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International Clinical Trials

Biological Conclusions

The sponsor of a clinical trial for a biological product requires the supply chain to deliver the drug to the destination on time, at the right temperature and for the lowest cost possible. This is not significantly different to the requirements of a non-biological product. However, to achieve these three simple requirements reliably for a worldwide Phase III trial involving a low temperature product can prove to be very difficult. This article will examine the supply chain, with an emphasis on the logistics, and identify ways to improve efficiency.

To begin with, it is useful to understand what biological products are and why they are so difficult to handle. Biological products are defined as medicinal products derived from blood, vaccines, toxins and allergens produced from naturally occurring sources. Biopharmaceuticals are therapeutic proteins or nucleic acids produced by biotechnology techniques. Both of these groups of products usually require cool chain storage, packing and distribution, and for the purpose of this article will be considered together as ‘biologicals’ or ‘biological products’. Some biological products require ultra low temperature (ULT) storage at temperatures below -60°C, as they contain enzymes which cause product degradation when active. Therefore, maintenance of the product below the temperature of enzyme activity is critical and must be maintained throughout the supply chain.

The supply chain for a low temperature biological investigation medicinal product (IMP) can be divided into three phases of activity. The initial phase involves importing the material to the storage site for distribution. This is often a different country to the manufacture of the product. Phase two involves the identification of shipping routes, including local storage depot requirements, and the final phase is the routine shipping of the material when the trial is up and running.

IMPORTATION PHASE

In the EU, IMP for use in a clinical trial must be stored and distributed from a licensed facility in compliance with good manufacturing practice (GMP) and good distribution practice (GDP). In the majority of trials, the material is not manufactured in the same country as the qualified person (QP) certification and needs to be imported. For biological products, the information required to obtain the import license can be very lengthy, and a slight discrepancy in a description can cause major issues. In the UK, the Department for Food, Environment and Rural Affairs (DEFRA) issues licences for the import of any animal or human derived product. Their website contains a table with all possible products one may wish to import, alongside the general license reference you require. Issues can occur if the product contains materials that are not covered on the list. For example, a product may contain human serum that has not been heat-treated. In the UK this material will require a specific license for import. This can cause delays on the initial import of the product while a decision is made by DEFRA to issue the license. It is vital at the initial set up phase of the trial that those responsible obtain all the details of the materials required for importing it to all countries in which the trial is taking place, and establishing timelines for obtaining the import licenses. This information may influence the decision of the sponsor to perform the trial in a particular country and should be considered alongside the regulatory authority requirements.

During the importation phase, the description of the product on the shipping documentation can be critical. For example, sheep serum containing antibodies to snake venom could be described on the shipping documents as containing ‘anti-snake venom’ or ‘sheep serum’. A shipment described as anti-snake venom would probably be stopped by customs for further inspection, while one described as sheep serum would usually pass without difficulty. Where shipping documents are prepared by the sponsor or a contract manufacturer, it is often useful to send a draft to the importer before submitting to customs as they will be able to identify any details which may cause issues.

Alongside the customs and import license requirements, the method of transportation is critical for biological products. Most biological products require cool chain conditions and are shipped by air to save time, as the time that product temperature can be maintained during transit is limited. Generally, the quantity of material for a biological trial is smaller than a traditional tablet trial. As there are fewer patients recruited, the material may comprise just a few pallets or boxes. Cold shippers are available that can hold a pallet and are the correct size to load directly into the cargo bay on a plane. Smaller box size shippers are also available; these shippers must be able to maintain the required temperature for the expected duration of the flight, customs clearance and delivery. In most cases, the material is transported using specialised couriers who have the capability to hold the material at 2 to 8°C, or top up the dry ice should the shipment be held up in customs. These shipments are usually very expensive because of the high standard of shipper and courier necessary to ensure product integrity. However, the cost implication of losing a shipment due to a temperature excursion far outweighs the additional cost of shipping securely.

There are new shipper products coming onto the market which are capable of maintaining temperatures of 2 to 8°C or below -20°C for up to 10 days. This may give the option of using a standard courier or freight carrier as even with delays, the shipping system would last long enough to reach its destination within temperature. However, these cheaper methods may only be realistically considered on a shipping route that is tried and tested, with a product that has been imported previously so that all customs and import queries have been addressed.

SHIPPING ROUTES & STORAGE DEPOTS

Increasingly, clinical trials are conducted worldwide with a single supply chain provider, rather than different providers for Europe, the Americas and the rest of the world. Where trials are conducted in Europe, regulations require a licensed facility to store and distribute the product. This is also the case for other non-European countries. In addition to the regulatory requirements when establishing the supply route for a trial, consideration needs to be given to the number of trial sites within a country, the delivery timescales and the volume of IMP the sites can store at one time. Where there is a large number of sites in a country, supplying a bulk shipment to a depot is often more economical. This can be particularly beneficial in some eastern European countries where the customs charges are on a per shipment basis. Also, for some trials, the turnaround time between a patient being screened and accepted into a trial, and the first dose can be short. Long customs processes (up to 10 days for some countries) make it impossible to meet the needs of the trial, and local depots in these countries are essential to provide the required standard of service.

Storage capacity at the trial site is also a consideration for biologicals: as they often require low temperature storage, there is a limit as to how much product can be stored at any one time. High recruiting sites will need frequent deliveries of product, and again, a local storage depot with a short delivery time may offer a quicker service and better value for money, even when the depot service charges have been considered. Alternatively, for sites with greater storage capacity, planned recruitment levels could be examined to enable a regular shipment to be set up, which would provide sufficient stock at site with far fewer shipments. The drawback of this option is that, once the product has been delivered to the site, it is outside of the controlled distribution chain, and it is good distribution practice not to transfer this product to another site. Therefore, there could be an increase in wasted product. Material held in a depot is still within the monitored supply chain and can therefore be diverted for use at other sites or even other countries, providing the labelling allows this.

For optimum efficiency, the supply route of a biological product trial must be considered on an individual product and country basis. The product, its replacement cost and availability for replacement, as well as the site storage capacity and recruitment rates, must all be considered to ensure a costeffective, secure route that meets the trial demands.

ROUTINE SHIPPING OF TRIAL MATERIAL

Once the product has been imported and the shipping routes have been established, routine shipments to the site can begin. Prior to the first shipments to site, the packaging and couriers have to be determined. The selection of shippers and shipper preparation is critical for temperature-controlled products. The shipper must be qualified to last the duration of the shipment and where possible, the courier should have the facilities to top up dry ice or hold refrigerated product. This is particularly important where there may be customs clearance required and usually specialist couriers are used. For shipments to countries where no customs clearance is required – for example within the EU – a standard next-day courier service can be used, which saves significant cost. Again, efficiencies are made by considering each country individually.

It is also recommended to include a temperature monitor with the shipment to ensure the product has remained within temperature, even where the shippers are qualified. Temperature monitors – even those for monitoring shipments as low as -80°C – are available with a USB connection, enabling a copy of the graph to be reviewed at site, and hence removing the wait for a monitor to be returned for download before approving product for use. In addition, many of these monitors are single-use, which reduces cost as a return shipment of the monitor is not required. While high quality shippers and monitors add additional cost to the trial, the amount of time spent reviewing graphs for out-of-specification shipments, or the loss of product from out-of-temperature shipments, can rapidly increase the costs of the trial above the savings initially made.

There are new shipping systems available on the market for 2 to 8°C shipments that do not contain chilled gel packs, but work via an active cooling system. These have a much smaller volume than traditional shippers with gel packs and can significantly reduce the cost of shipments, particularly in Europe where shipping is charged by volumetric weight. For example, the smallest traditional shipper capable of maintaining 2 to 8°C for 72 hours has a volumetric weight of 16kg; the equivalent in the new shipping system is 3.5kg.

All of the areas outlined are based on refining the supply chain for a product which is already packaged, or one where the final packaging has already been defined. However, greater efficiency could be achieved if the design of the product’s packaging is considered in an integrated design process tailor-made for each product. The design of a traditional clinical supply chain for a biological product generally flows as follows: 
  • Vial labelling 
  • Kit labelling 
  • Calculating the number of vials required per kit 
  • Kit packaging
The number of vials packaged per kit is devised from the protocol and the dosing requirements for the patients. The packaging of diluents may be considered, and if these are stored at the same temperature as the drug they may be contained within the drug kit. The blinding requirements of the trial are considered and resupply to patients. Generally, for blinded trials, IWR systems are used and the packaging formats must be in line with the IWR programming requirements. Finally, logistics are considered to ensure the IWR is programmed correctly for depots and transit times. Shipping systems for the product are specified based on temperature and kit dimensions, and are usually assigned from generic shipper stock that has been previously qualified.

Rather than follow the ‘here it is, now ship it’ method, an integrated kit design would turn this process on its head and design the kit and logistics supply chain together. The traditional method often results in kits which do not fit into the shipping systems efficiently, meaning larger sized shippers are required and the volumetric cost of shipping is increased. At the kit design stage of the project, however, there is usually scope to modify the dimensions so that the same number of vials can still be contained in a kit, while allowing it to fit into the shipper more efficiently – often allowing double the amount of product to be shipped. Alternatively, if the dimensions of the kits are known by the logistics team well in advance of the first shipment, shippers can be sourced and qualified specifically for the trial. The set-up costs for specific qualifications may be higher, but the long-term savings would easily outweigh the additional expenditure. Diluents, comparators and ancillary kits should also be considered at the design phase. Shipping formats and order forms can then be developed, which allow all products at the same temperature to ship together, further reducing the number of dispatches and shippers required.

CONCLUSION

There are efficiencies that can be achieved within the supply chain, with the logistics team working independently of the packaging team, including reduction in import delays, improvements in timely and within temperature-controlled shipments to sites. However, by setting up an integrated process in which the whole supply chain is considered upfront at the start of the design stage, or ideally at the proposal stage, a streamlined, well documented and efficient supply chain strategy for each individual trial and product can be developed, which is capable of delivering product on time, at the right temperature and at a cost that sponsors are able to pay.


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Rachel Griffiths is the Director of Operations at Biotec Services International. After joining Biotec in 2004, Rachel has maintained responsibility for the company’s production and warehousing. With a degree in microbiology and virology, Rachel has previous experience as a development scientist, a technical support scientist and a product support specialist. Rachel assists the team which specialises in the import, QP certification, labelling, assembly, storage and worldwide distribution of clinical supplies for Phase I to IV trials, through to commercial supplies.
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