Cold Chain Management for Clinical Trial Materials

By M Z Khaleeli, Commercial Director, Y M Shantala, QA Manager at Pharmaleaf India (P) Limited


Cold Chain Management (CCM) can be defined as the network of facilities and distribution options that performs the usual functions of a standard supply chain cycle, but with temperature and humidity control throughout the supply chain stages and entities.

The Cold chain supply has a position of criticality within the rapidly evolving research and development segment of the global economy, specifically in the field of medicine and significantly acute within the vaccine niche.

Clinical trial material (CTM) or investigational medicinal products (IMP) are probably the most critical components in the drug discovery chain of events and therefore their flawless delivery is vital.

Given the increased number of global regulatory and standards-based guidance documents issued over the past two years, members within the pharmaceutical supply chain are waking up and taking notice, resulting in far reaching changes aimed to ensure product quality is impeccably maintained thereby committing to protect patient safety during the CTMs/IMPs and commercial products.

Several medicinal products, chemicals, live samples cannot be moved unless they are within an ambient environment cold chain ensures that to them!

Research has ventured beyond the unchartered and the unknown and human derivative such as vaccines, insulin, biotech products and products derived from blood or plasma, fall within the ambit of being high risk.

High risk from the fact that they become redundant by freezing or at elevated temperatures. Some products, for example, chloramphenicol eye drops, may be labelled as requiring storage between 2 and 8C and a short deviation from this temperature range presents less of a danger to users.

Packaging is critical, the tolerance is minute to ensure that the stipulated temperatures are maintained spot on throughout the journey and the medicines are transported in accordance with their labelling requirements to prevent compromising their quality.

Clinical trials demand fast and stress-free delivery with seemingly irrational but short lead times, that are depicted by the progress of the trial and patient recruitment.

Consequently air transport has gained a pivotal role in as much as the drug delivery process and the world of pharma copeia in general.

Clinical research organizations (CRO), university labs, scientific institutions in general that use specific pathogen free animals in the research also rely on air transport to a large extent.

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 the safe and effective delivery of the temperature-sensitive chemical entity shipped in small quantities but in high frequency to the clinics/sites.

Vendors are required to validate 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 have become increasingly concerned about product integrity during delivery.

Challenges in the Cold Supply Chain:

Clinical trials are being run on a global scale and in some cases in markets with less thanideal 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.

General challenges of cold storage are:

  • Preserve the adequate Storage & Handling Conditions (temperature) throughout the Cold Supply Chain.
  • Document the Storage Conditions (temperature) throughout the Cold Supply Chain.
  • Maintain the Product Safety throughout the Supply Chain (temperature, counterfeiting).
Impact of Cold Chain Failure on Clinical Trial Material

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 with in batches
  4. The shipment can be rejected by the Quality department therefore leading to costly delays – increasing the complexity of trial management
Cold Chain: regulations & guidelines:

Food & Drug Administration (US)-21CFR 203.32 “Prescription Drug Marketing – Drug sample storage and handling requirements

World Health Organization (WHO) – International packaging and shipping of vaccines. Health Canada (HPFB Inspectorate) – Guide 069, Guidelines for temperature Control of Drug Product during Storage and Transportation; 2005.

Health Distribution Management Association (HDMA) -Guidelines for Managing Cold Chain & Temperature Sensitive Products (2009).

ICH Q1 (R2) – Stability testing of new drug substance and product.

With eight of the top 10 pharmaceutical products expected to need cold chain storage in 2016, regulators are stepping up their requirements. Yet, ensuring regulatory compliance across a global network of facilities, particularly in emerging markets, remains a challenge.

Better information is being seen as the key to ensuring regulatory compliance, using data logging technology to ensure they meet the tightened shipping requirements being introduced by not just the EU and the United States, but also emerging markets.


Environmental conditions such as temperature, relative humidity, and light, should be monitored in all receiving, transferring, storing and holding areas.

  • Should also apply onto temperature-controlled transports (and ideally on to all transports)
  • Monitoring system should enable temperature (excursion) alarming, day and night
  • Data should be stored securely. Temperature data should be available and check out regularly
  • Alarms used to monitor the temperatures of storage enclosures should be checked out regularly
  • Instruments used to supervise and control the temperature of products in stock should be calibrated at least once a year and should be placed in a preventive maintenance program
  • Measuring instruments in place (Monitoring) should be qualified. Monitoring software should be secured and compliant

The transportation and delivery of temperature-controlled pharmaceutical products is a fast-growing part of the overall healthcare logistics industry. There are three reasons for this:
Cold chain management and logistic system is required globally, so that every individual can be benefited from vaccines of assured quality, delivered in the right amount at the right time through efficient logistics, proper vaccine management, and a well-functioning cold chain system.

  • Growth (in type and volume) of pharmaceutical products.
    • Globalisation of pharmaceutical logistics as global trade rises, both for active ingredients being delivered to manufacturing sites, and finished products being delivered to more points on the globe.
    • A more detailed, and more rigorous, regulatory framework, with tighter specifications on “Good Distribution Practices” (GDPs) and more rigorous enforcement of industry standards.

Cold chain management and logistic system is required globally, so that every individual can be benefited from vaccines of assured quality, delivered in the right amount at the right time through efficient logistics, proper vaccine management, and a well-functioning cold chain system.

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 demonstratea 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.

PharmaLeaf India Private Limited, is an International Regulatory, GXP Audit/Compliance and Technical Project Management Consultancy Service supporting Biopharma, Devices and Life Science industry across product development, commercialization and life cycle management advancing global market access.

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