COUNTERFEITING - A GLOBAL ISSUE
The issue of counterfeit drug products is increasingly gaining in topicality. It is not a problem only concerning individual cases in developing countries any more. On the contrary, counterfeit drug products are now also detected on the European and US-American markets - considered to be secure. Although the problems differ from country to country - in Africa and Asia, for example, drug products available in pharmacies might also be counterfeited while in Europe counterfeit drug products are mostly traded on the Internet - the result is the same: a potential danger for the patient.
The international conference on "Strategies against Counterfeit Medicines" presented an outlook on the different aspects of the problem of counterfeit drug products. The lecturers discussed analytical, legal and regulatory aspects as well as how to safeguard imported raw materials for the manufacture of drug products. Speakers representing various drug manufacturers gave an insight into strategies for combating counterfeit drug products. Furthermore, participants were informed about product coding, protection thereof along the supply chain and the respective techniques available.
Dr Domenico di Giorgio, Agenzia Italiana del Farmaco (AIFA, Italian Medicines Agency), presented the International Medical Product Taskforce (IMPACT), an initiative of the World Health Organisation (WHO). He provided an outlook on the milestones in WHO's work in the anti-counterfeiting as well as definitions and guidelines. He specified the "Declaration of Rome" in February 2006 as a foundation act for establishing IMPACT. IMPACT defines itself as a voluntary coalition of stakeholders that considers collaboration with authorities, drug manufacturers, drug importers, the media and patients as central element.
Di Giorgio raised the issue of defining the term "counterfeit". According to him products that have no marketing authorisation in the country where they are sized should not automatically be stigmatised as "counterfeit". He continued that it is necessary to distinctly differentiate between "real" counterfeit items where counterfeit drug products are seized and patent infringements. Hence, when studying a statistic on counterfeit cases it is necessary to study closely the basis on and according to which definition the data was collected. He furthermore emphasised that not only the exporting country should be made accountable for the counterfeits, but also the importing side.
In another lecture, Di Giorgio talked about the activity of European organisations. He presented the European Directorate for the Quality of Medicines and HealthCare (EDQM). The EDQM's main function includes controlling medicinal products and products for blood transfusion. A newly founded department, entitled the "Committee of Experts on minimizing public health risks posed by counterfeiting of medical products and related crimes (CD-PPH/ CMED)" now also deals with minimising the health risks posed by the counterfeiting of drug products. Key aspects include training a national co-operation between customs, police, the marketing authorisation agencies, the supervising authorities, public relations, risk communication and the creation of a data base on the counterfeiting of drug products.
A similar concept was presented by Andy Charvill from the Medicines and Healthcare Products Regulatory Agency (MHRA). In 2008, the MHRA developed a strategy in the United Kingdom to improve communication, collaboration and regulation of counterfeit drug products cases at a national level. At an international level, the co-operation comprises the WHO, Interpol and the European Commission. At an industrial level, it also includes manufacturers and parallel importers and at the regulatory level, UK police and customs authorities. One function of the project involves targeted market surveillance of "at risk" drug products. The MHRA concentrates on 15 products with a high potential for counterfeiting; for example, drugs against erectile dysfunction. Samples of these drugs are taken from different points of the regular supply chain and bought online before they are analysed in laboratories. Charvill outlined near-infrared spectroscopy (NIRS) as an analysis technique and presented the results and their evaluation. The MHRA expects to find as yet undiscovered ways counterfeited drugs take, and ideally to identify and prosecute the offenders.
Michael S. Russo from Eli Lilly & Company gave an outlook on the organisations in the USA combating the counterfeiting of drug products. He underlined the distinction between the highest US federal law enforcement agencies (Federal Bureau of Investigations (FBI), Food and Drug Administration (FDA) and the local state law enforcement agencies (local police sheriffs)). He thus stressed the fact that in the USA, in the case of discovery of counterfeited drug products, jurisdiction might differ from state to state. Furthermore, he tried to motivate private companies and drug product manufacturers to take their own precautions towards protection against counterfeit drug products. He made specific suggestions which might help to establish protection measures. Russo gave examples such as developing a working relationship with the governmental authorities or using the media. These measures have already been adopted at Eli Lilly & Company.
Dr Stephan Schwarze gave an outlook of the counterfeit protection management practised by Bayer Schering Pharma AG (BSP). He presented a conceptual model divided into four action fields that is constantly improved and updated by a permanent learning process. This process is pushed by the knowledge of counterfeits, prevention, reactions to the appearances of counterfeits and by constant monitoring of the market. He substantiated the concept by showing the network of internal co-operation at BSP, the utilisation of security features, the raising of awareness in society by means of the media as well as collecting and tracking relevant data in a global data base.
Looking at drug product counterfeit cases that made it into the news in the last few years, Prof Dr Ulrike Holzgrabe from the University of Würzburg presented some especially analytical aspects. In the first case, she explained, a change in the production process of L-Tryptophan led to additional impurities, possibly causing the Eosinophilie- Myalgie-Syndrome (EMS). The occurrence of EMS was altogether reported in 1,500 cases after taking drug products or food supplements containing L-Tryptophan in 1989/1990. This led to 30 deaths. Holzgrabe showed how these impurities which did not arise in the production process customary until then, and which were presumably responsible for the development of the side effects, can be detected by the HPLC technique.
Prof Dr Holzgrabe talked about two further cases and the possibility of examining them analytically. Those cases involved the occurrence of contaminations in API batches of Gentamicin and the contamination of milk powder with melamine. She also dealt with the Heparin case which occurred in 2007. In this case, it was also the contamination in drug products containing Heparin that led to serious side effects which in some cases were lethal. This time, however, it was not the result of a change in the production process, but possibly intentional mixing at the supplier's of the raw material to feign the existence of the right amount of API. Prof Dr Holzgrabe examined several batches of different API manufacturers, named the substances responsible for the side effects and showed how they can be detected by the H-NMR technique.
Prof Dr Klaus-Jürgen Steffens from the University of Bonn presented x-ray diffraction (XRD) as further analysis technique. In contrast to the techniques of trace analysis presented by Holzgrabe, XRD makes it possible to measure pills non-destructively, even through the blister pack. Using different products, Steffens showed that XRD can provide evidence of the originality of the product in the blister.
Dr Chris Oldenhof from DMS Anti-Infectives spoke in his position as President of the Active Pharmaceutical Ingredients Committee (APIC) about the APIC initiatives to combat counterfeit APIs. Firstly, Oldenhof defined pharmaceutical ingredients from the point of view of APIC. APIC makes a distinction between counterfeit APIs and so-called "rogue APIs" (ingredients which do not meet the standards). Counterfeit APIs are defined as "active pharmaceutical ingredients for which source and / or quality are falsely represented on the label or on the certificate of analyses". "Rogue APIs" by comparison are substances which are either counterfeit or deliberately, severely non-compliant.
Oldenhof explained that a "rogue API" is not necessarily by definition a counterfeit API, but that a counterfeit API always is also a "rogue API". This distinction is applied when API manufacturers are compared at a global level. In Europe, only a few manufacturers are known to the authorities as producing "rogue APIs". But in Asia, 2/3 of all API manufacturers are regarded as rogue API manufacturers. Oldenhof stressed that this has to be seen critically, since European importers and drug producers increasingly buy cheaper APIs from China. In this context, Oldenhof showed the fundamental differences in API manufacture between Europe and Asia influencing the APIs' quality. Theses differences mostly have historical reasons. In Europe, for example, API manufacturers have been inspected by the authorities for decades now. In Asia on the other hand, it is rather seldom that an API manufacturer has been inspected and has passed this inspection.
Referring to recent instances - like the Heparin case already mentioned by Holzgrabe - Oldenhof used current examples to confirm the high relevance of inspecting the manufacturers and the assurance of the APIs' quality by doing so.
Oldenhof concluded by presenting a 10 points plan to reduce the presence of "rogue APIs". This concept includes a mandatory API GMP certification by a European inspectorate and setting up a Central European unit to co-ordinate API inspections worldwide.
The Conference „Strategies against Counterfeit Medicines“
The development and implementation of appropriate systems for the protection against counterfeit medicines were in the centre of attention of the conference "Strategies against Counterfeit Medicines" in Würzburg last November. Authority and industry activities were introduced and discussed. In detail, the conference covered effective, but also affordable strategies as well as improving the cooperation of both sides and further efforts in fighting counterfeited drugs. The conference was organised jointly by the University Würzburg, the German Pharmaceutical Society (DPhG), the FECC (European Association of Chemical Distributors), the European Compliance Academy (ECA) and the European Qualified Person Association.
In one of his lectures, Karl Metzger represented the European Association of Chemical Distributors (FECC). He presented the role of wholesale traders in the pharmaceutical supply chain and described their organisation within the FECC. Like Oldenhof, Metzger regards it as potentially dangerous that counterfeit APIs or APIs with less quality access the regular supply chain. This is why Metzger underlined the FECCs measures to minimise this risk. These measures are strictly oriented towards the ICH guidelines.
Dr Martin Wesch from Wesch & Buchenroth, concentrated in his lecture on the legal aspects related to the personnel working in quality control. Wesch underlined the personal responsibility of each qualified person. He strongly recommended a clear, contractual definition of liability within the respective enterprise. Furthermore he explained the legal environment according to different national and international laws.
There are different technologies for tracing drug products throughout the regular supply chain. Andrea K. Brunson from Pfizer presented the utilisation of a combination of Radio Frequency Identification Codes (RFID-Codes) and 2D Matrix Codes in the USA in the case of Viagra. RFID offers the possibility of reading and storing data without the need for any contact or line of sight.
Dr Stephan Schwarze from Bayer Schering Pharma AG presented the concept of the European Federation of Pharmaceutical Industries and Associate (EFPIA) on the coding and identification of drug products. The principle of this concept is based on an unequivocal coding and identification of single, regularly produced packages. For this purpose, a 2D Matrix Coding and the storage of data in a central data base is intended. Schwarze stresses the circular unity of the concept: before being dispensed in the pharmacy, the relevant packages are verified by means of comparison with the central data base. Only after a positive identification the package can be dispensed and thus the supply chain closed. Furthermore, this concept can help to harmonise the coding system in Europe which differs greatly from nation to nation.
Roberto Rosito from Essex Animal Health talked about his practical experiences in the use of the 2D Matrix Codes on primary and secondary packages of animal drugs. In 2004, the International Federation for Animal Health (IFAH) implemented the 2D Matrix Code as a global and mandatory standard on all packages of animal drugs.
Geoff Power, a former Director of Packaging Security at GlaxoSmithKline, talked about the different possibilities of authentication of packages. He differentiated between overt, covert and forensic features and explained their advantages and disadvantages. Power illustrated his lecture with examples of genuine and fake features of packaging material from his long-standing experience.
Conclusion
Different measures to combat the counterfeiting of drug products have already been taken. The activities range from analytical examinations through security of packaging material and coding to national and international regulatory initiatives. These activities are regularly adjusted according to the respective circumstances. Nevertheless, a common, global strategy combining all initiatives with their various strong points has not apparently been reached to date. In doing so, the protection of the patient should always be kept in mind as the main goal.
Author:
Maren Müller-Späth
... is a doctoral candidate in the analytical development at Bayer Schering Pharma. There she works on optimising and developing applications for the identification and quantification of pharmaceutical products through NIR and Raman spectroscopy.
