For many unlicensed medicines there will be little or no data on the physico-chemical stability of the formulation that is prepared. By contrast, products with a marketing authorisation are required to have robust and validated stability data to justify their shelf life and storage conditions. Consequently, the assigned shelf life for unlicensed medicines will, in many cases, be based on the professional judgement of the person responsible for its preparation or manufacture, using either available scientific information and published data or a limited amount of stability testing data.
Assigning storage conditions for unlicensed medicines is a complex issue for a number of reasons.
1. Degradation pathways for chemical actives are often complex and are not always predictable.
2. Many unlicensed preparations require the reformulation of solid oral dosage forms as oral liquids or suspensions to facilitate their administration to paediatric and geriatric populations and via naso-gastric tubes. Thus, environmental and physicochemical factors such as heat, light, moisture, and pH will become more critical since, in many cases, very little will be known about the stability profile of the active substance in liquid formulations.
3. Whilst extemporaneous preparations will normally be freshly prepared, the storage and shelf life during use needs to be considered if it becomes impractical to prepare the product each time, immediately prior to dispensing.
4.
Excipients such as chemical and microbiological preservatives that prolong the in-use shelf life of products are sometimes deliberately omitted from unlicensed formulations due to the possibility of adverse reactions. This may limit the period over which the product can be stored and used.
5. One of the reasons for the absence of a licensed medicinal product can be that large scale batch manufacture is impractical due to poor stability profiles and hence short shelf life. The product, therefore, becomes uneconomical to manufacture commercially, resulting in the need to prepare an unlicensed version.
6. Whilst it might be possible to produce a stable formulation under suitable controlled conditions prior to use, once the container is opened the risk of degradation can increase significantly, particularly where the in-use storage conditions differ from those applied before opening.
7. The stability of an unlicensed medicine depends not only on the intrinsic stability characteristics of the active substance but also on the influence of formulation
excipients and potential interactions with the packaging components. These factors may be especially complex in cases where a liquid formulation is prepared from a previously formulated solid dosage form.
8. The type and size of the container closure system, and the number of doses it contains, should be consistent with the known stability and dosage regimen of the product.
In the monographs for unlicensed medicines, a storage statement has been included where data on the stability of the formulation are available. Storage statements of the British Pharmacopoeia are non-mandatory but give a recommended shelf life under defined storage conditions. Similarly, where information on the shelf life during use is known, this is also included in the storage statement. As a general rule the information in the storage statement relates only to the physico-chemical stability of the formulation and not to its microbiological quality. Such information applies only to the product formulation described in the monograph. Where a different formulation is used, it cannot be assumed that the storage statement in the monograph will still apply.
Where no storage statement is given in the monograph no assumptions should be made about the stability or shelf life of the product. Pharmacopoeial monographs apply throughout the shelf life of the product and so any assigned storage conditions and shelf life should be validated by the persons responsible for the preparation or manufacture of the product, who should satisfy themselves that the product complies with the monograph during storage and use, and that any assigned shelf life is appropriate.