Cold chain logistics have had to adapt to accommodate more sensitive drug materials and this complex area has become highly regulated. Marc Weinzweig, managing director of Biotec and a Qualified Person (QP), reviews the current process from a QP perspective
?The clinical trials directive came into being in May 2004 defining the requirements of release in the EU. There is still confusion concerning this role for those outside the EU. To understand the qualified person (QP) role in the cold chain clinical trials, it is important to understand the definition of what the QP is.
As defined in Article 48 of Directive 2001/83/EC, a QP "shall be in possession of a diploma, certificate or other evidence of formal qualifications awarded on completion of a university course of study, or a course recognised as equivalent by the Member State concerned, extending over a period of at least four years of theoretical and practical study in one of the following scientific disciplines: pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical chemistry and technology or biology".
It is the responsibility of the QP to be clear on the following:
That the Investigational Medicinal Products Authorisation requirements for the medicinal products have been met for the batch concerned.
That the principles and guidelines of GMP as stated in Directive 2003/94/EC (Human) as interpreted in the EU Guide to GMP have been followed.
It must be recognised that the QP depends on many of their working colleagues for the achievement of quality and regulatory compliance in the manufacture of medicinal products. It is therefore important that they have a good working relationship with other people in positions of responsibility.
These are likely to include those responsible for1: processing and packing operations; QC labs; validation; application and maintenance of Manufacturing and Marketing Authorisations; provision of engineering services; procurement of starting and packaging materials; storage, transport and distribution; and contract services.
EU requirements and guidelines on Good Distribution Practice (GDP) require distributors to "ensure that storage conditions are observed at all times, including during transportation". The requirements are applicable not only to medicines that need to be stored at low temperatures (cold chain products) but also to medicines that should be stored below 25°C or 30°C (temperate chain products). In addition, an increasing number of products require storage and transportation at sub-zero temperatures and the application of appropriate controls to these is equally important.
The route and time of transportation, local seasonal temperatures and the nature of the load should all be considered when arranging cold-chain distribution. For small volumes of cold-chain goods, insulated containers may be used; in this case it is vital that products damaged by freezing are prevented from coming into direct contact with ice packs at sub-zero temperatures.
The QP role starts before the product is imported into the EU and the Product Specification File (PSF) is key to the process of import and should be continually updated as development of the product proceeds, ensuring appropriate traceability to the previous versions. It should include, or refer to, the following documents:
Specifications and analytical methods for starting materials, packaging materials, intermediate, bulk and finished product;
Manufacturing methods
In-process testing and methods
Approved label copy
Relevant clinical trial protocols and randomisation codes, as appropriate
Relevant technical agreements with contract givers, as appropriate
Stability data
Storage and shipment conditions.
The above list is not intended to be exhaustive but forms the basis for assessment of the suitability for certification and release of a particular batch by the QP. The product specification file is regularly audited by the MHRA on site visits to issue or renew licences.
Among the sections of the PSF that are of particular importance to cold chain products is storage. The specification of the storage temperature is defined at the beginning of the trial. It is not uncommon that storage temperature specifications are amended during a trial, for example -20°C to 2-8°C, as more data become available. It is expected that there will be appropriate justification for the QP to review and agree. The change will also require a substantial amendment to the Investigational Medicinal Product Dossier and a subsequent amendment of the PSF.
For the storage facilities the following are expected:
Storage areas validated with temperature mapping to ensure consistency of storage temperature
Continuous temperature monitoring with a manual check daily
Monitoring connected to an alarm, with out of hours cover
Periodic QA/QC review of data for trending
A back up system in case of failure
Adequate segregation - cold chain product storage is usually at a premium. However adequate space is equally, if not more, important because of the particular constraints of correct product picking under conditions that are not meant for humans!
shipping/distribution
The shipping specification is often wider than that for storage and is obtained from the stability testing work. It is set this way so that if the product goes out of specification in transit there is no delay in making the decision on whether to use it or not.
Shipping validation is not part of the PSF, but is part of GMP; its execution is expected, to ensure that there is adequate evidence to support the methods of packing to verify that correct temperatures are achievable during transit.
There is a constant argument about how one achieves validation - measuring one parameter over time with all others being controlled - in shipping. The outside temperature cannot be controlled, so the validation process should be considered as qualification only. Tests can be carried out in temperature-controlled chambers, remembering that product left on the tarmac of an airport in winter can easily freeze.
For marketed products, it can be imagined that the shipping configuration may be relatively constant, however with clinical trials it is rarely the case. Again for marketed products quantities and values may justify more complex and controllable methods.
shipping boxes
Shipping for cold chain clinical trials is usually in small quantities and so individual shipping boxes are chosen, rather than complete vehicles. Types of shippers commonly used are:
Polystyrene one-piece base and a lid
Polyurethane one-piece base and closed cell foam lid - difficult to dispose of later
Dry ice powered boxes - e.g. Envirotainers and Lufthansa's Uni-cooler
Electric powered boxes
Insulated boxes that are loose assembled from polystyrene slabs are to be avoided. It is easy to recognise these as they arrive by the lines of condensation at the joints.
Common coolants are:
Gel packs - the conditioning of the gel packs should be validated. Pre-conditioning storage should be controlled and monitored and the time allowed for pre-conditioning must be defined and adhered to.
Dry ice - this deteriorates over time and fresh product should be used. Validation of the shipping system must include an indicator of the freshness of the dry ice. New dry ice is shiny and easy to recognise.
Use of temperature monitors is expected in all cases for cold chain trials. For 2-8°C shipments, these are normally placed inside the boxes. They can be the crude paper types, often used where it is difficult or impossible to get the monitor returned - Russia for example. The data can be shared over the internet or by fax but the quality of copies is not good. The monitors are also easy for the receiver to find!
Alternatively, the smarter electronic varieties can be single-use and the record is visual or they can be single-use and the record is transferred to a PC by special docking station or through the USB port, which then gives a PDF file that is easily shared.
These smarter devices can also be multi-use - then returned to the depot for reading. However, the smaller ones can get "lost" in the shipper, and receivers often deny they are even sent with the product. Discussions with the Clinical Research Associate and site training may help.
For shipments at or below -20°C, the "probe-less" type of devices can be placed in the box if the temperature is kept above -35°C. Batteries don't normally work below -35°C, so they would not be usable with dry ice frozen products. There are claims that battery improvements allow for probe-less monitors but there is strong evidence of higher failure rates of these types.
Probe type devices are placed outside the frozen box and the probe passes into the area containing the product and dry ice. For shipments <-60°C, only probe types are recommended. Dry ice can be down to -90°C so can stop the devices. Probe types, such as Madgetech TC400, are used as these have a changeable probe and can also be used with liquid nitrogen at -196°C. Those with changeable probes are best because these can be damaged on receipt by the trial sites.
Information from a temperature logger is critical in ensuring the quality of the product and all temperature monitors should have a calibration certificate. Calibration should be carried out as a periodic check with reusable temperature monitors logged so that their use can be traced.
As mentioned, shipping validation is difficult because the parameters are constantly changing and a defined box configuration is very difficult with clinical trials. The best that can be done is to simulate a worst case - usually very light or small box contents, 20-25°C outside temperature, on a four day transit.
packaging options
Box manufacturers often supply packing formats; however, it is still the obligation of the user to verify the packing format meets their needs. The suggestions are not always good and it is important to pay attention to the free spaces and this should be defined in the qualification process.
Dry ice powered boxes can prove to be a problem and some are good only if the internal temperature is set at >5°C lower than the expected outside temperature. A setting of 2-8°C will need an ambient minimum of 13°C. Lufthansa has recognised this - its Uni-Cooler has a heater as well as a cooler.
Aircraft used to be set at 12°C in the hold - however, it is worth checking as there have been incidences of product freezing as aircraft relax temperature control to reduce fuel use. It is also important to know that the control of the hold temperature is defined by the pilot, and the other contents, which may be livestock.
Logistics are dependent on the weather, the product, the aircraft, the pilot and political situations. The only thing a QP can expect to do is to have a good team around them and be aware that at some time it will go wrong. At this time, experience is valuable and an analytical approach is required.