Counterfeit Medicines - The Global Hazard

By SAURABH DAHIYA - 08/31/2008

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A counterfeit medicine is a product, which is deliberately and fraudulently mislabeled with respect to identity and/or source, ingredients or the packaging while substandard medicines are genuine medicines produced by legitimate manufacturers that do not meet the quality specifications that the producer says they meet.

Even countries with advanced regulatory systems are seriously challenged by this deceptive practice. An analysis conducted by International Medical Product Anti-Counterfeiting Taskforce (IMPACT) shows that counterfeiting is greater in those areas where regulatory and legal oversight is weaker. This easy and lucrative business has attracted organized crime and in most of the countries, the punishment is not sufficiently strong to deter criminals. The fight against counterfeit medicines requires collaboration at national, regional and international levels. The absence of deterrent legislation, non implementation of Good Manufacturing Practices (GMPs), lapses in the product supply chain and unauthorized internet based sales of pharmaceuticals remain the major reasons of the proliferation of this crime. To deal with this problem strict measures are to be taken by the governments,complementing the legislation with effective law enforcement. RFID (Radio frequency identification technology) and OVDs (optically variable devices) can help track and authenticate the drugs.

Introduction

Counterfeiting is deceptive and immoral in any field. But in healthcare, it is criminal and simply unacceptable.¹ According to World Health Organization the definition of counterfeit medicines is “A counterfeit medicine is a product which is deliberately and fraudulently mislabeled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products and counterfeit products may include products with the correct ingredients or with the wrong ingredients, without active ingredients, with insufficient active ingredients or with fake packaging”.^{2, 3} It is important to make a distinction between counterfeit medicines and other kinds of substandard medicines. All counterfeit medicines are substandard because they are manufactured and distributed outside of regulatory control and their composition is unpredictable. On the other hand, not all substandard medicines are counterfeit because not all of them have been ‘deliberately and fraudulently mislabeled’.¹ According to WHO, Substandard medicines are genuine medicines produced by legitimate manufacturers that do not meet the quality specifications that the producer says they meet. For example, they may contain less (or more) active ingredient than written on the package. This may not be an intention to cheat, but may be due to problems with the manufacturing process.⁴ Many cases of counterfeiting have been uncovered while investigating therapeutic failure or adverse events observed in patients. Such cases lead to a serious consequence i.e. the erosion of confidence in health-care systems. Counterfeit drugs particularly affect the most disadvantaged people in poor countries.

One of the most worrying implication of counterfeit medicines is the emergence of drug resistant pathogens, bacteria, viruses, parasites.⁵ Substandard or counterfeit drugs increase the risk of spreading the resistance. Such a situation will lead to therapeutic failure and a need for discovery and development of new drugs will arise. The counterfeit medicines could also cause adverse effects through excessive dose or due to the presence of potentially toxic active ingredients or pathogenic contaminants.⁶ Loss of confidence and faith in the medicines and in the health care system is also a very serious damaging consequence of the counterfeit medicines. Not only the patient but also the health professional, pharmaceutical manufacturers, distributors, suppliers, retailers etc. loose confidence in the medicine that they rely upon. The pharmaceutical companies may loose the interest to invest in research and development and future innovation because the counterfeit product deprives the pharmaceutical companies of significant amount of revenues.

Some facts highlighting the presence of counterfeit medicines globally

The problem is truly global. Counterfeit medicines are increasingly detected not only in developing countries but also in European and North-American countries. This suggests that even countries with advanced regulatory systems are seriously challenged by this menace.¹ Rough estimates suggest that up to 10% of the medicines circulating in the world could be counterfeit. They are present in all regions but developing countries face the worst part of the problem. An estimated 25% of the medicines consumed in developing countries are believed to be counterfeit. In some countries, the figure is thought to be as high as 50%. ⁷ According to a prediction made by the Center for Medicine in the Public Interest, in the United States of America, counterfeit drugs sales will reach US$ 75 billion globally in 2010, an increase of more than 90% from 2005. ⁷

• WHO conducted a survey of counterfeit medicines in 20 countries between Jan 1999 to Oct 2000 and found that 60% of counterfeit medicine cases occurred in poor countries and 40% in industrialized countries.⁷In 2001, China had roughly 500 illegal medicine manufacturers and the Lao Peoples Democratic Republic had about 2100 illegal medicine sellers.⁸ In Thailand 8.5% are substandard medicines in the market,^{8, 9} 8% in Vietnam and 16% in Myanmar^{6, 9}WHO estimated in 2003 that there were 2800 illegal medicine sellers in Combodia^{8, 9} and 1000 unregistered medicines in the market.⁸

• In Mekong countries a study undertaken in 2001 indicated that more than one third of antimalarial Artesunate products in Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Viet Nam contained no active ingredients. A follow-up study in 2004 showed that the situation had worsened, with 99 out of 188 Artesunate samples found to be counterfeit.¹⁰

• In Africa a recent survey of quality of antimalarials has found that between 20% and 90% of the products failed quality testing. The survey was done in Gabon, Ghana, Kenya, Mali, Mozambique, Sudan and Zimbabwe.⁸

• A recent study in The Lancet concluded that up to 40% of products labeled as containing Artusenate (the best medicine to combat malaria today) contain no active ingredients and therefore have no therapeutic benefits.⁷

• Many of the former Soviet republics have a proportion of counterfeit medicines, which is above 20% of market value.³ In Russia, 3.6% of all drugs were found fake.¹¹ Aventis Pharma recently recalled antibiotic Cefotaxime (Claforan) after fakes were discovered containing dangerous levels of methanol.¹¹

• In Niger during meningitis epidemic in 1995 more than 50, 000 people were introduced with fake vaccines, received as a gift from a country which thought they were safe. The incident resulted in deaths of 2500 people.⁷

• In Haiti the consumption of Paracetamol cough syrup prepared with diethylene glycol (a toxic chemical used in antifreeze) resulted in deaths of 89 people in 1995 and also 30 infants died in India in 1998.⁷

• In Combodia about 30 people died in 1999 after taking counterfeit antimalarials prepared with Sulphadoxine-Pyrimethamine which were sold as Artusenate.⁷

• In Phnom Penh and Bangkok the National drug-testing laboratories investigated 230 samples of 24 pharmaceuticals purchased on the Cambodian market in 2000, including antibiotics and painkillers. About 3.5% of them contained less than 60% of the labeled quantity of active ingredient. When the study was repeated in 2003, 11% of the samples fell into this category, while some contained the wrong ingredient.¹²

• In Netherlands counterfeit Tamiflu capsules were found containing lactose and Vitamin C and no active substance.⁷

• In the United Kingdom, 5000 packets of Counterfeit Tamiflu were seized, estimated to be worth 500 000 pounds.⁷

• Counterfeit medicines have also been found in Latin American countries with instances from Argentina, Brazil, Colombia, Venezuela, Mexico, Peru, and Guatemala. Mexico is a major source of counterfeit medicines with trade of US $ 650 million per year equal to 10% of total drug sales in Mexico.^{13, 14}

According to International Medical Product Anti-Counterfeiting Taskforce (IMPACT established by World Health Organization) most developed countries with effective regulatory systems and market control (e.g. USA, EU, Australia, Canada, Japan, New Zealand) currently have a very low proportion, i.e. less than 1% of market value of counterfeit drugs.³

Frequently counterfeited medicines

Widely used medicines such as Atorvastatin and Paracetamol are found to be counterfeited, so are other, less commonly used products. The most frequently counterfeited medicines are expensive life style medicines such as hormones, steroids and antihistamines.⁷ Even the life saving drugs are also not spared. Anti-malarial drugs, anti HIV/AIDS, anti-cancer and anti-viral, antibiotics are among the most counterfeited drugs found in developing countries.⁷ Other than drugs, the problem extends to medical consumables also such as syringes, gauzes and other medical equipments.¹⁵ It is clear that counterfeit medicines are not limited to a particular category of pharmaceuticals but can be found in many therapeutic categories of medicines.

Obstacles in overcoming the problem

·Ineffective control on pharmaceutical manufacturing, importation and especially distribution:

In many countries the official supply chain fails to reach rural areas. Poverty, and the lack of an official supply chain, are major factors in creating markets for counterfeit products. Also international shipments are not searched or verified in free trade zones ¹⁶ making the infiltration in supply chain easier.

· Inadequate legalframework and ineffective punishment:

counterfeiting medicines is not properly defined and is dealt with in the same way as all other types of counterfeiting. The absence of deterrent legislation in many countries also encourages counterfeiters since there is no fear of being apprehended and prosecuted. Currently the penalties are not matching the crime and are therefore not acting as a sufficient deterrent. There is also lack of dedicated work force to handle the problem; also no uniform international obligations and no specific treaty exist to tackle the problem.¹⁶

·Weak administrative and coordination measures:

The Lancet published in October 2002, the conclusion of a conference on counterfeit drugs held in Geneva, saying that there is a glaring lack of political will to tackle a seriously underestimated problem of counterfeit drugs. ¹⁷ Combating counterfeit medicines requires collaboration, at national, regional and international levels involving all stakeholders of the public sector and the civil society including health professionals, patients, manufacturers, distributors, as well as communication professionals and the media.

An important step is to sensitize and obtain the commitment of lawmakers to introduce adequate legislative measures that clearly define and recognize counterfeiting of medicines as a crime that is different and far more serious than the counterfeiting of other kinds of goods. Because of a lack of regulation and enforcement, the quality, safety and efficacy of both imported and locally manufactured medicines in many developing countries cannot be guaranteed. Smuggling and illegal importation of drugs are rife. Counterfeit drugs are not only sold in these countries but also exported or re-exported.

Players in this important battle are the health professionals. Nurses and pharmacists should stay vigilant to the presence of counterfeits and report suspicious products. Similarly, physicians should rule out counterfeits as a possible cause of adverse reactions or therapeutic failure. Patients must report to their pharmacists and doctors if they sense any irregularity with their medication, if they experience a side effect or a decrease in beneficial effect.

· IPR disputes:

Inability to settle intellectual property rights (IPR) disputes and weak intellectual property protection leads to occurrence of more and more counterfeit cases in developing countries. Pharmaceutical companies should be asked to register and use of trademarks be enforced. Trademark owners have strong incentives to ensure that the quality of their product is maintained. In poor developing countries enforcing the trademark is difficult. If trademark are not enforced, poor quality drugs or counterfeits drugs will sideline the good quality medicines.¹⁵ A milestone step in stopping the counterfeiting is to respect the intellectual property rights and to protect it. Reforms in the IPR sector are a must in developing countries to save numerous lives from counterfeiters.

Measures and efforts towards combating counterfeit drugs

A. Ensuring regulatory control and international collaboration

The onus to address this global problem lies with various agencies like Governments, Regulatory Authorities, World Health Organization, Pharmaceutical industry, Pharmaceutical associations, Non-governmental organizations working in the health sector etc. The importance of lobbying national governments to prioritize the problem and to take necessary actions has often being emphasized. In many countries the punishment for dealing and involving in trade of counterfeit medicines is very light. Different authorities with in a country, the customs, the police and the court system could achieve a lot by enhancing their collaboration in the fight against the menace of counterfeit medicines. Medicines need to be safe, effective and of good quality in order to produce the expected therapeutic effect. Ensuring these properties requires the creation of competent national drug regulatory authorities with the necessary human and other resources to control the manufacture, importation, distribution and sale of medicines.^{1, 2, 7, 18}

Legislation forms the basis for drug regulation. Legislation must be complemented with effective law enforcement. Governments need to develop strategies to reduce corruption and criminal activity and promote inter-sectoral cooperation between regulatory authorities, police, customs services and the judiciary to effectively control the drug market and enforce drug regulation. When that regulation is infringed, sanctions against the manufacture and distribution networks must be commensurate to the crime.Consistent and systematic efforts are needed at the international level. These should include the timely exchange of information and the harmonization of international measures to prevent the spread of fake medicines.^{1, 2, 7, 18}

Cooperation between different law enforcement agencies should reflect the seriousness of the problem because combating of counterfeits is a shared responsibility of all interested parties. Also coordination among various agencies for international surveillance of fake and substandard drugs is a must to combat counterfeits.

B. Technological initiatives

The U.S.F.D.A. has recommended the use of Radio Frequency Identification Technology (RFID) as a means of tracking drugs. Several pharmaceutical companies are experimenting with RFID and Optically Variable Devices (OVDs) or using Bar Codes or other technologies such as web portals that can help track and authenticate the drugs.⁷RFID tagging of products can be an effective way to track and trace drugs from the point of manufacturing to the point of dispensing. RFID places electromagnetic chips and tags containing a unique serial number onto cartons and individual drug products. Other important anti-counterfeiting technologies include color-shifting inks, holograms, and chemical markers incorporated into a drug or its label.¹⁹ The RFID initiative was welcomed by many major pharmaceutical companies in USA.²⁰

C. Rapid reporting of counterfeit drugs

WHO established a Rapid Alert System for combating counterfeit medicines, where cases of counterfeit medicines can be reported through the system by using an electronic reporting form. Alternatively the reports can be submitted by other means like e-mail or fax to the secretariat, which immediately incorporates the information into the system. The system transmits information on cases of counterfeit medicines in an effort to alert authorities so that they can take timely action. The system was initiated by the Western Pacific Regional Office of the World Health Organization in collaboration with partner organizations to protect public safety.

In a similar initiative in USA, pharmaceutical industry announced a voluntary programme in which companies agreed to notify the FDA’s Office of Criminal Investigations of suspected counterfeiting.¹⁹

D. Education and awareness programmes

There is a little awareness of the problem of counterfeit medicines in the mind of the common people. Governments, N.G.O.s, and other groups working for the social and health concerns should educate the general public by setting up information campaigns, advertisements, banners, hoardings and other means of mass communication. Public should be advised to buy medicines from legitimate sources only. Consumers should be encouraged to report any deficiency in improvement of their health status or any adverse reaction observed by them to the physician or health care worker immediately. Dedicated websites should also be established to spread the message among the educated masses especially the Internet users. Media should play an important role in making the people vigilant about the seriousness of the problem.

E. Development of suitable analytical methods to identify counterfeit drugs

· Many researchers and their groups are working at various laboratories worldwide with the aim to develop suitable, fast, reliable, cost-effective and less time consuming methods for easy identification of counterfeit drugs present in the markets world over. Although advances in forensic chemical analysis have enhanced drug quality monitoring but pharmacopoeial analyses are still very time consuming and expensive to perform and can be carried out in specialized laboratories only. The development and use of simple tests should therefore facilitate a balance between the need to increase the amount of drug testing on the one hand, and the need to contain costs on the other.⁹ The simplest and cheapest way to detect counterfeit drugs is to compare the printing, embossing, shape, odour, taste, and consistency of a suspected sample with a genuine product.^{6, 21} Physical and chemical properties such as weight, density, refractive index, viscosity, osmolarity, pH, crystal morphology, solubility etc. can also be used to identify counterfeit drugs.^{6, 22}

The identification system may also consist of color reactions, based on functional groups in molecular structures of active ingredients and TLC methods can be used to screen fake drugs.²³Forensic analysis of the suspected samples can be performed in specialized laboratories using state of the art analytical equipments like High Performance Liquid Chromatography, Gas Chromatography, MS Spectroscopy, Colourimetry, Nuclear Magnetic Resonance Spectroscopy, Infra red Spectroscopy, Ultraviolet-visible spectroscopy, Refractometery, Polarimetery etc. Sophisticated techniques are now a days used to produce chemical fingerprints. Identification is most commonly accomplished by matching the UV visible spectrum or the retention time of the unknowns to the candidates stored in database.⁶

· The German Pharma Health Fund has developed methods for easy identification of counterfeit drugs. GPHF has developed a portable, tropics-compatible and easy-to-use mini-laboratory, which could verify the drug’s content and thus detect counterfeit and substandard quality medicines by employing inexpensive analytical techniques.^{9, 24, 25, 26} GPHF-Minilab test methods have initially been developed for 30 active ingredients. The testing of quality of drugs by GPHF minilab involves four steps. First step is the careful visual inspection of the product, it’s packaging and labeling, second step is to perform simple tablet and capsule disintegration tests, third is to perform simplified color reaction and then the final step is to run thin layer chromatography for a quick check whether the quantities of drugs claimed on the label are actually present in the product.⁹

· To counter the problem of counterfeit drugs, technologies such as global positioning system (GPS), bar/chip coding and hazard analysis and critical control point (HACCP) management should be coupled to the nanotechnology based marker assays.²⁸ Bar code technology has gained wide acceptance world over. The bar coding give important information about the drug viz. name of the item, manufacturers name, manufacturing date, expiry date, quantity, price etc. and thus simplifies the process of identification as well as proper storage of the pharmaceuticals. These technologies provide an accountable data to the user.

Conclusions

Counterfeiting of medicinal products is frequently encountered in many countries and areas, jeopardizing treatment outcomes and wasting resources. Counterfeiting is a crime, which cannot be dealt with by the health sector alone. Enforcement of legislation is of utmost importance for combating counterfeiting. The production of counterfeit or substandard medicines is a widespread but under-recognized problem that contributes to morbidity, mortality, and drug resistance, and leads to spurious reporting of resistance and toxicity and loss of confidence in health-care systems. The problem of substandard quality occurs when medicinal products are manufactured without compliance with Good Manufacturing Practices (GMP). So enforcement of GMPs by drug regulatory authorities in all manufacturing facilities throughout the world should be mandatory. Combating counterfeit medicines requires collaboration, at national, regional and international levels involving all stakeholders including health professionals, patients, manufacturers, distributors, lawmakers and law enforcement agencies. Media should also play its role by assisting national regulatory bodies and international health organizations in educating the masses against the counterfeit medicines.

References and Suggested Readings:

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2. World Health Organization, Geneva. General information on counterfeit medicines. Available from: http://www.who.int/medicines/services/counterfeit/overview .

3. IMPACT (International Medical Product Anti-Counterfeiting Taskforce). Counterfeit medicines: an update on estimates.

4. World Health Organization, Regional Office for the Western Pacific. Counterfeit medicines: some frequently asked questions.

5. Bate Roger and Boateng Kathryn. Bad Medicine in the Market. American Enterprise Institute for Public Policy Research. June 2007; 8: 1150.

6. WHO counterfeit action plan (Editorial), Scrip World Pharmaceutical News. 2003;2904.

7. World Health Organization, Geneva. Counterfeit medicines. Revised February 2006; Fact sheet No.275.

8. Pincock Stephen.WHO tries to tackle problem of counterfeit medicines in Asia. BMJ. 15 November 2003; 327: 1126.

9. Richard W.O. Jahnke, Counterfeit Medicines and the GPHF-Minilab for Rapid Drug Quality Verification. Pharm. Ind. 2004; 66, Nr. 10: 1187-1193.

10. World Health Organization, Regional Office for Western Pacific. WHO goes online to fight fake drugs (Press release).

11. Schofield James. Counterfeit pharmaceuticals flood Russian market. BMJ. 30 June 2001; 322: 1564.

12. World Health Organization, Regional Office for Western Pacific. Rapid Alert System for combating counterfeit medicine (Fact Sheets).

13. Patel N.K, Mishra A.D, Suhagia B.N, Shah D.R, Bhatt S.S, Marolia B.P. Drug counterfeit - A global menace and its remedial measures. Pharmainfo.net. Available from: http://www.pharmainfo.net

14. Latin America Battles Counterfeit Drug Threat. Daily International Pharmacy Alert; Washington Business Information. 2006: 292.

15. Morris Julian and Stevens Philip. Counterfeit medicines in less developed countries. First published by International Policy Press a division of International Policy Network. 2006.

16. Charatan Fred. Fake prescription drugs are flooding the United States. BMJ. 16 June 2001; 322: 1446.

17. Kapp Clare. Counterfeit drug problem “underestimated”, says conference. The Lancet. 5 October 2002; 360: 1080.

18. European Federation of Pharmaceutical Industries and Associations. Counterfeit Medicines.

19. U.S. Food and Drug Administration. Protecting consumer from counterfeit drugs, FDA consumer magazine.

20. U.S. Food and Drug Administration. Radiofrequency Identification Technology: Protecting the drug Supply, FDA Consumer magazine.

21. WHO Geneva. Counterfeit Drugs-guidelines for the development of measures to combat counterfeit drugs. WHO/EDM/QSM/99.1. 1999.

22. Green MD, Newton PN, Fernandez F. simple low-cost strategies to rapidly identify counterfeit drugs in developing. In combating pharmaceutical fraud and counterfeiting. SMI Conference Documentation. London: SMI Publishing, 2003.

23. Hu Chang-Qin, Zou Wen-Bou, Hu Wang-Sheng, MA Xiao-Kang, Yang Min-Zhi, Zhou Shi-Lin, et al. Establishment of a Fast Chemical Identification System for Screening of Counterfeit Drugs of Macrolide antibiotics. Journal of Pharmaceutical and Biomedical Analysis. 2006; 40: 68-74.

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25. Jahnke, R. W. O., Kallmayer, H.-J., Breyer, C. et al., Concise Quality control Guide On essential drugs, Vol. I, Colour Reactions, German Pharma Health fund, Frankfurt (1998): supplements 1999 and 2002.

26. Jahnke, R. W. O., Pachaly, P., Gobina, N. P. et al., Concise Quality control Guide On Essential Drugs, Vol. II. Thin Layer chromatography, German Pharma Health Fund, Frankfurt (1998); supplements 1999, 2002, 2003 and 2004.

27. German Pharma Health Fund. Available from: http://www.gphf.org/web_en/projekte/minilab.

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30. German Health Pharma Fund, GPHF News, Nr. 1/2006: 4.

31. Khan Azhar Yaqoob, Ghilzai Maushad M. Khan. Counterfeit and substandard quality of drugs: The need for an effective and stringent regulatory control in India and other developing countries. Indian J.Pharmacol. August 2007; 39(4): 206-207.

32. Rovner Julie. US Food and Drug Administration bill signed into law.The Lancet.6 December 1997; 350: 1690.

33. Ault Alicia. FDA homes in on counterfeit and imported drugs. The Lancet. 11 October 2003; 362: 1208.

34. Lewcock Anna. Portable drug anti-counterfeiting device to hit market. In-Pharma Technologist.com. Available from http://www.in pharmatechnologist.com/printNewsBis.asp?id=73031.

35. Balakrishan Reghu. ‘Supply of counterfeit APIs from India on rise’. Available from http://www.financialexpress.com/printer/news/238563.

36. IFPMA (Internationa Federation of Pharmaceutical Manufacturers and Associations. Trade in counterfeit drugs is widespread and affects both developing and developed countries. Available from http://www.ifpma.org/Issues/issues_quality.aspx.

37. Newton Paul N, Green Michael D, Fernandez Facundo M, Day Nicholas PJ, White Nicholas J. Counterfeit anti-infective drugs.Lancet infect Dis. 2006; 6: 602-13.