More Than Just a Pretty Color

In an ideal world, an anti-counterfeit solution would provide protection throughout the supply chain, allow for easy product identification by physicians, pharmacists, and patients, be easily implemented without ongoing costs—and improve brand image and marketability while it's at it. Yet most current anti-counterfeiting measures involve packaging technologies such as holograms, inks, bar codes and radio frequency ID (RFID) that, although useful, cannot ensure the integrity of the pharmaceutical supply chain, because drugs do not remain in their original packaging. Legitimate repackaging regularly occurs in the pharmacy and elsewhere, and authentic packaging—recycled or stolen—can contain adulterated, counterfeited drugs.

No single anti-counterfeiting technology can provide adequate protection. Pharma's objective must be to design products and packaging with features that are so hard to duplicate that counterfeiters will turn their sights elsewhere.

It is, after all, the counterfeit medications, not the containers, that are harmful to patients and costly to manufacturers. For tablet manufacturers, the solution is to modify the medication itself with on-tablet technologies that make pills difficult to fake but easy to identify. These technologies are also cost-efficient and stay with the medication from the factory to the patient.

Protecting Patients

A great number of counterfeits have been uncovered by patients and pharmacists who noticed that the tablet's color, shape, size, or taste was different from what they had experienced before. Several pharma companies have reported that a majority of the calls they receive from consumers questioning whether they have a counterfeit product are triggered by some type of sensory response related to the dosage form itself. A patient's personal detection system consists of eyes, nose, mouth, and hands, so a tablet's unique visual appearance, aroma, taste, or texture is important.

Many patients, especially the elderly who tend to take the most oral medications, often have trouble identifying drugs by reading labels, so this type of sensory identification helps protect patients at the point just before they consume the medication. Each individual sensory identifier on a tablet significantly enhances the likelihood of a patient calling the manufacturer, or their pharmacist or physician to question the authenticity of a medication.

With pearlescent coatings, a rainbow of colors is possible. These colors can only be duplicated by knowing the specific pigment grade combination and the processing procedures used in the drug's manufacture. They cannot be reverse engineered.

Simple visual and sensory means of identifying drugs can aid patients with compliance and safety. When patients can readily identify the right drug, they are more likely to take the right drug. A standardized tablet imprint system, for example, that identifies the dosage strength and name of a drug, combined with readily available information resources for patients and pharmacists, would help prevent many medication errors.

A United States Pharmacopeia (USP) survey on standard imprint codes drew the following comments from pharmacists:

• "We should be inventing a system where a patient would be able to identify a tablet."

• "The difficulties come in identifying tablets or capsules without any markings. They may be OTC or one of the many generics that are white, typically round, biconvex shaped."

• "The lack of a standardized and easily identifiable code on many medications makes the identification process too cumbersome. A national standard should be adopted. In addition, a manufacturer's unique identifier should also be employed to distinguish particular brands or products."

On Pharma's Shoulders

The United States has the safest supply of drugs in the world—when they are acquired through standard distribution channels. However, the public now encounters increasingly aggressive internet marketing that falls outside of the normal physician/pharmacy supply chain and is a ready outlet for the distribution of counterfeit or illegal drugs. The actual size of the US internet counterfeiting problem is uncertain. But according to a September 29, 2003 FDA News report, an estimated 80 to 90 percent of these products do not meet US regulatory requirements, and more than 40 percent of the drugs coming into the US through the internet, from countries such as Mexico, are fake. (For more information about counterfeit drugs, see "Resources".)

Both FDA and Congress are now relying on pharmaceutical companies to design their packaging and products in a manner that deters counterfeiters. The responsibility of finding innovative methods of ensuring the security of the nation's drug supply is being put squarely on the shoulders of pharmaceutical manufacturers.

On January 15, 2004, a congressional letter was sent to major pharmaceutical companies, requesting that they provide information about the development of plans to prevent counterfeiting and diversion of their products. Congress also wanted to know what actions and countermeasures were being taken relating to specific products being marketed by the illicit internet sites of foreign pharmacies.

At the same time, FDA plans to publish a guide about notification procedures for changes made to products, packaging, or labeling for the purpose of detecting and deterring counterfeit drugs. Regulatory hurdles to making these specific types of changes are now being lowered.

With high-definition imaging technology, coded images can be designed into logos, acting as fingerprints that make tablets difficult to duplicate.

No single anti-counterfeiting technology can provide adequate protection. Pharma's objective must be to design products and packaging with features that are so hard to duplicate that counterfeiters will turn their sights elsewhere. Fortunately, there are many proven on-tablet technologies available today that can make drugs difficult to fake but easy to identify. These technologies include:

• visual identification—unique colors, shapes, sizes and logos

• electronic identification—bar coding

• chemical identification—edible markers in the film coating

• sensory identification—flavors and aromas with a unique profile

Visual Appeal

Round, white, uncoated, debossed tablets are easy to copy and cheap to produce. A tablet press is all that's needed. On the other hand, unique colors, sizes, shapes, and high-definition logos can aid in quick and accurate identification of tablets, making counterfeiting extremely difficult. The more technologies that are used, the more difficult they are to counterfeit.

New pearlescent coating technology allows pharma manufacturers to visually distinguish their products from counterfeits and other drug products. The uniquely colorful pigments created with this technology all meet current 21 CFR colorant regulations and are custom-produced to exact specifications in a single-use, GMP facility, the only one of its kind in the US. Because this technology is only available through controlled channels, the opportunity for counterfeiters to gain access to pearlescent pigments anywhere else in the marketplace is effectively eliminated.

With pearlescent coatings, a rainbow of colors is possible. These colors can only be duplicated by knowing the specific pigment grade combination and the detailed processing procedures used in the drug's manufacture; they cannot be duplicated by using analytical or reverse-engineering techniques. Several products using this technology are in clinical trials and should enter the market by 2007.

Any number of colors and images can be achieved with the same chemically stable, inert, light-refracting ingredient, both qualitatively and quantitatively, by controlling processing variables. Various coating systems are available that can give the same pearlescent effect while meeting each country's regulatory requirements.

As an additional benefit, the ease of visual identification by caregivers, pharmacists, and patients can reduce medication errors by ensuring that the right tablets are taken appropriately. Although the current FDA bar code regulation only addresses medication errors that occur in the hospital, visual identification methods are effective throughout the supply chain, right to the patient at home.

Typical costs to use this technology are minimal and can range from 0.02 to 0.04 percent of drug revenue. So, for a typical $1 billion blockbuster product, a nominal annual cost of $200,000 to $400,000 would enable these technologies. This represents a technology investment of $0.001 per tablet, based on a selling price of $3.00 per tablet.

Electronic ID

Innovative electronic technology now allows manufacturers to use common, edible inks to apply two-dimensional (2D) Datamatrix bar codes directly on the tablet surface. Smaller than their linear counterparts, 2D bar codes can be used to code specific information such as National Drug Codes, which provide identification control all the way from the manufacturing plant to the bedside. Plus, the unique bar code technique used in this process cannot be easily duplicated.

Tablet bar coding restricts the potential for error even after the tablet has been removed from the packaging, either for delivery to the patient's bedside or for repackaging. During bulk repackaging operations, bar code GMP controls can now be implemented to assure that there is no chance for mix-up, either in the packaging or the dispensing.

High-resolution imaging now provides a wide range of new identity options. Tablets can contain images with bar codes as small as 2.5 millimeters that are readable by typical high-resolution bar code scanners. For easy identification by patients, readable numbers, codes and logos can be combined with bar codes. With high-definition imaging technology, coded images can be designed into logos, acting as fingerprints that make tablets very difficult to duplicate. These images may also be made scannable to provide visually appealing electronic identification.

High-definition imaging can also be combined with number codes to make tablets highly recognizable and even harder to counterfeit. Multi-coded tablets can be easily traced through the supply chain, and pharmacists and physicians can readily identify individual drugs that patients present for verification. Some products currently in Phase II are being developed with this technology.

Chemicals, Flavors, Aromas

Incorporating covert chemical markers into the film coating of tablets adds even greater security against replication. Taggants—simple, stable, inert, organic chemicals that are present in the product in trace quantities—can be added to film coating solutions under tight security during product manufacture. Undetectable by the human senses, taggants are also difficult, if not impossible, to detect through normal analytical techniques and cannot be copied or removed from the dosage form. Available with wide regulatory acceptance, manufacturers can include taggants in new products or incorporate them into existing products with minimal regulatory requirements.

Because they are detected through the use of a specific recognition molecule and can be quantitatively measured using inexpensive equipment, taggants are also being used as chemical bar codes. With this methodology, manufacturers can provide additional information (such as manufacturing location) that goes beyond the data available in the 2D electronic bar code on the tablet surface. Robust taggants provide immediate chemical authentication when tested by pharmacists or customs agents using in-field testing kits.

Specialized flavors and aromas incorporated into tablet film coating systems can also provide unique characterization profiles identifiable by patients. In addition, they act as covert forensic fingerprint profiles that can be tracked and traced. Flavors and aromas can be difficult to duplicate because oxidation can change the sensory profile if counterfeiters do not use the same stable grade that is in the genuine product. And it is difficult to identify the specific grade used in an individual drug.

A whole palette of globally compliant flavors and aromas for use in tablet film coating systems has been developed. Not only are these sensory additions recognizable by humans, but aroma and taste scanning detectors also are available for electronic identification of specific aroma and flavor profiles.

Branding Bonus

On-tablet technologies not only protect against counterfeiting and product diversion, but they also create a higher profile image that can enhance branding and marketability. Two of the best known Rx examples are Nexium, the purple pill, and Viagra, the blue diamond-shaped tablet. Much as the Coca Cola bottle was the first US trademarked object, a uniquely designed Rx product can be established as a trademark globally. This serves to maintain the uniqueness of the tablet design. Not to mention, the visual branding of a tablet reinforces the product identification with patients every time they take the medication.

Rules and Regulations

Before incorporating these technologies into their products, pharma companies may ask: What type of change notification requirements will there be with the FDA? Here's a summary of regulatory information for each technology:

Pearlescent coatings FDA's Scale-up and Post-Approval Changes Guidance for Immediate Release Products (SUPAC-IR) Level 1 allows for the deletion or partial deletion of a colorant and allows the film coat weight gain to vary by up to one percent. The addition of a pearlescent coating to a tablet, adding less than one percent weight gain, would involve a qualitative change, but there would be no effect on tablet dissolution. Such coatings can provide a multitude of colors with the same pigment chemistry, allowing for the same label claim for different colored tablets.

High definition, logos and bar codes SUPAC and FDA guidance for changes to a new drug application or supplement application (NDA/ANDA) already allow for the addition or modification of a code imprint when the ink components have been previously used on an approved drug.

Covert chemical markers (taggants) FDA has said that a trace marker can be added to the coating of an existing IR solid oral dosage form with the only requirement being notification to FDA. The markers must be either a GRAS (generally regarded as safe) substance or an inactive ingredient already present in a CDER-approved product. The addition of parts-per-million or parts-per-billion levels of food or excipient grade markers to a film coating on an existing drug should not affect drug dissolution.

Flavors and aromas Supac-IR allows for the deletion or partial deletion of a flavorant as a Level 1 annual reportable change. Flavors are typically added at low levels into the film coating and have minimal contact with the drug, therefore, the addition of a flavor is not likely to affect dissolution.

Resources

Here are a few sources for more information about the prevalence of counterfeit drugs.

Physician's News Digest, "Vulnerability to Counterfeit Drugs," May 2004, available at: http://www.physiciansnews.com/law/504shay.html

FDA News, "FDA/U.S. Customs Import Blitz Exams Reveal Hundreds of Potentially Dangerous Imported Drug Shipments," September 29, 2003, available at: http://www.fda.gov/bbs/topics/NEWS/2003/NEW00948.html

Chemical and Engineering News, "Counterfeit Drugs—Sophisticated Technologies and Old-fashioned Fraud Pose Risks to the Prescription Drug Supply in the U.S.," November 10, 2003

National Drug Intelligence Center, "Pharmaceuticals Drug Threat Assessment," November 2004; available at: http://www.usdoj.gov/ndic/pubs11/11449/diversion.htm

David R. Schoneker is director of global regulatory affairs for Colorcon. For more information, contact (800) 452-3207 or info@colorcon.com.