Although counterfeiting is perceived mostly as a problem with finished medicines, excipients can also be targetted. Phil Taylor, of PJT Communications, outlines some recent initiatives set up by regulators and non-governmental organisations around the world to tackle the problem
The usual perception of counterfeit medicines is an illegal copy of a finished medicine slipped into the supply chain by illicit manufacturers. But the reality is far more complex and individual components, including excipients, are also vulnerable to counterfeiting.
That is one of the reasons why the European arm of the International Pharmaceutical Excipients Council (IPEC Europe) made the issue of counterfeit, diverted or mis-labelled medicines a cornerstone of its seminar this year.
Incidents involving excipients remain rare. A 1998 World Health Organisation (WHO) report said that there had been 500 avoidable deaths in the previous 10 years caused by substandard excipients, including a notorious case in Haiti in 1996 when 88 people died from taking cough syrup contaminated with poor quality glycerin. There is no telling how many other cases have gone unrecorded.
Professor Henk de Jong of Servier, a past chair of IPEC Europe, presented data from the Pharmaceutical Security Institute (PSI), an industry body set up to monitor medicines counterfeiting activity, showing clearly the increase in detected cases of fake medicines in the supply chain.
In 2006, there was a 22% rise in total documented cases reported through PSI's Counterfeit Incident System (CIS) compared with 2005, mainly affecting oral dosage forms and spread across therapeutic categories. Respiratory, alimentary, cardiovascular and genito-urinary medicines were the top segments targeted by the counterfeiters, while China headed the list of countries of origin, followed by Russia, the US, Brazil and India.
"If we lose trust in our pharmaceutical manufacturing and distribution chain, from the source of raw materials to the patients, then our whole system runs the risk of being undermined," said Professor de Jong. "That is the real message from these figures."
International regulatory bodies are also becoming increasingly concerned about the increase in pharmaceutical counterfeiting and the risk of counterfeit excipients entering the supply chain.
Dr Steven Wolfgang of the US FDA's Center for Drug Evaluation and Research (CDER), updated delegates on recent regulatory changes in the US and the agency's efforts to stop counterfeits entering the market. Alluding to recent cases involving the substitution of melamine for protein and diethylene glycol (DEG) for glycerin, Wolfgang noted: "Commodity ingredients - not necessarily expensive drugs - are being targeted by unscrupulous individuals out to make a quick profit."
The FDA is worried that identity testing and certificates of analysis - currently the main safeguards for ensuring quality in imported substances - are not sufficient to guarantee quality of glycerin imports. Last year, it issued guidelines recommending that a specific limit test for DEG be added to glycerin identity testing, and to shore up the supply chain the agency now asks that every time a shipment of glycerin changes hands it should be tested.
The US government also set up an Interagency Working Party on Import Safety last year to improve the safety of imported products, and in November 2007, this body published an action plan that marks a shift from the current import safety system to a risk-based approach that focuses on prevention. Among the proposals that could have a bearing on excipient producers, are a certification system for foreign producers, expanded laboratory capacity for testing and greater use of electronic track-and-trace technologies.
Europe is also reacting to the threat, and Dr Susanne Keitel, director of the European Directorate on the Quality of Medicines (EDQM), noted that counterfeiting has been brought into the agency's remit by its controlling body, the Council of Europe. "Counterfeiting is a major public health concern, and the number of cases is increasing in both legal and illegal supply chains," Keitel said. EDQM's role in co-ordinating the European Official Medicines Control Laboratories (OMCL) network means it has the capability to play a key role in the fight against counterfeits.
"EDQM could contribute to knowledge-sharing on analytical methods, setting of reference standards, and the co-ordination of testing and inspections," she suggested.
The WHO is taking a leading role in the fight. In late 2006, it set up its IMPACT (International Medical Products AntiCounterfeiting Taskforce) programme to bring together industry, regulators and other stakeholders to see what can be done to curb the trade. Representing the WHO, Dr Sabine Kopp detailed the measures that the organisation is undertaking in the area of supply chain security, including a revision of its Good Trade and Distribution Practices guide, which is being updated to tackle the rise in counterfeit medicines.
The WHO has also set up a pharmaceutical starting materials certification scheme (SMACS) under which starting material manufacturers can be certified by a national authority or other competent body, and Kopp noted that this is becoming more widely accepted.
She also issued a formal invitation for IPEC Europe and its counterparts in the US and Japan - collectively known as TriPEC - to become a partner in the IMPACT initiative and encourage the implementation of WHO tools.
For its part, IPEC Europe has been providing tools and guidance to help stakeholders across the pharma industry to ensure that counterfeit or substandard excipients do not enter the supply chain. The latest of these, launched at the seminar, is The IPEC Good Distribution Practices Audit Guideline, a joint initiative with IPEC Americas.
The guideline provides a tool for those auditing companies in the pharma excipients supply chain and is designed to be used in conjunction with the 2006 IPEC Good Distribution Practices Guide. Through the GDP committee and part of a broader guideline on excipient qualification, IPEC Europe is also working with IPEC-Americas on principles for a document on excipient pedigrees.
New analytical tools such as near infrared (NIR) spectroscopy are also proving valuable in identifying counterfeit pharmaceuticals. Andrew Charvill, an analytical assessor with the UK Medicines and Healthcare products Regulatory Agency (MHRA), said NIR provides a simple and quick tool to compare a suspect item with a reference standard. However, he called for pharma manufacturers to co-operate with the network of OMCLs to provide reference samples for testing.
Yves Michel Ginot, head of the analytical division of Technologie Servier, told the meeting about another NIR process - hyperspectral or NIR chemical imaging - that could complement conventional NIR spectroscopy and provide additional critical analytical information in the fight against counterfeiting.
Hyperspectral chemical imaging - which in essence marries microscopy and spectroscopy and involves taking readings of a sample across all wavelengths - can effectively look inside the tablet and determine the spatial distribution of APIs and excipients, and can even give an estimate of the content of a tablet without access to reference samples, said Ginot.
Professor de Jong sounded an optimistic note, however, pointing out that with arrests relating to manufacturing and transportation of counterfeits up 63% and 89% in 2006 respectively, there is evidence that concerted efforts by stakeholders are having an effect. "Pharmaceutical crime is still concentrated in some countries, so you can do a good risk-based analysis to concentrate activities," he said.
Furthermore, law enforcement agencies have been spurred into action thanks to organisations such as WHO and the pharmaceutical industry, amid growing recognition that - unlike other industry sectors - counterfeiting of medicines has both an economic and a public health impact.