The technologies for the detection of fake medicines

The war against trafficking of falsified medicines is also fought in the field of technology.

Developed by experts and used by manufacturers and distributors, they can help ensure the integrity of the drug at any point in its lifecycle and to distinguish with certainty the authentic from the fake. The systematic, large-scale use of such tools in coherent strategies has demonstrated their effectiveness.

1. Terminology

Whether in the field of pharmaceuticals or not, the fight against counterfeiting calls on concepts that sometimes lend to confusion.

Each of these concepts answers different needs in the fight, but they are all instruments that are usually deployed in a complementary way to ensure perfect security of the product.

1.1 Identification

The identification of a product refers to the ability to differentiate it among others in a batch. A number or a bar code for example performs this function.

It also meets other needs than those related to the fight against counterfeiting (inventory management, invoicing, etc.), and the affixing of an identification device is also a prerequisite to the traceability of a product.

Identification differs from authentication: identification does not guarantee the authentic character of a product.  Identification processes are often reproducible (for example, a bar code can be photocopied).

Identification devices play a role in the implementation of the strategies to combat counterfeiting, but cannot rightly be qualified as “anti-counterfeiting technologies.”

1.2 Authentication 

The authentication of a product is the ability to certify that a product is what it claims to be. The value of an authentication (or authenticating) device is therefore based on this character of non-falsifiability and on the degree of certainty it confers to the user. A consumer should be able to spot any attempt to imitate an authentication marker, and it should be extremely difficult, if not impossible to for counterfeiters to have access to the technology necessary for reproducing marker of authenticity.

The most reliable available authentication technologies are inseparable from the product itself (chemical markers for example) and others may be simply affixed to its packaging (holograms for example). In the latter case, to retain their effectiveness, they must be associated with an inviolability device which prohibits any substitution of the protected product. Authentication is therefore at the heart of the issue concerning the preventive fight against counterfeiting and these devices can be rightly characterized as “anti-counterfeiting technologies”.

1.3 Traceability 

The traceability of a product refers to the ability to locate it throughout the complete lifecycle of the production and distribution processes. Traceability is linked to the movement of the product in time (historic) and in space (localization).

A traceability system requires a device which can identify, collect and register information, and deliver this information on-demand.

Unlike authentication which concerns the integrity of the product itself, traceability technologies are attached to the dynamic aspect of a product, or, its integration within a process. The effectiveness of tracking devices depends on the systematic character of the control procedures involved.

The implementation of a traceability system thus presupposes harmonization of large scale logistics.

Traceability plays a major role in the fight against health product counterfeiting.

1.4 Inviolability

The inviolability of a product refers to the ability to reveal any attempt to open it, thus prohibiting the substitution of its content and ensuring its integrity.

In the fight against counterfeit drugs, many devices are now applicable to the primary (blisters, pill canisters, etc.) and secondary (casing, etc.) packaging, such as safety labels, pre-perforated boxes, special glues…

The large scale deployment of these relatively inexpensive devices sometimes meets with legal obstacles, particularly within the European Community which allows the repackaging of drugs for parallel imports.

This opportunity for wholesalers to adapt the packaging and utilisation notice of a drug purchased in a neighbouring country to the national market to which it is destined is incompatible with the concept of inviolability.

The bodies of the European Community have understood the problem and are working – still imperfectly – to find a solution.

2. Authentication technologies

Today need for authentication technologies to combat medicine counterfeiting is evident.

Use is recommended by the WHO which advocated (in Rome in February 2006, for example) the development of innovative solutions to prevent counterfeiting while even more recently, the European Directive 2011/62/EC on “falsified drugs” confirmed and strengthened this recommendation by an obligation.

2.1 The principle of authentication

Unlike other types of counterfeiting (in which the consumer is sometimes aware of the illicit nature of the product purchased), trafficking in falsified medicines is based on the deceit of the patient who always believes that he is in possession of a real drug.

Indeed, the quality of counterfeit medicine packages now often reaches such a level of perfection that even a thorough and comparative inspection of the products cannot distinguish the copy from the original.

This is where authentication technologies play a strategic role. Drug manufacturers can therefore allow intermediate resellers and/or patients to verify with certainty the authenticity of the product, and this causes counterfeiters to lose a major advantage in the organization of fake trafficking.

2.2 Two types of authentication technologies

Although there is no official classification of authentication technologies, they are generally divided into two families.

Each solution has advantages and disadvantages, so their joint use is pertinent in the context of a coherent anti-counterfeiting strategy.

• Visible technologies (“overt”)

The patient and all stakeholders in the chain of distribution (wholesalers, pharmacists, hospitals, etc.) are invited to verify for themselves the authenticity of the product by means of the visible presence of a marker on the drug or, most of the time, on its packaging. Among such authenticating solutions are, for example, holograms or labels printed with special inks whose colour changes according to the inclination of the product.

Benefits of these solutions:

– They allow actors in the chain of production and distribution of drugs to easily verify the authenticity of the product.

– The verification of the marker requires neither special equipment nor specific knowledge, which make it accessible to all patients.

– They deter counterfeiters.

– They contribute to making the patient more responsible.

Disadvantages of these solutions:

– They rely on the principle that counterfeiters cannot imitate the marker. They must be developed with trusted technology for which the manufacturing process is inaccessible to the public. And unfortunately, today, traffickers have considerable financial means to procure such equipment.

– They are also transparent to the counterfeiter who can identify with precision the obstacle to circumvent.

– They imply that the device is for single use, without any possibility of recycling.

– When they are applied to the packaging of the drug, they must be accompanied by a device ensuring inviolability.

– If the marker is forged (more or less successfully) or if the patient does not take the habit to check, they may induce a false sense of security.

• Invisible or “hidden” technology (“covert”) 

Authentication is performed using a marker that is not visible by the patient but is detectable by a third party (manufacturer, pharmacist, customs officer, etc.) having the necessary expertise and/or appropriate technical means. These markers can be within the drug itself or inside their packaging (inks, glues, etc.). Among these invisible authentication devices, chemical markers for example, constitute the product signature and allow it to be identified with certainty.

Benefits of these solutions:

– They are extremely reliable, simple and usually inexpensive to implement.

– They allow rights holders to identify with certainty the infringing products.

– As the marker is hidden, the infringer is not alerted to its presence.

Disadvantages of these solutions:

– The control processes required to test the authenticity of the drug are more difficult to carry out than a simple visual inspection of the product.

– Their effectiveness relies essentially on the secrecy around the presence of the marker and its nature. The disclosure of this information could jeopardize the interest of the device.

– The patient is excluded from the authentication procedure.

2.3 Should authentication devices be standardized?

As we have seen, there are different types of markers and many available technologies to ensure the authentication of medicinal products. Today, every industrialist has the latitude to develop his own authentication system. Of course these choices depend on the intrinsic technical characteristics of the device, but also on many other criteria. Among these, we can cite:

– the direct cost of the implementation of a process and its indirect implications in the distribution chain;

– the ease with which the devices can be implemented at the operational level;

– the impact on the impression of security that the drug gives to the patient;

– the security of supply of these technologies;

– the evolutionary development of the processes and the protection they bring.

In view of all these constraints, there is no evident superiority of one authentication system over the others and therefore each company endeavours to secure its products with different methods. Is this diversity of systems detrimental to their effectiveness?

This question is at the heart of the reflections undertaken by the technology commission of the Impact group. Its work has led to the following conclusions:

 

– No technological solution for drug authentication is universally applicable, neither in developing countries nor in developed countries.

– Each approach must take account of the habits of consumers and the level of economic development in the geographical area in which it will be implemented.

– A standardization of the technological means of drug authentication would be counterproductive and would facilitate the work of the counterfeiters.

Indeed, this diversity of drug authentication technologies reinforces product security by reducing the risk of copy. As the value of such devices depends on the technological advance that industrialists will be able to keep on counterfeiters, this lack of standardization is an asset. This benefit must also be maintained by regularly changing technology, which involves maintaining investments in research and development in the sector.

3. Identification technologies / traceability

The traceability of medicines is not a tool exclusively dedicated to the fight against counterfeiting.

In terms of safety, for example, it is essential for ensuring the withdrawal of batches in case of potential anomalies and is mandatory in many countries.

Used in the perspective of the fight against counterfeiting, the traceability of a drug presents a means for a pharmaceutical laboratory to mark its product in order to trace it and thus ensure the security of its distribution.

Its principle is based on the application and the systematic control of the medium containing the information. Comparison of information with that contained in a centralized and secure database allows the verification of product compliance. From there, any anomaly (and a fortiori any absence of marking) enables the deduction that the examined drug is counterfeit.

The European Commission said in 2008 “that an efficient traceability system for health products is crucial to combatting counterfeiting.” 

3.1 European directive 2011/62/EC on “falsified medicinal products”

Reinforcement of the security devices

Item 11 of the preamble to the directive recommends the harmonization of the safety devices applicable to medicinal products: “Those safety features should allow verification of the authenticity and identification of individual packs, and provide evidence of tampering.”

The Directive makes it mandatory to affix security devices on the packaging of certain drugs. These devices should allow the stakeholders of the pharmaceutical chain to:

 

1. Verify the authenticity of the drug;

2. Identify the individual boxes of medicines;

3. Check if the external packaging of the drug has been tampered with.

3.2 Traceability systems

Among the many available technological tools for the traceability of pharmaceutical products, here are the two main systems that have been studied:

• Datamatrix (2D) 

GS1 Datamatrix is a two-dimensional (2D), high-density, matrix bar code.

This coding system is an identification and serialization tool presented in the form of a matrix of juxtaposed points or squares allowing the display of a very large amount of information on a very small space: product code, batch number, expiry date, serial number, etc. It is therefore not, strictly speaking, an authentication system.

In addition, the most recent versions of Datamatrix enable the automated processing of data and the interoperability of the systems, which facilitates its implementation on a large scale.

The Datamatrix is robust and extremely competitive in terms of cost (0.1 to 0.3 eurocentimes by label). This system was used successfully to encode products intended for animal health. (On October 26, 2004, the Board of Directors of the International Federation of Animal Health adopted – Data Matrix ECC 200 – a world-wide standard for the marking of veterinary drugs enabling to hold all the information necessary to meet the traceability requirements of the entire food chain).

The systematic use of the Datamatrix for the traceability of medicines subject to market authorization (AMM) has already been made compulsory in some countries and is in the process in others: 

– In France: it has been mandatory since January 2011.

– In all other European countries: mandatory by 2016 at the latest with the exception of Belgium, Greece and Italy: by 2022 at the latest.

– Korea (scheduled January 2012).

– Canada (scheduled December 2012).

The WHO is in favour of the use of the Datamatrix system to ensure the traceability of medicines.

Its application has a significant impact on the supply chain as from the packaging lines and requires firms to create internal databases containing all the serial numbers applied on their boxes.

Its main assets are:

– guarantees the quick and easy recall of batches in the case of manufacturing defaults or health emergencies;

– secures drug delivery right through to the patient;

– permanently monitors the flow of drugs;

– fights against counterfeiting;

– fights against parallel circuits for the sale of drugs;

– fights against fraudulent claims for reimbursement;

– passes from the single objective of recalling batches to a real optimization of the upstream and downstream security of the drug chain by individually and systematically marking each secondary packaging (case).

Disadvantages:

– It is not possible to read at a distance,

– difficulty to modify the contents of the code (which can also be seen as a benefit from the security point of view).

• The “Radio Frequency Identification” (RFID) 

The acronym RFID designates a technology that allows the identification of a distant object and the collection of information relating to this object.

Its principle is to affix on the product itself or on its packaging a label emitting radio waves. These waves transmit the information to a reader.

The capacity to read from a distance is the main advantage of this technology: the RFID allows the reading of labels through fine layers of materials (tarpaulins, cardboard, paint, snow, etc.).

Designed as a tool of traceability in the fight against counterfeit drugs, the RFID did not ultimately convince the WHO and most of the industry.

Indeed, its lack of robustness (interaction with metals and liquids disrupting the reading), the absence of harmonized standards, confidentiality issues and especially its high cost (from 20 to 40 eurocentimes per label) are barriers to its development. Problems of access to the stored data can also be noted when in the presence of an electromagnetic shielding (on the principle of a “Faraday cage”) in the body of a lorry, the hull of a boat, the fuselage of an aircraft etc.

RFID can be of one-time benefit for the marking of certain cases or pallets for logistical purposes but this technology cannot be considered today as a universal tool for marking, identification and traceability.

• Pedigree 

The “Pedigree” is not a technology but a system of monitoring the marketing of drugs designed in the United States. Its implementation involves the use of the above technologies (Datamatrix and/or RFID).

Defined by the FDA, the principle of the Pedigree is based on the creation of a paper or electronic (e-pedigree) document which contains the financial and logistics information registered at each movement of a prescription drug. This document therefore provides the traceability of the medicinal product at every step of its distribution from its first commercialisation by the manufacturer until its final sale in a pharmacy or to a third party that administers or dispensed the drug (hospital, clinic, etc.).

This document is updated at each transaction between intermediaries.

It contains the name, dosage, the size of the boxes, their numbers, batch number, the name and address of the operator as well as the date of each transaction.

The pedigree can be established for a batch or a box (pack). Establishing the pedigree for a box requires having the knowledge and a precise record of the hierarchy of the packaging and media distribution throughout the supply chain (pallet, case, box).

With this system, the industrialist must be able to match each product code with the container in which it is located (through the Datamatrix for example)

The mPedigree 

The most recent development in the fight against counterfeit drugs, the mPedigree is a tool allowing consumers (exclusively consumers in Africa for now) to verify the authenticity of a drug at its purchase by sending a simple SMS.

The principle is as follows: upstream, the drug manufacturer affixes a rub-off label on each package. It is the same system as used for prepaid telephone cards, whose efficiency in terms of security has been proven. Once scratched by the patient, this label indicates a unique verification code (number) which is simply sent by SMS to a server that instantly checks the drug by controlling the validity of the serial number and the number of queries performed on the same number in a database and validates by return of SMS.

Designed by a Ghanaian company and tested in the country since January 2008, this device is the fruit of a partnership between a computer manufacturer, pharmaceutical laboratories, a telecommunications operator and the Government health authorities.

As a non-profit organization, the mPedigree has the advantage of being completely free for consumers; it’s funding has been provided by pharmaceutical laboratory partners.

The system is due to be deployed in five other countries: Niger, Tanzania, the Kenya, Uganda and Cameroon.

4. Fast (field) physico-chemical tools for drug analysis 

While these may not be strictly “anti-counterfeiting devices” (they do not protect authentic products), some tools can play a complementary role in strategies destined to fight against counterfeit drug trafficking by allowing quick verification of a product’s authenticity.

Here are the two main technologies available for a reliable and rapid out-of-laboratory product analysis.

4.1 The portable spectrometer, Truscan

Based on the design of Raman Spectroscopy, the Truscan is a method for analysing the molecular composition of a product.  It is a portable device that allows the verification of product authenticity directly in the field (loading dock, warehouse, road, etc.).

Easy to use for even a novice user, the instrument combines several advantages: robustness, mobility (1.8 kg), speed (result in under a minute), adaptability (analysis of solid and liquid compounds), reliability (the method has been approved by most of the pharmaceutical laboratories).

In addition, the system allows the analysis of the inspected drugs through various types of packaging (plastics, blisters, glass, etc.), without destroying the product.

Following the analysis, the Truscan displays the result in binary (“passed/failed“) mode. If the sample is rejected, the Truscan can also identify the unknown chemical components

The major strategic advantage of the Truscan is its extreme portability and its ability to be used by staffs who are not specialists in chemical analysis (police, customs officers, doctors, pharmacists, nurses, etc.).The Truscan is used more and more frequently by the services of control and repression of counterfeit drugs everywhere in the world.

Its main drawback is its cost, but also the need to load into its database the characteristic information concerning molecules (spectral data banks containing Spectra reference).

4.2 The GPHF-Minilab 

Developed by a German public/private partnership, the “Global Pharma Health Fund Minilab” is a kind of compact and mobile analytical laboratory for detecting drug infringement quickly and at low cost.

It allows the analysis of a sample in 4 steps (Visual inspection, disintegration test, colour reaction test, and thin layer chromatography) and compares the results with a database composed at present of 40 drugs (antimicrobial, anthelmintic, antiretroviral, malaria, etc.).

The use of this material requires specific analytical training.

To date, more than 440 minilabs have been provided in 70 countries including Cambodia, Laos, Madagascar, Nigeria and Tanzania.