serialization of pharmacetical products: eu … · 2019-10-04 · union in february 2016, and came...

Nikolay Karev, Dimitar Raychev

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SERIALIZATION OF PHARMACETICAL PRODUCTS: EU DELEGATED ACT 2016/161 TO PROTECT AGAINST FALSIFIED MEDICINES

(REVIEW)Nikolay Karev, Dimitar Raychev

ABSTRACT

The European Union’s Falsified Medicines (FMD) Directive 2011/62/EU modifies Directive 2001/83/EC to ensure public health by protecting the pharmaceutical supply chain from infiltration by counterfeit medicines. It also intro-duces new rules to regulate more strictly the supply chain. The Commission Delegated Regulation (EU) 2016/161 completes Directive 2001/83/EC with detailed rules regarding safety features for the packaging of medicinal products for human use. The regulation was adopted in October 2015 and published in the Official Journal of the European Union in February 2016, and came into force at the end of February 2019. This article will provide an overview of the directive, its impact on the distribution of medicines, and the latest update affecting pharmaceutical manufacturers.

Keywords: counterfeit medicines, serialization, EU directive, delegated regulation, BgMVO.

Received 08 May 2018Accepted 19 July 2019

Journal of Chemical Technology and Metallurgy, 54, 6, 2019, 1165-1170

Department of Economy and ManagementUniversity of Chemical Technology and Metallurgy 8 Kliment Ohridski, Sofia 1756, BulgariaE-mail: [email protected] [email protected]

INTRODUCTION

The number of falsified medicines on the European market has significantly increased over the past few years. In particular, stolen pharmaceutical products, a form of falsified medicines, have increasingly been in-troduced into the legal supply chain via parallel trading. The reasons why parallel trading serves as a gateway for falsified medicines are most likely the complex suppling chains and routes of transport. It is hardly possible for national authorities to trace the history of a medicinal product that was bought and sold by several interme-diaries in different EU member states. In addition, the various external shapes of imported and relabelled pharmaceutical products makes easier the introduction of counterfeit products onto the market.

Falsified pharmaceutical products are multi-faceted. The health risks for patients who are frequently very seriously ill are high. The problem in Europe has been recognized. It is the declared objective of the Falsified Medicines Directive 2011/62/EU to further improve the protection of patients from falsified pharmaceuticals. Therefore, it attaches measures for easy identification

of falsified medicines in the supply chain. This is the European legislature’s reaction to an increase in falsified medicines. The EU Falsified Medicines Directive aims to create a uniform, standardized solution for protection from falsified drugs. From 9 February 2019 onward (ac-cording to the EU Regulation No. 2016/161), manufac-turers may only release prescription drugs bearing two safety features into circulation and pharmacies may only dispense these drugs to patients following a successful authentication. The EU legislature demands that each EU member state establish a non-profit national medicines verification organization (NMVO) that sets up and oper-ates a national medicines verification system (NMVS) for the authentication of pharmaceuticals.

In Bulgaria, this is Bulgarian Medicines Verification Organisation (BgMVO), an alliance of the pharmaceuti-cal industry, wholesalers and pharmacies. BgMVO was established on 14 March 2016 in Sofia as a non-profit association to support the implementation in Bulgaria of Directive 2011/62/EU for preventing entry of falsi-fied medicinal products into the legal supply chain. The founders of the BgMVO are five organizations represent-ing the stakeholders involved in the manufacturing and

Journal of Chemical Technology and Metallurgy, 54, 6, 2019

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distribution of pharmaceutical products - Association of the Research-based Pharmaceutical Manufacturers in Bulgaria, Bulgarian Generic Pharmaceutical Associa-tion, Bulgarian Association of Medicines Parallel Trade Development, Bulgarian Association of Pharmaceutical Wholesalers and Bulgarian Pharmaceutical Union. The main responsibilities of the BgMVO include above all support of the pharmacy market supplying authentic medicinal products as well as establishment and also maintenance of an effective drug verification system in the Republic of Bulgaria. BgMVO closely cooperates with Healthcare authorities in Bulgaria.

BACKGROUND AND CURRENT SITUATIONFalsified medicines are a worldwide problem. There

are only estimates referring the proportion of counterfeits in the market. The investigative authorities assume a high number of unreported cases [1]. The International Federation of Pharmaceutical Manufacturers & Associa-tions (IFPMA) estimated that in 1998 approximately 7 % of medicines on the world market were counterfeit medicines [2]. That was already at this time a forgery volume of more than $ 20 billion [3]. The threat of coun-terfeit medicines varies in different regions of the earth. Since 2013, WHO has received more than 1500 reports of cases of substandard or falsified products whereby antimalarials and antibiotics are the most commonly reported. Most of the reports (42 %) come from the WHO African Region, 21 % from the WHO Region of the America, and 21 % from the WHO European Region. Unfortunately, this is just a small part of the total prob-lem and many cases will probably remain unreported [4]. According to an annual report for 2017, based on data collected by WHO Global Surveillance and Moni-toring System for substandard and falsified medicines, vaccines and in vitro diagnostic tests (GSMS) 10,5 % of all medicines in low- and middle-income countries are substandard and falsified medical products. If this is applied to the estimated market size in low- and middle- income countries, the estimated spend corresponds to $ 30.5 billions [5]. The University of Edinburgh developed a modelling exercise based on GSMS report according to which 72 000 to 169 000 children may be dying each year from pneumonia due to substandard and falsified antibiotics. Moreover, another model developed by the London School of Hygiene and Tropical Medicine estimates that nearly 116 000 additional deaths from

malaria could be caused every year by substandard and falsified antimalarials in sub-Saharan Africa, with will generate costs of $ 38.5 million to patients and health providers for further care due to failure of treatment [6].

Experience obtained from investigations and raids made in EU countries, as well as in the USA and Canada, demonstrate that the consumption of counterfeit pharmaceuticals is not confined to only less developed countries [7]. Although, the official statistics of the WHO estimate that counterfeit medicines do not exceed 1 % of market value in developed countries, those markets are very vulnerable and demonstrate some weaknesses that allow counterfeit medicines to infiltrate and develop new illegal opportunities [8]. It is a striking fact that European countries and their national authorities are facing continually growing share of counterfeit medi-cines for years because of possible inefficiency of the state regulatory mechanisms but also increasingly glo-balized supply chain of the pharmaceutical industry. In 2005, the Spanish police raided six laboratories located in the autonomy province Catalonia and confiscated nearly 30 million doses (10 tons) of counterfeit anabolic steroids and hormone-boosting substances as well as cancer drugs. The substances came in different dosage forms including vials, tablets, capsules and injectables. The falsified products were destined for distribution in various EU countries and considerable amounts had been already forwarded to Italy, France and Portugal. The most counterfeit products have been distributed via Internet. Although the falsified substances had been manufactured in Spain, the authorities detected that the ingredients used for their production originated from Mexico, Brazil and Thailand [9].

European customs have already in 2006 reported a significant increase of seized counterfeit medicines of 380 % compared to the previous year. China, India and also the UAE were identified as the main source countries [10]. In 2007, 4.081.056 counterfeit medicines were seized by customs officials, this was an increase of 56 % in comparison to the 2006 with 2.711.410 confis-cated products [11]. There was a new trend in 2012 as reported cases (2.530) and confiscated articles (712.220) decreased significantly, estimated retail value of goods was 8.152.653 €. Hence, China came first with 48,84 % as country of provenance, followed by India (16,20 %) and Hong Kong (14,15 %) [12]. In 2017, there were still 1.835 cases with total 568.122 seized counterfeit prod-


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ucts and an estimated retail value of goods amounting to 6.909.674 €. Anyhow, China (17,16 %) was replaced as number one country of origin by India (71,74 %) [13].

With opening of drugs commerce on the Internet as of 1st January 2004 illegal trade with pharmaceutical products has increased significantly.The Internet has completely changed customer behavior and creates new mechanisms trading in parallel with legal provisions. A report titled “Counterfeit medicines: facts and practical advice” and published in 2009 provides accurately and thoroughly insights of the e-commerce with medicines. According to this report legal pharmacies are over-whelmed in number by fraudulent pharmacies selling uncontrolled medicines that may not comply with legal standards and regulations. According to the figures of the USA accreditation center LegitScript, the number of legal, licensed e-pharmacies is under 1 % of the online offer, in terms of number of sites. The rest of the web offer, according to many different independent stud-ies is nearly equally divided between fake and rogue websites [14]. EUROPEAN PROTECTION REGULATIONS AND INITIATIVES

According to WHO counterfeit medicines are “deliberately and fraudulently mislabelled with respect to identity and/or source” [15]. Counterfeit medicines could be both branded and generic products and may “include products with the correct ingredients but fake packaging, with the wrong ingredients, without active ingredients or with insufficient active ingredients” [16].

The European Commission issued a first specific Directive 2001/83/EC [17] already in 2001 with the aim of standardizing and tightening the pharmaceutical supply chain in European Union. Directive 2001/83 / EU imposed new rules on manufacturers, wholesalers as well as pharmacies and drugstores but it has missed to implement a clear definition of the counterfeit medi-cines. Moreover, it has been proven to be too weak to ensure the safety of European patients. The world’s growing problems with counterfeit, ineffective, illegally traded and expired medicines have not been resolved for European Union.

This critical situation uses the following Directive 2011/62/EU amending Directive 2001/83/EC to estab-lish a community code related to medicinal products for human use, with regards to the prevention of the

entry into the legal supply chain of falsified medicinal products. This Directive sets common rules for, inter alia, manufacturing, importing, placing on the market, and the wholesale distribution of medicinal products in the EU member states as well as rules relating to ac-tive substances. Past experience shows that counterfeit medicinal products do not reach patients only using il-legal channels, but through legal supply chain as well. Directive 2011/62/EU also entails international audits, reviews, inspections, sanctions of all distributing agents, drug control over the internet. Moreover, safety features which will allow in a near future the verification of the authenticity and identification of individual packs and provide evidence of tampering have to be implemented. Those safety features should be harmonized within the EU in order to take account of new risk profiles, while ensuring the functioning of the internal market for me-dicinal products [18].

DIRECTIVE 2011/62/EU

The Directive 2011/62/EU was adopted on 8th June 2011 and extends the provisions made in 2001. It provides changes that are designed to ensure the safety of the legal channels of distribution and to ensure trust in them. The aim of the Directive is, on the one hand, to ensure the functioning of the internal market for medici-nal products while ensuring a high level of protection of public health against counterfeit medicines. The entry of counterfeit drugs into the legal supply chain should be successfully prevented.

The Directive defines new terms such as e.g. “Falsi-fied medicinal product” and “Excipient”. According to the official definition falsified medicinal product is “any medicinal product with a false representation of:

(a) its identity, including its packaging and label-ling, its name or its composition as regards any of the ingredients including excipients and the strength of those ingredients;

(b) its source, including its manufacturer, its country of manufacturing, its country of origin or its marketing authorization holder; or

(c) its history, including the records and documents relating to the distribution channels used” [19].

The directive extends the obligations of manufac-turers, they are obliged to purchase only those active substances that have been marketed in accordance with Good Distribution Practice (GDP) for active substances.


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Authorities’ inspections and also audits of drug manufac-turing facilities can be carried out not only on suspicion of non-compliance, but also on the basis of a risk analy-sis. Active ingredients must be manufactured according to the standards of Good Manufacturing Practice (GMP). This also applies to active substances produced in third countries and imported into the EU.

Active substances may be imported if they are manufactured in accordance with the standards of GMP and written confirmation from the competent authority confirms that the standards are at least equivalent to those of the EU, the manufacturer is subject to regular, strict and transparent controls, and In case of breaches, and the exporting third country shall immediately inform the EU [20].

Another focus of the Directive is the obligation to affix safety features for medicinal products. These secu-rity features make it possible to verify the authenticity of individual packages and to identify tampering. Those significant changes are obligatory for all participants in the supply chain (manufacturers, packagers, brokers, etc.) and are expected through the implementation of Article 54 (o). It requires the integration into the pack-aging of safety features which “wholesale distributors and persons authorized or entitled to supply medicinal products to the public to verify the authenticity of the medicinal product and identify individual packs” [21] and a device that makes it possible to check whether the outer wrapping has been manipulated.

Article 54 requires that packaging should contain authentication features, that individual coding must dis-tinguish the individual packaging, and that the packag-ing have to be secured against tampering in such a way as to preclude an undetected opening and exchange of content. The provision applies to all prescription medi-cines in the EU, with some special rules. Transferred at the national level, EU members are free to extend the regulations, for example to modernize labeling or health insurance billing.

In order to have a more reliable supply chain, whole-salers have an obligation to ensure that their suppliers are in possession of a valid wholesaling license. Mediators which are involved in trading of medicinal products without selling or purchasing of these medicines in their own name, without the ownership of the medicines or the physical handling of the medicines are also affected by those regulations. The European Commission’s GDP

Guidelines now contain special provisions on the media-tion of medicinal products [22].

Hence, EU law deals for the first time with the sale of medicines via Internet. The illegal sale of medicines via Internet poses a significant threat to public health, as counterfeit medicines can easily reach the public. Member States are granted a discretionary power over the distribution of medicinal products. Member States may independently decide on the distribution of medici-nal products via the retail market (Internet, mail order). However, the Court of Justice of the European Union has recognized that the member states may in principle reserve the respective retail sales of medicines solely to pharmacists. When it comes to mail order business, a common logo has to be implemented recognisable on the websites of legal pharmacies and wholesalers within the EU. The implementation of a common logo will enable the identification of the Member State where the person offering medicinal products for sale at a distance to the public is established. The Commission has adopted an Implementing Regulation which specifies the logo No 699/2014 of 24th June 2014 on the organization of the common logo and the technical, electronic and crypto-graphic requirements for checking the authenticity of the same [23].

DELEGATED REGULATION (EU) 2016/161

Commission Delegated Regulation (EU) 2016/161 of 2 October 2015 supplementing Directive 2001/83/EC of the European Parliament and of the Council lay-ing down detailed provisions concerning safety devices which are listed on the packaging of medicinal products for human use, published in the Official Journal on Feb-ruary 9th 2016, describes the characteristics of the safety features, how medicine authenticity should be verified and who is responsible for. The delegated Regulation, and the new medicine verification system it lays down, will apply as of 9th February 2019 [24].

Various authentication mechanisms and traceability requirements for medicinal products may affect the distribution of medicinal products and increase costs for all involved parties in the supply chain. Therefore it is necessary to establish common rules for the im-plementation of the safety features for medicinal prod-ucts, especially with respect to the characteristics and technical specifications of the unique identification, the modes for the verification of the safety features, and the


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establishment and management of repository database on the safety features.

This Regulation sets out a system of rules ensuring the identification and the authentication of medicinal products by an end-to-end verification of all medicinal products bearing the safety features, supported by an ad-ditional verification by wholesalers of certain medicinal products at higher risk of falsification [25].

In practice, the authenticity and integrity of the safety features placed on the packaging of a medicinal product should be verified when the medicinal product is supplied to the public. Moreover, medicinal products at higher risk of falsification should be additionally verified by wholesalers throughout the supply chain process. The verification of the authenticity of a unique identifica-tion code has to be carried out by reconciliation with existing national database and also repositories system of EU hub. When a pack is supplied to the public, or is distributed outside the European Union, the unique identifier on that pack should be set to inactive in the repositories system so any other pack bearing the same unique identification code could not be successfully verified [26]. However, the Delegated regulation does not provide any specific technical options for the anti-tampering device, so that every manufacturer is free to choice the most appropriated device in accordance with its needs [27].

CONCLUSIONSThe European Union’s (EU) Falsified Medicines

(FMD) Directive 2011/62/EU amends Directive 2001/83/EC to protect public health by safeguarding the pharmaceutical supply chain from infiltration by coun-terfeit medicines. The Commission Delegated Regula-tion (EU) 2016/161 supplements Directive 2001/83/EC with detailed rules regarding safety features for the packaging of medicinal products for human use. The regulation was adopted in October 2015 and published in the Official Journal of the European Union in Febru-ary 2016, and it came into force on 9th February 2019.

This directive impacts the entire pharmaceutical supply chain, from drug substance manufacturers to pharmacists dispensing medicines at point of sale. The delegated regulation applies to all medicinal products available only on prescription, except for products on the whitelist (e.g., medicinal gases and radionuclide generators). Nonprescription drugs (OTC) are generally

not affected, except for those on the blacklist (i.e., at risk of falsification).

The delegated regulation applies to all 28 countries in the EU and also includes the European Free Trade As-sociation (EFTA) countries (Switzerland, Lichtenstein, Norway, and Iceland). Three countries have received exceptions to extend the compliance deadline to nine years (2025): Belgium, Greece, and Italy. The main com-ponents of the delegated regulation are: implementing of safety features - unique identifier (UI) and a tamper-evident device, establishing of an end-to-end verification model and a verification of high-risk practices within the supply chain.

REFERENCES

1. H. Stürmann, Arzneimittelkriminalität - ein Wachstumsmarkt?, Köln, Hermann Luchterhand Verlag, 2007, p. 41.

2. H. Stürmann, Arzneimittelkriminalität - ein Wachstumsmarkt?, Köln, Hermann Luchterhand Verlag, 2007, p. 42.

3. F. Stieneker, M. Beck, K. Gronwald, D. Schnädelbach, S. Throm, M.W. Wesch, Arzneimittelfälschungen, Pharm. Ind., 63, 4, 2001, 321-326.

4. WHO, 1 in 10 medical products in developing countries is substandard or falsified, Press release, Geneva, Switzerland, 2017.

5. WHO, WHO Global Surveillance and monitoring system for substandard and falsified medical prod-ucts, Geneva, 2017, p. 2-3.

6. WHO, 1 in 10 medical products in developing countries is substandard or falsified, Press release, Geneva, Switzerland, 2017.

7. UNICRI, Counterfeit medicines and organized crime, Turin, 2012, p. 43.



10. G. Lalis, WHO IMPACT International Conference „Developing Effective Legislation to Combat Counterfeit Medical products”, Introductory Speech of Director Georgette Lalis, Lisbon, Portugal, 2007, p. 2.

11. Europe Economics, Policies to combat counterfeit medicines. Contribution to impact assessment, London, United Kingdom, 2008, p. 2.


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12. European Commission, Report on EU customs en-forcement of intellectual property rights. Results at the EU border 2012, Luxembourg, 2013, p. 27-32.

13. European Commission, Report on EU customs en-forcement of intellectual property rights. Results at the EU border 2017, Luxembourg, 2018, p. 21-24.

14. D. Di Giorgio, Counterfeit medicines: facts and practical advice, Milano, 2009, p. 127-132.

15. WHO, Fact Sheet No. 275, Counterfeit medicines, revised 14.11.2016, www.who.int.

16. WHO, Fact Sheet No. 275, Counterfeit medicines, revised 14.11.2016, www.who.int.

17. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use.

18. European Commission, Falsified medicines - major developments, 2018.

19. Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relat-ing to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products, Article 1.

20. Ministerium für Gesellschaft, Vernehmungsbericht der Regierung betreffend die Abänderung des Gesetztes über den Verkehr mit Arzneimitteln sowie den Umgang mit menschlichen Geweben und Zellen im Europäischen Wirtschaftsraum, Lichtenstein, 2015, p. 13.

21. Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending

Directive 2001/83/EC on the Community code relat-ing to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products, Article 54(0).

22. Ministerium für Gesellschaft, Vernehmungsbericht der Regierung betreffend die Abänderung des Gesetztes über den Verkehr mit Arzneimitteln sowie den Umgang mit menschlichen Geweben und Zellen im Europäischen Wirtschaftsraum, Lichtenstein, 2015, p. 15.

23. Commission Implementing Regulation (EU) No 699/2014 of 24 June 2014 on the design of the common logo to identify persons offering medicinal products for sale at a distance to the public and the technical, electronic and cryptographic requirements for verification of its authenticity.

24. Commission Delegated Regulation (EU) 2016/161 of 2 October 2015 supplementing Directive 2001/83/EC of the European Parliament and of the Council by laying down detailed rules for the safety features appearing on the packaging of medicinal products for human use.

25. IHE Pharmacy Technical Committee, Falsified Medicines Directive - Supply chain interoperabil-ity in support of safer medication usage, Brussels, 2017, p. 6.

26. IHE Pharmacy Technical Committee, Falsified Medicines Directive - Supply chain interoperabil-ity in support of safer medication usage, Brussels, 2017, p. 6.

27. J. L. Valverde, Illegal medicines as threats to public health, Pharmaceuticals Policy Law, 1–16. DOI: 10.3233/PPL-170449, 2017.

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