Pill-Level Product Protection

The worrisome headlines never stop. The first seven months of 2009 brought warnings about counterfeit products such as insulin-pen needles in The Netherlands, malaria drugs in Ghana, and inhalers in the United Kingdom. In the United States in 2008, more than 80 deaths and hundreds of allergic reactions were linked to counterfeit heparin. According to the Partnership for Safe Medicines (Vienna, VA), batches of contaminated heparin were detected in 11 other countries, and the death toll reached nearly 150 worldwide.

As drugmakers and their suppliers ratchet up their defenses against counterfeiters, the battlefield appears to have moved to the dose level. At Interphex in March 2009, at least three exhibitors displayed pill-level authentication tools. On July 13, 2009, the US Food and Drug Administration issued a draft guidance document titled Incorporation of Physical–Chemical Identifiers (PCIDs) into Solid Oral Dosage Form Drug Products for Anticounterfeiting (1).

Security features are built into CPI Security Foil during the rolling process.

"FDA's publication of the draft guidance document emphasizes the need to look beyond traditional technology to prevent counterfeiting and illegal diversion," says Dean Hart, executive vice-president of NanoGuardian (Skokie, IL), a supplier of overt, covert, and forensic anticounterfeiting technologies. "In order to be truly effective in the fight against counterfeiting and illegal diversion, it's extremely important for manufacturers to employ on-dose technology," he adds, noting that every layer of security makes it more difficult to successfully counterfeit or divert a product.

Physical–chemical identifiers

FDA's draft guidance document provides recommendations about the nature of the identifier itself and about the supporting documentation needed for new drug applications, abbreviated new drug applications, and postapproval changes. The draft guidance document focuses on pill-level defenses involving the addition of a trace amount of an inactive ingredient with a unique physical–chemical characteristic that makes it possible to authenticate legitimate product and visually or automatically identify counterfeit pills. Possible additions include inks, pigments, flavors, and molecular taggants. "FDA anticipates that many of the ingredients that will ultimately be employed as PCIDs are already used as food additives, colorants, or excipients with established safety profiles." In fact, the document recommends "using permissible direct food additives [such as those listed in 21 CFR parts 172, 182, and 184], including those affirmed as generally recognized as safe [such as those listed in 21 CFR part 184], or those ingredients listed in the FDA Inactive Ingredient Guide" (IIG) (1).

The online or stand-alone DTS 1200 printer can add security features to blister foil.

Caution should be used when selecting an ingredient that is not included in these lists or one that might cause an adverse effect such as an allergic reaction or irritation. The draft guidance document also notes that PCIDs should be used at the levels prescribed in the IIG or CFR chapter on direct food additives and should not interfere with the release rate of modified-release products.

Labeling changes may alert healthcare practitioners and patients to the presence of a PCID, but are not required. However, labeling changes are subject to reporting and approval requirements under 21 CFR Part 314.70.

Solid dosage forms can be linked to the die that made them by comparing surface images.

Other provisions include "recommendations regarding (1) evaluation of toxicological and other concerns for PCIDs that are incorporated into packaging and labeling and (2) procedures for reporting or requesting approval to add PCIDs to packaging and containers as a postapproval change" (1).

A packaging-related PCID should not adversely affect the quality, performance, or stability of the solid oral dosage form. If toxicology has not been established for the proposed PCID, then the manufacturer should provide assurance that the identifier does not migrate into the solid oral dosage form.

According to the draft guidance, the addition of a PCID to packaging can be handled as a postapproval change. If the PCID is a permitted direct or indirect food additive, listed in IIG, or previously approved for use in primary packaging, the addition can be noted in the company's next annual report. If the PCID does not meet one of these criteria, the change may be submitted on a CBE-30 supplement that should include data addressing toxicological concerns and provide assurance that the PCID will not migrate into the product.

"If the safe use of a PCID cannot be ensured (i.e., if the toxicology has not previously been established and migration potential exists), the applicant may not market the drug product using the PCID in primary or secondary packaging unless a prior-approval supplement is submitted and approved" (1).

FDA accepts comments related to guidance documents at any time. To be considered by agency personnel preparing the final version of the document, however, comments should be submitted by Oct. 13, 2009.

On-dose authentication

Increasingly, drugmakers and regulators view on-dose defenses as essential components of a multilevel anticounterfeiting strategy. With some forms of pill-level identification, it's possible to nondestructively authenticate pills anywhere in the supply chain even if no packaging is present.

Not all on-dose authentication tools involve PCIDs such as inks or taggants. One additive-free solution makes nano-scale changes to the coating of the solid dosage form without changing its dissolution or other characteristics. The encryption machine is designed to be mounted on the production line and also can mark vial caps. Three levels of protection include semiovert, covert, and forensic.

For those who know what to look for, semiovert marks are visible to the naked eye. Covert marks are visible at the micrometer level and can be customized per dose, per drug, or per manufacturer. They are read with a handheld loupe or 20× microscope.

The forensic level is a nanoscale code that can carry large amounts of data, including batch identification, manufacturing date and location, distribution country, and the serialized information from two-dimensional or pedigree barcodes. Decoding requires proprietary equipment and software because the codes are so small that 350 of them can fit in the width of a human hair (NanoEncryption technology, NanoGuardian).

FDA approved one drugmaker's supplemental new drug application that relied on nanoscale technology. Its commercial debut should occur before the end of 2009 or early in 2010. To further enhance the nanomarking technology's ability to provide an early warning about counterfeit and diverted product, it can be coupled with a pharmacy auditing program that is expected to be in commercial use in 2010 (analytical services, SDI, Plymouth Meeting, PA, for Closed-Loop Protection market monitoring program, NanoGuardian).

Another on-dose, additive-free anticounterfeiting tool relies on high-magnification imaging to capture a picture of each dose as it is blister packed. This image is stored in a database and linked to the serialized code on the primary package. To authenticate product, a proprietary algorithm compares regions of interest on the tablet with images in the database. When a match is found, users can quickly locate its history by linking to a pedigree database (ISTARx image storage, tracking, and recognition in AuthentiTrack suite of anticounterfeiting technologies and services, Pharmorx Security, Southborough, MA). The system also can be configured to print a unique code on each blister cell.

A similar technology relies on the fact that each punch-die set used in a tablet press has a unique fingerprint and imprints it on each pill. A photo of the punch-die surface is taken by an ordinary flat-bed scanner or digital camera and stored in a database on a secure server. To authenticate a pill, an image of its surface is captured by a scanner or camera and compared with the stored punch-die images. A match confirms product authenticity (Fingerprint technology, AlpVision, Vevey, Switzerland).

Another on-dose technology prints a unique 12-character alphanumeric code on each solid dosage form using foodgrade ink. The web-based authentication process requires only about 60 s. The consumer simply keys in the code on a computer or cellular phone (Serialization technology, Pharmorx). However, because coding an existing product would require stability testing and the filing of an abbreviated new drug application, this technology may be best suited for new products, according to Steve Wood, president and chief executive officer of Pharmorx, which also supplies taggant-equipped labels in conjunction with its partner, MSO Group (Belfast).

Packaging-level authentication

Packaging-level authentication tools can be overt, covert, or forensic. Many experts recommend a multilevel approach, and numerous suppliers offer an array of anticounterfeiting tools.

One company combines booklet labels with custom forensic markers that include digital tracking (SecurBook labels, ATL Security Label Systems, Menomonee Falls, WI, using Nano-Molecular Markers technology from IDGLOBAL, Kelowna, Canada). To authenticate product at virtually any time, the same forensic marker can be used on item-level labels, pedigree papers, and distribution packaging. Other security products from this firm include single-ply labels with a forensic marker (SecurDetek), anticounterfeiting holograms (SecurMark), three-tier overt or covert levels of anticounterfeiting (Triple-Ply), and destructible tape (PharmaVoid).

A camera-based technology photographs the unique natural microstructures of the package itself and stores the image for future reference. This image also can be linked to other data such as date, product, and serialized codes. Because the digital signature is based on the random characteristics of the material, it is virtually impossible to duplicate. A handheld reader–verifier provides easy field authentication. In fact, the system could be set up to enable consumer verification through a cell-phone camera (Biometric Authentication, Cortegra Group, Fairfield, NJ).

Cortegra also produces packaging with integrated anticounterfeiting technologies such as forensic markers; inks with ultraviolet-reactive, color-shifting, or thermochromic properties; microprinting; holography; varnishes; threads; frangible papers; and digital watermarks.

Digital watermarking incorporates machine-readable data into graphics or text so that they are invisible to the naked eye, but detectable by a security-class reader with patented software. The hidden data are virtually impossible to duplicate so if the original packaging is copied, the watermark will be missing from the copy (Digimarc Digital Watermarking, Complete Inspection Systems, Indialantic, FL).

Anticounterfeiting features can sometimes be applied on the packaging line. A digital printer capable of overt or covert marking runs as a standalone unit or can be mounted on the blister-packaging line. The system prints background information, identity codes, sequential numbers, time and date stamps, and ultraviolet-visible colors in 1200-dots-per-inch resolution. It operates at speeds as high as 20 m/min and handles four colors simultaneously. Digital printing technology allows each pack to be printed with a randomly generated unique number that is 100% traceable to its time, date, and location of origin. Printing without mechanical stretching protects the foil against microcracks that result from elongation. Printed information withstands heat, pressure, abrasion, and solvent exposure (DTS 1200 blister printing unit, CSAT America, Louisville, CO).

Anticounterfeiting characteristics also can be imparted to blister foil during the production process. A patented technology imprints fine-line graphics, text, logos, and microfeatures on the surface as the foil is rolled without affecting the material's gauge, strength, or machinability. Virtually any aluminum gauge or alloy can be used, and the foil can be converted, lacquered, laminated, coated, printed, and slit like conventional foil. The embedded images cannot be removed and are difficult to duplicate because the high-precision laser technology used to create them is not readily available. In addition to child-resistant and non-child-resistant blister foil, applications include cold-form foil, pouches, sachets, and induction seals for bottles (CPI Security Foil, Constantia Hueck Foils, Wall, NJ).

Hallie Forcinio is Pharmaceutical Technology's Packaging Forum editor, 4708 Morningside Dr., Cleveland, OH 44109, tel. 216.351.5824, fax 216.351.5684, editorhal@cs.com

Reference

1. FDA, Guidance for Industry: Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting (Rockville, MD, July 2009), www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM171575.pdf, accessed Aug. 18, 2009.