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Good Cold Chain Management Practices for
Clinical Trial Materials/Investigational Medicinal Products
Dr. Marlene Llópiz AvilésCEO
Investigación Farmacológica y Biofarmacéutica, S.A.P.I. de C.V.
IFaB
Contents
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
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.
Introduction
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.
Introduction
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.
Importance of the Cold Chain
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.
Importance of the Cold Chain
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.”
Importance of the Cold Chain
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.)
Definition – Cold Chain
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.
Types of Cold Chain
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.
Types of Cold Chain
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).
Types of Cold Chain
Definition – Logistics and Management
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!
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.
Definition – Logistics and Management
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.
Definition - Management
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.
Definition - Management
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.
Validation
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.
Cold Change Challenges
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.
Cold Change Challenges
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.
Challenge of Clinical Trials
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
Impact of Cold Chain Failure on Clinical Trial Material
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.
Partners in Crime
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.
Partners in Crime
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.
Partners in Crime
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.
Realistic Approach
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.
Shipping, Customs Clearance and Storage
StorageAfter 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.
Shipping, Customs Clearance and Storage
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.
Shipping Systems – Take Aways
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.
Regulatory Trends
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.
Global Regulatory and Standards-Based Requirements
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.
Conclusion and Recommendations
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.
Conclusions
CEO’s Message
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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 LLOPIZCHIEF EXECUTIVE OFFICER
