It is important for medicines to be stored at correct temperature to maintain their effectiveness and safe use, including their storage temperature during transit. The aim of this post is to bring awareness of some of the issues that need to be considered regarding transportation, receipt and storage of cold chain products.
The requirement for pharmaceutical wholesalers to comply with the principles of Good Distribution Practice (GDP) is stated in European Directive 92/25/EEC, which also provides that member states will perform inspections of their premises. As a consequence, MHRA is responsible for inspection and ensuring that distribution of medicines comply with GDP, prior to issuing the licence.
During the inspection, the GDP inspectorate focuses on the many issues including storage and distribution of medicinal products that need to be stored between 2C and 8C.
Cold Storage Of Medicines
Following manufacture, some medicinal products need to be stored and shipped at lower than ambient temperatures (20C to 25C) to assure their quality and efficacy. These are often referred to as “cold chain products” or “fridge lines” (0C to 5C) and wholesale dealers are expected to store and distribute them in strict accordance with the product labelling requirements.
Some cold chain products, such as vaccines, insulin, biotech products and those products derived from blood or plasma, can be classified as high risk because they are at risk from freezing as well as higher temperatures.
Other products, for example, chloramphenicol eye drops, may be labelled as requiring storage between 2C and 8C but a short deviation from this temperature range presents less of a danger to users.
Once the products are despatched for delivery, the distribution chain for medicinal products can be complex, potentially involving a number of storage locations, wholesalers and modes of transport, before the it finally reaches the pharmacy.
The transportation arrangements from one location to another should be regarded as an extension of the storage activities and distributors are expected to treat each journey as unique with the length and complexity, as well as any seasonal variations, being considered when choosing the packing method and mode of distribution.
Cold chain medicinal products should be packed in such a way as to ensure that the required temperatures are maintained throughout the journey and the medicines are transported in accordance with their labelling requirements to stop it from affecting their quality adversly.
For small volumes of lower risk products, with short journey times of less than three hours, insulated containers are generally used. For longer journeys, gel or ice packs are added to the packaging to maintain appropriate temperatures throughout. The positioning of these packs within the consignment is extremely important and they must not be allowed into direct contact with the products being shipped.
Bespoke packaging with compartments for the gel or ice blocks are available, although securely encasing the blocks in some form of wrapping, such as bubble wrap, or installing some other form of a buffer can be equally as effective.
Larger volumes of refrigerated products are normally shipped in refrigerated transport. This is particularly important if transportation times may be protracted or likely to be delay.
Whatever method of transport is used, it is important to show that the required temperatures can be maintained for a stated period of time. Wholesalers are therefore required to undertake validation studies of their distribution activities and may use, for example, temperature loggers in deliveries during the summer and winter months for the most difficult journeys.
Best practice in this area as a matter of routine for all refrigerated deliveries, but especially within shipments of high risk products, where the temperature should be strictly controlled and monitored with calibrated temperature probes, is to provide temperature data for the entire journey.
Temperature should be monitored and recorded daily of all storage locations. Any recording devices should be calibrated annually against a certificated standard.
The temperature records should be reviewed for each consignment and there should be a procedures in place for implementing corrective action in case of any deviations from the expected temperature. They should also ensure that consignments of refrigerated goods are clearly labelled with the required storage and transport conditions to be maintained.
When wholesalers employ couriers, they must satisfy themselves that they also follow the procedure laid out.
To ensure this, some wholesalers enter into a technical agreement with their chosen courier.
Receipt in the pharmacy.
When cold chain products are received at a pharmacy, it is important that they are promptly checked in and placed in a refrigerator. The person responsible for receiving the delivery must also satisfy themselves that the goods have been transported under appropriate conditions, such as, there has been no direct contact between the products and gel or ice blocks.
If it cannot be confirmed that the products have been transported under required conditions and there is concern that their quality may have been compromised, the delivery should be quarantined in a suitable refrigerator whilst enquiries of the supplier are made. Until the issue has been clarified to the pharmacist’s satisfaction the products in question should be considered as unsuitable and should not be supplied or sold to patients.
If, following enquiries, there is still doubt as to the quality of the medicines received, the delivery should not be accepted and should be returned to the supplier. As with any delivery, staff receiving goods should also be alert for the presence of counterfeit medicines.
Cold chain returns.
Returns of cold chain products is an area that receives a great deal of attention during a GDP inspection. MHRA have issued guidance on refrigerated returns which states that if a cold chain product is to be returned to the wholesaler, this must occur within 24 hours of the original dispatch. After this time, the returned product cannot be considered for resale and must be disposed.
In practice however, because of the inherent dangers of returning cold chain products, many wholesale dealers will not consider them for subsequent resale in any event. All such returns are immediately stored in a dedicated and marked area awaiting collection by a licensed disposal company.
In the event of a wholesaler accepting a return of a refrigerated product, possibly because of its high monetary value, the product must be returned within 24 hours following dispatch, in an appropriate method of transport, with supporting documentation, such as a returns form. The returns form would normally include the reason for the return, contain details of the product and how it has been stored and
should be signed by an authorised and identifiable signatory.
The Responsible Person at the wholesalers will examine the returned product to check for tampering and to confirm that the return has been made within the stated 24 hours. If this examination cannot be undertaken immediately, the product should be stored in a dedicated and marked area in a refrigerator until the checks can be made. Provided the checks are satisfactory the product may be returned to saleable stock.
Temperature monitoring
- As with transportation, products stored in a refrigerator should be monitored daily.
- Temperature records should identify any temperature deviations and give details of corrective actions taken as a result. For instances where there has been a temperature deviation, best practice would be to take a further reading later the same day, to ensure that it was a transient deviation and show that the temperature was now back within specified parameters.
Common MHRA Inspection Findings
During GDP inspections of pharmacies that also hold a wholesale dealer’s licence there have been instances where the refrigerator is also being used by staff for the storage of milk and food as well as medicinal products.
Domestic refrigerators.
Standard domestic refrigerators are not ideal for storing cold chain products for a number of reasons, including an uneven temperature distribution (as a result of minimal air circulation) and a normal operating range of between 0C and 10C. Opening and closing the fridge door can cause significant temperature fluctuations, making monitoring of the internal temperature difficult. There is also a risk that products
could freeze if they come into contact with the chiller plate or coil at the back of the fridge.
Pharmaceutical refrigerators.
A purpose-built pharmaceutical refrigerator is recommended for the storage of cold chain products, especially those identified as high risk. The air within this type of refrigerator is circulated by a fan, which provides a uniform temperature profile and a rapid temperature pull down after the door has been opened.
Temperature is usually monitored by a calibrated electronic min/max thermometer, with an accuracy of
±0.5C, which can be read without opening the refrigerator door. Additional benefits are that these refrigerators can be locked and some have the option of either an audio or visual alarm system to alert staff in the event of temperature deviations. Many also have glass fronted doors giving greater visibility to stock levels, aiding stock management and also deterring the storage of non-medicinal products, as mentioned
above.
When purchasing a new refrigerator therefore, factors to consider might include how long the unit can maintain the recommended temperatures if the power is turned off and to what extent the cabinet temperature is affected by ambient temperature variation, for example, in hot spells.
Good Distribution Practice of Medicines
Irrespective of the type of refrigerator used, the medicinal products should be stored in an orderly manner
on the shelves - not on the floor of the unit or anywhere inappropriate- to ensure air circulation and consistent temperatures throughout.
- Temperature monitoring probes should be sited in a central location within the refrigerator and, preferably, between the products. They should not be placed in the door.
- The refrigerator should be cleaned regularly (as part of a general cleaning rota) and serviced at least annually. If fitted with an audible or visual alarm this should routinely tested to confirm correct operation.
- The stock within the refrigerator should be subject to effective stock rotation based on first expiry, first out, and it should not be assumed that the most recent deliveries will have a longer expiry period.
