Why is Cool Chain so important in Clinical Trials?
Clinical Trials are most commonly performed to analyse new drugs, medical devices, biologics, psychological therapies or other interventions. They are a requirement before the relevant national authority approves marketing of the drug or device. There are several different types of Clinical Trial:
- Prevention Trials – testing new approaches that doctors believe to lower the risk of developing a disease
- Screening Trials – testing the best was to find a condition/disease in it early stages
- Diagnostic Trials – testing better procedures for existing diseases or conditions
- Treatment Trials – testing new medicines or new approaches to surgery/therapy
- Quality of Life Trials – ways to improve comfort and Quality of Life for patients (e.g. incontinence drugs)
- Compassionate Use Trials – treatment option for patients suffering from a disease for which no satisfactory, authorised alternative therapy exists
There are four phases to a Clinical Trial involving new drugs, and each phase of the drug development process is managed as a separate Clinical Trial. These phases are usually known as:
- Phase I Studies
- Phase II Trials
- Phase III Trials
- Phase IV Trials
Phase I Studies
This is the first stage of testing in humans. Normally, a small (20-100) group of healthy volunteers will be selected. Phase I Studies most often include healthy volunteers, however, there are some circumstances when real patients are used. Cases where patients who have terminal cancer or HIV and lack other treatment options (Compassionate Use Trials).
Phase II Trials
In these, the potential drug is tested in around 20 to 300 volunteer patients suffering from whatever condition the drug is to potentially treat. They are designed to show whether the drug is safe in the specific patient population and to look for signs that it might be effective.
Phase III Trials
If Phase II trials are successful, then the potential drug will undergo Phase III trials, which are widespread multicenter trials on at least 300 to 3000 patients in clinics to test the efficiency of the product. They are usually randomised and double blind (this is where neither the patients or the researcher know who’s being given the active drug).
Once Phase III trials are completed, the drug is filed with the relevant country authority for review. In the UK, this is the Medicines and Healthcare products Regulatory Agency (MHRA); in the US, it is the Food and Drug Administration (FDA); in Australia it is the Therapeutic Goods Administration (TGA) and in Japan, the Ministry of Health and Welfare. Some Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions.
Phase IV Trials
After the drug is launched, further Phase IV studies are carried out to monitor possible adverse reactions or other responses when large numbers of patients begin using the drug.
During the ‘drug pipeline’ or ‘drug discovery process’ drugs may also go through a ‘pre-clinical studies phase’.
This stage of the drug development pipeline is a study to test a drug, procedure or other medicinal treatment. They involve in vitro and in vivo experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. The aim is to collect data in support of safety. Preclinical studies are required before clinical trials start.
So, as you can see when coordinating shipments from a Clinical Trial the need for Cool Chain assistance is heightened.
It is understood that drugs that are intended to be used on humans, must be tested on humans to ensure they are safe for use. It is due to this fact that quite often the samples taken are blood or tissue samples, and need to be sent to the research laboratories quickly, efficiently and undamaged. It is well known that the different stages of Clinical Trials can take place in many different global locations. This makes the ‘need for speed’ and temperature control even more vital.
For example, the drug could be created in a University in Poland, administered to the patient in a hospital or clinic in Africa and the sample be sent to a Research Laboratory in India or China. This is a very long chain of transportation where the drugs and samples will experience a variety of different climates. Appropriate Cool Chain packaging measures must be in place to ensure the shipment arrives at optimum viability.
We have all read the articles and seen the trend emerging – where countries such as India, China, Russia and more recently many African countries are becoming hotspots for conducting Clinical Trials. Just last month in this publication there was much conversation about Australia and the Caribbean being the ‘Ones to Watch’ in Clinical Studies.
The popularity of these countries only amplifies how ‘international’ a Clinical Trial can be. And its this ‘internationality’ that is really beginning to test the Cool Chain. Samples need to be sent quickly, efficiently and carefully to ensure they arrive at their destinations in a usable state, i.e. in perfect condition
How do I assemble and use a pellet dry ice Shipping System?
Dry ice is available in solid blocks or as individual pellets of a few centimetres length. Pellet dry ice is most convenient for assembling dry ice shipping systems as it is easy to pour and naturally fills available space. Dry ice block would need to be prepared to the correct size to fit.
A dry ice shipping system for moving frozen product starts with an insulated box. The product being shipped is normally loaded into the box first. A temperature monitor may also be included and should be started at the correct time.
Now the dry ice needs to be loaded. Caution must be exercised when handling dry ice and all relevant Health & Safety procedures must be followed. Dry ice is very cold (around -80°C) so there is a risk of cold burns. It also gives off gaseous carbon dioxide – an asphyxiant – so must only be stored and used in appropriately ventilated and supervised areas.
Dry ice pellets are usually simply poured on top of the product and temperature monitor. Guidance from the packaging manufacturer will determine how much dry ice is to be added. The shipping system should have been correctly validated to meet pharmaceutical documentation needs.
Pellets usually come in 10kg bags – it’s worth bearing in mind that these bags will likely have a little more than 10kg in them when they arrive from the supplier but will lose weight in storage over time as carbon dioxide gas is given off. Thus a bag of dry ice used several days after delivery could have significantly less than 10kg inside. Thus weights may need to be checked against the expected bag contents.
Once the desired quantity of dry ice has been loaded in the lid can be sealed. It’s important at this time to check pellets aren’t stuck in the seal of the lid – this could keep the lid ajar and allow a warm draft into the internal of the box.
The sealed dry ice system is now ready to go off into the specialist logistics network.
What are the Pros and Cons of shipping with Dry Ice?
It is commonplace to use dry ice for shipping frozen pharmaceutical industry product. Under this process, dry ice is usually filled into an insulated container in which the product is being shipped. All methods have their pros and cons and it is worth considering them for shipping product this way.
On the plus side, dry ice shipping is a reliable method of maintaining temperature. Temperature fluctuations are always seen in data logger traces (with dry ice shipments there are temperature variations above and below the level of dry ice. A temperature monitor will pick these up as it moves about inside the box in transit). The energy stored within the sublimation phase change is relatively high so, providing a sensible amount of dry ice is loaded into the shipper when assembled, temperature excursions are usually less frequent than when shipping under Cool chain temperature ranges.
However, there are precautions to consider when shipping under dry ice. Solid dry ice is very cold, subliming at -78.5°C in the package. Because it gives off carbon dioxide gas, it is also an asphyxiant. Thus there are significant Health & Safety issues when storing, handling and using dry ice.
Secondly, when shipping it, dry ice is covered by Dangerous Goods legislation under Class 9 (Miscellaneous Hazardous Materials). The outer box must be appropriately labelled and the weight of dry ice inside the box declared.
What are the differences between Qualifying and Validating Cool Chain Packaging?
The pharmaceutical industry has rigorous procedures for demonstrating that equipment and processes give the necessary level of performance quality.
For example, when a pharmaceutical company installs a new piece of manufacturing equipment, the equipment undergoes a validation process consisting of the manufacture of a number of batches of product. All settings and inputs on the machinery and raw material are controlled and recorded. The manufactured product is then assessed to ensure it matches the required specification.
This validation process is more difficult to manage when it comes to using Cool Chain packaging. This is because the environment the packaging operates in (i.e. when being shipped from dispatch point to the consignee) is uncontrollable. While the manufacturing equipment described above can have its working environment and its settings controlled, Cool Chain packaging experiences a wide range of environments in warehouses, vehicles, aircraft and customs. Temperatures of these locations couldn’t be specified in a test setting to enable a robust validation of all likely circumstances to be conducted.
With Cool Chain packaging, a qualification is performed on the packaging before its approval for use. This is conducted in an environmental test chamber by the packaging supplier. The test chamber is set up to run through a predetermined temperature profile that simulates what likely temperatures the packaging will experience in transit. Because this testing is conducted in simulated conditions rather than the real world, this is a qualification rather than a validation.
At Biocair, we’ve selected a range of correctly qualified Cool Chain shipping systems for use in our shipments for clients. Biocair manage the preparation of the shipping system and take it on-site to our client to load in the product. The sealed box is then taken away for distribution and delivery.
Why does my Cool Chain shipping system take up so much more volume than the product that it is shipping?
Cool Chain packaging usually consists of a thick-walled insulated outer shipper, an arrangement of cool packs inside and a volume inside this arrangement in which the shipped product can be loaded. Usually, this volume of payload space is only a fraction of the total volume of the outer shipper.
For somebody who is unfamiliar with Cool Chain packaging and shipping, it may at first be a surprise how much the shipped volume increases when a product or sample is placed inside the specialist packaging. In some ways, this is just the “nature of the beast”. It is simply the laws of physics that determine this combined with the specification requirements the user has on the shipping system (e.g. the validation duration required, the external temperatures the system is designed to work under, etc).
Some technologies enable smaller the outer volume to be smaller – for example the choice of insulation material in the outer shipper. Using materials with a higher insulative capability enables thinner walls to be used in the outer box. Ultimately, the choice of system will be a balance between cost, external volume and performance.
At Biocair, we have access to a wide range of Cool Chain shipping options from a number of specialist packaging suppliers. By working with the detail of our clients’ requirements, we can determine the most appropriate packaging for their shipments.
What external temperature environments is my shipment likely to experience in transit?
Depending on how far, where and when your shipment is travelling will directly relate to the external temperature environments it will encounter.
It has been widely documented that the average temperature of the Earth is between 13°C and 15°C, but this – being an average – isn’t always the case.
Shipments are generally shipped in controlled environments along most shipping routes, so shouldn’t experience any extremities in temperature change. When in transit, they are often where people are too – in warehouses, planes and cargo-holds etc. Therefore, the temperature will not vary much from what a human would experience. Some warehouses are temperature controlled, but this isn’t always guaranteed.
You can better prepare for a shipment for transit by collecting sufficient knowledge on the route with a shipping lane trial. This is where a temperature data logger is sent on the same route the shipment will be taking, to record the external temperatures the shipment will potentially experience.
Boxes will experience ‘normal hot & cold temperatures’ (+30°C and -20°C) in transit, but the specially chosen insulation inside the box should prevent the product from being effected.
There will always be odd scenarios, things you don’t expect – so its just a case of being prepared for those odd excursions.
Quite often shipments are going in all directions, so it becomes difficult to maintain a ‘shipping lane’ or route. In these cases, we would obtain an average temperature for a certain region, e.g. Europe. You can even go as far as to divide the temperature by season and look for a temperature that will work under a range of environments.
How can a Specialist Logistics Company become part of a Cool Chain?
When working with a ‘Cool Chain’ you will need a logistics provider that is capable of moving the shipment in line with Cool Chain requirements. Our involvement can be as little or as much as you like. If you would prefer to pack the product yourself, a logistics provider could pick up the pre-packed box and move it to a destination in one of our temperature-controlled vans.
Alternatively, the logistics provider can be involved to a much higher level. We can come onsite with a predesigned packaging system to suit the exact needs of your shipment, then pack and fully prepare your product for its journey. Once the product has reached its destination, the temperature monitor should be sent back to the logistics provider so we can download the data and send your report to you.
What are the insulation materials used in Temperature Controlled Shipping Systems?
There are many different types of insulation that can be used to control the temperature of a product in transit. The most common of these are:
- Expanded Polystyrene (EPS)
- Expanded Polypropylene (EPP)
- Extruded Polystyrene (XPS)
- Vacuum Insulation Panels (VIP)
Expanded Polystyrene (EPS)
This tends to be the most popular choice, because it is relatively inexpensive and has a high capacity for insulation. Its low cost is reflected in its quality, as it can be easily damaged in transit making it very difficult to reuse. But it is a sustainable product as it can easily be recycled into useful household products or back into bead material to make more EPS.
Expanded Polypropylene (EPP)
This engineered plastic foam material is remarkably both durable and lightweight. Although recyclable, reusable and far more robust – EPP doesn’t hold the same insulating capacity as EPS.
Extruded Polystyrene (XPS)
XPS is trademarked as Styrofoam, but it is not to be confused with other polystyrene products, as it has become a generic term used by America to describe all polystyrene forms.
This is perhaps the strongest packaging system – manufactured through a plastic extrusion system process, leaving a product that is almost 100% closed cell. Very easy to cut and shape and resistant to water.
The XPS system is one of the only systems that requires the user to assemble the panels together themselves. This leaves more room for potential heat-leakage.
Vacuum Insulation Panels (VIP)
These are evacuated panels of Silica, contained within a foil outer membrane.
A VIP system uses the insulating effects of a vacuum to produce a thermal resistance level that is much higher than conventional insulation products. Their insulation properties are seven times as effective as the expanded polystyrene used in typical shipping systems.
They are more expensive than conventional systems but you can end up with a smaller box – therefore saving on shipping costs.
Active and Passive Temperature Controlled Shipping Solutions?
There are two types of temperature controlled packaging; active and passive. What’s the difference? The short answer to that is as follows:
An active system controls the heating or cooling of a product by either an electronic or a chemical performance. Thermostats will indicate that the systems needs to either cool down or heat up to keep the product at the Customer’s desired temperature, in response to outside weather conditions.
A passive system is less intelligent. Here, a product is put into an insulated box with enough gel packs or cool packs to last its mapped journey. The difference here, is that if the box enters unusual circumstances (e.g. a random heat wave) then the gel packs/cool packs can’t react like an active system could. There are no thermostats, they just ‘are’.
When using a Cool Chain shipping system, why are frozen Cool Packs usually left to stand at room temperature before assembly?
Cool Packs / Frozen Cool Packs are stored in the fridge / freezer respectively. Cool Packs are stored at 5°C in the fridge and can therefore go directly into the Cool Chain shipping system as they are in the same temperature band as the product.
When Frozen Cool Packs need to be used in a shipment, they need to be removed and left to acclimatise before being used. This is usually known as ‘conditioning’. This is because they are stored at -18°C and they must start their chilling process and come down to 0°C before they can go into the System – else they will take the product too cold.
Can Cool Chain packaging be recycled and can they go in normal waste streams?
Yes, nothing is hazardous about the water in the cool packs. The easiest and least environmentally damaging way to dispose of the packaging is to put it into your normal waste bin.
The polystyrene is easy to dispose of, but it can sometimes be impractical. If you are a large company you can save up the waste and sometimes the packaging supplier will come and take it away. Its not cost efficient to come back and forth for a small load.
What can be done to increase the duration of Shipping Systems when held in Customs warehouses?
One of the main advantages of being a global logistics company, is our worldwide offices. With these, we are able to top up shipments with dry ice where necessary.
If, on the rare occasion a shipment is held in Customs – it can be topped up with dry ice to keep the package at its required temperature. Thus keeping the product in a usable state.
What are Phase Change Materials (PCMs) and how are they used?
There are three main states of matter – solid, liquid and gas. A phase change is a change between two of these states. For example, in a boiling saucepan, water becomes steam – it changes from its liquid state to its gas state. The ‘magic’ of these phase changes is that it takes a lot of energy to pass through them – for example, it would take a lot longer on the hob to boil off all the water in your saucepan than it took to heat the water up to its boiling point in the first place.
Think of the phase change as an energy store. A Phase Change Material (PCM) is one where the energy of this phase change is used advantageously in a temperature controlled shipping system. As discussed above, water is certainly a PCM, however within temperature controlled shipping, the terminology ‘Phase Change Material’ usually refers to materials that are not pure water but are others that melt or freeze at a constant temperature to provide temperature control within a package.
As an example, consider a simple ionic water-based PCM. Consider this PCM liquid as having a freezing temperature of -20°C. Cool packs containing this liquid could be prepared in a -30°C deep freezer – they would then be frozen solid, as -30°C is ten degrees below their freezing point.
When these frozen cool packs melt inside an insulated shipper they absorb energy from around them. This has the effect of keeping their surroundings (i.e. the inside of the shipping system) cool. In our example, this means the internals of this shipping system will be kept at a temperature of -20°C (the melting point of our PCM). The product sample we’ve included inside will be maintained at this temperature.
While water-filled cool packs are the frequent choice for Cool Chain shipping systems, PCM-based systems are often chosen for other temperature bands. This is because PCMs are available with a wide range of melting temperatures and so can be used to keep shipped product at other temperatures. Because of costs being higher than simple water-filled cool packs, PCM shipping systems are largely intended to be reusable.
At Biocair, we have access to PCM system manufacturers worldwide. We regularly select PCM shipping systems from the marketplace to fulfil our customers’ needs in shipping their product in a specialist temperature band. We have the capability of preparing the PCM cool packs to the correct temperature – our trained drivers typically bring the shipping system to our client ready for their product to be loaded straight in before the box is sealed. We then take the assembled system away for its distribution and delivery.
What's the difference in preparing a warm product PCM shipping system to protect against extreme hot or cold external ambient temperatures?
Warm temperature product systems have varying temperature band requirements depending on the particular product being shipped. A typical temperature band might be +15°C to +25°C – let’s use this as an example to answer this question.
A PCM-based solution to this shipping challenge would use PCM packs where the Phase Change Material in the packs had a melting temperature of, say, +20°C.
There are two principle ways of preparing these PCM packs for this shipping system. Either they can go into the insulated shipper a few degrees above their +20°C melting point (and hence would be in their liquid form) or they can go in a few degrees below their +20°C melting point (and hence would be in their solid form).
Consider these +20°C PCM packs being melted and placed inside the insulated shipper with the product. The PCM would be a little warmer than their melting temperature and be in liquid form. If the shipper is subjected to a cold external environment, heat will leave the box but the Phase Change Material in the PCM packs will solidify and maintain the inside environment at +20°C as they do this. Thus, this system arrangement keeps the internals warm at +20°C while the external temperature is colder.
In the opposite case, consider these +20°C PCM packs being solid (i.e. prepared a couple of degrees below their +20°C melting point) and placed inside the insulated shipper with the product. If the shipper is subjected to a hot external environment, heat will enter the box but the Phase Change Material in the PCM packs will melt and maintain the inside at +20°C as they do this. Thus, this system arrangement keeps the internals cool at +20°C while the external temperature is hotter.
There is a third approach – some validated shipping systems include PCM packs in both solid and molten forms. This way the internal product is protected from both hot and cold external temperatures as the relevant PCM packs perform as above depending on the environment the package experiences.
At Biocair, we have access to a wide range of PCM manufacturers. We choose the appropriate shipping system for our client’s needs and are experienced in preparing PCM packs to the correct temperature. Our usual procedure is to arrive on-site to our client with the packaging pre-prepared and then load the product to be shipped inside. We then take the sealed system for distribution and delivery.
What PCM systems can keep material frozen in transit?
Temperature controlled shipping systems based on Phase Change Materials are a frequent choice for frozen product shipments. Using dry ice is a common solution but miscellaneous hazardous goods legislation must be considered when shipping it and with some products the -78.5°C sublimation temperature of dry ice risks damaging the samples or their containers.
A frozen product PCM shipping system will utilise PCM packs that have a freezing temperature of -20°C or thereabouts. These PCM packs are prepared frozen solid at a colder temperature than this, perhaps in a -30°C deep freezer.
When inside the insulated container of a validated shipping system, these PCM melt to liquid at their -20°C phase change temperature. This keeps the product in the system at this temperature during transit and thus frozen until delivery.
At Biocair, we can prepare and supply frozen product PCM shipping systems for our clients and advise on when a system such as this is a better alternative to conventional dry ice.
What are good methods of preparing PCM panels?
One of the fundamentals of using PCM-based temperature controlled shipping systems is that the PCM packs must be prepared at specific temperatures. In particular, care must be taken to ensure the PCM materials are completely in their correct phase – that is, either fully solid or fully liquid as required. Because PCM-based shipping systems can be sourced for a wide range of product temperature bands with corresponding variability of PCM melting points, the temperatures to which the PCM cool packs need to be prepared vary depending on the system too.
Cool chain packaging with water-based Cool packs uses a fridge cold store at +5°C and a freezer cold store at around -18°C. Cold store equipment like this is commonplace in pharmaceutical environments. These can be used where their set temperatures are right for the PCM shipping system in question but more often than not, PCM preparation requires a temperature different to these.
For example, a PCM-based temperature controlled shipping system designed to keep product frozen might be based on a PCM with a freezing point of -20°C. For use in the system, the PCM cool packs might need to be frozen at -30°C. This could be performed with a deep freezer set to this temperature. In some cases the purchase of specialist equipment may not be practical so there are alternatives. The PCM cool packs could be frozen by first storing them under dry ice. They would then be given a period of conditioning time in a conventional -18°C cold store – long enough for them to warm up from the dry ice temperature of -78.5°C but short enough such that they don’t begin to melt. Allowing them to melt would shorten their cooling lifetime and affect the validation of the system.
As another example, a PCM-based temperature controlled shipping system designed to keep product warm might be based on a PCM with a freezing point of +20°C. For use in the system, the PCM cool packs might need to be melted at +25°C. This could be carried out in a controlled environment at this temperature such as a oven or autoclave. Other methods that can be used involve heaters or heating blankets. It is always important to have an assessment procedure to ensure the PCM cool packs are fully molten throughout.
At Biocair, we are experienced in using PCM-based shipping systems for transporting pharmaceutical product under specialist temperature bands. PCM preparation is taken care of – we select the appropriate system for our client’s needs from a wide range of packaging suppliers and arrive on-site to our client with the packaging and PCM cool packs ready. After loading the sample, we then take the sealed system for distribution and delivery.
How does the performance of PCM systems compare to conventional Cool Chain shipping systems?
Many people in Pharmaceutical Logistics are familiar with the performance of conventional Cool Chain shipping systems that use water-based cool packs to keep payload between +2°C and +8°C.
It is interesting to consider how this performance and behaviour compares to the Phase Change Material shipping systems that are available for a wide range of temperature bands. Specifically, how do weights, costs and achievable validation durations compare to those that would be familiar from conventional Cool Chain system use.
This performance variation clearly depends on the system in question but there are several common themes. Shipping frozen product, for example, requires more power from the PCM than a Cool chain system requires from water-based cool packs for shipping +2°C to +8°C product. This is because the temperature difference between the inside of the box (at about -20°C) and the ambient air outside is greater than when the inside of the box is between +2°C and +8°C. Because of this, more heat comes through the insulated shipper and a corresponding higher weight and volume of PCM is needed. This is augmented by the fact that PCMs tend to have less of an energy store in their phase change than water.
Some PCM shipping systems counter this by using premium insulation materials to slow back down the rate at which heat enters the box. Vacuum Insulation Panels (VIPs) are often chosen to achieve this – as an example they have seven times the insulative capability of expanded polystyrene.
On the other hand, there are sometimes features in PCM temperature-controlled shipping systems that mean a solution can be less of a challenge than +2°C to +8°C systems that use water-based cool packs. Correspondingly, shipping systems can be smaller and easier to pack.
The +2°C to +8°C temperature band is 6°C wide while a typical warm product shipment may have a 10°C temperature band of +15°C to +25°C. By having a wider temperature band, this gives more of a safety margin as the product temperature fluctuates during the journey.
Some other temperature requirements usually fulfilled by PCM-based systems can be more straight-forward to maintain as they only contain one threshold. For example, an “above +15°C” temperature requirement on product being shipped in a cold environment has no upper temperature threshold so simply consists of an appropriate PCM surrounding the sample to be shipped. Some of the intricacies needed in the design of +2°C to +8°C systems such as spacing material and chilled cool packs – both needed to protect the sample from the 0°C ice cool packs – are not necessary thereby simplifying the PCM packing layout.
At Biocair, we’re experienced in shipping product under specialist temperature bands. We choose and supply the correct shipping system for our client’s needs and arrive on-site with everything prepared and ready to load the sample being shipped. After this, we then take the sealed system for distribution and delivery.