The importance of being compliant – packaging and labelling processes8 July 2016
The developmental issues have been resolved and now the new drug that is to be used in a clinical trial needs to be packaged and labelled in a way that is economical and compliance-friendly. Kerry Taylor-Smith investigates how best to deal with packaging and labelling processes within global clinical supply chains, and why it can, at times, present problems for trials.
The packaging and labelling of supplies in clinical trials is important – and the watchword is compliance. Not only do pharmaceutical companies have to adhere to the rules and regulations governing medicines and clinical trials, but they also need volunteers to see the study through from start to finish. It is, therefore, important to have packaging that is easy to open and labelled with clear, precise directions on how to take the medication.
The appearance and packaging of clinical trial supplies can be crucial to creating a professional image, influencing compliance and ensuring the integrity and quality of a product. The packaging needs to be designed for function, always bearing in mind the end user. It needs to ensure patient safety and meet the regulatory requirements, while also being patient-friendly. The drug needs to be accessible, which means it may be necessary to offer different types of packaging to cater for a range of users and their respective capabilities.
The choice of packaging will be driven by what phase a trial is in, and the number of volunteers available.
Blister packs, for example, have been proven to drive compliance in clinical trials: they protect individual doses and prevent contamination; they have calendar printing to remind volunteers to take the next dosage; and they can be made from a wide range of materials.
Blister packs can also be difficult to use, however, and they may not be suitable for all trial volunteers, for example, for those who lack manual dexterity. Another option might be a vial or bottle. Bottles are generally seen as cheaper and an easier alternative, but are less protected against contamination or abuse.
Equally important to consider is labelling – the material to be used and the information that should be included. Packaging and labelling of clinical trial products is complex and more liable to errors than marketed products – especially if the trial is blinded or the products have a similar appearance.
It would be impossible to label clinical trials strictly in accordance with the regulations for labelling pharmaceuticals, and it is important to avoid conflict with hospital and pharmacy labelling. To avoid mislabelling and errors, the European Clinical Trial Directive, in annex 13 of the ‘EU Guidelines of Good Manufacturing Practice’, suggests that in order to ensure the protection of the trial subject, enable identification of the product and the trial, and assist in the proper use of the product, labels should include:
- contact details of the sponsor, contract research organisation or investigator (the main contact for information on the product, clinical trial and emergency unblinding)
- the pharmaceutical dosage form, route of administration, quantity of dosage units and, in the case of open trials, the name/identifier and strength/potency
- a batch or code number to identify the contents and packaging operation
- a trial reference code identifying the trial, site, investigator and sponsor
- the trial subject identification number, treatment number and visit number
- directions for use
- warnings such as ‘for clinical trial use only’ and ‘keep out of reach of children’
- storage conditions
- period of use – use-by date, expiry date or retest date.
Labels must have precise specifications as errors can be dangerous to the patient and detrimental to the trial. All of this information, however, can be overwhelming, as most people focus only on what they consider the important bits on the label. It might be necessary, therefore, to embolden or highlight dosage instructions, include visual aids and provide step-by-step directions if the instructions are complex.
The global nature of today’s clinical trials means that medicines are sent to multiple countries, which have their own requirements and regulations for packaging and labelling. Regions within a country may even have particular labelling requirements, so flexibility is required in terms of what is printed on the label. Annex 13 says that details and instructions should appear on primary and secondary packaging in the official language of the country in which it is being used. It will also be necessary to consider any errors that could creep in when instructions are being translated, as these could be damaging to the trial and dangerous to patients.
There is more to consider than patient-friendly packaging and whether they adhere to current regulations: the medicine might be sensitive to temperature, for example. More trials are using biopharmaceuticals or advanced cellular and gene therapies, which require precise control of environmental conditions to maintain efficacy. Temperature can change during storage, handling or distribution, and affect the quality and efficacy of the product, the accumulated data, the drug’s safety and the trial’s financial investment.
These medicines, therefore, must use labels that can withstand a range of temperatures, paying attention to using ink that will not run, smudge or smear. The options include polyester labels stuck on with permanent acrylic, and thermal transfer print technology.
The supplies must then be packaged for distribution. Normally, a simple cardboard or insulated shipper will suffice, but temperature-sensitive medicines require greater care. Packaging and insulated container/refrigerant systems need to provide protection for temperature-sensitive items to avoid:
? administering unsafe products
? non-compliance with global regulations and standards
? thermal variability, which can lead
to inconsistent results
? rejected shipments, which can cause costly delays and increase the complexity of trial management.
Shipping large volumes of refrigerated supplies globally, while maintaining and documenting appropriate environmental conditions is challenging to distribute. Given the increasing number of clinical sites – some in remote regions – it can be difficult to maintain product quality and mitigate the risk of thermal excursions. Dry ice was the standard way to ship cryogenically frozen biologic materials for many years, but it also poses risks to product quality, logistics and safety; its use is even restricted in some regions. Packaging supplies in liquid nitrogen offers an alternative, and advanced cryoshipping technology makes it easier for facilities to organise, manage and gather samples for testing and evaluation at a fraction of the cost, time, hassle and risk. It eliminates the need for HAZMAT documentation, labelling, training and facilities, and the shipments are not restricted by airlines or couriers.
Rise of the trials
A successful clinical trial supply chain requires efficiency and flexibility. A good working relationship between all those involved – clinical researchers and operators, contract manufacturers and internal supply chain staff – will ensure a smooth process. Proper planning is important as clinical trials grow more complex. Not only have they increased in number – the US has seen a rise from 24,924 clinical trials in 2006 to 213,747 by April 2016 – but their test period has lengthened and their geographical reach broadened.
Clinical operations personnel suggest the increased globalisation of clinical trials, and the resulting problems in distribution management that can lead to delays, is a major weakness in the supply chain. Global trade regulations present a particular difficulty to distribution as they can prevent movement of supplies between sites, delay deliveries and even unblind trial supplies. Problems include delays when clearing customs, poor distribution capacity and distribution lanes.
Expiration dating can also be problematic. Many trial products have a short expiration date and require relabelling, which must be done by the pharmaceutical company or under the supervision of one of their representatives. Failure to do so can result in discarded products.
Tracking the drug through the supply chain can also be difficult. It is essential, therefore, to have a reliable and efficient accountability process to recover any unused drugs. Establishing local coordinators to monitor market and governmental developments, manage local depots and supplier relationships, troubleshoot shipments, and supervise depots is helpful in controlling this link in the supply chain.
Labelling and packaging supplies for clinical trials is complex. Packaging needs to be attractive and practical, while labels need to be precise and clear. The end user – the volunteer patient – needs to be kept in mind at all times, as their compliance is vital to a successful trial. At the same time, guidelines, regulations and good manufacturing processes must be respected. The supply chain needs to be robust, flexible and constantly evolving to keep up with today’s global clinical trials.