Care packaging: Inside the Falsified Medicines Directive

pharmafile | April 16, 2018 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing biotech, drugs, packaging, pharma, pharmaceutical 

When it comes to the pharmaceutical supply chain, patient safety has and will always be a primary concern for all parties involved. To tackle this ever-present risk in Europe, the ambitious solution has been to come together to form a region-wide safety net to ensure the utmost standards of product validity, in part by leveraging new innovations in medicinal packaging. And so, the Falsified Medicines Directive (FMD) was born.

The directive itself, known formally as European Directive 2011/62/EU, published in 2011, came into force in Europe in January 2013, amending Directive 2001/83/EC on the community code relating to medicinal products for human use. Its primary purpose is to prevent the entry of falsified medicines into the legal supply chain, and to achieve this it enforces significant changes on the European framework concerning the supply of medicines, extending to businesses that have in the past not been directly subjected to medicines regulation.

While the directive covers a wide range of changes to the supply chain from a medicine’s manufacture to its distribution to patients, it principally works by introducing a serialisation system by which each and every product can be authenticated by cross-referencing its unique serial code against a Europe-wide database, which manufacturers will be required to update as they generate new products. This element of the FMD was clarified by the publication of a delegated regulation, published in 2016, and is due to come into play, on a full scale, in February 2019.

These codes, that will be mandated to appear on product packaging, can be scanned at any point in the chain, so a pharmacist at one end of the chain can easily confirm that a pack has the same code that the manufacturer originally put on it in the production line, ostensibly solving the problem previously inherent in accurately authenticating falsified products. When the patient is ready to receive the medication at the end of the supply chain, the package is then decommissioned and removed from the system to confirm receipt.

On a product packaging level, the safety measures of the FMD outlined in the 2016 delegated regulation are to be achieved through two elements: the aforementioned serialisation of the supply chain, manifested on the product itself as a barcode that will contain important data that can be referenced against the database, and a tamper-proof seal to determine whether a package and its contents have been modified in any way before reaching the patient.

Safety first

So, why do we need the FMD? Falsified medicines have always been a key concern when it comes to protecting patient safety and the investments of manufacturers, and the necessity for the directive was referenced in the directive itself, included in the [Official Journal of the European Union]: “There is an alarming increase of medicinal products detected in the Union which are falsified in relation to their identity, history or source. Those products usually contain sub-standard or falsified ingredients, or no ingredients or ingredients, including active substances, in the wrong dosage thus posing an important threat to public health.

“The falsification of medicinal products is a global problem, requiring effective and enhanced international coordination and cooperation in order to ensure that anti-falsification strategies are more effective, in particular as regards sale of such products via the Internet.”

In order to fight this problem, the two packaging elements mandated by the FMD are a key part of the battle. To learn more about these features and the impact of the FMD on packaging and the supply chain, [Pharmafocus] spoke to two experts on the topic: Dr Richard Greville, Director of Distribution & Supply at the Association of the British Pharmaceutical Industry (ABPI), and Aileen Bryson, Scottish Policy and Practice Lead at the Royal Pharmaceutical Society (RPS).

The first and foremost safety feature, the barcode, will need to be on every pack of medicine in order to remain FMD compliant, and each will be required to carry a set of data integral to the success of the system.

“The 2D barcode contains at least four bits of information: product information, by means of a product code; a serial number unique to that pack; information on the batch that that pack has come from; and the expiry date of that pack,” explains Dr Greville. “All of those components together make up the unique identifier, and the bottom line is that this clearly identifies and differentiates each pack of medicine.

“In the future, each pack of medicine will have this unique identifier on it, and the verification system will allow those who supply medicines to patients to check that the medicine they have in their hand aligns with an entry in the system, which manufacturers will have uploaded previously.”

Bryson adds: “All of those codes are uploaded onto the European hub – a huge job, with every pack from every manufacturer in Europe. It’s adding another step into the workflow every day, so it’s quite considerable.”

The second feature is the tamperproof seal – not an entirely new or revolutionary feature, but one that could prove much more effective once it is required on each and every box in the supply chain. As Dr Greville notes, the verification of the barcode alone “only means that the box is as intended, so you also need an anti-tamper device to show that that pack hasn’t been tampered with. Should it comply, the pack and its contents can be considered as being verified and in line with the information that the manufacturer will have uploaded into the verification system on manufacture.

“It’s really important that the unique identifier is a collection of data, and it’s really important that it doesn’t sit alone and works alongside the anti-tamper device – otherwise you could just say that the carton itself is verified but the contents wouldn’t be.”

Bryson added her thoughts on the extra safety features required by saying, “A lot of packs already have a tamper-proof seal on them, but the directive puts in a statutory requirement to have one. The security is quite high on any kind of pack nowadays – not just medicines, but retail goods – and they’ve all got something that makes it obvious that it’s been opened before you’ve got to it.

“It’s not very specific in the legislation on how they can do that, so there’s a lot of leeway” she expands. “The manufacturers can decide to do a sticky over-label or a wrap-around cellophane, but there’s got to be something that makes it obvious that a pack has been opened.”

However, while these two features alone could prove game-changing, there is also the interesting prospect of added potential inherent within the barcode feature of the packaging, as Bryson explains:

“Barcodes can hold a lot of different information, so there is a capacity to do all sorts of extra things that would be above the legislation, and would provide additional patient safety checks and features. Our take on that as a professional body is that if all packs have to be scanned, it would be good to have an additional benefit, rather than just the counterfeiting ‘yes or no’ answer. In the future, you could, for instance, link that code to an electronic prescription so that you would have an extra check in the dispensary that a particular pack was what was actually requested on a particular prescription for each patient. That would easily help with recalls in the supply chain.

“You could have patient information, you could have videos of how to use your inhaler – you can store all kinds of things on barcodes.”

The potential is very promising, and while Dr Greville agrees that these benefits could eventually materialise at some point in the future following the FMD deadline, he does highlight a sobering caveat which could somewhat deflate the prospect.

“You could envisage that there could be a code capture in the 2D matrix that would allow a patient to access an information leaflet or support materials via the internet. There is scope to do that,” he explains. “However, 2D matrixes do not hold as much information as some people think. The standard size of the 2D matrix that’s going to be out there on a standard box won’t be able to hold much more information than the four components that it currently has to hold. If you put more information in, then the matrix itself has to grow, and that may not always align with the size of the pack of medication that you’ve just barcoded.

“There is scope, and it’s very interesting and holds much potential; however, it’s not necessarily straightforward and it isn’t necessarily true that manufacturers will opt immediately to put extra information in that 2D matrix. Some may do, but others may hold back a little bit, for technical reasons rather than anything else in a lot of cases.”

A new threat

With the advent of the internet, fighting the threat of falsified medicines suddenly became a lot more complicated. As the directive itself states, one of the most immediately dangerous avenues for falsified medicines to reach patients is via the worldwide web, and while the FMD focuses almost entirely on the legal supply chain, there are concerns over the impact it will have on plugging this glaring leak in the system. Dr Greville is confident though that the benefits of the system are robust, logically concluding: “If it’s actually an illegal pharmacy that’s put themselves online, I don’t envisage that they would try to satisfy the requirements of this regulation. The activity is criminal and is being led by criminals, so I can’t see them trying to follow the regulations in any way.

“A system isn’t going to deter criminals from establishing themselves, but those that operate legally will benefit from the opportunity to verify that the medicines that they are dispensing are correct, appropriate, and expected to be within the supply chain system.”

Bryson, however, is more sceptical as to whether the FMD will do much to curb the threat of illegal online pharmacies and drug distribution. “No, no it won’t,” she replies. “The Medicine and Healthcare Products Regulatory Agency (MHRA)’s inspection arm does a lot of border work in confiscating medicines as they come into the country – I can’t see how the FMD will affect that at all because we’re talking about the legitimate supply chain. They’re two completely different things.”

A window of opportunity?

Another major concern that has been put forward by pharmacists, the ones on the front lines whose day-to-day work will be among the most impacted by the directive. The issue lies with the stipulation by the directive that, should a patient not actually physically receive a pack that has been decommissioned and is ready to be handed over and that same pack is therefore required to be put back into the system to be reused, then this must be done within a period of ten days.

Given that the functional requirements of the directive will already weigh heavy on daily pharmacy operations, there have been concerns that this timeframe will not always be feasible, and any medicines not re-entered within this window will have to be disposed of, leading to a potential surge in the unnecessary wastage of medicine.

This issue is particularly alarming when it becomes apparent that the period was previously much shorter under the original plans, numbering only a few days, but work by the Bryson and the RPS, alongside other organisations, saw this increased to the ten-day period now enshrined in the directive.

Dr Grevile weighs in on these concerns: “It’s to nobody’s advantage to waste medicines. We’ve been reassured that pharmacists will develop work processes that will allow them to reintegrate or recommission medicines if, for whatever reason, they decided to decommission those medicines well ahead of supply to the patients. The directive states that medicines should be validated and decommissioned from the system at the time of supply to the patient; if that was literally interpreted, there wouldn’t be a problem, but I do understand that medicines are boxed up well ahead of passing them on to the patient, and in those instances, the ten-day rule may have impact.

“This is all depending, of course, on how the regulatory authorities intend to interpret that ten-day rule in the UK; my understanding is that they don’t have much flexibility in their interpretation, but time will tell.”

Bryson was keen to point out the impact that the timeframe and the directive as a whole will have on regular drug distribution operation, warning that greater training will be required to ensure a smooth adoption: “In practical terms, all pharmacies are going to have to look at how they run their day-to-day business to accommodate that ten-day window, otherwise there is a lot of scope for things to go wrong,” she notes. “That’s going to be one of the biggest changes that the legislation will bring in, because systems are going to have to adapt to that. There will be ways of doing that, but everybody is going to have to be aware that that is the case.

“You order something from the GP practice – that takes two days; it takes a couple of days to get to the pharmacy and they work through it then the patient has to make sure they come in to collect it within that window. Everyone is going to have to be trained and on-board with this because it’s going to affect every single person involved in dispensing.”

The MHRA has been hard at work to assuage these concerns and ensure that that the deadline is workable and realistic. The organisation told [Pharmafocus]: “MHRA and the Department of Health and Social Care have been working closely with the UK FMD working group for community pharmacy to understand and address implementation issues whilst delivering the positive benefits for patients. In January, the group published [The Way Forward] which provides comprehensive guidance on the different options open to pharmacy contractors including on the ten-day rule.”

The cloud on the horizon

The big question on everyone’s lips, just as it is in just about any issue concerning Europe in the pharmaceutical industry or beyond, is how the UK’s divorce from the EU, officially set for March 2019, will affect the rollout and long-term future of the FMD. Bryson reveals that it’s usually the first question that people ask regarding the directive.

“With the complications involved, everyone is asking: “do we still have to do FMD?” And the answer to that is yes,” she laughs. “The directive comes into effect in February next year, a few weeks ahead of the date we have for Brexit. We have to comply with it, and then it will automatically go into the EU Withdrawal Bill, where all the legislation from Europe will be put back into the UK.”

Dr Greville adds: “Initially, Brexit won’t have an impact, because the legislation comes into play in February 2019, and the UK doesn’t leave the EU in any form of Brexit until at least the 29 March. The bottom line is that there is an obligation on all stakeholders to be able to fulfil the requirements of the regulation that will come into play in February. However, one of the challenges we have is that of a transition or implementation period; we’re very keen to be notified and advised on such an agreed period between the EU and the UK. At the moment, I think both sides are encouraging in their tone, most of the time, but what we need is certainty and a commitment from the UK government, and obviously that can’t be given in isolation so it’s part of the negotiation process with the EU.”

The MHRA’s stance on the issue is clear: “Until we have left the EU, the UK remains a member of the EU with all the rights and obligations that membership entails. We continue to play a full role in all procedures of the EU medicines and devices network as well as other networks.

“We will be looking to consult formally on the flexibilities within the delegated regulation shortly, and this will provide the necessary clarity on implementation from February 2019.”

But there is more to this commitment to the system than simply being required under EU law to do so, as Bryson explains: “The only reason we have to comply, on a practical level, is we cannot be the only country in Europe who doesn’t have a system or safety net around us like this; that would make us the weak link, and we would be the ones most vulnerable to counterfeiters. Other parts of the world are also doing a similar thing to what’s happening in Europe, so it’s very much the way things are going. My understanding is that, if we get the Brexit that they’re looking for, all of our legislation will align very closely and we will still work within this system. But if things do change with the Brexit negotiations, we would have to have some kind of standalone system, which would ensure that we were keeping the same safety net around the supply chain.”

A break from the directive or a similar system therefore would paint a target on the UK as a welcome haven for counterfeiters in a newly reinforced European supply chain. Even in the distant future, efforts to remain in alignment with the wider system would be imperative for the safety of patients.

“There are also questions, once we are out of Europe, around how closely we have to comply with the European directive, but that would all be part of the negotiations,” Bryson adds. “If we want to stay within the European system, I’m sure we won’t be allowed to deviate from it – why would Europe say to us, “you can be part of our system but you’re going to be different from everybody else”? That’s not going to work, is it? It depends on how the negotiations go, but at the moment it’s absolutely business as usual going forward.” 

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