This is the second of two blog posts dealing with the management of refrigerated medicinal products and like the first, draws on some of the findings from GDP inspections, references to the EU GDP Guidelines 2013, the Green Guide and an article I wrote for the Pharmaceutical Journal a few years ago.
Packing of consignments and temperature management during transportation
Before being transported, refrigerated 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. Chapter 9.3 of the EU GDP Guidelines mentions this.
Additionally, the same chapter states,
“Containers should bear labels providing sufficient information on handling and storage requirements and precautions to ensure that the products are properly handled and secured at all times. The containers should enable identification of the contents of the containers and the source”.
For small volumes of lower risk products, with short journey times of less than three hours, validated insulated containers can be 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 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 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.
Again, chapter 9 of the EU Guidelines is helpful.
Best practice is the implementation of temperature monitoring as a matter of routine for all refrigerated deliveries, but especially within shipments of high risk products. The temperature should be strictly controlled and monitored with calibrated temperature probes, to provide temperature data for the entire journey.
This data should be retained by the wholesaler for the required 5 years.
Daily minimum and maximum temperature monitoring and recording should also be carried out at all storage locations. Any recording devices should be calibrated.
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 to be maintained as stated above.
“The application of Mean Kinetic Temperature (MKT) to temperature monitoring of wholesale products is only appropriate where an acceptable MKT value is provided by the MA holder for a specific product, and the recording of temperature can be confirmed to be consistent and complete from the moment of leaving the manufacturer’s premises. In practice the application of MKT fails where a complete chain of temperature recording cannot be allocated to a specific consignment of a product. Attempts to apply MKT have been proposed by wholesalers as an alternative to having adequate temperature control within their warehouses as well as attempting to downgrade the impact of temperature excursions. The use of MKT in the wholesale environment without robust supporting information and methodology is therefore discouraged”.
A risk based approach should be in place when planning transportation and should include the method of transport and delivery routes.
“Quality Risk Management is a systematic process for the assessment, control, communication and review of risks to the quality of medicinal products. It can be applied both proactively and retrospectively”. EU GDP Chapter 1.5.
If you also look at ICH Q9, this gives examples of QRM processes.
Some refrigerated items, such as vaccines, biotech products such as insulin and products derived from blood, plasma or serum may be classified as high risk because they are vulnerable to freezing as well as exposure to high temperatures.
Other products, for example, chloramphenicol eye drops, may be labelled as requiring storage between 2 and 80C but a short deviation from this temperature range may present less of a danger to patients.
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 patient.
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.
Third party couriers
When wholesalers employ couriers, they must satisfy themselves that they can adhere to the EU GDP Guidelines and can provide the service for which they are engaged.
The selection of third party service providers is very important and roles and responsibilities must be defined by a written contract.
Chapter 7 of the EU GDP Guidelines (Outsourced Activities) provides advice in this area and Chapter 1.3 covers the Management of Outsourced Activities.
More details on transportation can be found at my earlier post.
Returns of refrigerated medicinal products
Because of the inherent dangers of returning refrigerated products, many wholesale dealers will not consider refrigerated returns 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 should be returned in accordance with the MHRA guidance (below), 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 should examine the returned product to check for tampering and to confirm that the return has been made in accordance with MHRA guidance.
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 and are documented, the product may then be returned to saleable stock.
The MHRA has provided guidance on managing returned non-defective (ambient) and refrigerated medicinal products;
Returns of non-defective medicinal products
Any person acting as a wholesale distributor has to hold a wholesale distribution authorisation a Wholesale Dealer’s Authorisation (WDA).
Article 80(g) of Directive 2001/83/EC provides that distributors of human medicines must comply with the principles of and guidelines for good distribution practice (GDP).
The Commission has revised its guidelines for GDP which are now contained in the Guidelines on Good Distribution Practice of Medicinal Products for Human Use (2013/C 68/01).
Paragraph 6.3 of GDP refers to returned medicinal products, the key elements being that;
“Products that have left the premises of the distributor should only be returned to saleable stock if....
"the medicinal products are in their unopened and undamaged secondary packaging and are in good condition; have not expired and have not been recalled;
"it has been demonstrated by the customer that the medicinal products have been transported, stored and handled in compliance with their specific storage requirements”; and
“they have been examined and assessed by a sufficiently trained and competent person authorised to do so;”
The MHRA re-affirm that a licenced site can only be interpreted as being under full GDP control at a licenced WDA site.
This applies to all categories of medicines.
Medicinal products held in unlicensed storage and distribution sites are not considered to be within the licenced WDA distribution network.
Ambient returns from a licenced WDA site
The MHRA will adopt a pragmatic approach to the return of non-defective medicinal products for those products returned from a customer operating from a licensed WDA site.
In such circumstances, the return should be completed as expeditiously as possible and the most expedient and appropriate method of transportation must be used.
The Responsible Person or the authorised person receiving the return, must be able to demonstrate evidence of “full knowledge” of the storage of the returned products throughout the period it has been with the customer, including transportation.
Ambient returns from an unlicensed WDA site
For those non defective ambient medicinal products returned from an unlicensed site, the return should be completed within five days, including transport.
The Responsible Person or the authorised person must be able to demonstrate evidence of “full knowledge” of the storage whilst at the unlicensed site, including transportation.
Refrigerated returns from a licenced WDA site
The MHRA will adopt a pragmatic approach to the return of non-defective medicinal products for those products returned from a customer operating from a licenced WDA site.
In such circumstances, the return should be completed expeditiously and the most expedient and appropriate method of transportation must be used.
The Responsible Person or the authorised person receiving the return, must be able to demonstrate evidence of “full knowledge” of the storage of the returned products throughout the period it has been with the customer, including transportation.
Refrigerated returns from an unlicensed WDA site
For those non defective refrigerated medicinal products returned from an unlicensed site, the return should be completed within 24 hours, including transport.
The Responsible Person or the authorised person must be able to demonstrate evidence of “full knowledge” of the storage whilst at the unlicensed site, including transportation.
