1.1.1 Serialisation of Folding Cartons in the Pharmaceutical Industry
Dipl.-Ing. Roland Kleissendorf
Medicinal products must be safe. This means first and foremost protecting patients against counterfeit medicinal products in the legal supply chain. Serialisation plays a key role in this.
126.96.36.199 What is meant by serialisation?
Serialisation means giving a serial number, for example in the form of a machine-readable code, to each individual medicine pack sold. Labelling each individual sales unit with a unique number allows it to be tracked all the way from the pharmaceutical manufacturer to the customer. If incoming and outgoing goods are logged in the system at each stage of the commercial chain, this is referred to as „Track and Trace“.
When dispensed to the patient in the pharmacy, each pack is checked to verify the unique serial number. However, serialisation does more than simply increase the safety of the medicinal product. Full traceability over the entire supply chain also provides valuable information that can serve to optimise the supply chain.
This approach is based on recommendations passed by the International Medicinal Products Anti-Counterfeiting Taskforce (IMPACT) of the WHO in 2010 to combat the global counterfeiting of medicinal products.
188.8.131.52 What do the legislative authorities expect?
In Europe all medicinal products are to be serialised by the year 2019. The required legal basis for this, in the form of Commission Delegated Regulation (EU) 2016/161 of October 2, 2015, was published and adopted on February 9, 2016 after many years of delay. As a result, the implementation date for prescription medicines in the EU is February 9, 2019. Packs without serialisation made before this date may be sold off. From time to time the European Commission answers frequently asked questions in a Q & A paper (latest version no. 9 of February 2018); these provisions are not legally binding, but do reflect the technical aspects of the implementation of the Regulation. In the field of packaging, issues affecting bundle and/or multiple packs, the positioning of the 2D matrix code on the pack, and the use of UI adhesive labels for identification are addressed.
The regulation applies to all member states of the EU as well as to the EEA (Norway, Iceland, Liechtenstein) and Switzerland (where necessary with a different timetable). Great Britain wants to participate in the EU system within the prescribed time limit regardless of Brexit. Due to their existing systems (see Section 184.108.40.206), Italy and Greece will set a longer changeover period, running until February 9, 2025 at the latest.
The Delegated Regulation provides for the following exemptions:
- Black List: prescription-free products that should be subjected to serialisation due to the risk of counterfeiting (currently only omeprazole 20mg/40mg hard gelatin capsules),
- White List: prescription medicines that can be exempted from compulsory serialisation due to a low risk of counterfeiting.
Since the identity of the affected products can be determined nationally, final decisions are still pending. Similarly, national decisions regarding the choice of product identification code have yet to be made (GTIN, NTIN or, for example, PPN (Pharma Product Number)).
The directive also requires a device that makes it possible to check whether the outer wrapping (usually a folding carton) has been manipulated. EN 16679:2014 serves as a guide here.
The implementation of the Delegated Regulation is an enormous challenge for all concerned. What plans are already available to implement these requirements? How far has this already been done in practice, and what experience has been gained so far?
These questions will be answered on the following pages.
220.127.116.11 The EFPIA initiative
The EFPIA (European Federation of Pharmaceutical Industries and Associations) has developed a scheme for coding and serialisation using a 2D matrix code applied to commonly used folding cartons, to which EU legislation has made further additions. This approach will be explained in the following pages.
The EFPIA utilises a 2D matrix code for its serialisation scheme. In contrast to the bar codes customarily used for pharmaceuticals (e.g. PZN in Germany), the 2D matrix code comprises black and white squares in a checkerboard pattern bounded by two solid adjacent borders in an L-shape (see Fig. 1).
Fig. 1: A 2D matrix code
The main advantages of this type of code are its minimal space requirements and greater information content. The 2D matrix code shown here contains:
- a globally unique product code, usually the GTIN (Global Trade Identification Number),
- the batch number,
- the expiry date and
- the randomised serial number with a maximum of 20 digits.
When written out in full, the code shown in Fig. 1 provides the following information:
The following encryption applies:
- (01) GTIN item number
- (10) Batch number
- (17) Expiry date
- (21) Serial number
In the author’s view, the information content of the 2D matrix code needs to be examined critically. Aspects that need to be discussed are the use of the GTIN, since this is not applied to pharmaceuticals in all European countries, and the incorporation of the batch number and the expiry date, which poses problems in terms of practical implementation. In most cases, the incorporation of order-related data such as the batch number and the expiry date compels pharmaceutical manufacturers to print the 2D matrix code during or immediately after the packaging step. This requires the integration into the packaging line of an additional machine, which often poses a problem in terms of space, necessitates further adjustments and requires direct integration into the IT systems. This leads to additional investment costs, higher running costs and reduced machine performance. Since the batch number and expiry date always have to be printed legibly on the outer packaging as well, and there is a guaranteed link to the article number and the serial number in the data base, the requirement to incorporate order-related data in the 2D matrix code needs to be reconsidered, notwithstanding the legislation already introduced. Removing order-related data from the 2D matrix code also makes sense given that manufacturers of folding cartons and/or adhesive labels can print the 2D matrix code to a far higher quality and much more economically.
Field trial carried out by securPharm in Germany
In 2009 a number of companies based in Germany participated in an EFPIA-initiated trial run in Sweden. Although the project demonstrated the basic feasibility of the concept, it could not be regarded as a rigorous application test because of its limited scope. It was therefore decided to repeat the trial on a much broader scale in Germany. To this end the Bundesvereinigung der Deutschen Apothekerverbände (ABDA – National Federation of German Pharmacists’ Associations), the Pharmaceutical Industry Associations (BAH, BPI, VfA), the Wholesale Pharmaceutical Traders’ Association (Phagro), the Information Office for Pharmaceutical Specialities (IFA) and the Advertising and Sales Company of German Pharmacists formed a partnership and established securPharm, an association whose remit was to set up and carry out a pilot project in Germany on a much larger scale which could then be carried over into the system required by European legislation. According to a news release from securPharm, 24 pharmaceutical companies involved in this nationwide trial distributed 3.5 million packs (92 different products) labelled with the 2D matrix code between January 2 and May 23, 2013. Over 30,000 packs were verified in the more than 280 pharmacies that took part. The system availability during this period was 99.5 per cent.
securPharm and the associations involved considered this trial run to be a success and decided to incorporate the system into standard practice. The experience gained in the securPharm project and the technical solutions had a significant influence on the establishment of the binding EU standards that will come into force as of 2019 in the Delegated Regulation (EU) 2016/161.
As of December 2017, more than 200 out of 400 pharmaceutical companies in Germany have participated in the securPharm project. These include large global companies with experience in the serialisation and coding of drugs in other markets (such as Turkey, Korea or China), as well as German pharmaceutical SMEs, some of which were dealing with these sorts of problems for the first time.
securPharm is the first national system in Europe that complies with the mandatory requirements due to come into force in 2019. The securPharm website offers a wealth of information material covering the entire subject area.
18.104.22.168 Serialisation schemes that have already been implemented
The individual labelling of every single pharmaceutical package can be realised in a number of different ways:
- By means of adhesive labels
- By means of a 2D matrix code
- By means of a bar code
All of these options have been used in the serialisation schemes already implemented, with many countries developing and establishing their own solutions. This makes uniform application of the serialisation scheme beyond national borders difficult. In addition, it places the pharmaceutical company in the difficult position of having to cope with different serialisation schemes and satisfy the basic technical requirements of the particular country to which the products are to be exported.
Some of the most important serialisation schemes already implemented are described in the following.
A) Use of adhesive labels
For some years now all pharmaceutical packs in Belgium have been provided with a simple adhesive label printed with a serial number and a bar code that is verified by the pharmacist at the time of sale. In addition, useful information about the product is displayed on the pharmacist’s computer screen. Participation of the pharmacists is voluntary, and market acceptance is very good. This scheme is operated by the Aegate company in collaboration with Belgian pharmacists.
This model does not fully meet the requirements of the Delegated Regulation. There is a transitional period of 5 years.
In the Q & A paper of February 2018, the European Commission states that Belgium will forgo a transitional period and observe the serialisation rules from February 2019 onwards.
Fig. 2: Bar code in Belgium showing the item number and the serial number
According to Aegate, this scheme is also operated in Italy and Greece in conjunction with the adhesive labels that are already in use there. Aegate claims that market acceptance is very high in these countries too.
B) Use of a 2D matrix code
Although Turkey does not fall within the scope of the Delegated Regulation, it was the first country to adopt the main principles of the EFPIA scheme and make them into a legally binding requirement for the entire supply chain. This action was taken to put a stop to widespread billing fraud, which involved taking the coupon used when billing the pharmaceuticals (which was generally printed on a flap of the folding carton) and then returning the product to the supply chain in a new, counterfeit folding carton. In order to overcome any problems caused by pharmacists being resistant to the scheme, or lacking the technology to participate, the EFPIA scheme was modified in such a way that the content of the code had to be printed in human-readable text next to the 2D matrix code. As a result the 2D matrix code takes up much more space.
Fig. 3: 2D matrix code in Turkey
In very many cases there is now no longer sufficient space to print both the legally required variable data with the appropriate prefix and the 2D matrix code on the flap of a folding carton. For this reason both sealing flaps of the folding carton are often used, or the 2D matrix code is applied subsequently outside the packaging line.
Turkish law also requires all the logistic units used within the supply chain to be labelled so as to ensure full monitoring along the entire supply chain. For this reason bundles, corrugated board boxes and pallets are also labelled with 2D matrix codes and linked to data bases with the serial numbers of the packages contained. The progress of every medicine pack can now be tracked along the entire length of the supply chain by reading the 2D matrix code – a system known as aggregation.
The initial problems encountered in Turkey show that this scheme (which was introduced between 2010 and 2012) is very complex and difficult to implement for all those concerned. It is questionable whether the huge effort involved solves the actual problem of fraud, because although the packaging is tracked along the supply chain, the whereabouts and use of the medicines cannot be monitored.
Preparations for the implementation of the EFPIA scheme are already well advanced in France. The 2D matrix code is currently still being used without a serial number, which means that only the CIP number (The CIP number in France corresponds to the PZN in Germany), the batch number and the expiry date are machine-readable. Since the 2D matrix code does not include a serial number, it cannot be seen as serialisation, but only as encoding. Thus the essential requirement of the Delegated Regulation has not (yet) been met.
Currently, an additional adhesive label is used in France that includes the article number and serves as a check at the dispensing stage. To this end, the adhesive label is removed by the pharmacist and stuck on the prescription. This additional verification will no longer be necessary with IT-based serialisation. It remains to be seen whether the additional adhesive label used in France will be discontinued.
Fig. 4: 2D matrix code in France
B.3) Republic of Korea/Hanguk
In the Republic of Korea (South Korea), as in France, the 2D matrix code was initially introduced without a serial number. The system has now been modified to include the serial number. The design of the code corresponds to that already used in Turkey, i.e. the coded content is printed in human-readable text next to the 2D matrix code. With respect to the sequence of the contents, the serial number can occupy position 2 or 4.
Fig. 5 shows one version of a code permitted in Korea.
Fig. 5: 2D matrix code in Korea
Since the batch number and the expiry date are printed in the top and bottom lines of the human-readable text, the necessary prefixes can be printed above and below this text. As a result no further labelling is needed on the folding carton – in contrast to the requirement in Turkey. The space available for printing must, of course, be sufficiently large.
The technical specifications for the 2D matrix code correspond to those of the EFPIA and Turkey. In addition to the 2D matrix code, South Korea also allows the use of linear barcodes and RFIDs, but these are rarely employed.
B.4) Saudi Arabia
Like Korea, Saudi Arabia introduced a national serialisation scheme based on a 2D matrix code without a serial number. Since March 21, 2015, all medicinal products (prescription only, non-prescription and veterinary, the only exception being bulk orders for large institutions) must be provided with the data matrix code ECC 200 (GS1 Standard). Locally manufactured products must be marked with the date of manufacture and imported products with the import date.
The code must be printed directly on the folding carton. Since the date of manufacture, which is mandatory in Saudi Arabia, does not form part of the code, the code corresponds broadly to the 2D matrix code as it was in Korea before the introduction of serial numbers. It should be noted that both the prefix GTIN and the date of manufacture with the prefix MFD are included in the human-readable text. Fig. 6 shows an example of this.
Fig. 6: 2D matrix code in Saudi Arabia
Since March 12, 2017, the 2D matrix codes in Saudi Arabia have had to be provided with a serial number chosen by the manufacturer. Further details on data usage will be made public at a later date by the Saudi Food and Drug Authority (SFDA). At present Saudi Arabia has no plans for aggregation of the serial numbers along the supply chain.
C) Use of a bar code
C.1) Republic of China
A control scheme for medicines traditionally produced in the People’s Republic of China was first introduced as long ago as 2007. In the years that followed, the first foreign-manufactured products were affected, including those packaged outside of China. As from the beginning of 2016, all medicines marketed in China were to be labelled as described below. In February 2016, however, the system was unexpectedly suspended as part of a 5-year plan approved by the People's Congress. It is expected to be replaced in 2020 with a new, unified coding system for many product groups (including packaged food, for example), and a 2D matrix code will most likely be used.
Since the scheme developed in China was very advanced and could play a pioneering role for other countries, the essential features are briefly explained below.
In contrast to the EFPIA system, the bar code used in China consisted of a seven-digit article number and a thirteen-digit randomised serial number. These serial numbers had to be obtained from the Chinese system provider for a fee. In a similar manner to Turkey, all the logistic units (bundles, corrugated board boxes and pallets) were labelled and tracked along the supply chain (aggregation). Fig. 7 below shows a Chinese bar code with the encrypted serial number. The quality of the offset-printed Chinese characters is just as good as the elements of the code that are produced by UV-inkjet printing.
Fig. 7: Bar code in China
The dispensed pack was verified not by the pharmacist, but by the customer, who could either read the code using the camera in his cell phone or enter the twenty-digit number in an internet “app”. This "track-and-trace" application and the data stored and collected in the IT system provided the patient with information about the dispensing pharmacy, as well as a wealth of other data, such as the expiry date and the batch number of the medication. It also showed whether this code had already been interrogated and, if so, how often. Since the Chinese authorities are the system owners, they could intervene immediately in the event of irregularities and deal with any problems.
The barcode was printed in advance by the manufacturer of the folding cartons. They used stand-alone UV-inkjet printing machines which applied the barcode to a very high quality standard (generally Grade A!!) to the print sheet before or after the folding cartons themselves were printed. Depending on the type of printing machine and the size of the folding cartons used, it was possible to print up to 150,000 boxes per hour.
This system could potentially be further developed by, for example, integrating the UV printing step into the offset printing machines, using the folding carton manufacturer’s gluing machine as the location for printing the UV bar code, or switching to 2D matrix codes.
The gradual introduction of this system allowed for continuous improvements, and was certainly ideal for a mass market like China. Compared with the system used in Turkey, the PRC managed to implement a monitoring system covering the entire distribution chain that set new standards in terms of both simplicity and cost. The problem of counterfeiting within the Chinese pharmaceuticals market has been significantly reduced as a result.
22.214.171.124 Overview of Global Serialisation Activities
In Kapitel 126.96.36.199 set out the main coding and serialisation options and described their implementation in different countries. As the examples of Turkey and Korea show, the EFPIA scheme is also implemented in countries outside the scope of the Delegated Regulation. On the other hand, there is still no uniform implementation of the requirements within Europe.
Worldwide, other countries are constantly adding their own serialisation proposals and specifications. There are differences in detail (code content, e.g. only recording the serial number in the second step), speed of implementation and legal framework that need to be permanently monitored on a country-by-country basis. The table in Fig. 8 is intended to give an idea of these varied activities and does not claim to be exhaustive.
Global serialisation activities as of September 2017:
Fig. 8: Overview of global serialisation activities
188.8.131.52 What does the future hold?
Given this background, it is becoming clear that no uniform verification system will become established in Europe, let alone worldwide, in 2019. Countries such as Italy and Greece will not alter their tried-and-tested systems in the short term, and other countries will doubtless adopt the same attitude. To what extent countries such as Poland, Bulgaria, Romania, Spain, Portugal and others will be able to verify on-the-spot in all pharmacies by the deadline of February 2019 remains to be seen.
Worldwide developments result in constantly new and/or changing requirements in the field of serialisation which make for difficult baseline conditions for multinational companies in terms of their packaging machines.
The system suspended by the People’s Republic of China had advantages in terms of both cost and simplicity, and enabled patients to verify the packs they had received/purchased. This model could be suitable for countries that are in a similar position, especially in Asia, Latin America and Africa. Some West and Central African countries have already successfully introduced a label-based serialisation system for antibiotics and antiparasitic agents.
It would be relatively simple to steer the EFPIA scheme in a similarly favourable direction – by omitting the variable data batch designation and expiry date.
Serialisation is just one of many anti-counterfeiting options for pharmaceutical packs. Others include technical packaging measures such as anti-counterfeiting elements in the packaging components and tamper evidence, and organizational measures such as safeguarding the distribution chain, fraud control, dispensing information in pharmacies and information for patients. In order for all these measures to work together, a holistic approach and international harmonisation are urgently needed. As the example of serialisation shows, this is already an almost insurmountable task in Europe.
In revising this article, I was able to draw on extensive information provided by Mr Horst A. Kastrup (formerly MEDA Pharma GmbH & Co. KG). I would like to express my sincere thanks to him for this assistance and for reviewing this paper.