Counterfeit peptide (revision 16)

A counterfeit peptide is material misrepresented as to what it is or where it came from. Three forms are usually distinguished: substitution of a different compound, dilution of the correct compound with an undeclared bulking agent, and misrepresentation of origin where the compound is correct but the stated source is not.^[1]

The determination that detects substitution is identity — mass confirmation, and where available sequence confirmation — not purity. A substituted compound analysed alone will return an excellent area percent figure, because it is a pure sample of whatever it actually is.^[2]

Dilution is detected by content rather than by purity, for the same reason underfilling is: a bulking agent that does not absorb at the detection wavelength is invisible to a chromatographic purity determination. See Underfilling.

Substitution replaces the ordered compound with a different one, usually cheaper and often structurally unrelated. Because purity determinations are normalised and identity is frequently not determined, substitution can pass every check a purchaser typically makes.^[2]

Identity determination is the remedy and is not expensive relative to the purchase. A mass determination compares the observed molecular mass with the calculated one; agreement to within a few daltons excludes most substitutions outright. It does not exclude an isobaric substitution — a different molecule of the same mass — for which sequence-level confirmation is required.

The confounding case is a peptide of similar mass in the same family. Analogues within the incretin class differ by hundreds of daltons and are readily distinguished; a deletion sequence of the intended peptide differs by a single residue and is a synthesis defect rather than a counterfeit, though the analytical challenge is comparable. See Analytical method validation.

Dilution adds an undeclared excipient — mannitol and lactose are the ones most often reported — to a genuine peptide, so that a nominal quantity of solid contains less peptide than stated.^[1]

Chromatographic purity does not detect it. A sugar does not absorb appreciably at 214 nm and will not appear in the chromatogram; the purity figure is computed over what was detected, and the bulking agent is not part of it. The determination that detects dilution is peptide content, which measures the mass fraction of the solid that is peptide.

Some legitimate lyophilised products contain excipients by design, as bulking agents or cryoprotectants, and a declared excipient is not a counterfeit. The distinction is disclosure: an excipient stated on the label and accounted for in the content figure is a formulation choice, and one that is neither is a misrepresentation.^[3]

The visual observation sometimes reported — that a cake looks larger or denser than expected for the stated mass — is weak evidence but is not worthless, since a few milligrams of peptide produce a very small cake.^[1]

• Underfilling
• Repackaging
• Lot traceability
• Peptide content
• Test report forgery