pepi.ninja

Regulatory dispatch

FDA's history of nominating bulk substances for compounding

Dateline
2026-05-03
Byline
pepi.ninja editorial
  • pcac
  • fda
  • compounding
  • primer
  • bulk-substances

Background

The 503A and 503B bulk drug substance lists are the central “what is compoundable” registries in U.S. compounding policy. Section 503A of the Federal Food, Drug, and Cosmetic Act, added by the Food and Drug Administration Modernization Act of 1997, directed FDA to develop a list of bulk drug substances that could be used in pharmacy compounding when no USP or NF monograph existed and the substance was not a component of an FDA-approved drug. Section 503B, added by the Drug Quality and Security Act of 2013, directed the agency to maintain a parallel list for outsourcing facilities, restricted to substances for which there is a “clinical need.”

Neither list was created in a single rulemaking. Instead, both have evolved through repeated rounds of public nomination, FDA evaluation, PCAC consultation, and notice-and-comment rulemaking (FDA — Bulk Drug Substances Used in Compounding).

How nominations work

FDA’s standing 503A bulks page outlines the criteria the agency applies to each nominated substance. The agency described its approach in a 2018 guidance, Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503A, which lays out four factors the agency balances:

  1. The physical and chemical characteristics of the substance.
  2. Any safety issues raised by the use of the substance in compounding.
  3. The available evidence of effectiveness, or lack of evidence, of the substance when used to compound drug products.
  4. Historical use of the substance in compounded drug products, including information about medical conditions for which the substance has been used and any documented patient harm.

No single factor is dispositive. The 2018 guidance frames this as a balancing test in which historical use and safety profile are weighed against the strength of effectiveness evidence and the substance’s chemical characterizability.

FDA opened the original public docket for 503A nominations in 2013–2014, after the DQSA was enacted. The agency received hundreds of nominations from compounding pharmacies, trade associations, individual physicians, and members of the public (FDA — Bulk Drug Substances Used in Compounding). The 503B docket opened on a similar timeline.

The interim Category system

Because the rulemaking process moves slowly and many nominated substances had to be reviewed individually, FDA issued an Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A describing how it would exercise enforcement discretion while the formal list was under development.

Under earlier versions of the interim policy, FDA placed each nominated substance into one of three categories:

  • Category 1 — substances under evaluation for which adequate supporting information had been submitted and no significant safety risks had been identified. Compounding with these substances was permitted under enforcement discretion while review continued.
  • Category 2 — substances FDA identified as raising significant safety concerns; compounding with these substances was not eligible for enforcement discretion.
  • Category 3 — substances for which submitted information was insufficient for FDA to evaluate, pending further data.

A revised interim policy issued in January 2025 ended the categorization of new nominations into Categories 1, 2, or 3 prospectively. FDA stated it would continue to consider newly nominated substances “in accordance with the process and criteria established in the FD&C Act and FDA regulations” but without the prior bucketing scheme (Interim Policy, Jan. 2025). Substances already in Category 1 retained that posture; substances flagged for safety concerns continued to appear on the agency’s Significant Safety Risks page.

How a substance gets to PCAC

Once FDA has reviewed the nomination materials and prepared an internal evaluation, the agency convenes the Pharmacy Compounding Advisory Committee. For each substance, FDA presents a briefing document with its preliminary recommendation, the original nominator may make a short supporting presentation, public comments are entered into the record, and the committee deliberates and votes.

FDA is not bound by the committee’s recommendation, but in practice the votes carry substantial weight in subsequent agency rulemaking. After PCAC review, FDA typically publishes a proposed rule in the Federal Register adding (or declining to add) the substance to the 503A or 503B list, with another public comment period. Final rules are then promulgated and codified in the regulations.

Several substances have already moved through this pipeline. The 503A Bulks List as it stands today reflects multiple rounds of PCAC review, with rules adding specific substances after favorable votes and others where FDA declined to add a substance after an unfavorable vote or insufficient supporting evidence.

Where peptides fit

Most therapeutic peptides currently in compounding circulation — including BPC-157, KPV, TB-500, MOTs-C, GHK-Cu, and semaglutide-related peptides — were nominated to the 503A list during the original 2013–2015 window. Several were subsequently placed in Category 2 because FDA’s preliminary evaluation noted unresolved safety questions, manufacturing-purity questions, or insufficient human data.

In April 2026, FDA announced that BPC-157, KPV, TB-500, and MOTs-C — among others — had been removed from Category 2 after the original nominations were withdrawn by the nominators, and that the agency intended to take these substances directly to the PCAC for full review. The July 23-24, 2026 PCAC meeting is the formal review step for those four (FDA — July 23-24, 2026 PCAC meeting).

What’s at stake

The bulks-list nomination process is the only pathway through which a non-FDA-approved, non-monograph substance can be lawfully compounded under section 503A or section 503B. For peptides, where finished-drug FDA approval is rare, the bulks list is the entire regulatory aperture. The PCAC’s July 2026 vote — and FDA’s eventual proposed rule — will determine whether four high-profile peptides have a regulated compounding pathway in the United States, or whether their lawful supply remains restricted to FDA-approved drugs (none, in the case of these four) and research use.

Sources