Day Two of PCAC opened with FDA returning to the quality guardrails repeatedly requested during Day One—but reframing the problem. Before standards for potency, purity, sourcing, or testing can be applied, FDA argued that the substance itself must first be expressly identified and defined.
FDA read from materials submitted by public commenters. According to FDA, those materials stated that TB-500 “typically” refers to a particular peptide fragment, while acknowledging that its exact amino-acid sequence and terminal modifications may vary among vendors.
FDA then posed the following question to prescribers and the Committee:
“When you write a script for TB-500, what form do you think your patients are getting? Does anybody know?”
An FDA representative summarized the concern directly:
“Before I can even put guardrails around quality, I need to define what it is, and I don’t know how to do that.”
The issue goes beyond free base versus acetate. FDA emphasized that this is not merely a question of whether a substance is supplied as a free base or acetate salt. Products marketed under the same common peptide name may have different amino-acid sequences, terminal modifications, or even different active moieties.
Using FDA’s regulatory definition in 21 C.F.R. § 314.3(b), “active moiety” is the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt—including a salt with hydrogen or coordination bonds—or other noncovalent derivative, such as a complex, chelate, or clathrate, of the molecule responsible for the physiological or pharmacological action of the drug substance. In simpler terms, changing the salt may leave the same core active molecule, although the free base and each salt remain distinct bulk drug substances and may have different physical, chemical, pharmacokinetic, safety, or effectiveness characteristics. Changing the amino-acid sequence or adding a covalently attached component may create a materially different molecule that behaves differently in the body.
FDA’s June 2015 final salt-naming guidance generally calls for the name and strength of a prescription drug product containing a salt to be expressed in terms of the active moiety, with the specific salt identified separately. The guidance addresses prescription drug products approved under section 505 and does not itself establish naming requirements for compounded preparations. The underlying USP Salt Policy, however, also addresses USP monograph titles for drug products and compounded preparations. Salt nomenclature alone cannot resolve ambiguity involving different peptide sequences or covalent modifications.
“The USP Salt Policy is a naming and labeling policy applicable to drug products that contain an active ingredient that is a salt. The policy stipulates that USP will use the name of the active moiety, instead of the name of the salt, for such a drug product when creating a drug product monograph title. The USP Salt Policy also states that USP will base the strength of the product on the active moiety. The policy allows for exceptions under specified circumstances. The USP Salt Policy became effective on May 1, 2013, and USP is now applying it to all new drug product monographs for products that contain an active ingredient that is a salt. It affects the development of new drug products, because a USP monograph title for a new drug product, in most instances, serves as the nonproprietary or ‘established’ name of the related drug product. A drug product with a label or labeling that contains a name that is inconsistent with the applicable monograph title risks being misbranded. The USP Salt Policy only applies to the monograph titles for drug products. The policy will not apply to the titles of monographs for drug substances (active ingredients). Accordingly, the names of active ingredients (e.g., salts) will not be affected.”
Source: Naming-of-Drug-Products-Containing-Salt-Drug-Substances.pdf
FDA used CJC-1295 as a less contentious illustration because it was not one of the substances being voted on. Products may be described as CJC-1295 with DAC, without DAC, in different salt forms, or with different sequences. FDA’s point was that a prescription that says only “CJC-1295” may therefore leave unanswered what the prescriber intended and what the patient ultimately received.
FDA also raised a potential intellectual-property issue. The discussion became more complicated when FDA considered whether it could simply select one version of a commonly used peptide name and define that version as the substance placed on the Bulks List. Using MOTS-c as a hypothetical example, FDA questioned what would happen if the version most commonly sold were not the same version identified or developed by its inventor. FDA then explained that selecting one structure could prompt an intellectual-property dispute or a challenge that FDA had defined the substance incorrectly.
FDA did not find that a particular patent exists or would prevent Bulks List inclusion. Its point was narrower: the agency questioned whether it should choose among competing molecular versions and treat one version as the substance represented by a common peptide name.
That places FDA and the Committee in a difficult position. PCAC is being asked to vote on named bulk drug substances while FDA is simultaneously questioning whether some of those common names reliably identify one molecule.
Industry participants have already begun addressing the issue. One Committee member suggested that future nominations include a monograph or monograph-like standard identifying the exact sequence, salt form, terminal or covalent modifications, active moiety, and required analytical testing.
Through the public comment process, industry participants have already submitted certificates of analysis and monograph-like materials addressing sequences, salt forms, characterization, and analytical methods. FDA expressly indicated that it had not yet fully evaluated those materials in great detail and referenced resources and “competing priorities.”, though some PCAC members communicated having reviewed all public comments submitted ahead of the meeting. The issue may therefore be less about whether sufficient information has been provided and more about whether FDA has sufficiently understood and evaluated the available materials to determine whether they can support a consistent identity standard and inform the Committee’s vote.
The opening message from Day Two was clear: before there can be meaningful quality guardrails, there must be agreement on the identity of the molecule inside them.
Industry has begun providing that information. The next step is creating a streamlined process through which those materials can be appropriately reviewed, refined, and translated into consistent nomenclature and enforceable quality standards.