Elke Sternberger-Rutzel04.04.12
Counterfeit products can be found in all areas of life; almost everyone has come into contact with fake lifestyle or sporting goods, spare parts or technical equipment. But worst of all, counterfeiters are increasingly targeting the pharmaceutical supply chain — a dangerous trend that can have fatal consequences. All supply chain players can contribute to increased safety, from producers of active pharmaceutical ingredients (APIs) through to packagers and equipment manufacturers, supported by numerous initiatives and legislative efforts.
According to a statement by the International Anti-Counterfeiting Coalition, worldwide damage caused to national economies runs to at least $600 billion each year, and this figure is rising fast. The World Customs Organization estimates that counterfeit products account for between 5% and 7% of global trade. However, the actual figure is likely to be much higher, as many counterfeit goods go undetected. On the pharmaceutical market, figures are even more alarming. Counterfeit medicines are thought to account for as much as 10% of the global medicines market, and are responsible for many instances of serious illness and death. For example, counterfeit heparin, a drug used primarily to treat blood clots, was linked to the deaths of 81 people and hundreds of allergic reactions in the U.S. during the first half of 20081.
Counterfeit pharmaceuticals are those that have arrived on the market as licensed drugs without having passed through the official channels. In such cases, the counterfeit drugs may contain the wrong or any active ingredient or the correct active ingredient in an incorrect quantity. Here, the best-case scenario may find a drug becoming ineffective. But in the worst case, fatalities may occur if the illegitimately made drugs do not have the desired effect. Counterfeiters not only manufacture imitations of prescription-only drugs, but also over-the-counter (OTC) products, generics, originator products and traditional drugs.
New Distribution Channels
The World Health Organization (WHO) estimates that every second pharmaceutical product purchased via the internet is counterfeit. Anabolic drugs and potency pills range among the most frequently ordered products. Apart from these so-called lifestyle medicines, more and more prescription drugs like antibiotics and medicines for cancer treatment are sold by online pharmacies.
A study conducted by the European Alliance for Safe Medicines (EAASM)2 found that in 90.3% of all cases, no prescription was required for the online purchase of prescription-only drugs. And more than 50% of medicines purchased from illegal websites concealing their physical address have been found to be counterfeit. But the internet is not the only channel by which counterfeits enter the market. Pharmaceutical wholesalers especially are targeted by counterfeiters. By introducing large quantities of falsified medicines into the legal supply chain, lucrative transactions can be made in a very short time. This depends strongly on the geographical area. For example, in most of Europe, the amount of falsified medicine is estimated at approximately 1%, while the developing world sees figures of as much as 50% of counterfeit pharmaceuticals.
The most important question is: How can patients be protected from this growing threat? Drug manufacturers assume an important role in the fight against counterfeiting by applying one or more of the technologies3 described below.
Overt and Semi-Overt Technologies
Holograms, well-known from their use on credit cards, can display a wide range of images and are printed onto folded boxes, blisters or labels in the pharmaceutical industry. Other Optically Variable Devices (OVD) are similar to holograms but without the three-dimensional effect. Packaging can also be marked with color-shifting security inks or films, which change color depending on the viewing angle. Different security graphics consisting of micro-texts or images are further overt variants: an additional text or image appears only when viewed with a magnifier. Sequential or randomized product numbering, overtly printed on the packaging, is the most common semi-overt anti-counterfeiting technology. As opposed to the serialization number (see below), it is not employed EU-wide or globally, but constrained to a certain product.
On-Product Marking
Analogous to the overt technologies, some anti-counterfeiting measures can be applied directly onto the product instead of traditionally onto packaging materials. For example, color-shifting inks are admixed to film-coated tablets, changing color depending on the viewing angle and incidence of light. Microtaggants and mechanical micro imprints can be administered to the film coating and identified using special equipment. Individualizing pharma products in terms of color, form and graphic or mechanical features also helps to protect patients by making drug copying a more laborious business.
Covert Technologies
While these approaches make use of visual effects, covert technologies rely on the opposite property: invisibility. A number of anti-counterfeiting features on the market are invisible to the naked eye. For example, special ink that is printed onto primary or secondary packaging and can only be seen under ultraviolet (UV) or infrared (IR) light. Digital watermarks are only decodable using special software programs. Microscopically small color-codes, in turn, consist of multiple color layers. They can be applied onto the packaging either manually or by means of dispenser technology, and are identified with a microscope. Techniques used for producing banknote paper — that is, paper with special fibers and additional watermarks — are also applicable to packaging. Furthermore, the finely structured pattern of the so-called ‘anti-copy’ or ‘anti-scan’ design only becomes visible when copied or scanned. This method was commonly used to prevent copying of secure documents.
Forensic Markers
More recent technologies rely on chemical and biological parameters, and belong to the category of forensic markers. They are neither visible to the naked eye nor by common analytical processes. Chemical taggants are added to inks and result either in a characteristic peak in the IR spectrum or in particular chemical reactions. Biological markers can be incorporated into product formulations or coatings, or onto the packaging. The latter also applies to DNA taggants. In addition, packages can be examined for their isotopic ratio, which is stored as a natural fingerprint. Microtaggants are unique numeric code sequences in a multi-color layered format that can be applied either on or in the packaging.
Tamper-Evident Features
All the technologies explained above belong to the category of authentication features. Apart from authentication, tamper-evidence is a further important aspect of anti-counterfeiting. Closure seals are a classic method for tamper-evidence applied to packaging. An intact seal proves that the package is being opened for the first time by the patient. In fact, this is the aim of all tamper-evident features. While they do not actually prevent counterfeiting, they nonetheless protect patients by clearly indicating whether a package has been opened before it reaches them. This also applies to so-called VOID foils, which immediately tear when tampered with. As soon as someone tries to open the package or remove the foil, the lettering “void” appears under the damaged surface. Perforation is a further means of making packaging tamper-proof: the packaging is irreversibly damaged once the perforation is torn.
Serialization Methods
Serialization with adaption of a machine-readable code is one of the most important strategies laid down in recent guidelines and legislation. A serialization number is a unique number attributed to pharmaceuticals on the package or bulk level. This number can be applied to the package by various technological means. One of them is the data matrix code. It can contain a distinct serial number attributed to the individual package, as well as variable data like batch number and expiry date. A radio frequency identification (RFID) label checks and records each product movement. This method is used for in-house stock control and was long considered one of the top track & trace solutions. Due to high costs and some implementation difficulties, the pharmaceutical industry is in favor of the data matrix code. In the long term, data matrix codes are intended to serve as traceability devices for all supply chain players, including pharmacies and patients.
Combined Strategy
Due to globalization and production outsourcing, the supply chain of pharmaceutical products includes many different steps between the producer and the end-consumer. Therefore, pharma companies opt for a combined strategy in most cases, depending on the individual counterfeiting risk, budget and technical abilities. This strategy should ideally consist of a combination of different technologies. Several layers of security can be created by combining tamper-evident, serialization and authentication technologies to form a multi-layer approach for the best possible patient protection.
Recently, international organizations such as the WHO have worked alongside governments and producers, largely through their International Medical Products Anti-Counterfeiting Taskforce (IMPACT), to help curb this damaging practice. Future initiatives to combat counterfeiters will also rely heavily on manufacturers. International guidelines and regulations have been developed, but regional and local regulations still vary considerably and in parts they are contradictive. For this reason, EU serialization is due to be introduced in 2014, followed by the long-awaited Food and Drug Administration (FDA)/California serialization standard, expected to be launched in 2015. The main goal of these regulations is to harmonize the coding of pharmaceutical products on an international level.
Taking It One Step Further
The FDA’s final guidance4 for the standardized numerical identification of prescription drug packages recommends the introduction of a serialized National Drug Code (sNDC) at package level. This code is composed of two distinct codes: the National Drug Code (NDC) contains labeler, product and packaging code. The unique serial number is composed of a maximum of 20 characters. The implementation of California’s ePedigree5 is now due to take place on a staggered basis from January 2015 to July 2017 for full traceability. Most of the guidance and regulations concentrate mainly on serialization to make pharmaceuticals traceable throughout the supply chain. The EU is currently taking these endeavors a step further.
In June 2011, the EU published its Directive 2011/62/EU6, amending Directive 2001/83/EC. In addition to the introduction of serialization standards for prescription medicines, the directive initializes the search for appropriate safety features which has not been finalized yet. It also provides for stricter regulations regarding the import of active substances and the improved control of the supply chain, including wholesale. Regulations for Internet trading of medicines, the harmonization of Good Manufacturing Practice (GMP) inspections and the introduction of a pan-European early warning system upon discovery of a falsified medicine are also an integral part of this Directive. Member States are expected to bring into force the laws, regulations and administrative provisions determined in the Directive by January 2013.
European Milestone
Directive 2011/62/EU represents a milestone in European attempts to set up legislation for a safe pharmaceutical supply chain. Uniquely coded, serialized packs for almost all prescription drugs are the Directive’s most important component. But the EU also recognizes the need for a combined strategy and requires a second layer of security: tamper-proof closures. These security components will be obligatory for nearly all prescription drugs, but not for OTC drugs. Exceptions defined in white and black lists will be determined by the European Commission, based on a risk assessment defined by price, sales volume, previous cases of counterfeiting, the degree of severity of the treated illness and other possible health hazards.
The required safety feature — the so-called “unique identifier” — will be determined in delegated acts, of which the first was published in November 2011. The paper has now been submitted for public consultation, and stakeholders are invited to contribute their comments before the end of April 2012. Technical implementation details and the process are still to be defined. Therefore, some of the methods described in the WHO IMPACT listing (see table) might become obsolete before long. The aim of the delegated act is to define the characteristics and technical specifications of the unique identifier, as well as the modalities of verification and the establishment, management and accessibility of the repositories system (database). The adoption of the delegated act is scheduled for 2014. It will be some time until all required steps are implemented and harmonized on an international level. But the industry is clearly moving in the right direction in its fight against pharma counterfeiters.
References
Dr. Elke Sternberger-Rützel is a Pharma Trendscout and Innovation Manager at Robert Bosch GmbH, Packaging Technology – Business Unit. She can be contacted at elke.sternberger-ruetzel@bosch.com.
According to a statement by the International Anti-Counterfeiting Coalition, worldwide damage caused to national economies runs to at least $600 billion each year, and this figure is rising fast. The World Customs Organization estimates that counterfeit products account for between 5% and 7% of global trade. However, the actual figure is likely to be much higher, as many counterfeit goods go undetected. On the pharmaceutical market, figures are even more alarming. Counterfeit medicines are thought to account for as much as 10% of the global medicines market, and are responsible for many instances of serious illness and death. For example, counterfeit heparin, a drug used primarily to treat blood clots, was linked to the deaths of 81 people and hundreds of allergic reactions in the U.S. during the first half of 20081.
Counterfeit pharmaceuticals are those that have arrived on the market as licensed drugs without having passed through the official channels. In such cases, the counterfeit drugs may contain the wrong or any active ingredient or the correct active ingredient in an incorrect quantity. Here, the best-case scenario may find a drug becoming ineffective. But in the worst case, fatalities may occur if the illegitimately made drugs do not have the desired effect. Counterfeiters not only manufacture imitations of prescription-only drugs, but also over-the-counter (OTC) products, generics, originator products and traditional drugs.
New Distribution Channels
The World Health Organization (WHO) estimates that every second pharmaceutical product purchased via the internet is counterfeit. Anabolic drugs and potency pills range among the most frequently ordered products. Apart from these so-called lifestyle medicines, more and more prescription drugs like antibiotics and medicines for cancer treatment are sold by online pharmacies.
A study conducted by the European Alliance for Safe Medicines (EAASM)2 found that in 90.3% of all cases, no prescription was required for the online purchase of prescription-only drugs. And more than 50% of medicines purchased from illegal websites concealing their physical address have been found to be counterfeit. But the internet is not the only channel by which counterfeits enter the market. Pharmaceutical wholesalers especially are targeted by counterfeiters. By introducing large quantities of falsified medicines into the legal supply chain, lucrative transactions can be made in a very short time. This depends strongly on the geographical area. For example, in most of Europe, the amount of falsified medicine is estimated at approximately 1%, while the developing world sees figures of as much as 50% of counterfeit pharmaceuticals.
The most important question is: How can patients be protected from this growing threat? Drug manufacturers assume an important role in the fight against counterfeiting by applying one or more of the technologies3 described below.
Overt and Semi-Overt Technologies
Holograms, well-known from their use on credit cards, can display a wide range of images and are printed onto folded boxes, blisters or labels in the pharmaceutical industry. Other Optically Variable Devices (OVD) are similar to holograms but without the three-dimensional effect. Packaging can also be marked with color-shifting security inks or films, which change color depending on the viewing angle. Different security graphics consisting of micro-texts or images are further overt variants: an additional text or image appears only when viewed with a magnifier. Sequential or randomized product numbering, overtly printed on the packaging, is the most common semi-overt anti-counterfeiting technology. As opposed to the serialization number (see below), it is not employed EU-wide or globally, but constrained to a certain product.
On-Product Marking
Analogous to the overt technologies, some anti-counterfeiting measures can be applied directly onto the product instead of traditionally onto packaging materials. For example, color-shifting inks are admixed to film-coated tablets, changing color depending on the viewing angle and incidence of light. Microtaggants and mechanical micro imprints can be administered to the film coating and identified using special equipment. Individualizing pharma products in terms of color, form and graphic or mechanical features also helps to protect patients by making drug copying a more laborious business.
Covert Technologies
While these approaches make use of visual effects, covert technologies rely on the opposite property: invisibility. A number of anti-counterfeiting features on the market are invisible to the naked eye. For example, special ink that is printed onto primary or secondary packaging and can only be seen under ultraviolet (UV) or infrared (IR) light. Digital watermarks are only decodable using special software programs. Microscopically small color-codes, in turn, consist of multiple color layers. They can be applied onto the packaging either manually or by means of dispenser technology, and are identified with a microscope. Techniques used for producing banknote paper — that is, paper with special fibers and additional watermarks — are also applicable to packaging. Furthermore, the finely structured pattern of the so-called ‘anti-copy’ or ‘anti-scan’ design only becomes visible when copied or scanned. This method was commonly used to prevent copying of secure documents.
Forensic Markers
More recent technologies rely on chemical and biological parameters, and belong to the category of forensic markers. They are neither visible to the naked eye nor by common analytical processes. Chemical taggants are added to inks and result either in a characteristic peak in the IR spectrum or in particular chemical reactions. Biological markers can be incorporated into product formulations or coatings, or onto the packaging. The latter also applies to DNA taggants. In addition, packages can be examined for their isotopic ratio, which is stored as a natural fingerprint. Microtaggants are unique numeric code sequences in a multi-color layered format that can be applied either on or in the packaging.
Tamper-Evident Features
All the technologies explained above belong to the category of authentication features. Apart from authentication, tamper-evidence is a further important aspect of anti-counterfeiting. Closure seals are a classic method for tamper-evidence applied to packaging. An intact seal proves that the package is being opened for the first time by the patient. In fact, this is the aim of all tamper-evident features. While they do not actually prevent counterfeiting, they nonetheless protect patients by clearly indicating whether a package has been opened before it reaches them. This also applies to so-called VOID foils, which immediately tear when tampered with. As soon as someone tries to open the package or remove the foil, the lettering “void” appears under the damaged surface. Perforation is a further means of making packaging tamper-proof: the packaging is irreversibly damaged once the perforation is torn.
Serialization Methods
Serialization with adaption of a machine-readable code is one of the most important strategies laid down in recent guidelines and legislation. A serialization number is a unique number attributed to pharmaceuticals on the package or bulk level. This number can be applied to the package by various technological means. One of them is the data matrix code. It can contain a distinct serial number attributed to the individual package, as well as variable data like batch number and expiry date. A radio frequency identification (RFID) label checks and records each product movement. This method is used for in-house stock control and was long considered one of the top track & trace solutions. Due to high costs and some implementation difficulties, the pharmaceutical industry is in favor of the data matrix code. In the long term, data matrix codes are intended to serve as traceability devices for all supply chain players, including pharmacies and patients.
Combined Strategy
Due to globalization and production outsourcing, the supply chain of pharmaceutical products includes many different steps between the producer and the end-consumer. Therefore, pharma companies opt for a combined strategy in most cases, depending on the individual counterfeiting risk, budget and technical abilities. This strategy should ideally consist of a combination of different technologies. Several layers of security can be created by combining tamper-evident, serialization and authentication technologies to form a multi-layer approach for the best possible patient protection.
Recently, international organizations such as the WHO have worked alongside governments and producers, largely through their International Medical Products Anti-Counterfeiting Taskforce (IMPACT), to help curb this damaging practice. Future initiatives to combat counterfeiters will also rely heavily on manufacturers. International guidelines and regulations have been developed, but regional and local regulations still vary considerably and in parts they are contradictive. For this reason, EU serialization is due to be introduced in 2014, followed by the long-awaited Food and Drug Administration (FDA)/California serialization standard, expected to be launched in 2015. The main goal of these regulations is to harmonize the coding of pharmaceutical products on an international level.
Taking It One Step Further
The FDA’s final guidance4 for the standardized numerical identification of prescription drug packages recommends the introduction of a serialized National Drug Code (sNDC) at package level. This code is composed of two distinct codes: the National Drug Code (NDC) contains labeler, product and packaging code. The unique serial number is composed of a maximum of 20 characters. The implementation of California’s ePedigree5 is now due to take place on a staggered basis from January 2015 to July 2017 for full traceability. Most of the guidance and regulations concentrate mainly on serialization to make pharmaceuticals traceable throughout the supply chain. The EU is currently taking these endeavors a step further.
In June 2011, the EU published its Directive 2011/62/EU6, amending Directive 2001/83/EC. In addition to the introduction of serialization standards for prescription medicines, the directive initializes the search for appropriate safety features which has not been finalized yet. It also provides for stricter regulations regarding the import of active substances and the improved control of the supply chain, including wholesale. Regulations for Internet trading of medicines, the harmonization of Good Manufacturing Practice (GMP) inspections and the introduction of a pan-European early warning system upon discovery of a falsified medicine are also an integral part of this Directive. Member States are expected to bring into force the laws, regulations and administrative provisions determined in the Directive by January 2013.
European Milestone
Directive 2011/62/EU represents a milestone in European attempts to set up legislation for a safe pharmaceutical supply chain. Uniquely coded, serialized packs for almost all prescription drugs are the Directive’s most important component. But the EU also recognizes the need for a combined strategy and requires a second layer of security: tamper-proof closures. These security components will be obligatory for nearly all prescription drugs, but not for OTC drugs. Exceptions defined in white and black lists will be determined by the European Commission, based on a risk assessment defined by price, sales volume, previous cases of counterfeiting, the degree of severity of the treated illness and other possible health hazards.
The required safety feature — the so-called “unique identifier” — will be determined in delegated acts, of which the first was published in November 2011. The paper has now been submitted for public consultation, and stakeholders are invited to contribute their comments before the end of April 2012. Technical implementation details and the process are still to be defined. Therefore, some of the methods described in the WHO IMPACT listing (see table) might become obsolete before long. The aim of the delegated act is to define the characteristics and technical specifications of the unique identifier, as well as the modalities of verification and the establishment, management and accessibility of the repositories system (database). The adoption of the delegated act is scheduled for 2014. It will be some time until all required steps are implemented and harmonized on an international level. But the industry is clearly moving in the right direction in its fight against pharma counterfeiters.
References
- www.safemedicines.org/counterfeit-heparin-blamed-for-worldwide-deaths.html
- www.eaasm.eu/Media_centre/EAASM_reports
- www.who.int/impact/events/IMPACT-ACTechnologiesv3LIS.pdf
- www.fda.gov/RegulatoryInformation/Guidances/ucm125505.htm
- www.pharmacy.ca.gov/about/e_pedigree_laws.shtml
- ec.europa.eu/health/human-use/falsified_medicines/developments/index_en.htm
Dr. Elke Sternberger-Rützel is a Pharma Trendscout and Innovation Manager at Robert Bosch GmbH, Packaging Technology – Business Unit. She can be contacted at elke.sternberger-ruetzel@bosch.com.