Cold chain management for sensitive goods

Packaging, route planning and risk analysis ensure safe conditions during transportation of delicate drugs. Drugs are sensitive goods to transport, which can be subject to irreversible damage if they are stored or transported at temperatures outside the tolerated range. If the temperature falls below or rises above the specified range the quality of drugs requiring refrigeration can be seriously affected and they may cease to be effective. This article therefore describes how transport conditions during the transportation of drugs can be optimised through suitable packaging, individualised process design, the analysis and assessment of potential risks and close collaboration between the sender and the freight carrier.

Nowadays drugs are transported over long distances both over land and by air . In addition to choosing the right packaging and correct cooling system, the transport process must ensure that the drugs reach the patient without having suffered any loss of quality as a result of the negative effects of inappropriate temperatures.

During transportation drugs are subject to the same provisions with regard to maintaining a specified temperature range as applicable during storage. Drugs requiring refrigeration - medication which must be stored at temperatures between 2 °C and 8 °C - can either be transported using a controlled active cooling system or an uncontrolled passive cooling system. By active cooling system we mean the use of refrigeration units in appropriately equipped vehicles or active air freight cargo containers. Passive cooling systems involve the use of insulated cool boxes in which cool packs are packed along with the goods to be transported in order to cool them.

Requirements in respect of the transportation of drugs
Legislation requires proof that medical products incur no damage as a result of storage or transportation1. In Annexure 5 of Guideline 937 under the heading 'Good Distribution Practices for Pharmaceutical Products' (GDP), the WHO stipulates the storage conditions to be complied during transportation and the permitted deviations2. The US Pharmacopeia (USP) also demands temperature control and monitoring during transportation3. In the EU, the 1994 'Guidelines on Good Distribution Practice of Medicinal Products for Human Use' apply. These guidelines likewise require that for drugs which need to be stored at a specific temperature, suitable conditions are to be maintained during transport4. However, since there have been considerable changes in transport and logistics since 1994, the European Commission has issued new draft guidelines (EU Commission Guidelines on Good Distribution Practice of Medicinal Products for Human Use). These new guidelines take into account the general advances in the practices employed in storage and transportation, as well as the 'Directive 2011/62/EU' on combatting counterfeit drugs, and will replace the 1994 guidelines in the coming months.



Figure 1: IATA Standard Time and Temperature Sensitive Label.




The above brief summary of the legal requirements shows that there are differences between the conditions for the storage and transportation of drugs set out in the GDP (Good Distribution Practice) guidelines issued by the authorities in different countries. These include quality assurance requirements which must be taken into account by both the pharmaceutical companies and their logistics partners during the storage and transportation of drugs. The fact that the GDP guidelines are not harmonized globally adds to the complexity of transporting drugs. For example, American legislation requires temperature monitoring, which is not required in the existing EU guidelines. Exceeding or falling below the specified temperature range for a particular product during transportation can have a decisive effect on the quality of the drug, even if these limits are exceeded only briefly.

A practical example will demonstrate exactly how problematic that can be. Let us take the example of a passive transport packaging being used to transport goods requiring refrigeration (temperature range 2 °C to 8 °C), and is stocked with frozen cool packs. If the goods are being transported in December and are leaving winter temperatures in Europe to arrive in summer temperatures in South America, the risk of the goods warming up on reaching the destination airport is factored in, and the level of cooling required is therefore often exaggerated. By contrast, the risk of the goods freezing at the departure airport is barely considered. As a result of the excessive level of cooling, the temperature of the drugs briefly falls below 0 °C. Being frozen, even if only briefly, can cause irreparable damage to the drugs and cause lasting changes to its characteristics.




This entails the risk that the safety of the drugs may be reduced and can endanger the patients, e.g. by reducing the shelf life, making the drugs less effective or because of toxic by-products created during degradation. It is therefore essential to ensure that the specified temperature range for that drug is maintained throughout the whole period from production to delivery to the patient.

Process analysis and risk assessment
As the above example demonstrates, the choice of appropriate packaging for transportation is not sufficient to ensure that the drugs continue to be safe. It is necessary to analyse the whole transport process and to assess the potential risks for each individual stage of the process with regard to drug safety.

When drugs requiring refrigeration is transported in packaging with passive cooling systems, it is usual to apply one packaging solution for general consignments to all destinations worldwide. This packaging is aimed at catering for every extreme circumstance. In practice, this means using large packing cases with thick insulation, special foil on the outside and many cool packs, which have often been cooled to different temperatures prior to packing. These standard packagings have a poor internal - external volume ratio, are heavy and therefore result in increased transportation costs. A first step towards reducing transportation costs, whilst at the same time reducing the risk of quality problems arising as a result of transportation is to select suitably adapted packaging, i.e. packaging which meets the demands of the drugs and the route.






















In order to be able to assess the risks faced by drugs requiring refrigeration whilst in transit, it is necessary to analyse every stage in the transport process. A detailed analysis is a vital prerequisite if the whole transport process is to be organized in such a way that the temperature requirements can be maintained during transportation of the medicinal products along with reduced cost of transportation. Ideally, the sender (i.e. the pharmaceutical company), and the logistics service provider should collaborate closely in the process analysis and risk assessment.

Whilst the pharmaceutical company has the relevant knowledge with regard to its product, the logistics service provider can add its expertise regarding the transport aspects. Together, both parties should conduct the process analysis, which shall include the study and documentation of the individual sections of the route, as well as the procedures and protocols to be followed by every party involved in the logistics operation (handling agent, airline company, etc). On the basis of this process analysis, a suitable route and the packaging are to be determined. This results in individualised transport routes that have taken into account all the relevant factors like the seasons in the departure and arrival airports, the quality of the handling agents, the logistics, the airport, etc.

In order to comply with the legal requirements in force in the relevant country of dispatch, and in order to be able to react quickly, if the temperature is not kept within the specified limits, both parties should ensure temperature monitoring. For example, the guidelines set by the American health authority, the FDA, require temperature monitoring throughout the whole transport process5. The measuring equipment for this can be attached either on the inside or the outside of the package. Measuring equipment using RFID (Radio Frequency the temperature to be measured and recorded throughout the transportation period. Thus, it is possible to check immediately upon arrival at intermediate points or at the destination, whether the temperature range has been exceeded during transportation, thereby making it possible to react quickly. In this context , the IATA Time and Temperature Sensitive Label (Fig. 1), the use of which has been compulsory for the transportation of drugs requiring refrigeration since 1st July 20126, has improved handling of goods in transit. It contains all the information that those involved in the process need in order to deal correctly with drugs which require refrigeration. It is internationally recognised and hence is understood correctly at all interim points along the transport route.

When pharmaceutical companies and logistics service providers work together to conduct the process analysis, they should start by answering the following questions:
  • What kind of drugs are to be transported?
  • What storage and transportation conditions apply for these drugs?
  • What are the absolute temperature limits for these drugs? Do these limits also apply for the packaging?
  • What kind of packaging is to be chosen? Is the packaging suitable for the job? Based on what temperature profile was this type of packaging selected?
  • Is the most important information clearly displayed in a form that is easily understood on the outside of the cooling packaging?
Once the answers to these questions have been arrived at, the next step is to establish and document the process with all parties involved in it. For this, the process documentation is broken down into the following points:
  • preliminary phase,
  • handling at the airport,
  • interim storage,
  • loading,
  • main phase (flight),
  • unloading,
  • separating the package components, customs clearance and preparing
  • the goods for collection.





















In some cases the next phase, i.e. delivery to the patient, is also considered. The risk analysis is conducted based on the process documentation. In short, all potential sources of errors are analysed and assessed. For this, one should attempt to take as objective a viewpoint as possible, and the process should be undertaken by all the parties involved. The FMEA (Failure Mode and Effects Analysis) model is a suitable method for analysing and assessing potential risks. The risk analysis should be undertaken for every stage in the whole process and should consider every risk that could endanger the quality of the drug as well as list the likelihood of that risk becoming real.

Once the process has been set out in detail and all risks assessed, the plan for monitoring the temperature is to be drawn up. Depending upon the country and the legal requirements in force in that country, this may entail comprehensive monitoring or random sampling.

The recorded temperature data should provide the following information on
  • whether the specified temperature range has been maintained throughout the entire transportation period;
  • whether the temperature rose above or fell below the tolerated range and what caused this;
  • whether the anticipated risks were successfully eliminated;
  • whether the process requires adaptation, and
  • whether the packaging used is suitable for transportation.
Ultimately, the temperature monitoring data determines whether the drugs are to be released in the market at their destination.

Conclusion
When it comes to the effects of transportation on drug safety, it is not only the correct choice of packaging which is decisive, but also the design of the transportation procedure and route based on risk analysis and assessment. Individualised transport protocol design, the choice of packaging, sensible planning of transport routes and close collaboration between pharmaceutical companies and logistics service providers enable optimisation of the transportation of drugs that require refrigeration, thereby ensuring the quality and safety of the drugs.

References
1. Arzneimittel und Wirkstoffherstellungsverordnung(AMWHV); Section7 - Lagerung und Transport.

2. WHO; Expert Committee on Specifications for Pharmaceuticals Preparations Technical Report Series 937 (Annex 5 - Good Distribution Practices for Pharmaceutical Products); 2006.

3. US Pharmacopeia (USP); Chapter 34; 1079.

4. European Union; Guidelines for Good Distribution Practice of Medicinal Products for Human Use(94/C 63/03); Official Journal of the European Communities (No. C 63/4); 1st March 1994.

5. Lucas, T. I., Bishara, R. H., and Seevers, R.H.; A Stability Program for the Distribution of Drug Products; Pharmaceutical Technology; July 2004; 68 -73.

6. IATA Time and Temperature Sensitive Label to Become Mandatory from 1 July 2012; www.iata.org; June 2012.