A global solution to protect consumers from counterfeit drugs remains elusive as regional conflicts rage over intellectual property rights, free trade and public health.

Countries reliant upon emerging generic drug manufacturing sectors have rebuffed an effort by the World Health Organization to treat substandard drugs as counterfeit.

Generic drug manufacturers in India opposed the move, casting it as a veiled effort to stop them from competing against higher-priced Western drug makers. Emerging nations in Latin America and Southeast Asia also opposed it, seeking to preserve access to more affordable drugs from India.

With the global initiative unraveling, regional and country-specific anti-counterfeiting efforts continue to emerge and are approaching the problem in different ways.

The U.S. is pressing ahead with a track-and-trace system, while the European Union is piloting a pharmacy-based verification scheme and other countries such as Nigeria are establishing consumer cell phone based approaches.

The war against counterfeit drugs also is being waged on a new front of intergovernmental collaborations and agreements.

Despite the impasse at the global level, industry officials expect to see regional progress against counterfeiting. They predict that European Union and U.S. regulators will soon require manufacturers to label their products with standard numerical identifiers, and this mass serialization could become a reality within the next five years.

Counterfeit drugs continue to proliferate

The counterfeit drug problem is getting worse, or at least regulators and industry groups are reporting more cases of alleged drug counterfeiting.

David Dorsey, FDA acting deputy administrator for policy, told a Nov. 30, 2009, meeting of the Healthcare Distribution Management Association that the number of counterfeit drug cases opened by FDA's Office of Criminal Investigations per fiscal year increased from 56 in 2008 to 65 in 2009.

The Pharmaceutical Security Institute, an industry organization set up in 2002 that includes 27 drug companies as members, reports that between 2002 and 2008, the number of reported counterfeiting incidents has multiplied nearly tenfold from 196 1o 1,834. Not all of the growth may be from increased counterfeiting; some may result from better tracking.

"We used to say if you are a blockbuster or a lifestyle product you are in danger," Dean Hart, executive vice-president of commercial operations of Nanoguardian, observed at the Fifth Global Forum on Pharmaceutical Anti-Counterfeiting sponsored by Reconnaissance International on Feb. 24-26 in Hollywood, Fla.

"It doesn't matter anymore. All kinds of medicines have been counterfeited, including generics. I was at a conference last year and I had at least five generic manufacturers come up to me and say, 'wow I need to talk to you about your technology because we are getting counterfeited right and left and we need to protect our brands.'"

While they are waiting for either harmonized or region-specific legislation to ward off counterfeiters, manufacturers can start taking steps now to protect their supply chain, said speakers at the Reconnaissance meeting.

Pharmaceutical security experts advised industry to adopt a layered approach to protecting their products, mixing overt or non-hidden features with covert or hidden features, on the drug packaging and in the drug product itself.

Global IMPACT derailed over definition

There were expectations that WHO's International Medical Products Anti-Counterfeiting Task Force (IMPACT), launched in February 2006, would be able to develop a coordinated global response to the counterfeit problem.

IMPACT, comprised of health regulators and representatives of the pharmaceutical industry, developed a slate of recommendations in March 2007 to address how to coordinate anti-counterfeiting activities (¹ Also see "As Anti-Counterfeiting Approaches Diverge, Industry Calls for Harmonized Solutions" - Pink Sheet, 1 July, 2008..

Yet the work of IMPACT has derailed over difficulties agreeing on a definition of counterfeit drugs, said Laurie Self, a partner in the Washington office of the law firm Covington and Burling. Her practice focuses on U.S. and international intellectual property and technology law. She has spearheaded campaigns to reform and enforce intellectual property law.

Self explained that IMPACT proposed to change its 1992 definition of a counterfeit drug in 2007 to address concerns that it was too narrow in scope, and avoided the larger global problem of substandard drugs.

Proposed definition provoked controversy

To accommodate these concerns, IMPACT proposed to change the definition of a counterfeit drug so that it would no longer require a showing of fraudulent intent.

A drug would no longer have to be "deliberately and fraudulently mislabeled with respect to identity or source" to be deemed as counterfeit. There would merely have to be "a false representation in relation to its identity and/or source."

The proposed counterfeit drug definition asserts that it "applies to the product, its container or other packaging or labeling information." It clarifies that generic drugs can also be counterfeited, and includes slightly revised wording about the misrepresentations involved: "counterfeits may include products with correct ingredients/components, with wrong ingredients/components, without active ingredients, with incorrect amounts of active ingredients, or with fake packaging."

The proposed definition includes new language aiming to protect "legitimate" products that happen to have quality issues from getting labeled as counterfeit: "quality defects or non-compliance with Good Manufacturing Practices/Good Distribution Practices (GMP/GDP) in legitimate medical products must not be confused with counterfeiting."

A draft resolution on counterfeit medicines, which included this definition, was presented at the 61 World Health Assembly in May 2008 in Geneva, Switzerland.

Self noted that at this meeting a coalition of generic drug companies and anti-corporate activists raised concerns that the proposed definition could forseeably encompass legitimate generic drugs.

"Unfortunately that effort from WHO was derailed or at least temporarily derailed by political tensions," she said. "When the model framework came for a vote, concerns were raised by the Brazilians, Indonesians and Indians and other developing countries that this will open a back door way to suppressing parallel trade."

After objections were raised by member states over the implications of the draft resolution, WHO decided to table the matter.

Self further noted that "even though WHO was very clear that they were differentiating between patent law violations and counterfeiting violations, there were real concerns that this resolution was in fact impeding in the area of intellectual property rights - where it did not belong."

Dutch customs seizures exacerbated conflict

Self noted that this development occurred against the backdrop of a larger debate brewing between developed and developing countries over the need for access to affordable medicines versus the need to encourage research in new medicines through patent protection.

She observed that "a challenge we face in the political arena is tension between intellectual property rights, free trade and public health goals. We have seen that tension play out for many years. We are starting to see that same tension play out in the counterfeiting space where a developing country and parallel trade groups are questioning the motivations of policymakers that are trying to strengthen the anti-counterfeiting laws. Are these laws a backdoor way of blocking parallel trade? And this is very unfortunate because this is one area where everyone should be viewed as amicable. We need to overcome this suspicion in order for there to be progress."

Fueling the controversy was a series of four drug seizures by Dutch customs beginning in October 2008 and culminating with the Dec. 12, 2008, seizure of a consignment of bulk losartin that Dr. Reddy's Labs in India was shipping to Brazil, which customs declared to be a counterfeit of Merck and DuPont's Cozaar.

The cases involved generic drugs made in India for markets in Latin America that Dutch customs branded as counterfeit. None of the generics could be marketed in Europe due to patent protection. The issue was whether they could be transported through Europe.

India and Brazil threatened to file a complaint with the World Trade Organization. Health Action International and other non-governmental organizations seeking to preserve access to affordable medicines in the developing world wrote to the World Health Organization's director-general, Margaret Chan, seeking to protect goods in transit from the proposed IMPACT definition and certain other threats.

The Dutch case, said Self, "did underscore this suspicion in the developing world" that anti-counterfeiting activities could involve "overly stringent interpretation of patent laws that would prevent generic entry of drugs into developing countries."

Future of IMPACT unclear

As the result of this stalemate over the proposed definition, Self noted that "frankly it is unclear whether IMPACT can exist and this would be unfortunate and a real tragedy for everybody. We really do need an umbrella tent for all developing countries and all the relevant countries to come together."

IMPACT's two major accomplishments, Self noted, were bringing to the forefront the magnitude and depth of the counterfeiting problem as well as bringing all the players in the supply chain together.

Yet one official from IMPACT asserted that despite the setback, the group is forging ahead with its work plan, which includes ongoing discussions on the definition of a counterfeit drug.

Ilisa Bernstein, FDA's director of pharmacy affairs, addressed the situation with IMPACT during a March 18 interview with "The Gold Sheet." She chairs the task force's regulatory implementation working group.

Bernstein acknowledged that "there were some different interpretations of the definitions that were proposed by IMPACT, and it did create some controversy."

However, despite reports to the contrary, it has not stopped the organization, she said. "IMPACT over the last year has continued to function and in fact has created regulatory tools for regulators, has done enforcement activities and actually has gone into countries and is working with INTERPOL (the International Criminal Police Organization) and has had various operations, as well as a global Internet operation. So the work of IMPACT has been continuing despite the issues with respect to the definition."

Bernstein noted that a WHO forum was scheduled for March 26 in Geneva, where the chairs of the IMPACT working groups were to present updates on their activities.

Also in December 2009 IMPACT sent a letter to all member states asking them to submit the counterfeit drug definition that is in their national legislation, as well as to comment on IMPACT's current and proposed definitions.

WHO is evaluating survey responses it received from 60 member states.

Bernstein acknowledged that the definitional issue is complex and varies from country to country. "In one country it may be a substandard, in our country sometimes those products would be considered unapproved but not necessarily counterfeit under the legal definition in the United States, so I think some of that is at the root of the controversy."

Legal landscape growing more complex

In the meantime, divergent regulatory approaches to handling drug counterfeiting continue to hamper the ability of regulatory agencies to keep counterfeit drugs out of the pharmaceutical supply chain.

Self noted that "in terms of the legal landscape the problem we are facing is that we have a kind of hodgepodge of laws that are not adequately equipped to deal with pharmaceutical counterfeiting. One of the major challenges we face is the definition of what pharmaceutical counterfeiting is and without that uniform definition it is very difficult to develop a response to the problem."

For example, Self noted that in China a counterfeit medicine requires proof of harm, while other countries tend to view pharmaceutical counterfeiting merely as a trademark violation.

"We need that kind of common terminology. There is also a lack of coordination between regulatory authorities and pharmaceutical counterfeiting is very often a lack of investigative powers and enforcement authority."

U.S. and EU take different approaches

There are also different legislative approaches emerging from the U.S. and the EU in dealing with this problem, which adds to the cost and complexity of global compliance.

While U.S. regulators are exploring a full track-and-trace system, the EU favors relying on verification at the end of distribution when the product is about to be dispensed.

The European Commission on Dec. 12, 2008, proposed a counterfeit drug directive, which is part of a larger package on pharmaceutical reforms. The proposal would require that safety features, such as serialization number or a seal, be affixed on the packaging of all prescription medicines; require companies to audit all firms manufacturing APIs; and strengthen the rules for inspections by requiring inspection results to be posted on the EudraGMP database.

The EU's counterfeit drug proposal is expected to be adopted by the end of 2010. There will be an 18-month implementation period. An open issue is whether the directive should address Internet sales, which is a major source of counterfeit drugs (² Also see "As Anti-Counterfeiting Approaches Diverge, Industry Calls for Harmonized Solutions" - Pink Sheet, 1 July, 2008.).

In testing whether end product verification programs can actually work, a representative of the European Federation of Pharmaceutical Industries discussed some of the results at the meeting from EFPIA's traceability pilot, which just concluded.

EFPIA pilot supported by Swedish pharmacists

Anthony Barron of EFPIA said that a survey of pharmacists who participated in the pilot program reported favorably on it.

"The survey overall showed that the feedback was positive," Barron said. "Eighty-four percent said that it was easy to use. And 85 percent said there were no problems with response time."

The only drawback was that pharmacists were confused over which code to scan, "especially if there was more than one pack of the same product."

The pilot, which started in October 2009, established a harmonized coding system for pharmaceuticals that allows pharmacists to verify each medicine pack before it is dispensed through the use of 2D barcodes. Fourteen manufacturers and 25 pharmacies in the greater Stockholm area participated in the pilot. (³ Also see "Biotechs Urged to Prevent Viral Risks That Cost Genzyme Nearly $300 Million" - Pink Sheet, 1 January, 2010.)

Barron said that the federation supports a layered approach to protecting medicine packaging. It supports as a first step the use of harmonized coding and identification systems for pharmaceutical packaging, the use of overt and covert features to authenticate products.

Tracing off track; numerical identifiers on track

A federal court in December 2006 blocked FDA from enforcing requirements in the 1988 Prescription Drug Marketing Act for drug makers to establish pedigrees for tracking their drugs through the supply chain.

However, the threat of counterfeit drugs prompted new legislative concerns over the safety of the supply chain and in 2007 Congress passed the FDA Amendments Act to give FDA the authority to develop standards for drugs for identification and tracking and tracing.

However, to date FDA has not been successful in issuing standards for a full track-and-trace system. The cost of such systems and the lack of agreement on the technology to be used are the major stumbling blocks.

A study conducted by Accenture found that it would cost a large chain pharmacy in the U.S. about $1.3 billion to implement the hardware, software, infrastructure and labor for a track-and-trace system that would fully comply with FDA's e-pedigree requirement. Accenture is a management consulting and technical services company contracted by pharmacy groups to examine the impact of e-pedigree on pharmacies.

The cost is driven by the fact that the retail pharmacy is at the end of distribution network and therefore its systems must be interoperable with all the technology choices made by others in the supply chain.

In the absence of a federal track-and-trace standard, states are continuing to go their own way and attempt to implement their own pedigree standards, but without much success.

California, which has been at the forefront of the electronic pedigree movement in the U.S, has repeatedly delayed implementing its pedigree requirements. It was supposed to go into effect on Jan. 1, 2009. Now it is not slated to take effect until Jan. 1, 2017. The state's e-pedigree model has been held up as a possible future prototype for FDA to emulate as it grapples with devising its own e-pedigree requirements.

FDA has made more progress under FDAAA in developing standards for numerical identifiers.

FDA Commissioner Joshua Sharfstein announced at a House Energy and Commerce Health Subcommittee on March 10 that FDA is about to release a final guidance on standard numerical identifiers on drug packages. A draft guidance document was issued in January 2009 (⁴ Also see "Rx-360 Consortium Aims to Curb Pharmaceutical Supply Chain Threats" - Pink Sheet, 1 February, 2009.).

The guidance, called "Standards for Securing the Drug Supply Chain: Standardized Numerical Identification for Prescription Drug Packages," is focused on developing standardized numerical identifiers for the smallest saleable unit of prescription drug packages. A draft was released in January 2009 (⁵ Also see "Attention Turns to the Business Case for Quality by Design" - Pink Sheet, 1 January, 2009.).

FDA has also been working with Reps. Jim Matheson, D-Utah, and Steve Buyer, R-Ind., to reintroduce their anti-counterfeiting legislation.

The two congressmen first introduced the Safeguarding America's Pharmaceuticals Act in 2008. It calls for FDA to develop a numerical identifier system and to identify drugs for which a track-and-trace system would be initiated first because they are at a high risk of being counterfeited.

The bill could also be incorporated into the FDA Globalization Act, which was introduced by Rep. John Dingell, D-Mich, last year and is expected to be reintroduced this year. The bill would strengthen FDA's inspections of foreign food production facilities with oversight of foreign drug and medical device facilities to come later.

Council of Europe tries new approach

In the absence of a worldwide collaborative effort, the war against counterfeit drugs is being waged through intergovernmental collaborations and agreements, according to Self.

These include a new Council of Europe draft international convention, or agreement, issued in November 2009 that aims to criminalize the manufacturing of counterfeit drugs as well as the falsification of any document related to a medical product, or the possession of counterfeit medical products.

The group, which is comprised of 47 member organizations that seeks to develop common principles on human rights, has been working since 2006 on an international agreement on pharmaceutical crime. However, the convention is open to all countries, not just the convention's 47 members.

The convention is scheduled to be adopted by the Council of Europe on May 12, 2010. A major difference between this group and IMPACT is that the convention will bind those countries that ratify it, while IMPACT is more of a coordinating body and agreements are not legally binding and do not have the force of law (see sidebar: " ⁶ WHO IMPACT Timeline ").

USP and AID partner to help developing countries

On another front, the U.S. Pharmacopeia (USP) recently announced a partnership with the Agency for International Development (AID) to fight the proliferation of substandard as well as counterfeit drugs in developing countries.

The Promoting the Quality of Medicines (PQM) program, announced in October 2009, operates in 28 countries in Latin America, Southeast Asia and Africa.

Patrick Lukulay, USP's director of drug quality and information, explained that "our main focus is building capacity of drug regulatory authorities in developing countries. We conduct training activities on how to test the drugs in country. We believe in empowering [drug authorities] to test their medicines."

The program is funded jointly by USP and AID and will run until 2014 at a cost of $35 million. Lukulay noted that "the money is spent on the training activities to support our staff that conducts the training as well as equipment and raw materials that we buy for national laboratories."

USP and AID purchased about 100 minilabs, which are located in 15 countries. These minilabs do the initial screening for substandard and counterfeit drugs. Results are sent to public health authority labs for confirmatory testing.

These minilabs were procured from the Global Pharma Health Fund, a non-governmental organization in Germany. Lukulay noted that these minilabs consist of two transportable units, each about the size of a suitcase filled with drug testing equipment.

The partnership is also starting to explore the use of TruScan Raman hand-held spectrometers to screen for counterfeits.

Through its initial work in Ghana using the TruScan, Lukulay concluded that "spectroscopic tools are excellent identification tools, they are useful for brand control and protection and are useful for customs inspections. Spectroscopic tools are primarily good anti-counterfeiting tools."

Lukulay listed some of the approach's benefits: "The unique Raman signature of compounds makes it a good identification tool, it's excellent for raw material inspection, it's nondestructive to the sample, it has a fast analysis time, it's portable and mobile, and there is no extensive training required for use."

However, Lukulay noted that Raman spectroscopy does not work well for some drugs, which do not have a strong near infrared spectrum. For example, he noted that artesunate, an anti-malarial drug, "has a very weak Raman fingerprint."

One third of antimalarials were substandard

The prevalence of substandard medicines in developing countries is a serious public health concern, Lukulay told the Reconnaissance meeting.

A joint study released by WHO, USP and AID in November 2009 under the auspices of the Quality of Antimalarials in Sub-Saharan Africa (QAMSA) project found that one of every three anti-malarial drugs circulating in three sub-Saharan African countries was substandard.

The study sampled 197 antimalarial drugs circulating in Madagascar, Senegal and Uganda. The samples included both artemisinin-based combination therapy (ACT) currently WHO's recommended form of first-line treatment for uncomplicated malaria, and sulfadoxine-pyrimethamine (SP) products, often used for preventative treatment of malarial during pregnancy.

QAMSA sampled imported products as well as some that were manufactured locally.

The substandard percentage of the 197 samples that underwent full-scale quality control testing varied by country: 44 percent in Senegal; 30 percent in Madagascar and 26 percent in Uganda.

Testing was performed at the National Medicine Control Laboratory in Madagascar and Uganda and at the University of Dakar Laboratory in Senegal. All samples were analyzed through visual inspection of the dosage form and packaging, thin-layer chromatography (TLC) identification testing, TLC estimation of drug content and disintegration testing.

Of the 197 samples, 29 percent failed impurity tests, 20 percent failed dissolution tests and 3 percent failed assay tests.

The study did not look for evidence of counterfeiting among the samples, although the study's authors indicated that "it is noteworthy that all the samples (ACTs and SPs) passed their respective identification test requirements and no products lacking the active ingredients were identified."

Of the drugs that failed testing, Lukulay noted that "they all had the right active ingredients, they just had the wrong amount. They also had high impurities that were not supposed to be in the product. Some were locally made and some were imported from China and India and all over the world."

Lukulay noted that after the study, a consortium of officials from USP, WHO and AID met with drug regulators to explore next steps. "We shared the full data with them and the products involved and we encouraged them to take action."

Lukulay said "one of the lessons learned is that the strength of the regulator is critically important in keeping poor quality drugs out of the country. Manufacturers are testing the competency of the regulator. If they are pushed harder and challenged they will make better products."

Ghana, he said, withdrew 22 brands of antimalarials as a result of the study.

He further noted that following the study other regulators "were reviewing their procedures for assessing quality."

Substandard and counterfeit distinctions

Lukulay noted even though the QAMSA study did not specifically look at drug counterfeiting, he observed that in many developing countries, substandard medicines are more of a problem than counterfeit products.

"In Africa with antimalarials, 99 percent of what we find is substandard medicines. ...The majority in India is substandard. In Latin America we are sampling antimalarials and we see more substandard medicines then counterfeit."

He further noted that "counterfeit is a deliberate attempt to deceive the consumer by either putting no active ingredient in the drug or putting the wrong one in or making the wrong claim. Substandard is a product that is made generally to specifications but fails to meet specifications because of poor GMPs."

With substandard drugs, "there is no attempt to deceive. They are just made in conditions that are very poor. That is the distinction. There is a mixture of poor GMPs, sloppiness, or using poor quality raw materials because they are cheap. And some of them are doing this legitimately and they don't have the right amount of active ingredients."

"Industry has been very diligent not to copy someone's products. The debate really is what should be the focus protecting people's health or something that affects the bottom line operations. Ultimately the bottom line is key. When they are talking about counterfeit they are talking about counterfeit. Lifestyle drugs such as Viagra and Cialis are heavily counterfeited because they are expensive but in developing countries it is slightly different. You are dealing with life-saving medicines so it is not so much of an issue."

Nigeria uses cell phones against counterfeiters

Nigeria's head health regulator explained an anti-counterfeiting program that relies on directly involving the consumers in detecting fakes drug as well as strong collaborations with other agencies.

Dr. Paul Orhii, the director-general of Nigeria's National Agency for Food and Drug Administration and Control (NAFDAC), described a program that enables consumers to use their cell phones to verify that their drugs are safe after scratching a code from the drug's packaging and transmitting the code via a text message. The pilot is called the mobile authentication service (MAS). About one minute after sending the message, the patient is notified whether the drug is safe or unsafe.

Orhii noted that Nigeria is the first country in the world to experiment with this technology for addressing drug counterfeiting.

The pilot only includes the packaging for Glucophage (metformin) but NAFDAC is working with the pharmaceutical industry to expand the program to other types of drugs at risk of counterfeiting.

Orhii noted that "this is a world class technology. Verification uses asymmetric encryption" used by banks and other financial institutions.

"The advantage of using this system is that it empowers consumers to help detect if their drugs are counterfeit. There is authentication at the point of purchase. There are easy to use and to scratch and carry."

The country has a major problem with counterfeit drugs, which reached tragic proportions in 2008 with diethylene glycol substitution being linked to the deaths of 84 children, leading to increasing efforts to tackle the problem.

The country is largely dependent on imports, and typically sources about 80 percent of its drugs from India and China.

Orhii said that 40 percent of drugs imported to Nigeria in 1999 were fake drugs, meaning they were either counterfeit or substandard. As evidence of an aggressive fake drug campaign, he noted that by early 2008, this number dropped to 15 percent.

Agencies cooperate to seize fake antimalarials

Another part of NAFDAC's anti-counterfeiting mission is working with Nigeria's National Drug Law Enforcement Agency (NDLEA) as well as the Nigerian Customs Service.

Under this cooperation, the latter two agencies release the manifests of drug products to NAFDAC for examination before they are released to pharmacies.

NAFDAC inspectors then go to the borders or to the airports to inspect the packages for counterfeits. They use TruScan hand-held Raman spectrometers developed by Ahura Scientific to detect counterfeits. Field inspectors generate and send reports from TruScans to NAFDAC's central lab.

Through TruScan, he said, the authority has seized 10,000 doses of fake antimalarials at the Lagos airport.

There is also a "public enlightenment" campaign and the establishment of consumer safety clubs. Consumer education includes posters, roll-up banners, and still to come are TV ads, radio jingles and newspaper ads.

Baxter: Layering works best

In their fight against counterfeiting, pharmaceutical industry officials are devising their own solutions and seemed to agree at the Reconnaissance meeting that a layered approach works best in mixing covert and overt technologies.

Overt or unconcealed technologies include color-shifting dye, holograms, 2-D barcodes, tamper-evident seals and serialization, while covert or concealed technologies include packaging taggants and RFID.

Stephanice Brecht, quality manager of Baxter Bioscience, described the company's use of a multi-layered program to foil drug counterfeiters, who have faked the company's albumin products in Latin America.

The products are ADVATE and Gammagard liquid, which are lyophilized products for treatment of hemophilia and immunodeficiency disorders.

She said that BioScience products were counterfeited in various ways:

Counterfeiters reused the company's albumin product containers by filling bottles with saline solution and capping with newly purchased stoppers and caps;
A manufacturer of a biosimilar drug applied a counterfeit Baxter label to its product, human albumin, to capitalize on Baxter's position in the market, receiving a higher price; and
A counterfeit Baxter label was applied to similar drug product to receive a higher price, which involved cross labeling and up-labeling to a higher dosage.

She said that to deter potential counterfeiting, up-labeling, cross-labeling and tampering, the company uses a multi-layered approach.

In terms of the labels, the Baxter logo will be contained in a stripe using color-shifting ink. In addition, security slits are placed around the perimeter of the base label, which causes part or all of the label to be destroyed if removed from the bottle. There will also be covert features that are not visible to the consumer but will allow Baxter to confirm that a product in the field is an authentic product.

Other security features include tamper-evident features to maintain product purity include flip-off caps on bottles that serve as tamper evident devices, and Baxter investigated additional tamper evident measures such as tapes.

The company plans to soon implement a serialization and e-pedigree program. It plans to eventually use 2-D barcodes to capture and track the movement of pallets, cases and individual units through the distribution chain.

She advised manufacturers to monitor their processes in terms of personnel, inventory and suppliers, monitor their distribution chain and know what is happening to their products and assess risks.

Brecht also advised manufacturers to be proactive in designing an anti-counterfeiting program and to "learn about counterfeiting" and to "think like a counterfeiter."

She said that "with the ever-present and growing counterfeit issues within the pharmaceutical community worldwide, a product integrity program is critical to the continued success of our business. Counterfeited pharmaceutical products are a global problem that impacts a significant portion of the drug supply. Our strategy is to implement authentication and security measures to protect our customers and patients from counterfeit and altered products."

Pressing need for on-dose protection

Dean Hart, the executive vice-president of Nanoguardian, observed that with the vast majority of U.S. prescriptions, repackaging and e-pedigree initiatives are "years away," and there is a "pressing need" for on-dose protection.

Hart noted that overt security features such as color manipulation, marking schemes and on-dose printing on the dose as well as color-shifting dye, holograms, 2-D barcodes, tamper-evident seals and serialization on the package "are often easily copied by counterfeiters."

The optimal security strategy, he noted, also has an added layer of covert protection on the dose, such as taggants and nanotechnology, as well as threads, packaging taggants and RFID on the packaging.

He noted that "with on-dose you get the optimal security. Layering is the key. You need bar codes, taggants, and RFID. What we have seen is that counterfeiters are adept and capable at copying all packaging elements. They can copy the vial cap and the label and quite honestly it is untrained hospital staff that opens the package and it could be difficult to detect. The deception is incredible. They will go to great lengths to copy your product."

The company has a nanoencryption technology that is used on the dose covertly as well as nanofabrication techniques to apply layered security features to tablets, capsules, vial caps and single use syringes. The on-dose technologies do not affect the drug's bioequivalence or dissolution.

Noting that the first original deadline for California's e-pedigree law has been delayed yet again he said that "counterfeiting diversion is escalating today. We can't wait seven years to take action. We have to take action today."

PCID guidance criticized by industry

FDA is also promoting the use of on-dose technologies and will grant regulatory relief to those manufacturers that incorporate physical-chemical identifiers, or PCIDs, on their products.

The agency issued guidance in July 2009 that recommends pharmaceutical manufacturers use "pharmacologically inactive" substances as PCIDs in solid oral dosage forms to fight drug counterfeiting. ⁷ Also see "Quality by Design Crossing Threshold from Development to Manufacturing" - Pink Sheet, 1 July, 2009.

The guidance is titled "Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting."

It notes that inks, pigments and flavors are some examples of substances that may be incorporated into solid dosage forms. Manufacturers that incorporate these techniques may only have to file annual reports provided that certain parameters are met.

For example if the PCID is incorporated in the coating or ink of an existing immediate release product it may be an annually reportable change.

However drug makers expressed scepticism about affixing PCIDs on their products in their public comments on the guidance. They worried that the information they would have to disclose to FDA on these technologies could potentially be made available to counterfeiters.

GlaxoSmithKline said that "any feature (product formulation related or otherwise) used for covert authentication of a product must remain confidential to the original manufacturer. Therefore GlaxoSmithKline requests consideration is given to either the inclusion of a simple statement only, such as "an inert anticounterfeiting feature is included" or that the details of the PCID are provided within a DMF."

Merck concurred that "in order for certain covert PCID feature to have any security value, they must remain secret. The agency needs to put measures in place to ensure that covert PCID information is not publicly disclosed when he company intends to have an identifier (or an aspect of an identifier) remain secret."

There were also complaints about the amount of work involved in this initiative; a PCID approved formulation would have to be approved for the U.S. and a non-PCID formulation for the rest of the world.

Sanofi Aventis wrote that "incorporating PCIDs into solid oral dosage forms, its packaging or labelling requires significant work, time and resource investment to establish the toxicological safety, quality, performance, migration behavior and/or stability impact of the PCID on the drug product. It also significantly increases the regulatory burden to both applicants and health authorities."

Serialization will occur first

Some pharmaceutical security experts predicted that in the absence of a global solution, one area that will probably be tackled first by regulators is the development of uniform serial identifiers on drug products as reflected in FDA's guidance on uniform serial identifiers.

While regulators may shy away from mandating technologies s for detecting counterfeit drugs and from mandating e-pedigree solutions, one of the easiest places to start will most likely be the development of standard numerical identifiers.

Jim Rittenberg, the vice-president of Authentix, noted at the Reconnaissance meeting that "I don't think there is any question that mass serialization will be here and it will be here in a big way. It's just question of how we will use it in an effective way. One of the things that will come of that is that products moving through the supply chain and at various point in the supply chain will be scrutinized a lot more than they are today."

Rittenberg further noted that "most of what is happening is not proactive screening of the supply chain. It is reaction to issues that have arisen in the supply chain. Once serialization comes into effect there will be a lot more incidents of questionable products for a variety of reasons, duplicates, products not scanned and ... they will either be dealt with in one way or another very quickly."

Yet this stage is still in its infancy, he said. "I feel like we are at the gestation stage trying to give birth. With serialization the arms and the legs are poking through."

EFPIA's Barron also predicted that "mass serialization in Europe should be a reality over the next three to five years."

Mass serialization and authentication needed

Rittenberg further noted that mass serialization alone will not eradicate drug counterfeiting, but that authentication of the product is also needed.

He noted that "mass serialization with associated data management, is viewed by some as the panacea that will eliminate counterfeiting and diversion. Others believe that serialization and authentication are distinctly different. Both are necessary and complementary tools in the fight against counterfeiting and diversion."

Both types of systems are necessary, he suggested, to track products in a very diffuse distribution network that starts with the raw material supplier, then goes to the manufacturer, the wholesaler, the retailer and ultimately the consumer.

"We have very complex distribution channels depending on what region we are in. The complexity varies. The U.S. is less complex than other parts of the world. EU distribution channels are a lot more complex with how it is set up."

Incentives needed to promote data sharing

Rittenberg noted that "one of the biggest issues that gets lost in this whole discussion is that current business models that guide the distribution of pharmaceutical products do not incentive data sharing and all these programs that we discussed in terms of serializing products and trying to follow this through the supply chain are stymied by this lack of a business model that would incentive this more effectively."

He further noted that to stay one step ahead of the drug counterfeiters, the need for physical authentication will increase as digital verification, or mass serialization, becomes routine.

He noted that "counterfeiters are already adding their own security features to make the fake product appear more authentic than the real product."

"When you are shopping and you want to buy the product and you look at the two, which one is the real one? They are not stupid. It is like playing a game of chess about what it going to happen."

Incremental advances envisioned

Rittenberg noted regulators may be focusing on what he calls "panacea solutions" to the counterfeiting problem, which he said is "trying to solve the entire problem in one fell swoop."

"The problems," he said, "went back to 1988 with the paper pedigree through the RFID phase and the e-pedigree. There is a lot of focus on these things that are distracting the industry from doing other things. We need to take a step-by-step approach and we need to think about that as we are taking different approaches to tackling this problem."

He predicted that "over the next five years we will be leaning towards global standards for data structure and mass serializing the product at the unit level with barcode technology."

Over the next 10 years, he predicted that there will be changes in business models and involvement of third party distributors to achieve full traceability.

And after that, in Phase 3, he observed that there could be the phase-in of RFID at the unit level and the "build out" of infrastructure for these anti-counterfeiting programs for widespread use.

- Joanne S. Eglovitch ( ⁸ j.eglovitch@elsevier.com) and Bowman Cox ( ⁹ b.cox@elsevier.com )

Anti-Counterfeiting Advances Regionally Despite Global Impasse

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