Illicit Ingredients and Counterfeit Medicines

By Merlin Goldman, Ph.D.
Concern among European fine chemicals companies over the large volume of illicit active pharmaceutical ingredients (APIs) imported into the European Union (EU) should be dampened by stricter EU regulations on the licensing of medicines introduced earlier this year. However, API producers in Europe fear that the legislation, due to come into effect late next year, does not go far enough. The European Parliament has adopted measures to control the trade in two compounds used for both legitimate pharmaceutical applications and the manufacture of illicit drugs. The measures are designed to prevent the diversion of acetic anhydride and potassium permanganate, used in the production of heroin and cocaine, respectively. The aim is to reduce the regulatory burden on companies by rationalizing current legislation in this area, which includes no less than 6 separate directives and regulations.

Both compounds are sold in large quantities for application in the pharmaceutical and chemical industries. Potassium permanganate is used in analytical applications and in synthetic organic chemistry and as an ingredient in antibacterial and antifungal preparations. Acetic anhydride is mostly used in the manufacture of cellulose acetate for films and plastic goods, but a proportion also goes to make aspirin and other pharmaceutical agents. The new measures are designed to improve the control and monitoring of these substances, as well as increasing the accountability of companies--and specific individuals within them--o discourage diversion. For example, manufacturers must obtain a license to make the compounds and nominate an officer to oversee the business who will be the point of contact for regulatory bodies. The authorities must be notified of any changes in personnel, premises etc. Customers wishing to use the substances must provide a declaration of their intended use, for each shipment that passes through the European Union. The import and export of such substances is covered by separate legislation.

Diversion of APIs can contribute to the manufacture of fake medicines, which are sold illegally, increasingly through the Internet. Counterfeiting of medicines has become a global problem but there is no common definition that captures all aspects of the problem. The World Health Organization definition is: "A counterfeit medicine is one which is deliberately and fraudulently mislabelled with respect to identity 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 ingredients, or with fake packaging. The United States Food and Drug Administration estimates that counterfeits make up more than 10% of the global medicines market and are present in both industrialized and developing countries. It is estimated that up to 25% of the medicines consumed in poor countries are counterfeit. These figures place the annual earnings from the sales of counterfeit and substandard medicines at over $32 billion globally.

Discriminatory regulation and control of medicines intended for export as opposed to use in the country of manufacture compromises the quality of medicines moving in international commerce. Often, medicines labelled "For export only" are not subject to the same strict regulation as those for internal use. Poor regulation of exports from manufacturing countries exposes countries with weak or non-existent regulation to dumping of fake pharmaceuticals. Other contributory factors include ignorance and poor public awareness about counterfeit medicines, illegal and deceitful advertisements, and indifference by governments. Counterfeiting of medicines was first mentioned at the international level at a WHO Conference of Experts on the Rational Use of Drugs held in Nairobi, Kenya, in 1985. WHO has been collating information about counterfeiting activities since 1984. Between 1984 and 1999, 771 reports of counterfeit drugs were received and added to the WHO database. The majority (78%) of these reports came from developing countries. In recent years the trend has shifted somewhat; from January 1999 to October 2000, 46 confidential reports of counterfeit drugs were received from 20 countries--60% from developing countries and 40% from developed countries.

Factors that contribute to medicine counterfeiting are their high value in relation to their bulk and that demand for them is endless. Worldwide, corruption and conflicts of interest result in weak regulation and lack of enforcement. Before 1998, the United States and other developed countries were not particularly concerned about counterfeit pharmaceuticals. The security departments of the major pharmaceutical companies devoted few, if any, resources to the problem. It was indeed one of the well-accepted "truths" of counterfeiting that it was a problem only in China, India, and other less-developed countries. However, between 2001 and 2003, Pfizer began to see counterfeit versions of their products throughout Europe, Asia, Africa, the Middle East, and the Americas. With the exception of Italy and Luxembourg, counterfeit Pfizer products were found in each of the EU member countries, as well as in eight of the fifteen candidate countries (Bulgaria, Estonia, Hungary, Malta, Poland, Romania, Slovakia, and Turkey). Pfizer now employs more than 40 people to investigate and prevent the sale of counterfeit Pfizer products.

Many governments refuse to acknowledge the counterfeiting problems for fear that patients will be put at risk if fear of fakes prevents them from taking the real product. In Africa, a variety of factors, including weak regulatory authorities, political instability, and low levels of literacy, make it difficult to estimate the true prevalence of fake medicines. Pharmaceutical manufacturers, for example, have put a variety of anti-counterfeiting measures into place the use of holograms and other devices on the packaging. When it is difficult to identify a counterfeit product by visual inspection, new analytical methods may be needed. This is particularly important if a prosecution is anticipated. Infrared spectrographic analysis shows excipients as well as active ingredient. They are useful for screening because they can be used to show differences between genuine and counterfeit products although they cannot identify the different constituents. More information can be gained by looking at related substances using high-performance liquid chromatography (HPLC) to examine extracts of products. Different manufacturing processes lead to different impurity profiles and these are clearly visible in HPLC spectra. A much more powerful technique is near-infrared (NIR) spectroscopy. It is a non-destructive technique that allows examination of the whole formulation and not just the active ingredient. As a result, the spectrum gives much more information about the manufacturing source than other methods. It can provide both qualitative and quantitative data: "It fingerprints the whole matrix." An International Laboratory Forum on Counterfeit Medicines has been formed in an effort to combat global counterfeiting operations. This is an alliance for collaboration and exchange of information on analysis and surveillance of illegal medicines including counterfeit products.

The most frequently observed product is Viagra (sildenafil). Examples found include a product labelled sildenafil that contained caffeine, and tablets that looked like Viagra but which turned out to be crushed "clones" that had been bulked out with lactose and recompressed to form tablets containing about 30mg of sildenafil. Some counterfeit products are difficult to identify as such from visual examination; in one sample of counterfeit Viagra, the only visible difference was a minor change in the angle of slope of the letter "f" in the name Pfizer. Analysis to standard specifications may not identify such products as counterfeit. There is widespread recognition that, at its worse, counterfeiting can lead to significant morbidity and mortality. This is particularly serious with regard to the high percentage of counterfeit antibiotics and steroids available.

At the national level, there is a need to encourage increased reporting of possible counterfeit drugs. A basis for suspicion of counterfeiting and reporting would be different appearance of drug or packaging from the original, ineffective action, or very low price. At the national and international levels, industry should be more closely engaged in identifying possible counterfeit medicine outlets. Many countries should focus attention on the appearance of counterfeit drugs on the domestic market. Equally important is the regulation of exports. Maintaining the standards of exporting companies must be seen as an integral role of legislation and regulation. The need for improved international cooperation is essential through organizations such as WHO, UNICEF, and Interpol.

--------------------------------------------------------------------------------
This discussion of counterfeit medicines and the difficulties in controlling them was written by Merlin Goldman, Ph.D. ( mhgoldmanuk@yahoo.com ).

To view and purchase D&MD reports click here!