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Basics of Cold Chain Monitoring

Find out more on how to manage your temperature-controlled supply chain. Get a general introduction into Cold Chain Monitoring and discover information on topics like Stability Budget, Mean Kinetic Temperature and more!

Basics of Cold Chain Monitoring

Find out more on how to manage your temperature-controlled supply chain. Get a general introduction into Cold Chain Monitoring and discover information on topics like Stability Budget, Mean Kinetic Temperature and more!

01

Definition Cold Chain Monitoring

02

History of Cold Chain Monitoring

03

Pharma Cold Chain vs. Food Cold Chain

04

The Clinical Trials Cold Chain

05

Stability Budget Explained

06

Mean Kinetic Temperature explained

What is the Definition of Cold Chain Monitoring?

The spread of cold storage facilities, temperature controlled trucks, freezers and refrigerators in the second half of the 20th century have nurtured the trend to frozen and fresh food. While in past centuries, food preservation was one of the major challenges, today it is a given that we eat fresh food every day and everywhere – in restaurants, at home but even in airplanes and remote locations. The series of actions and processes in a multi-step supply chain using specialized equipment to keep an unbroken cool chain is today commonly known as “cold chain” (or cool chain).

Cold Chain is an Industry

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Ultimately, Cold Chain Management has become an industry with many different players:

  • Freight forwarding companies (3PL or 4PL), or Logistics Service Provider (LSP), coordinating dedicated trucking suppliers with temperature controlled trucks and air cargo services. 
  • Container leasing companies renting out temperature controlled air cargo or ocean freight containers
  • Packaging companies providing custom designed transport boxes using Phase Change Material (PCM) and Vacuum Insulated Panels (VIP)
  • Solution providers for temperature monitoring using electronic temperature sensors, software and database solutions

Cold Chain is a Technology

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Cold Chain is also a technology using various different physical principles to maintain and document defined temperature conditions along the supply chain:

  • Compressor heating and cooling
  • Phase Change Materials (PCM)
  • Insulation and vacuum insulation
  • Electronic temperature measurement
  • Wireless data transmission
  • Database and business process management software

Cold Chain is a Process

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Cold Chain Management is also a process since a series of tasks must be performed to manufacture, store, transport and monitor temperature sensitive products along the entire supply chain. Thus, every single step in the supply chain requires adherence to a defined process – often called Standard Operating Procedures (SOP). They include:

  • Using the right equipment for packaging and monitoring
  • Transporting products in time, avoid exposure to extreme conditions
  • Following the defined release process at destination

Cold Chain is a Science

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Today Cold Chain is a science, understanding the chemical and biological processes driving the degradation of perishable products. While pharmaceutical products are well protected in primary packages and only sensitive to temperature, food stuff is much more sensitive to all kinds of external influences:

  • Food: Impact of bacteria, gases, temperature and humidity on degradation
  • Pharmaceuticals: Impact of time and temperature on the product potency (Stability Budget)
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The History of Cold Chain Monitoring

"Cold Chain Monitoring” has its roots in the food and beer brewing industry. Until the early 20th century, people harvested ice blocks to keep foodstuff cool during transport and storage. The invention of the “General Electric Monitor top refrigerator” in 1930 was not only the kick-start for refrigerators and freezers but ultimately also the beginning of temperature controlled trucks and transport containers.

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From Cold Chain Monitoring to Temperature Controlled Logistics

Although the principle of vaccination was detected already in 1796 and the first insulin was purified in 1922, today most pharmaceutical products still are chemical products, which have been considered “non-sensitive to temperature” until just a few years back. Therefore, while the food cold chain has grown big already in the 1960’s and 1970’s, the pharma cold chain started focussing on this topic in the 1990’s with fast growing markets in insulin, blood products and vaccines. Since those products are all “biological products” (substance derived from a living organism), the main focus of the (pharma) cold chain industry was technologies and processes for keeping product “cold” or refrigerated at 2-8°C. The main term used was therefore cold chain technologies and cold chain management.

Later in 2013, the new version of the EU-GDP guidelines changed the scope to include all pharmaceutical products and medical devices carrying a label condition; referred to as “room temperature products” or “Controlled Room Temperature (CRT)” with label conditions of 2-25°C or 15-25°C. Since then, the term used has shifted from “Cold Chain Logistics” to “Temperature Controlled Logistics” – in particular in specialized expert discussions.  

The Difference Between Food Cold Chain and
Pharma Cold Chain Monitoring

What are the commonalities and differences between the food and the pharma cold chain? Although both product types are sensitive to temperature, there are significant differences:

  • Food products are often “open” and exposed to bacteria, chemicals and humidity. They are therefore sensitive to various environmental parameters. Shelf-life of food products vary widely from a few days to many years depending on the product and the temperature range (frozen, fresh or controlled). Therefore, the lengths and complexity of the supply chain has a great variance. Most food products are in fact much more sensitive to temperature than pharmaceuticals and must therefore have shorter supply chains. For example, freshly cut roses are produced in India and must reach the consumer in Europe within 7 days before they fade and lose their commercial value. They are highly sensitive to temperature, start fading fast at temperature above 10°C and cannot be frozen at all.
  • Pharmaceutical products are “packaged” (at least as commercial product) and are therefore protected from bacteria, chemicals and humidity. Most commercial pharmaceutical products have shelf-lives of 18 – 36 months and they are often less sensitive to temperature compared to food products. The big challenge with most pharmaceutical product is that the quality and level of degradation is not visible to the patient: you cannot see or smell if a vaccine has been frozen and has lost its potency (or might even be harmful).

The Food Cold Chain is about preserving the commercial value.
The Pharma Cold Chain is about protecting patient safety.

The Clinical Trials Cold Chain

To prepare for an approval process, research investigations (clinical trials) are performed in which human beings volunteer to test new treatments. The purpose of clinical trials is to prove efficiency of an investigational medicinal product (IMP) and detect side effects. Clinical Trials are typically organized in different phases and involve more people, the further down the process.

CCM_Clinical Trials_Stability Budget

What Products Need Approval by Health Authorities?

  • Consumer healthcare products (e.g. skin care, functional food)
  • Over-the-counter medicine (OTC) (e.g. Cough syrup, vitamins, pain ointment)
  • Pharmaceutical products (e.g. Cardiovascular medicine, psychotropic drugs)
  • Biopharmaceuticals (or biologics) (e.g. Insulin, Cancer drugs)
  • Personalized medicine (e.g. Modern cancer therapies (Herzeptin))
  • Medical devices including (bio)pharmaceuticals (e.g. Coated stents, coated hip joint)
  • Vaccines (e.g. Polio vaccine, Ebola vaccine)
  • Blood and Blood Products (e.g. Fresh blood, blood plasma)

Are Investigational Medicinal Products (IMP’s) More Sensitive to Temperature?

Physically, drug substances don’t change their sensitivity to temperature. However, as a drug substance moves through clinical phases, researchers perform additional accelerated stability studies. These studies provide the information needed to define the product’s stability budget.

The longer a product is on the market, the more stability budget is available. Therefore, although IMP’s shipped in clinical trials are in reality not more sensitive to temperature, they typically have stricter shipment and storage requirements.

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Stability Budget – The Key to Patient Safety in Cold Chain

Most pharmaceutical products, in particular biopharmaceuticals, products change as they age. However, they are considered to be stable as long as their characteristics, or potency, remains within the specifications. The number of days that a product remains stable at the recommended storage or label condition is called “shelf life”. Typical label conditions of packaged pharmaceutical products, which are either used in hospital or sold over the counter, are 2-8°C, 15-25°C and sometimes 2-25°C. The experimental protocols used for data collection serving as the basis for estimation of shelf life are called “stability tests”.

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Example: Results from accelerated stability testing – potency of a biopharmaceutical at different temperatures and duration.

Who Owns the Stability Budget?

The owner of the stability budget clearly is the Marketing Authorization Holder (MAH) – the company that applies for registration of a product in a certain market. Within this company, the natural owner is the quality department. From a document or data perspective, the stability budget is a defined set of data under strict version control, which is typically documented in a pdf document, sometimes also stored in dedicated software.

How Often Does a Stability Budget Change?

Stability budgets and expiry dates can increase over time - but only in very early phase I clinical trials for drug substances which are really new. Already in phase II clinical trials, stability budgets and expiry dates are typically set and stable for the time of the clinical trial and also later in commercial use. In later (commercial) phases, it is very unlikely to change the stability budget or the expiry date. Expiry dates must be available in clear text on each kit as well as on the carton. So for example, each vial needs to be labelled as well as the carton containing the vials.

How to Conduct a Stability Test

Stability Tests can be performed increasing the time and temperature margin a pharmaceutical product can be exposed to. During stability testing, the active ingredient is exposed to temperatures outside the label condition for a certain time and afterwards tested to prove its safety and potency. There are two types of stability testing:

  • In real-time stability testing, a product is stored at recommended storage conditions and monitored until it fails the specification. This can take very long – and time is of essence in product development.
  • In accelerated stability tests, the product is stored at increased temperatures. After defined time periods, the degradation is assessed and compared with the prediction of the known relationship between acceleration factor “temperature” and the degradation rate (Arrhenius equation).

Is the Stability Budget Shared? What are Typical Transport Conditions?

The stability budget is owned by the Marketing Authorization Holder (MAH). They typically do not easily share the stability data with logistics providers (3PL, forwarders, wholesale) since they need to safeguard the product integrity up until the patient. Therefore, they purchase dedicated temperature controlled services from their Logistics Service Providers (LSP), which are typically "Refrigerated" or "Room Temperature" promising that they will never exceed conditions like 2-8°C or 15-25°C. Coming up with rules that are more comprehensive (like for example "2-8°C but it can have 10h excursions up to 20°C") would be much too complex for LSPs. However, if manufacturers control the stability budget and use it in an efficient way (e.g. build the limits into the acceptance criteria of the data logger and/or the database), their lives and workloads could be easier and save significant cost. 

How is a Stability Budget and the Expiry Date Predicted?

When developing new drug substances, the time to market is paramount. Therefore, besides performing real-time stability tests, pharmaceutical companies in most cases choose to also perform accelerated stability studies and predict the expiry date by the Arrhenius equation. During such accelerated stability studies, the various batches of the drug substance are exposed to defined elevated temperatures (e.g. 25°C, 30°C, 40°C) and after defined time slots (e.g. 6 days, 28 days, 3 months, 12 months, 24 months 36 months) the potency of the product is measured. So often during phase 1 in clinical studies, only a limited stability budget is available and later in the process more hours are added to the budget. This step-by-step approach is shortening the time to market compared to performing real-time stability tests only. As a "side result", the stability budget is created.

An example: A biopharmaceutical company has found a new drug substance and they are ready to perform clinical studies on patients. The product has a liquid form and is stored refrigerated.

Example: Early Phase Stability Study - Accelerated stability study of 3 months.

Tabelle1

Different lots or batches of the substance are exposed to different temperatures. After different periods (6 days, 28 days, 3 months), a test is performed if >80% of active ingredient is still potent. As a result of this early phase, a first version of the stability budget is issued (in above case 8-25°C for 3 months, 25-40°C for 28 days). Since after 3 months more than 98% of the potent is still there, a first (conservative) version of the expiry date is calculated using the Arrhenius equation and defined to be 6 months.

Example: Later Phase Stability Study - The Accelerated stability study is extended to 24 months.

Tabelle2

The same substances are still exposed to the same temperatures and tested after different periods to determine if the ingredient is still potent more than 80%. As a result, a new version of the stability budget is issued (in above case 8-25°C for 12 months and still 25-40°C for 28 days). After 24 months, still 91% of the potency is available if stored at 5°C. Based on stress tests and other safety and market considerations, the final expiry date is defined to be 24 months.

Mean Kinetic Temperature (MKT)

Mean Kinetic Temperature (MKT) is used in the pharmaceutical industry to evaluate the effect of fluctuating temperature over time on the efficiency and safety of a biopharmaceutical product. The MKT formula goes back to the Swedish scientist Svante August Arrhenius (1859 – 1927) who was born in Uppsala.

MKT is a weighted average temperature (one single number) which summarizes (or simulates) the thermal challenge a drug substance (or drug product) would experience over a range various temperatures for a defined time period. The mean kinetic temperature is by definition higher than the arithmetic average temperature since it takes into consideration the Arrhenius equation:

Mean Kinetic Temperature

 

The higher (and longer) a drug product is exposed to high temperatures, the faster it decomposes.

What Can Mean Kinetic Temperature be Used for?

MKT can be used for different purposes:

  • Stability Study: MKT can be used to simulate (predict) the decomposition of a drug substance during a stability study.
  • Storage: In regulatory documents, there is a wide consensus, that MKT can be used to assess temperature excursions outside label condition of refrigerated and room temperature products.
  • Transport: Some guidance documents also suggest using MKT in transport environments – but be aware of limitations.

Mean Kinetic Temperature Rules:

  • Mainly use MKT for storage – the longer the time period, the more informative is MKT
  • Only use MKT in set-ups where you have temperature control (refrigerated or room temperature)
  • MKT does not work for frozen product
  • Use MKT to evaluate temperature excursions (but not to compensate earlier excursions)
  • MKT is just another indicator to evaluate temperature excursions. Mind freeze/thaw cycles (which MKT is not taking into consideration)

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