S U P P LY C H A I N F O R U M

An Introduction to Cold
Chain Management
Ernest Castiaux

Welcome to “Supply Chain Forum.”

Control of the supply chain is an extremely important topic in pharmaceuti-
cal and medical device manufacturing. Supply chain involves all aspects of
product manufacturing to some degree. Raw materials, intermediates, bulk
product, packaged product, auxiliary materials such as filters and lubricants,
and other myriad materials all come through the supply chain. The 2008 Chi-
na heparin incident and the global diethylene incidents attest to the challenges
and criticality of control of the supply chain and the material quality system.
STOCKBYTE/GETTY IMAGES

This feature provides a forum for compliance practitioners to share informa-

tion about topics associated with the materials quality system. The information
provided will be helpful and practical so as to enable application in actual work
situations. “Supply Chain Forum” will address successful strategies, approach-
es, and practices associated with this important aspect of pharmaceutical and
device manufacturing. We intend “Supply Chain Forum” to be a useful resource
that provides valuable information and enhances compliance performance.
Reader comments, questions, and suggestions are needed to help us fulfill
the column’s objective. Case studies illustrating actual experiences associ-
ated with supply chain management and control are most welcome. Please
send your comments and suggestions to column coordinator Ernest Castiaux
at [email protected] or journal coordinating editor Susan Haigney at
[email protected].

KEY POINTS
The following key points are discussed:
• Cold chain can be defined as the supply and distribution chain for
products that must be kept within a specific temperature range.
• Loss of control of required storage conditions may cause the product
to lose integrity, stability, or potency rendering the product ineffective.
• All storage and handling practices for cold chain shipments are
regulated per US Food and Drug Administration current good
manufacturing practices. There are special requirements govern-
ing infectious or hazardous shipments as promulgated by the US
Department of Transportation and the International Air Trans-
port Association.

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S U P P LY C H A I N F O R U M

• United States Pharmacopeia 33 chapter <1079> tion also pertains to clinical sample shipments. The
“Good Storage and Shipping Practices” also distribution of clinical kits while ensuring that they
provides guidance for handling cold chain maintain proper temperature is just as critical as
pharmaceutical products. for commercial drugs. Medical devices containing
• A structured approach to cold chain manage- a drug or biologic product in combination will also
ment is recommended including packaging fall under these sections of the CGMPs.
process and shipping validation. Transport and Additionally, there are special requirements
storage are also included in the methodology. governing infectious/hazardous shipments as
• Written procedures are mandatory. Personnel promulgated by the US Department of Transporta-
training is essential. Temperature monitoring tion (DOT) (3) and the International Air Transport
during shipping is highly critical. Association (IATA) (4). They pertain to protect-
• Case studies demonstrating deficient cold chain ing the product container from damage that could
control practices illustrate key points. result in leakage and human exposure. There are
many cold chain drug products that are governed
INTRODUCTION by these requirements.
Cold chain can be defined as the supply and distri-
bution chain for products that must be kept within USP
a specific temperature range. The shipping of a In addition to the FDA Part 211 requirements and
drug product that requires temperature controlled possible hazardous materials requirements, the
packaging is a challenge. United States Pharmacopeia (USP) 33 chapter <1079>
Environmental conditions are critical to ensure “Good Storage and Shipping Practices” provides
drug product quality. If there is a loss of control guidance for handling cold chain pharmaceutical
in the cold chain at any time during the process, a products (5). This chapter provides the require-
temperature sensitive drug may lose its integrity, ments for ensuring a product’s “identity, strength,
stability, or potency. A temperature sensitive drug quality, and purity” across the entire distribution
may become ineffective if exposed to inappropriate channel—from manufacturer to end user covering
temperatures within the supply chain. Frequently, the handling and storage of products in warehous-
this means that during storage and transport the es, during transit, and in pharmacies.
drug temperature must be held between refrigera- USP 33 <1079> “Good Storage and Shipping
tion temperatures of 2°-8° C. Practices” states that “Operational and perfor-
The number of temperature-sensitive products mance testing should be part of a formal qualifica-
is rapidly increasing. Most shipments of biologics tion protocol.” This thermal testing qualification
are transported via cold chain. The Biotechnology may be performed using a validated controlled
Industry Organization (BIO) has estimated that the temperature chamber or actual transit testing us-
average growth of temperature sensitive products ing the expected transport method and shipping
will be 15% per year and that this growth exceeds lanes (origin to destination). Certified test labs use
that of the rest of the pharmaceutical industry (1). validated environmental chambers to simulate the
ambient temperature that the package may encoun-
Regulations ter using standard profiles. These profiles simulate
All storage and handling practices for cold chain the transit of the package through the distribution
shipments are regulated per US Food and Drug Ad- channel with changes in temperature and duration.
ministration current good manufacturing practice The profiles are established by the International
(CGMP) guidelines. 21 CFR 211.142 and 21 CFR Safe Transport Association (ISTA) and cover both
150 outline the basic requirements for the storage land and air transport of various times and package
and distribution of drug products (2). This regula- configurations (6). Detailed test reports are neces-

20 Journal of GXP Compliance

 Ernest Castiaux

sary in order to demonstrate support of the regula- An investigation revealed that the qualification
tory requirements. of the insulated container and gel pack configura-
tion had been performed retrospectively using
AN APPROACH TO COLD CHAIN MANAGEMENT actual transit data from shipments that had oc-
The need for special handling, regulatory consid- curred during the winter. The temperature data
erations, and the increase in the quantity of items for the product shipments was within range and,
being shipped requires a structured approach in therefore, the configuration was qualified. When
order to ensure that the drug product moves from this shipment was made during the late spring, at a
the manufacturing point to the patient under the much higher ambient temperature, the configura-
correct environmental conditions. The packaging tion did not have enough cooling capacity to hold
process must be qualified via documented testing the temperature and lacked sufficient insulating
to ensure that the packaging configuration and capacity to prevent the conduction of external heat
transit method being used meets pre-determined to the drug product payload. Thus the validation
acceptance criteria with a high degree of assurance. lacked a formal qualification that took into account
There have been several FDA 483 citations issued all of the conditions expected during transit to
for deficient shipping validation. demonstrate that the packaging configuration met
The cold chain system consists of not only the pre-determined specifications.
packaging of the insulated container with the ap- Validation protocols for cold chain supply chains
propriate proven quantity of refrigerants, but also should require representative worst-case maximum
the transport and storage of the drug product. All temperature exposure situations. When challeng-
of these elements should be analyzed, measured, ing the transportation of products that require
understood, and qualified to ensure that the quality controlled moderate temperatures, worst-case high
of the product and patient safety is not compromised. temperatures (summer conditions) and worst-case
There must be written procedures in place that low temperatures (winter conditions) should be
describe proper handling of the drug product utilized.
when it is being stored and transported. Personnel
should know how to monitor temperatures and how Case Study Number Two
to respond to conditions when the desired tem- A shipment was prepared using a qualified con-
perature is outside the allowed range. The method tainer and an approved SOP. The configuration was
of monitoring the temperature of the drug product validated by following Center for Drug Evaluation
during storage and in transit is critical. and Research’s (CDER) General Principles of Process
The following two cold chain case studies exem- Validation (7), yet the temperature monitor indicated
plify failures in the respective firm’s approach to that the shipment never achieved a temperature of
cold chain management. less than 8°C (temperature was high). The proper
product temperature range requirement was 2°-8°C.
Case Study Number One An investigation indicated that the correct quan-
The temperature monitor for a shipment indicated, tity and type of refrigerants were used and properly
upon receipt, that the drug product exceeded 8°C configured within the insulated container. The
for the duration of the shipment. The subsequent research determined that a pallet of refrigerants (gel
examination found that the shipment was packed packs) had arrived the day prior to the day of ship-
into the correct container configuration according to ment and were placed in the cold storage area. The
the approved standard operating procedure (SOP). refrigerants had felt cold to the individual packing
All prior shipments were received with the tempera- the container, so it was not noticed that the refriger-
ture monitor indicating the product had remained ants were not thoroughly chilled and, therefore, did
within the desired 2°-8°C temperature range. not have the cooling capacity required. The root

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cause was determined to be that the refrigerants 3. DOT, Federal Hazardous Materials Transportation Law,
had not been held long enough at the desired low Office of Hazardous Materials Safety, US Department of
temperature. Transportation.
If refrigerants are not held at the desired cold 4. IATA, Packaging Instruction UN2814, 51st Edition, Danger-
temperature, either frozen or cold, for a sufficient ous Goods Regulations, International Air Transport As-
amount of time, then the outer layer of the gel may sociation, 2010.
feel cold, but the gel will not be at a uniform tem- 5. USP, USP 33, <1079> “Good Storage and Shipping Prac-
perature. When cases of refrigerants are received tices,” US Pharmacopeia.
and stored on a pallet, several days in cold or frozen 6. ISTA, Test Procedures and Standards, International Safe
storage are required to ensure complete chilling Transport Association.
throughout prior to use. 7. FDA, Guideline on General Principles of Process Validation,
Procedures describing the preparation of refriger- Center for Drug Evaluation and Research, United States
ants must be clearly specified. This includes the Food and Drug Administration, May 1987. GXP
specific temperature range at which refrigerants are
stored, and the length of time refrigerants are stored ARTICLE ACRONYM LISTING
to prepare refrigerants for actual use in shipping. CGMP Current Good Manufacturing Practice
Simply feeling the refrigerants without documented DOT US Department of Transportation
storage conditions traceability is not adequate. FDA US Food and Drug Administration
IATA International Air Transport Association
CONCLUSION SOP Standard Operating Procedure
The special requirements for handling cold chain USP United States Pharmacopeia
pharmaceutical products can be challenging.
However, they are manageable with proper prepara- ABOUT THE AUTHOR
tion, using qualified processes, and ensuring that Ernest Castiaux is a senior supply chain consultant at Phar-
matech Associates. He has more than 30 years experience in
procedures are being correctly followed.
operations and supply chain management within the pharma-
ceutical and bio-tech industries. He may be reached by e-mail at
REFERENCES [email protected].
1. White Paper, Sensitech Corporation, Beverly, Massachu-
setts.
2. Code of Federal Regulations, Title 21 Part 211 Current
Good Manufacturing Practice for Finished Pharmaceuti-
cals, Subpart H, Holding and Distribution.

22 Journal of GXP Compliance