Refrigerated medicinal products: what pharmacists need to know
Patients and other healthcare professionals are entitled to expect thatmedicines sold or supplied from a pharmacy are fit for their intendedpurpose. In this article, Steve Todd looks at safeguarding the coldchain
Patients and other healthcare professionals are entitled to expect that medicines sold or supplied from a pharmacy are fit for their intended purpose. In this article, Steve Todd looks at safeguarding the cold chain
Identify knowledge gaps
1. List three actions that can be taken routinely to ensure the integrity of refrigerated medicinal products.
2. How would you advise a patient prescribed a refrigerated medicinal product and who is going on holiday?
3. What procedures can be followed with respect to fridge lines in the event of a power cut?
Before reading on, think about how this article may help you to do your job better. The Royal Pharmaceutical Society’s areas of competence for pharmacists are listed in “Plan and record”, (available at: www.uptodate.org.uk). This article relates to “provision of good quality medicinal products” (see appendix 4 of “Plan and record”).
This article draws on some of the findings from inspections performed by the Medicines and Healthcare products Regulatory Agency’s good distribution practice (GDP) inspectorate and focuses on the many issues relating to the storage and distribution of medicinal products that need to be maintained between 2 and 8C.
Readers’ attention is also drawn to relevant advice from the Royal Pharmaceutical Society and sections of the code of ethics but it must be understood that whereas a pharmacist can apply professional judgement in relation to the sale and supply of medicines within a retail pharmacy this is not the case for licensed wholesale dealers who must fully comply with GDP guidelines.
To ensure that medicines distributed to retail pharmacies and other persons entitled to sell products to the general public are of the appropriate quality, they must be manufactured in licensed facilities that comply with the principles and guidelines of good manufacturing practice (GMP). They must also be distributed through a network of licensed pharmaceutical wholesalers, who in turn, must comply with GDP.
The requirement for wholesalers to comply with the principles of GDP is stated in European Directive 92/25/EEC, which also provides that member states will perform inspections of their premises. Pharmacists are required by their professional standards and guidance for the sale and supply of medicines to ensure that pharmaceutical stock is sourced from a reputable source and that it is stored under suitable conditions, taking into consideration the stability of a drug.
Following manufacture, some medicinal products need to be stored and shipped at lower than ambient temperatures to assure their quality and efficacy. These are often referred to as “cold chain products” or “fridge lines” and wholesale dealers are expected to store and distribute them in strict accordance with the product labelling requirements.
Some cold chain items, such as vaccines, insulin, biotech products and products derived from blood or plasma, can be classified as particularly high risk because they are at risk from freezing as well as elevated temperatures.
Following dispatch from a manufacturing facility, the distribution chain for medicinal products can be complex, potentially involving a number of storage locations, wholesalers and modes of transport, before the delivery 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 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 prevent jeopardising their quality.
For small volumes of lower risk products, with short journey times of less than three hours, insulated containers are generally used. For extended 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: they must not be allowed into direct contact with the products being shipped.
Bespoke packaging with compartments for the gel or ice blocks is 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 effective. Larger volumes of refrigerated products will generally be shipped in refrigerated transport. This is particularly important if transportation times may be protracted or liable to delay.
Whatever method of transport is used it is important to show that the required temperatures can be maintained for a stated time period. 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 is the implementation of temperature monitoring 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 to provide temperature data for the entire journey.
Daily temperature monitoring and recording should also be carried out at all storage locations. Any recording devices should be calibrated annually against a certificated standard.
Distributors should review the temperature records or data for each consignment and there should be procedures in place for implementing corrective action in the case of adverse events. They should also ensure that consignments of refrigerated goods are clearly labelled with the required storage and transport conditions that should be maintained.
When wholesalers employ couriers, they must satisfy themselves that they also adhere to the above. To ensure this, some wholesalers will 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 (eg, 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 appropriate conditions and there is concern that their quality may have been compromised, the delivery should be quarantined in a suitable refrigerator while 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 (see Panel 1).
As with any delivery, staff receiving goods should also be alert for the presence of counterfeit medicines.
Panel 1: 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 sent for disposal.
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 should be 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.
A trained 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 a time when the checks can be made. Provided the checks are satisfactory the product will be returned to saleable stock.
Storage in the pharmacy
The code of ethics states that pharmacists should ensure that “refrigerators used for pharmacy stock are capable of storing products between 2 and 8C. They must be equipped with a maximum/minimum thermometer, or other suitable alternative, which is checked on each day the pharmacy is open and the maximum and minimum temperatures recorded.”
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 0 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.
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. Advice from the Royal Pharmaceutical Society inspectors is that a fridge containing medicines should not be used to store food and drinks in order to limit the chance of changes in temperature and contamination.
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 monitoring is usually 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 fridges 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.
Whatever type of refrigerator is used, products should be stored in an orderly fashion on shelves — not on the floor of the unit — 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.
As was applicable for transportation, products stored in a refrigerator should be subject to daily temperature monitoring. Different types of thermometer are available, from mercury maximum and minimum to digital devices. Guidance on the use of thermometers is available from the Society (see Resources).
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 prescribed parameters.
Temperature records are especially important in the event of a problem with a product and may be required as evidence of appropriate storage. With this in mind, they should be free from alterations or corrections and the person responsible for taking the readings each day should have a trained deputy to cover for absences. Additionally, the records should be routinely reviewed — the Society inspectors suggest monthly.
Handling pharmacy cold chain breaches
The two most likely causes of a major cold chain breach in the pharmacy are a power cut or fridge breakdown. Advice from the Society’s fitness-to-practise department is that pharmacists must use their professional judgement to determine whether the safety of the medicines stock has been compromised due to adverse temperatures.
The manufacturers of individual products should be contacted for guidance on the stability of medicines. Factors to take into consideration would be how long it is estimated the refrigerator has been out of action the medicinal products involved and manufacturers guidelines. Where there are concerns about the stability of certain medicines due to the exposure of adverse temperatures these medicines should be segregated from the rest of the stock and not be sold or supplied for use.
In the event of a power cut, if the fridge stock cannot be safely transported to a working fridge, the door should be kept shut so as not to let out the cold air. It may be useful to keep an hourly record of the temperature, if possible, so these details can be passed on to manufacturers. Key questions to ask manufacturers are whether the adverse storage conditions (highest temperature and duration) are likely to have any significant effect on the quality of a product and whether its expiry date will be affected.
Such cold chain breaches will be unusual, but it is wise to be prepared. For example, the Society recommends that, where possible, pharmacies ensure that they have an emergency power supply if there is a power cut (this should ideally supply power for a minimum of 24 hours). Pharmacies should also have defined procedures in place in the event of a fault or failure. An example of such a procedure was given in an article in the Canadian publication Pharmacy Practice and this is shown in Panel 2 (p452).
Panel 2: Handling cold chain breaches in pharmacies
1) Quarantine the products, label them “do not use” and communicate the incident to staff
2) Record the details of the adverse conditions, including the range of temperatures and duration
3) Assess each product (as described in the main text, p451)
4) Review all the information
5) Dispose of products that have been rendered unsafe (err on the side of caution to safeguard patients)
6) Document your actions and monitor the outcome
Advice to patients
Information about special storage conditions for a medicine should be given to the patient or customer at the point of dispensing or sale, as well as information about physical signs of improper storage. Good practical advice also includes recommending that people with a prescription for vaccines collect them just before a clinic appointment, so as to be sure that the product has been kept at the recommended temperature.
Pharmacists may be asked for advice on storage in situations, such as a long journey. According to Colin Cable, the Society’s pharmaceutical sciences information adviser, information sources for pharmacists in this respect include:
- Product data sheets
- Local hospital medicines information units
- The National Pharmacy Association
- Papers published in the pharmaceutical literature (usually summaries of information from manufacturers)
For example, the data sheets for some insulin products (eg, Humalog) state that, as long as they are protected from light, vials, cartridges and prefilled pens may be used for up to 28 days and that, when in use, they can be stored at up to 30C. Similarly the datasheets for some eye drops (eg, Xalatan) state that, while in use (four week maximum), eyedrops can be stored below 25C. However, products will differ and each must be checked individually.
More tricky is when a patient plans to visit a place where temperatures are well in excess of 25C or where refrigeration will not be possible. In such cases, the manufacturer should be contacted for advice. Some insulin manufacturers recommend the use of “cool bags”. Some of these are gel-based and activated by cold water so no ice or refrigeration is needed. Again, each individual product must be checked. In the event of a long trip, and depending on the country, some manufacturers recommend that patients take enough insulin for a month but then source insulin from the country they are visiting.
Information may not always be available. Dr Cable said that where manufacturers are unable to provide guidance, the specific stability data for individual products available in the scientific literature is, at best, limited. This makes it difficult to provide patients with definitive advice on the likely effect of storage at elevated temperatures on the stability of a preparation. On occasion, following discussion with the patient’s prescriber, it may be possible to switch the patient’s medicine to a product that does not require refrigerated storage.
As a last resort, he suggests that temperature co-efficient (Q10) calculations can be used to give a very rough estimate of the effect that storage of a product at a higher (or lower) temperature than recommended can have on the chemical stability and shelf life (see Resources).
Maintenance of the cold chain throughout the licensed wholesale network is assessed by MHRA GDP inspectors and it is hoped that this article has heightened awareness of some of the issues that need to be considered surrounding the transportation, receipt and storage of cold chain products. In recent years, UK wholesalers have generally been receptive to an increased inspection focus in these areas and there has been a noticeable improvement in standards.
Pharmacies are the final step of the supply chain and have a professional duty to supply medicines that are fit for purpose. Panel 3 lists a summary of tips for achieving this standard.
Panel 3: Safeguarding the cold chain in pharmacies
Avoid siting a refrigerator near a heat source and keep the surroundings clear (eg, paperwork, bags, etc, should not be stored on top of the unit)
Put a sign near the socket where the fridge is plugged in (and the circuit breaker box) saying that the power should not be turned off
Make sure that the refrigerator plug and cord is situated so that it is unlikely to be knocked out by accident
Put fridge lines in the refrigerator as soon as they are received
Do not overstock the fridge — make sure there is space for air to circulate
Only open the refrigerator door when necessary and keep it open for as short a time as possible
Read and record the maximum and minimum temperatures daily
Make sure dispensary staff know correct storage requirements (eg, ensuring the the fridge is not crowded and products are not allowed to freeze)
Designate responsibility of storing and handling fridge lines to at least two trained staff
Keep procedures to follow in the event of fridge failure near the fridge
Guidance from the Royal Pharmaceutical Society on fridge temperature monitoring and how thermometers should be used (PDF 90K)
The MHRA has published its anticounterfeit strategy on its website (www.mhra.gsi. gov.uk).
A previous Journal article gives MHRA recommendations on the control and monitoring of storage and transportation temperatures of medicinal products (PJ, 20 July 2001, pp128–131).
Information on Q10 calculations can be found in: Lund W (editor). The pharmaceutical codex: principles and practice of pharmaceutics. 12th ed. London: Pharmaceutical Press, 1994: 309; and Connors KA, Amidon GL, Stella VJ. Chemical stability of pharmaceuticals. A handbook for pharmacists. 2nd ed. Chichester: John Wiley & Sons, 1986: 22–31.
A document “Which medicines require storage in a refrigerator in my pharmacy?” produced by the Royal Pharmaceutical Society’s information pharmacists (PDF 80K)
An update of this list of fridge lines is produced each year and is usually published in The Pharmaceutical Journal in January.
Action: practice points
Reading is only one way to undertake CPD and the Society will expect to see various approaches in a pharmacist’s CPD portfolio.
1. Make sure your fridge is clean and tidy and has enough space for air to flow.
2. Investigate the range of products available for protecting fridge lines when travelling.
3. Write or review your standard operating procedure in the event of a power cut.
For your work to be presented as CPD, you need to evaluate your reading and any other activities. Answer the following questions:
Steve Todd has been a good distribution practice medicines inspector at the Medicines and Healthcare products Regulatory Agency for seven years
Citation: The Pharmaceutical Journal URI: 10036090
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