 Service Providers and Partners
 Regulatory Trends
 Realistic Approach
 Shipping Systems
 Take-aways
 Conclusions

3.  The storage, handling, and
distribution of temperature-
sensitive drugs represent an
increasingly important
component of the global
pharmaceutical supply chain.
 Clinical trial material (CTM) or
investigational medicinal
products (IMP) are an important
part of the earliest stages of
the life science supply chain.

4.  Given the increased number
of global regulatory and
standards-based guidance
documents issued over the
past two years, members of
the pharmaceutical supply
chain are taking notice and
making changes to ensure
product quality and protect
patient safety for both the
CTMs/IMPs and commercial
products.

5.  Of the greater than $980
billion of pharmaceutical
product sold world wide in
2013 and 1 trillion dollars in
2014, over 10% or $98 billion
were biopharmaceuticals.
 There is rapid growth in the
market and research
environment in emerging
economies such as Mexico,
Brazil, China and India, leading
to a gradual migration of
economic and research
activities from Europe to these
fast-growing markets.

6.  In 2013 the Brazilian and Chinese markets
grew by 17% and 14% respectively compared to
an average market growth of 1% for the five
major European markets and 3% for the USA
market (source: IMS Health, IMS Retail Drug
Monitor, March 2014).
 In 2013 North America accounted for 41.0% of
world pharmaceutical sales compared with
27.4% for Europe. According to IMS data, 55%
of sales of new medicines launched during the
period 2009-2013 were on the US market,
compared with 23% on the European market.

7.  At the end of 2013 some 3,500
molecules were in development,
up 7% from 2012 levels.
 In addition, a promising range of
drugs are now in Phase II clinical
trials or pre-approval stage.
 Of the total pipeline, 27% of these
products are biologic in nature.”

8.  A cold chain is a temperature
controlled supply chain.
An unbroken cold chain is an
uninterrupted series of storage and
distribution activities which
maintain a given temperature
range.
It is used to help extend and ensure
the shelf life of products –
pharmaceutical products (drugs,
blood samples, tissue samples, etc.)

9. Active Cold Chain (Materials for producing cold)
 These include active thermal systems that do not use any
phase change materials (PCM) such as water/ice or dry ice.
 These systems use mechanical or electric systems powered
by an energy source, combined by thermostatic control to
maintain proper product temperatures.
 The equipment used in active cold chain is split into two
categories as follows:
◦ compression refrigerators/freezers;
◦ absorption refrigerators/freezers.

10. Absorption models
 The energy sources are: kerosene, gas, electricity (heating resistor). They
use more energy and require more maintenance. They produce less cold
and are slower. However, they are suitable for situations where
electricity is not available or reliable.
 Since the cooling circuit is closed, it is not possible to fill it with gas or
repair it if there is a leak. However, these models are very reliable.
 Models used to store vaccines are particularly well insulated and
equipped with a temperature stabilizing device, except for the kerosene
model which does not have a thermostat (the best known manufacturers
are Sibir and Electrolux). They are used extensively for the Extended
Vaccinations Programs (EVP).
 Domestic absorption models are generally insulated less well and it is
occasionally difficult to maintain a low temperature for storing vaccines,
particularly when the external temperature is high (higher than 32°C).
 The efficiency of the models that run on oil depends on the quality of
the fuel. Decanting and filtering are often required. A kit is available to
modify certain burners, in order to improve operating efficiency, despite
oil of inferior quality.

11.  Passive Cold Chain (Shipping/storage materials)
 These include passive thermal systems that commonly use phase change materials (PCM) such
as water/ice or dry ice. These shipping systems are the most basic and cost effective. Some of
the basic systems in use are as follows:
◦ freezers for province, county and sometimes at the township level;
◦ refrigerators and, in some areas, the new water-jacket refrigerators for province, county and township
levels.
Some villages do not have access to a refrigerator for vaccine storage and therefore use:
◦ cold/cool Boxes at all levels for transporting vaccines;
◦ vaccine carriers to store vaccines during the immunization session or round;
◦ isothermal packaging/control materials like paper to wrap the vaccines up when using a vaccine carrier;
◦ ice packs or ice, as a last resort, to keep the vaccines at a temperature between +2°C and 8°C;
 a thermometer to measure the temperature inside the vaccine refrigerator and cold boxes; and
 a chart to record the day and time of the temperature of the vaccine refrigerator. The chart
should be used to record the temperature two times a day (morning and night).

12. Cold chain management includes all of the means used to
ensure a constant temperature (between +2°C and +8°C) for a
product that is not heat stable (such as vaccines, serums,
tests, etc.), from the time it is manufactured until the time it is
used.
It involves the equipment and people needed to keep vaccines
at the correct temperature (between +2°C to +8°C) during
transport and storage from the time they are manufactured up
until they are administered.
The cold chain must never be broken!

13.  The Logistics staff must be trained to both
use and manage these materials.
 They must acquire knowledge about the cold
chain, must develop thorough work
techniques, specifically with respect to
maintenance, and must be stable in order to
ensure better follow-up.
 Without training, the program will be
seriously compromised and put at risk.

14.  Cold chains need to be evaluated and controlled:
◦ Carriers and logistics providers can assist shippers. These providers have the technical
ability to link with airlines for real time status, generate web-based export documentation
and provide electronic tracking.
◦ The use of refrigerator trucks, refrigerator cars, reefer ships, reefer containers, and
refrigerated warehouses is common.
◦ Shipment in insulated shipping containers or other specialised packaging are often used.
◦ Temperature data loggers tags help monitor the temperature history of the truck,
warehouse, etc. and the temperature history of the product being shipped.They also can
help determine the remaining shelf life.
 Documentation is critical. Each step of the custody chain needs to follow
established protocols and to maintain proper records.
 Customs delays occur due to inaccurate or incomplete customs paperwork, so
basic guidelines for creating a commercial invoice should be followed to ensure
the proper verbiage, number of copies, and other details.

15.  Cold chain management has two categories:
◦ managing equipment and,
◦ managing people.
 Evaluations of existing means revealed that some countries needed to improve their systems of vaccines
management. Although there were many positive aspects to the functioning of the cold chain, the following
weaknesses were observed:
◦ frequent breakdowns in cold chain (sometimes for a long time) because of the lack of fuel, spare parts and
back-up energy source;
◦ lack of planning for maintenance and cold chain rehabilitation;
◦ incorrect use of the Vaccines Vial Monitor (VVM) as a management tool; and
◦ lack of planning for emergencies resulting in organizations not having effective cold chain systems during
responses.
 These problems slow down improvement in routine vaccination services and hinder efforts to eliminate and
eradicate disease. To solve these problems, it is necessary to:
◦ identify problems in the cold chain and their causes;
◦ undertake specific actions to remove these causes; and
strengthen management systems to prevent recurrence of the same or similar problems.

16.  A cold chain can be managed by a quality management system. It
should be analyzed, measured, controlled, documented,
and validated.
 The overall approach to validation of a distribution process is by
building more and more qualifications on top of each other to get to
a validated state.
 This is done by executing a Component Qualification on the
packaging components, an Operational Qualification to demonstrate
that the process performs at the operational extremes and finally a
Performance Qualification that demonstrates that what happens in
the real world is within the limits of what was demonstrated in the
Operational Qualification limits.

17.  Clinical trials are being run on a global scale and in
some cases in markets with less than ideal logistics
infrastructure.
 The complex clinical supply chain creates a
challenging distribution environment because of
shipping large volumes of refrigerated patient kits
worldwide while maintaining and documenting
appropriate environmental conditions.
 Given the great number of clinical sites, there is
increased complexity for maintaining product quality
and mitigating the risk of thermal excursions.

18.  The globalization of clinical trials
is driving programs in more
remote locations.
 This has fueled the need for
personnel to work with specialty
couriers, contracted depots, and
shipper manufacturers to improve
the performance of the supply
chain and build a more robust
clinical trial distribution process.
 Specialty service providers have
responded to changing market
needs.

19.  Product availability for test
shipments.
 Planning time to test shipping
containers.
 Short product life cycle - Is all
this really necessary?
 Urgency always associated with
trial start up.
 Shipping channels - many one
off or infrequent shipments.
 Shipping quantities vary
significantly.
 Clinical Trials require one system
to meet all needs.

20.  Temperature excursions during the storage,
handling, or distribution of temperature sensitive
clinical trial material pose significant safety and
financial risks.
 Cold chain failure may lead to 4 key risks:
1. The patient could be administered an unsafe
product
2. A lack of compliance with global regulatory and
standards-based requirements can increase
liability
3. Thermal variability can lead to inconsistency of
results between and within batches
4. The shipment can be rejected by the Quality
department therefore leading to costly delays –
increasing the complexity of trial management

21.  Many clinical trials include the shipping,
distribution, and delivery of temperature sensitive
articles whether it is the study drug, the clinical
specimens, or the ancillary supplies.
 As such, cold chain pre-qualified packaging plays a
critical role in safely and effectively transporting
the temperature-sensitive items shipped in small
amounts in high frequency to the clinics.
 Vendors have to prove their packaging and
insulated container/refrigerant systems provide
adequate protection for temperature-sensitive
items.
 As supply chains grow more complex product life
cycles decrease and regulatory authorities become
increasingly concerned about product integrity
during delivery.

22.  The pharmaceutical industry has
progressed from the point of
shipping being an afterthought to
exact controls on
materials/product in-transit and
proof of custody at the destination.
 The pharmaceutical
developer/manufacturer is paying
attention to temperature and/or
physical conditions which may
affect the good storage and good
distribution practices (GSP/GDP) of
their materials/products.

23.  Documentation and control for the
storage, handling, and distribution of
temperature-sensitive goods is most
appropriately addressed through a
sound shipping qualification.
 The cold/frozen chain Shipping
Qualification is a process involving
integration of the shipping system, the
product and the transportation
medium/route.
 The partners in this process: the
packaging designer/manufacturers,
testing labs, product development
scientist, corporate owners of the
product, carriers and shipper vendors,
mutually work together to produce the
best system for the entire cycle of
shipping and storage.

24.  When we consider shipping
Cold Chain products we must
start from the premise that
things may go wrong.
 Because of the nature of the
product this means that the
risks are extensive.
 It is our job to minimize this
risk and reduce the effect of
those things that can go wrong.

25.  Shipping
This involves:
◦ Cool Box – Vaccine Carrier
◦ Isothermal Packaging
◦ Control Materials
◦ Monitoring Means
All shipping documents for vaccine shipments should be sent in advance of
arrival of shipment.
The number of days will be determined by the destination country rules.
This requirement has been established to facilitate the pre-customs
formalities for clearance of vaccines to ensure prompt clearance of the heat
or cold sensitive items upon arrival.
Some countries have an exceptional early release procedure pending
document processing during emergencies.


26.  Storage
After arrival vaccines are cleared and
immediately offloaded from the
aircraft and directly loaded onto
trucks for further transportation to
the cold storage facility.
Delivery of vaccines at the cold
storage is strictly monitored to
ensure maintenance of the cold chain
in an appropriate manner.
Some countries have special
requirements for vaccines. There is
therefore no standard clearing
process.

27.  Utilize the expertise and service of
the solution providers.
 Understand exactly how the
systems works.
 Choosing the right system for your
drug and study requirements is key.
 Climate concerns - country of
origin, country of destination, and
time of the year.
 Qualify or Validate? - monitor
temperature?
 Air temperature versus product
temperature.

28. Four primary regulatory trends have been
identified:
1.Accountability for the cold chain ultimately
resides with the Manufacturer but
responsibility is shared across all supply
chain partners.
2.Increased oversight, management, and
control of environmental conditions across
the entire supply chain.
3.Increased importance of temperature
control and monitoring.
4.Heightened priority of patient safety – with
focus on product quality.

29.  Remaining compliant with
global regulatory requirements
for the storage, handling, and
distribution of clinical trial
materials can be a daunting
task.
 While the requirements tend to
be similar for both
investigational drugs and
finished goods, it is imperative
to first understand the specific
requirements for the countries
in which a trial will occur.

30.  The growth in the bio-pharmaceutical market
combined with the complexity of the clinical
supply chain and global regulatory environment
require that all supply chain partners are aware
of appropriate regulations, local requirements,
pharmacopeial standards, and industry best
practices related to the storage, handling and
distribution of temperature-sensitive products.
 Regulatory guidance and inspectional trends
demonstrate a focus on Good Cold Chain
Management Practices.
 All partners should have the distinct common
goal in terms of ensuring that each patient and
site is supplied with the correct medication at
the right time and in the right condition.

31.  Be Informed about the shipping process - your
knowledge will help protect your product.
 Question every aspect of the supply chain, don’t
assume your contractors will protect your product
as a matter of course.
 Plan time into your project for adequate testing
and analysis of the supply chain.
 Work to minimize the risk to your product at every
step of the process.

32. 32
IFaB has grown tremendously over the last
decade and will continue to do so over the
next few years.
Much of our success has been and is
attributed to our team’s experience,
commitment and desire to positively
contribute towards our society, clients, and
stakeholders by upholding the highest
standards in the pharmaceutical industry.
Going forward, the delivery on our
promises, goals and visions will continue to
play an instrumental role in achieving
further success so that together we can
continue on the road to achieving
sustainable and continued growth.
MARLENE LLOPIZ
CHIEF EXECUTIVE
OFFICER