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International Clinical Trials

Multiple Choice

Every clinical trial has its own specific requirements for the labelling of investigational products. However, they must all meet overarching legal requirements for Good Manufacturing Practice (GMP). In particular, trials taking place within the European Union (EU) have to comply with the EU Guidelines to Good Manufacturing Practice, while those in the US have to meet the Code of Federal Regulations (1,2).

In the EU Guidelines, label contents are specified in Annex 13, with structure and other aspects such as layout, font size and symbols defined in the Guideline on Readability (3).

Multinational Demands

Clinical trials are not usually limited to a single participating country, but are conducted in several countries. According to Annex 13, “Particulars should appear in the official language(s) of the country in which the investigational medicinal product is to be used” (4). As a result, the labelling of investigational products has to accommodate an increasing number of languages.

Labels may have to be printed in up to 40 different versions. With each language having its own label, this means having to produce 40 label variants in the volume required before applying and distributing them. In addition, separate batch documentation is required for each label version, which means that the paperwork involved is immense.

If the medication labelled accordingly is not available for a particular country, then significant delays will affect the trial timetable until subsequent production can ultimately ease the bottleneck.

Re-using medication that has already been labelled but is no longer needed will require an equally high amount of time and effort.

Booklet Labels

Another option is to integrate several languages into a single product. This can be achieved by using so-called booklet labels, which are now available in up to 113 pages. These are a combination of self-adhesive labels and leaflets. Thanks to their large volume, they can accommodate all languages in a clear structure and readable font size – providing an all-purpose solution that can be applied in every participating country.

At the start of April 2013, the International Society for Pharmaceutical Engineering – a not-for-profit association operating worldwide – published its Good Practice Guide: Booklet Labels with the aim of establishing uniform design and structure standards for booklet labels across markets (5). In addition to tables of contents, thumb indexes can help users find their way through booklets. Usually enhanced by contrasting colours, such indexes facilitate access to key information, while also improving patient compliance.

Creative Solutions

Regardless of whether complete marking is achieved by means of one-layer, multilayer or booklet labels, labels should always match the shape of primary packaging. For instance, vials, pens, syringes and inhalers can be labelled in different ways. Wrap-around labels are particularly suitable for small-diameter cylindrical containers. These labels, which are wrapped around cylindrical bodies several times, can be resealed after each opening.

Unusual shapes tend to require a high level of creativity, know-how and experience from label manufacturers. R&D departments are therefore becoming increasingly important. Labels are developed individually and tested for criteria such as adhesion and adaptability, as well as user-friendliness. Label performance during application can be simulated by specialist packaging and labelling providers or tested at the investigational drug manufacturer's facilities.

Booklet labels are often enhanced by additional functions. For example, should an infusion bottle require labelling, then a label with an integrated hoop for hanging the bottle offers improved ease of use. Another way of optimising the subsequent use of investigational products is to add documentary sections to labels. In this case, booklet labels are supplemented by one or several documentary stickers featuring trial-specific data, to provide complete and accurate documentation – for example in patients’ medical reports. Wrap-around booklet labels for small containers can also include documentary sections.

Security Features

In order for trial subjects and staff to be able to assess the integrity of investigational products, it is advisable to choose labels with tamper-evident features: the area around the mouth of the container should be fully or partly covered by the label, and opening the product will damage the label badly and make tampering clearly visible.

There is another type of security to be considered by the pharmacist whenever subjects take home investigational drugs – the risk of children accessing the drugs. If this is a consideration, then child-resistant packaging can protect them against improper use. Depending on the type of primary packaging used and the level of safety required, there are different ways of securing packaging. For example, blister packs can be covered with labels; these blister-label combinations contain mechanical and logical barriers which make them child-resistant, but easy enough for adults to open.

Another factor is that investigational products are usually stored in cool places or even temporarily frozen. As a result, product labelling must be capable of withstanding temperatures as low as -196°C without damage, while retaining full adhesion and legibility after the clinical trial products are heated. To exclude label deterioration caused by water, grease or chemicals right from the start, it is recommended that synthetic materials be used to manufacture labels.

Printing Variable Data

Labels can have different functions and adapt to tough constraints, but ultimately their primary purpose – when affixed on investigational products – is to convey information. In the EU, mandatory labelling data is stipulated in Annex 13. However, personalised data is not specified until very shortly before drug labelling takes place. This is why some label manufacturers offer variable data printing at short notice.

When printing variable data, the EU GMP Guidelines are complied with by using validated software, standalone camera inspection, non-contact printing systems and trained staff. A possible source of error can be eliminated by replacing faulty labels during printing in order for pharmacists or contract packers to process label reels of a consistent quality.

Ultraviolet inkjet technology delivers high-quality print with outstanding surface adhesion and high light fastness. These prints are waterproof, alcohol-resistant, as well as wear-, scratch- and smudge-proof. The quality of such prints will not even be affected by temperatures as low as -196°C.

Blinding Clinical Trials

Pharmaceutical manufacturers often face the challenge of having to blind their investigational products adequately to make sure that investigators, nursing staff, participating patients and data analysts are unaware of the treatment assignments. It is the only way of precluding unwanted biases in trials. The type of product selected for blinding depends on the primary packaging of the study drugs.

Vials, bottles, pots, jars and tubes can be fully covered. Optimal blinding can make the time-consuming colour matching between liquid placebo and active substance unnecessary. Some blinding solutions can only be used for single-blind trials, others for double-blind trials. They may be completed with various options, such as Braille embossing, variable data, tamper-evident and other security features or a code-break function, and documentary sections.

Masking Considerations

Vials can be blinded by using boxes made of opaque and robust cardboard. As a result, the volume and height of the containers, as well as the colour of the contents, are entirely masked and therefore unidentifiable.

Boxes can be printed on the inside in colour, in order to give the active substance and the placebo groups the impression that both trial products are the same colour. Furthermore, a control window can be added to these boxes. If it needs opening for some reason, it will become immediately visible.

In addition to the blinding box, another option features an opaque or transparent plastic cup with a separate lid, into which the container to be masked is placed. The cup can be partly or completely covered with a label. Placed directly across the opening area, the label can, at the same time, fulfil a tamper-evident purpose.

Pharmacists and contract packagers often use labels to blind tubes, jars or pots. Once labels are glued on the tubes, it is impossible for trial staff and volunteers to tell the placebo from the active substance. Furthermore, if trial-specific data needs additional masking, printable laser fields, scratch areas and sections with a code-break function can be subsequently incorporated into the secondary packaging.

Labels traditionally used as secondary packaging for investigational products have now changed into flexible, compact multifunctional tools which are able to convey variable data in different languages, blind contents, indicate first opening and product originality, and help ensure user-friendly products.

1. European Commission, EudraLex, The rules governing medicinal products in the European Union, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 13(3), Volume 4, 2010
2. US Food and Drug Administration, Code of Federal Regulations, Title 21, Parts 210-211, 1978
3. European Commission, Guideline on the Readability of the Labelling and Package Leaflet of Medicinal Products for Human Use, Revision 1, 2009
4. European Commission, EudraLex, The rules governing medicinal products in the European Union, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 13(3), Volume 4, p9, 2010
5. ISPE, Good Practice Guide: Booklet Labels, pp18-19, 2013

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About the author

Frank Jäger is Head of Sales and Marketing at Faubel. After completing his studies at the University of Bochum in Germany, Frank held various positions in the medical device industry for nearly ten years. Since joining Faubel in 2012, he has played a key role in expanding the company’s global activities in the US and Asia, while strengthening its service unit dedicated to the overprinting of randomised data.

Nurdan Citamak joined Faubel in August 2013 as Director of Business Development and Sales for North America. She graduated in Business Administration from Würzburg-Schweinfurt University in Germany, majoring in International Business from Bond University in Australia. Nurdan’s primary focus is developing client awareness of Faubel’s unique capabilities in clinical trial labelling.

Frank Jäger
Nurdan Citamak
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