FDA Guideline on Anticounterfeiting Medicines

The Guideline describes the use of so-called PCIDs (Physical-Chemical Identifiers) in solid dosage forms. PCIDs are substances or combinations of substances which possess a unique chemical or physical property that may be used for identification. For example inks, pigments, flavours or other chemicals may be used as molecular identifiers.

PCIDs should be identifiable already by the retailers or the pharmacists (e.g. through the smell) or later through the use of special analytical detection instruments, i.e. laser and fluorescence technologies, photolithography, microscopy and mass spectrometry.

Unlike the draft document, the Guideline excludes from the scope the incorporation of PCIDs into the packaging. The focus of this Guideline also lies on the incorporation of identifying agents into dosage forms. The use of these agents aims at complicating the falsification i.e. the counterfeiting of medicinal products.

The FDA says that many of these potential PCIDs are already used as food addictives. To avoid negative effects, PCIDs should only be added at the lowest level to ensure the identification. Moreover, the authority encourages the use of chemical substances which themselves have no medicinal effect or which don't interact with the API of the dosage form and can be treated as excipients. The FDA refers to the substances which have already been recognised as safe and listed as food additives (21 CFR 182 & 184) in the FDA Inactive Ingredient Guide (IIG)

The FDA sees toxicological risks in certain substances which have been used either at a level in excess of the limitations provided in the IIG Guide or in ingredients which have never been used in a PCID or as a food additive. The same applies to substances that pose the risk of allergic reactions.

One should also think about a differentiation between the core section of the dosage form which contains the API and the external section with the identifier (e.g. coating). Solid dosage forms with modified-release should not include PCIDs in sections which contain excipients causing the modified-release.

Furthermore, recommendations are made regarding the content of an application for initial approval of a drug product or for post-approval changes. These recommendations concern the stability of the drug product containing the PCID as well as toxicological characteristics of the PCID itself. In case of a post-approval change, comparative data will be required about the drug product with and without PCID identifiers. The categories for post-approval changes range from annual report (AR) to prior approval supplement (PAS). The question whether the addition of a PCID identifier only needs to be communicated or pre-approved by the FDA depends on the results of a risk analysis performed by the applicant.

A PAS is required when a substance in a proposed PCID is not a permissible food additive listed by the FDA. The FDA does not strictly require that PCIDs are labeled as ingredient of the dosage form. If the addition of a PCID changes the identifying characteristics (like the colour of a tablet), then this is a MUST and no option to make a revision in accordance with 21 CFR 201.57(c)(4).

You can find more detailed information in the Guideline for Industry "Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting".