In search of a real solution to the counterfeit problem

pharmafile | May 10, 2010 | Feature | Manufacturing and Production |  Plavix, counterfeits, supply chain 

For a great deal of the last decade, warnings from the pharmaceutical industry about the growing threat of counterfeit medicines seemed to go unheeded in Europe.

Increasing levels of seizures and detection of fake medicines gradually made politicians sit up and take notice, however, and by 2008 the European Commission was investigating how to introduce new laws and regulations.

Speaking in December 2009, European Commission Industry Commissioner Guenter Verheugen said trade in counterfeit medicines in the EU was “constantly growing” and had  “exceeded the Commission’s worst fears”.

Customs officials identified 2,000 cases of counterfeit medicines entering the EU’s borders in 2007, a 50% increase on 2006, and confiscated four million fake products. The following year saw an even greater increase – a 118% rise in cases and 32 million medicinal products stopped by customs – largely because of the coordinated MediFake campaign carried out by EU border control agencies in the autumn of 2008.1

Two-thirds of these products were uncovered in small quantities sent via postal traffic, which could be indicative of goods ordered over the internet, and it is clear that consumer purchases from websites is a major channel for the entry of fake pharmaceuticals into the EU. That view is reinforced by a recently-completed survey of 14,000 people in 14 western European countries. Funded by Pfizer, the Cracking Counterfeit Europe survey found that 21% of Europeans – around 77 million people – had bought a prescription medicine from an illegal source.2

Looking at the average spend on each purchase, the researchers were able to estimate the total market for illegal medicines bought in Europe was a massive €10.5 billion. It’s likely that a large proportion of that total was counterfeit, although some could also have been genuine product diverted into illegal channels.

Arguably more alarming than the headline figure, however, are the underlying findings on the sources European consumers use to get hold of illegal medicines. Contrary to expectations, the internet was not the biggest source in Europe, accounting for 29% of the total purchases reported. There were actually more transactions (44%) purchased from a retail outlet, for example from illegal pharmacies, market stalls and under-the-counter sales from other types of shop.

The Pharmaceutical Package – a solution?

Of course, legitimate supply chain is not immune. For example, between 2005 and 2007 in the UK there were a number of cases reported by the Medicines and Healthcare products Regulatory Agency (MHRA) of life-saving products – such as AstraZeneca’s prostate cancer drug Casodex, Sanofi-Aventis’ anti-platelet drug Plavix and Lilly’s Zyprexa – reaching wholesalers and even pharmacy shelves. One case during this period also involved a counterfeit version of a medicine used in a clinical trial.

All this has captured the attention of Europe’s authorities. In December 2008, the European Commission put forward a set of legislative proposals, known as the Pharmaceutical Package, which included three draft directives on combatting counterfeit or ‘falsified’ medicinal products, information to patients and improving pharmacovigilance.

The falsified medicines directive, that will amend Directive 2001/83/EC relating to medicinal products for human use, contains a number of provisions to help shore up Europe’s supply chain, such as an extension of regulations to include traders and brokers in medicines and increased auditing obligations placed on wholesale distributors.3

Another key aspect of the proposed directive is the adoption of obligatory, harmonised and safety features to identify, authenticate and trace medicines in the supply chain. The precise nature of the safety features remains undecided, but broadly come under three categories:

• authentication features

• tamper-evident seals

• individually-identified packs

Tamper-evident seals are already widely-used among products sold by larger pharmaceutical manufacturers, but the proposals will make this an obligatory rather than voluntary feature for all medicine products.

Similarly, big pharma has been investing heavily in authentication features to help protect its products, often employing a risk-management approach with layers of authentication used depending on how vulnerable the product is to counterfeiting. Many medicine packs already carry overt authentication features such as holograms, watermarks and embossing, covert features such as ultraviolet-reflecting inks that require special tools to detect, and forensic features, such as chemical ‘taggents’, that can only be detected in the lab.

Novartis is rolling out a hidden digital marker technology that allows customs officials, for example, to detect whether the secondary packaging of a product is authentic simply by placing it on a regular office scanner and sending the resulting image to the firm’s security division for verification. The aim is to add this feature to all 200-plus products in Novartis’ portfolio by 2011, and the company says it may also extend the approach to primary packaging in future.

Serial numbers – already in use

The safety feature grabbing the most attention  in the industry is the concept of unique serial numbers on packaging. Such a system would allow individual packs to be traceable and could also help authenticate products at the point of dispensing by the pharmacist. In some respects the EC is catching up with a trend already being implemented by EU member states. Many European countries already use some form of pharmaceutical product coding system, and there are at least 10 different schemes in operation across Europe. Belgium, Italy and Greece are already using serial numbers in addition to a national product code.

Spain and Germany are also looking at the introduction of serialisation, while France will require all pharmaceutical products to carry a barcode incorporating a product identification code called CIP13 (which is not serialised or randomised, but could be upgraded to a serialised system in future), plus the batch number and expiration date, by the end of the year.

Belgium was an early adopter with a serialisation system based on a 2D barcode allowing point-of-dispensing authentication provided by Aegate, which is already used in nearly 60% of all pharmacies in the country. Variations on that system, that checks to see if a serial number has already been dispensed, have been introduced in Greece and Italy, and another is being piloted in Germany.

At the moment all these systems are designed to provide what is known as ‘book ending’ authentication, i.e. a code is placed on the pack during manufacturing and scanned when the pack is dispensed at the pharmacy. In addition to authenticating products – achieved by checking to see if the serial number corresponds to the pack in hand and has not been scanned previously, the systems can provide valuable additional functions, such as identifying recalled or expired products before they come into the hands of patients.

Faced with an expansion of the use of serialised coding systems across Europe and an EC mandate, the pharmaceutical industry decided last year to carry out its own serialisation pilot in the hope of persuading the EC to adopt a single, harmonised coding system that could be rolled out across the EU.

The pilot – organised by the European Federation of Pharmaceutical Industries and Associations (EFPIA) – used a 2D datamatrix code that incorporated a randomised, unique pack identification number, a product code, batch number and the expiry date. The code was added to products at the time of manufacture and read when the pharmacist dispensed the pack to a patient.

The system processed more than 1,000 packs of medicine a day from 14 pharmaceutical manufacturers, and achieved accurate and quick read rates, with 94% of scans read within 0.5 seconds and 99.9% within two seconds. It was also well-received by the pharmacists involved in the trial, with 94% saying it was easy to use and 96% indicating that the additional effort required was acceptable or better.4,5 EFPIA and other proponents of the 2D datamatrix barcode maintain that it can be used as an all-purpose ‘carrier’ that can accommodate the national coding systems already in place, as well as serving as a credible model for national governments wishing to adopt their own scheme.

Questions, questions

As with most new pieces of legislation, the falsified medicines directive raises as many issues as it strives to solve. The requirement to use safety features seems a straightforward measure on the surface, but has led to contention on a number of issues, such as whether it should be extended to all or only certain higher-risk medicines.

The European Generic medicines Association (EGA) says generics should be excluded from the proposals because no cases of counterfeit generics have been seen in Europe; it believes the profit margins for fake generics are too small to make them an attractive option for the counterfeiter. Concerns have also been voiced in the European Parliament that the cost of implementing mass serialisation and authentication features could be hard for the generics industry to absorb without pushing up medicine prices.

There are also questions about parallel trade in medicines which often involves repackaging of drug packs. Proposals to allow parallel traders to apply ‘equivalent’ safety features to those placed on medicines by their manufacturers raise a number of issues, not least the definition of equivalency. Parallel trade industry association the European Association of Euro-Pharmaceutical Companies (EAEPC) is reportedly planning its own pilot to demonstrate the feasibility of such an approach.

There is also debate about the level of product identification required. In addition to a book-end authentication approach, serialisation could also be employed to provide a full pedigree system, where the code is checked at each point that a product changes hands in the supply chain. That could bring additional benefits, such as making it easier to identify the point in the supply chain where counterfeits enter, which will assist enforcement activities.

Organisations such as the Pharmaceutical Group of the European Union (PGEU), which represents Europe’s pharmacists, are deeply concerned that full traceability will raise costs of implementation dramatically, and simply may not be feasible in some markets.

An EC impact assessment report published in 2008 estimated the cost of setting up an all-inclusive product identification system to be in the range of €7 billion to €11 billion,6 depending on the level of implementation used. The PGEU’s secretary general John Chave said recently he believes a full track-and-trace system would not be possible in markets with a mix of full and short-line wholesalers, such as the UK, without a complete redesign of the distribution system. At the moment, the proposed directive is being discussed in the co-decision procedure by the European Parliament and Council of the European Union.

The first stage of this process was the review of the EC’s proposals by the European Parliament’s Environment, Public Health and Food Safety (ENVI) committee and in December 2009 the ENVI rapporteur, Portuguese MEP Marisa Matias, published an initial opinion on the proposal with a number of amendments. Among the highlights of the amendments are provisions to block internet sales of counterfeit medicines, something left out of the EC draft. This is because the Commission believes that illegal online distribution cannot be tackled effectively with new legal measures. Matias disagrees, and notes in her report that “a directive aiming at fighting the falsification of medicines, without dealing with internet, the most important route, is not explainable to the public”.

Others amendments included the need to draw up a clear definition of ‘falsified’ medicinal products, making a clear distinction between traders and brokers of medicines; levying tougher criminal penalties, and providing additional direction on mandatory safety features, including making them obligatory for certain generic medicines on the basis of a risk assessment.7 The amendments now go forward for a full plenary debate in the European Parliament in the coming weeks.

Raw materials

Finally, while the EC proposals include many measures designed to secure the supply chain from the pharmaceutical companies to the patient, it does not ignore the upstream supply of raw materials that are used by drugmakers in the manufacture of their products.

In light of cases such as the case involving contaminated heparin that killed more than 200 patients around the world in 2007-2008, the falsified medicines directive is calling for greater controls on imports of active pharmaceutical ingredients (APIs) from countries outside the EU.

Matias would like to see similar control measures applied to pharmaceutical excipients too, pointing to recent cases in Haiti, India and Nigeria where contaminated, mislabelled or substituted ingredients have caused several hundred fatalities in recent years.

Securing the raw material supply chain is just as important as preventing counterfeit medicines reaching patients, but the complexity of the trade makes this a major challenge for pharmaceutical manufacturers, ingredient suppliers and regulators alike.

References:

1 Report on EU customs enforcement of intellectual property rights – results at the European border – 2008 (http://ec.europa.eu/taxation_customs/resources/documents/customs/customs_controls/counterfeit_piracy/statistics/2009_statistics_for_2008_full_report_en.pdf)

2 Cracking Counterfeit Europe – Europeans fuel €10.5bn illicit medicines market (Nunwood) – February 2010

3 Directive of the European Parliament and of the Council amending Directive 2001/83/EC on preventing of the entry into the legal supply chain of counterfeit medicinal products (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=COM:2008:0668:FIN:en:PDF)

4 SecuringPharma.com: Pharmacists respond favourably to EFPIA’s serialisation pilot (www.securingpharma.com/40/articles/392.php)

5SecuringPharma.com: EFPIA update on Swedish serialisation project  (www.securingpharma.com/40/articles/369.php)

6European Commission Impact Assessment report (Dec 2008) (http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/pharmacos/pharmpack_12_2008/counterfeit-ia_en.pdf)

7 DRAFT REPORT on the proposal for a directive of the European Parliament and of the Council amending Directive 2001/83/EC on the preventing entry into the legal supply chain of medicinal products which are falsified  (http://www.europarl.europa.eu/meetdocs/2009_2014/documents/envi/pr/800/800835/800835en.pdf)

Phil Taylor is editorial director of SecuringPharma.com, a website focusing on supply chain and brand security issues in the pharmaceutical industry. www.securingpharma.com