The Black Triangle: Impact of the European Commission's New Packaging Legislation

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Just over a month ago, the European Commission implemented new laws regarding packaging for drugs that have a potential safety risk requiring them to be marked with an inverted black triangle; this will have profound implications for the packaging and labelling side of the pharma industry. Ryta Kuzel, Director and Owner of VigiReg Consulting Ltd, which specialises in Pharmacovigilance auditing and Regulatory Affairs, explains the impact of these new regulations and gives a summary of the regulatory framework requirements for pharmaceuticals in Europe.


 Pharma IQ:  What new information is coming out of the European Commission regarding packaging?

 R Kuzel: Last summer we saw one of the biggest changes to EU pharmaceutical legislation for nearly 20 years, which was the rewrite of the pharmacovigilance legislation. As a result of  the changes that were introduced, in March of this year, the European Commission introduced new legal requirements regarding packaging for all new drugs (approved since 01 January 2011), as well as some older drugs that have identified safety issues to be marked with an inverted black equilateral triangle. This triangle cannot be smaller than 5 millimetres on each side. The purpose of the inverted black triangle is for it to be displayed on the patient information leaflet (PIL), which is the paperwork that goes inside the blister pack carton, or vial carton  to flag to the doctor, pharmacist or patient that this is a product that needs extra monitoring in terms of adverse drug reactions.

 So if a product has one of these inverted triangles, and the requirements for how it’s presented are quite specific, and people see it,  they are  going to be actively encouraged to report any unexpected or unforeseen adverse drug reactions to the health authorities.


 The EMA first published a list of medicinal products that are subject to the black triangle and additional safety monitoring on their website on 25 April 2013. This list will be updated on a monthly basis.

 The timeline is tight for anyone who’s marketing a drug in Europe to implement this new regulation. Companies have 9 months to make sure that products which are subject to this additional safety monitoring, have the symbol in place by the end of 2013. So a very important change to artwork and packaging has come out of this huge rewrite of the pharmacovigilance legislation in Europe.


Pharma IQ: Can you give us a brief update on regulatory frameworks for submitting packaging mock-ups?

 R Kuzel: The importance of compliance with the packaging regulatory requirements in Europe is very clear. The purpose of it is to ensure the safe use of medicines by patients and health care professionals once they’re approved. Even at the time of submitting a licence application, when one has pulled all the clinical, preclinical, and manufacturing data together in a licence application, known in Europe as an MAA (Marketing Authorisation Application), one has to have a 2D colour mock-up of the blister pack, carton, and vial label (if applicable). This is in addition to the written words that one provides in the form of a PIL, or the SmPC, the Summary of Product Characteristics, which is the important medical and scientific information about the medicinal product provided to healthcare professionals.

 When one designs the outer packaging, there are certain regulatory requirements that must be met. These include what are known as standard written statements that must appear on packaging. Examples of these standard statements in Europe include “Keep out of the sight of children”, and “Read the package leaflet before use”.

 In Europe, we have also had to make sure that we pay particular attention to the braille requirements that need to be incorporated on the outer packaging of pharmaceuticals to ensure that people who are visually impaired can safely identify and take their medicines.

 The final aspect of the core packaging requirements for centrally authorised products in Europe is something known as the blue box, which is literally a blank box with a blue line around it. In each European country that one launches the product, one has to place specific national wording inside this box. This may relate to the legal status of the product indicating whether it is a prescription only medicine (POM), or a pharmacy-only product (P),  a product that can only be bought from a registered pharmacy, but without  a physician’s prescription, or a general sales list (GSL) medicine which  can be bought from any retail outlet.

 So the legal status has to be very carefully and clearly represented in a blue box in each of the countries in the European Union, but in some countries, this box can also contain information on the price of the product, or the reimbursement status, which indicates if the product has been entered onto the National Health Authority’s reimbursement formulary, in which case the government will be paying part or all of  the cost of the product.

 So that is a brief summary of the regulatory requirements for pharmaceutical packaging in Europe, all of which have to be complied with and included in, an initial licence application dossier in Europe.

 Pharma IQ:  What are the main challenges companies appear to experience around artwork control systems and packaging technologies when it comes to regulations?

 R Kuzel: We are constrained sometimes on a European level by having to comply with multi-language packs. So if one is launching a new pharmaceutical product in Europe, in Belgium for example, the national languages  used in Belgium are French, Dutch, and German, which means that any pharmaceutical product launched in Belgium has to have all 3 languages  on the box, and the blister pack. The PIL also has to be in all 3 languages to comply with the law, and that’s a challenge for many packs, especially if they’re only the size of a credit card.

 If one thinks about a carton containing some blister packed tablets, the space for fitting all the required English wording, and other requirements that I’ve just described, is often quite constrained. Therefore, it’s a real challenge to replicate everything three times if you have three national languages in one country. You may therefore be forced to use larger printed components, larger outer-boxes, larger blister packs and larger pieces of paper to print the patient information leaflet.

 A bigger challenge is when one has an intravenous product that is in a small glass vial in a box. If you imagine a small 5 millilitre glass vial, the space for the label on the body of such a vial is very small indeed, and again the challenge of printing the required information in three languages means one may have to move to a larger vial and label in order to meet the national regulatory and legal requirements for a multilingual pack, thus increasing costs.

 These are real examples of challenges that drugs developers are faced with when trying to marry-up how they would like their product to appear on a pharmacy shelf while still complying with the legal packaging and labelling requirements in each of the individual European Union (EU) Member States.

 Pharma IQ: What are the main artwork errors that most companies are guilty of?

 R Kuzel: One of the most common errors that the agencies pick up on while the dossier is under review is that no consideration has been given to the multilingual nature of the pack, and therefore people find themselves redesigning the pack  halfway through a regulatory approval procedure when they are planning to launch in a couple of countries on the day that they get their licence. This can in turn delay the launch date because they have to rework their entire packaging design and layout.

 Another area that applicants sometimes do not give due consideration to is the use of the font size on the artwork and packing. The use of too small a font size can reduce legibility which may lead to medication errors, the product being used inappropriately, and could result in a serious adverse drug reaction if the product is  not used correctly. So using too small a font size on the artwork and packaging is a common problem identified during the MAA review.

 Time management and resources can also have knock-on effects, such as not factoring in enough time and resource to let people absorb comments received from the regulatory authorities during their review of the MAA. One can have several versions of the artwork mock-ups being sent back to the regulators for their review, comment, and approval. People often focus on the technical aspects of a dossier, the clinical data, the preclinical data, the manufacturing data, and then leave the artwork and packaging to one side, regarding it as an afterthought, whereas really it should be managed with a dedicated resource in parallel with the dossier review.

 In particular, when one looks at the regulatory procedures in Europe for obtaining  product approval, the timelines are very short,  even though one can be dealing in English right through the regulatory procedure until the product is approved. When it does get approved, the product information and packaging have to be translated into the 24 national languages of the EU. Therefore, linguistic changes and translations are a big challenge for any drug developer who is trying to manage artwork and packaging during an EU product review.

 To summarise, my advice is to understand the regulatory requirements, particularly the multilingual pack, use the right font size to ensure legibility, and then thirdly, having dedicated resources for the management of artwork and packaging so that it does not unduly delay the launch your product after approval in Europe.

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