Pill-Level Product Protection

Authenticating tools help identify counterfeit drug products. This article contains bonus online-exclusive material.
Sep 02, 2009
Volume 33, Issue 9

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.

Security features are built into CPI Security Foil during the rolling process.
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 On July 13, 2009, the US Food and Drug Administration issued a draft guidance document titled Incorporation of Physical–Chemical Identifiers (PCIDs) into Solid Oral Dosage Form Drug Products for Anticounterfeiting (1).

"FDA's publication of the draft guidance document emphasizes the need to look beyond traditional technology to prevent counterfeiting and illegal diversion," says Dean Hart, executive vice-president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

The online or stand-alone DTS 1200 printer can add security features to blister foil.
FDA's draft guidance document provides recommendations about the nature of the identifier itself and about the supporting documentation needed for new drug applications,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 The draft guidance document focuses on pill-level defenses involving the addition of a trace amount of an inactive ingredient with a unique physical–chemical characteristic that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).

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.

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

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.

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