Distribution and transport are complex processes. Globalization requires global supply chains and cooperation with logistic service providers around the world in order to be able to deliver pharmaceutical products wherever and whenever they are needed.
Thus, various people and entities are involved in this process. Every step or "trip segment" - to use a denomination of the International Safe Transport Association( ISTA) - is comparable to a chain consisting of many links. Some are strong and some are weak. First we have to learn about the transit and its steps, then we should analyze and evaluate it. In the next step we can determine weak points and try to make them stronger. But finally we have to accept that there will always be weaker parts and/or segments that can hardly be controlled.
In the following article we concentrate on temperature profiles in transportation equipment.
We distinguish between profiles with constant temperatures (WHO, DIN) and those with cycling ones (ISTA, AFNOR). These profiles will be discussed in the following.
1. WHO: Cold Life and Warm Life Test1
In the early Nineties the World Health Organisation (WHO) began to question the safety of cold chain supplies driven by the need to reduce the quantity of vaccines spoilt during transit.
This led to the development of two temperature profiles:
Both scenarios are designed for a cold chain to be maintained over a period of 48 hours. Setting the ambient temperature to +43 °C or-5 °C clearly does not reflect realistic transport conditions, with the exception of remote places such as Novosibirsk or Death Valley. However, they are useful examples for worst case scenarios. This approach is more and more asked for by health inspectors auditing the transport and storage conditions.
2. Germany: DIN 555452
The test methods specified the German DIN 55545 are intended for use in the evaluation of temperature retention capacity in different insulation boxes, regardless of how the box is configurated. On the basis of such an evaluation the performance of different boxes can be compared. The test is performed at + 30 °C for a period of 72 hrs. 35 % of the internal net volume is filled with frozen cooling elements; these elements are placed on the bottom of the box.3
The temperature logger is located in the geometric middle of the box (see Figure 11.N-7).
Figure 11.N-7 Test set-up DIN 55545-01
The range of application of the DIN approach is limited to an initial evaluation of the cold chain duration. The result can serve as one criterion among others pro or contra the introduction of the insulation box.4 Its performance quality, however, can only be proved in a test surrounding with a closer link to real transport conditions.
The International Safe Transport Association (ISTA) is a first class player when transit safety is concerned. The maintenance of the set temperature range is one decisive criterion in this procedure. The temperature profiles developed by the ISTA do not pretend to cover a worst case scenario. Field shipments are strongly recommended after the test runs in climatic chambers. The ISTA was one of the first organizations promoting winter and summer profiles, resulting in different configurations of the passive cooling box throughout the year. A profile for a transit time of 48-hour runs is shown in Figure 11.N-8.
Figure 11.N-8 ISTA 48-hour profile
First of all the ISTA distinguishes between a summer and a winter profile. This differentiation has been adopted by many shipment departments. Shipping destination and climatic conditions are too manifold to be covered by one single profile. The profile and finally the configuration of the insulation box (number of cooling elements, way of preconditioning) should be based on ambient conditions. Clear written statements are required stating which configuration is applicable at which ambient temperature. This implies that limits are fixed (e. g. below +5 °C the winter configuration applies, between +5 to 25 °C normal configuration applies, and above +25 °C hot summer configuration applies).
4. Association Française de Normalisation (AFNOR)6
In autumn 2007, the French association of standards published a very detailed description of the qualification of insulation containers. They distinguish between a standard and a special qualification.
The standard qualification covers the following aspects:
The temperature profiles vary from destination to destination (mediterranean - continental - northern) and from summer to winter time (see Figure 11.N-9 and Figure 11.N-10).
Figure 11.N-9 AFNOR 48-hour summer profile
Figure 11.N-10 AFNOR 48-hour winter profile
In the summer profile, temperatures range from 22 °C up to 40 °C for mediterranean and continental destinations and from 20 °C up to 32 °C for northern destinations. Looking at these profiles the influence of the ISTA becomes evident. The transit chain is split into segments, duration and temperatures vary from segment to segment thus reflecting real transport conditions.
In the winter profile a minimum temperature of +8 °C (mediterranean destination) and minus 2 °C (northern destination) respectively is assumed. The approach focuses on ambient temperatures rather than outside temperatures. The ambient temperature is the decisive parameter. During transit the cargo is stored in a van, in an airplane, in a train or in a storage room for most of the time, which means in a closed surrounding. The exposure to open air is restricted to rare occasions such as loading of the aircraft and other ground handling operations.7
5. Which profile suits best for the individual transport case?
The choice of the most suitable temperature profile is not a question of 100 % congruence, but a question of getting it as close as possible to real transport conditions. Firstly the cold chain duration required for an individual transit has to be fixed. We presume that data from past trips are available and can serve as a first orientation. Import and customs procedures vary from country to country and this can extend the journey of the cargo to a greater or lesser extent (from a couple of hours to a couple of days). Therefore a safety margin is added. When doing so one should bear in mind that the cost for the insulation box will increase with the prolongation of the cold chain. For short trips simple polystyrene shippers are used that are cheap to produce. The polystyrene used has a low dimensional weight, thus the thermal capacity is limited to short-runs. For trips up to 96 hours the insulation capacity must be increased, polystyrene with a higher dimensional weight is used, the thickness of the wall increased (thus reducing the inner space for the cargo) or other insulation material is taken (aluminum-coated panels, foam cuttings). Compared to expanded polystyrene (EPS), extruded polystyrene (XPS) has better thermal properties, thus insulation boxes for longer shipments are made of this material. The high-value version consists of vacuum panels, which make the box ready for shipment exceeding 96 hours, but this material is expensive and requires sensible handling.
Many roads lead to Rome, and all these temperature profiles aim at the same goal: making the cold chain safer and more reliable. The temperature profiles are intended for evaluation and testing purposes, they do not intend to represent field shipment conditions. Most recent temperature profiles (AFNOR) have cycling temperatures. Prior to selecting one profile, the transport chain should be analyzed by means of a risk analysis to find out in which segment the potential risk level is the highest, what can be done to reduce it an and which are the main factors influencing it.8
1 „Guidelines on the International Packaging and Shipping of Vaccines" WHO/V&B/01.05).
2 DIN 55545-1 Prüfverfahren für Verpackungen mit isolierenden Eigenschaften Teil 1: Erstbewertungsprüfung, Beuth Verlag 2005.
3 Calculating the amount of cooling elements: 35 % of the inner volume are filled with preconditioned cooling elements (frozen).
Example: Inner volume 5 l, 35 % = 1,75 l ; approx. 6 cooling elements à 280 g are needed).
4 Spiggelkötter N.: Kriterien für eine praxisnahe Bewertung von Thermoversandgebinden. In: PharmInd 2006, 68, Nr. 9, 1112-1115. And an English version: Check list for the Evaluation of Insulation Containers. In: European Journal of Parenteral & Pharmaceutical Sciences, 2007, 12 (4), 79-82.
5"Thermal Controlled Transport Packaging for Parcel Delivery Shipment", ISTA 7D, 2002.
6 AFNOR NF S99-700, Octobre 2007, „Emballages isothermes et emballages réfrigérants pour produits de santé. Méthode de qualification des performances thermiques".
7 Under the assumption that the cargo is packed in an insulation shipper (over pack) the internal temperature within the shipper is strictly speaking the ambient temperature.
8 Spiggelkötter N.: Cool Chain for Vaccines: Where to find Murphy. In: ITJ - International Transport Journal, 2008, 3-4, 21-24.
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About the Author
Dr. Nicola Spiggelkötter is author of the GMP MANUAL chapter 11.N Transportation.