Key takeaways
- FDA removed five peptide bulk drug substances from Category 2 of FDA interim 503A bulks list
- Bulk drug substances that were removed will be considered for inclusion in 503A bulks regulation at October and December 2024 PCAC meetings
- FDA recommends that none of the substances being reviewed at October 29 PCAC meeting be included in 503A bulks regulation
FDA removes certain peptide bulk drug substances from Category 2 of interim 503A bulks list and sets dates for PCAC review
In September 2023, the Food and Drug Administration (FDA) placed several peptide bulk drug substances on Category 2 of the FDA's interim 503A bulks list (Interim 503A Bulks List). On September 20, 2024, the FDA announced that five of these bulk drug substances, AOD-9604, CJC-1295, ipamorelin acetate, thymosin alpha-1 (Ta1), and Selank acetate (TP-7), were being removed from Category 2 based on the nominators' withdrawal of these substances' nomination. These bulk drug substances were withdrawn from Category 2 as of September 27, 2024 (seven days from the date that FDA published its notice). The FDA further advised that these bulk drug substances and other peptide bulk drug substances will be reviewed for potential inclusion in the 503A Bulks Regulation at the upcoming October and December 2024 Pharmacy Compounding Advisory Committee (PCAC) meetings.
Section 503A, the 503A Bulks Regulation, and PCAC
Section 503A of the Federal Food, Drug, and Cosmetic (FD&C) Act describes the conditions that must be satisfied for the compounding of human drug products to be exempt from three sections of the FD&C Act: section 505 (concerning the approval of drugs under new drug applications or abbreviated new drug applications); section 502(f)(1) (concerning the labeling of drugs with adequate directions for use); and section 501(a)(2)(B) (concerning current good manufacturing practice requirements).
One of the conditions that must be met for a compounded drug product to qualify for these exemptions is that a licensed pharmacist or physician must compound the drug product using bulk drug substances that meet certain requirements.
- The bulk drug substances must comply with the standards of an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph, if a monograph exists, and the USP chapter on pharmacy compounding;
- If such a monograph does not exist, the bulk drug substances must be drug substances that are components of FDA-approved drugs; or
- If such a monograph does not exist and the drug substance is not a component of an FDA-approved drug, the drug substance must appear on a list developed by the FDA through regulation (the 503A Bulks Regulation).
In order to create the 503A Bulks Regulation, the FDA solicited bulk drug substance nominations from the public, advising the public to nominate substances that did not have a USP/NF drug monograph and were not a component of an FDA-approved drug. Following receipt of nominations, the FDA evaluates the bulk drug substances and then, consistent with section 503A's mandate, the FDA consults with PCAC. After consultation with PCAC, the FDA publishes a notice of proposed rulemaking, and the public is provided a comment period. Following the notice-and-comment period, the FDA issues an updated regulation that includes or excludes nominated substances from the 503A Bulks Regulation.
What is the 503A interim Bulks List?
The FDA's efforts to develop the 503A Bulks Regulation have been time consuming and drawn out. As a result, since 2017, the FDA has followed its interim policy for the use of bulk drug substances. Under the FDA's interim policy, the FDA evaluated nominated bulk drug substances and then placed them in interim classifications. The FDA advised last year that it would no longer be conducting interim categorizations for newly nominated substances. However, currently, the Interim 503A Bulks List remains in place, as described in our December 8, 2023 Client Alert.
Under the FDA's interim policy, the FDA outlined the manner in which it intends to exercise enforcement discretion over the use of bulk drug substances. Specifically, the FDA advised that bulk drug substances listed in Category 1 of the Interim 503A Bulks List may be used in the preparation of compounded drug products. Bulk drug substances listed in Category 2 are those substances that, in the FDA's view, were nominated with sufficient supporting information but raise significant safety concerns, and while the FDA continues to evaluate those substances for inclusion in the regulation, it will not permit compounders to use such substances in preparing drugs. Finally, Category 3 reflects those substances that have been nominated without sufficient support.
We note that the FDA's interim categorizations are not final determinations as to whether any bulk drug substance will be included in the 503A Bulks Regulation.
PCAC meeting and final determinations
At the October 29, 2024 PCAC meeting, the FDA will review ipamorelin acetate and ipamorelin (free base), ibutamoren mesylate, L-theanine, and kisspeptin-10 for inclusion in the 503A Bulks Regulation. In preparation for the meeting, the FDA released its analysis for each of these substances including the FDA's recommendation that none of these substances be included in the 503A Bulks Regulation.
Presently, the FDA has not released the detailed information about the December 4, 2024 PCAC meeting. However, in the FDA's September 20 notice, the FDA advised that AOD-9604; CJC-1295 (free base); CJC-1295 acetate; CJC-1295 with drug affinity complex (DAC) (free base); CJC-1295 DAC acetate; CJC-1295 DAC trifluoroacetate; thymosin alpha-1 acetate; and thymosin alpha-1 (free base) would be assessed during this PCAC meeting for inclusion in the 503A Bulks Regulation. Interested parties will have to wait for the FDA to identify its position on these bulk drug substances.
Again, once PCAC has reviewed these bulk drug substances and the substances have undergone a notice-and-comment period, the FDA's action on these substances will be the final determination as to whether these substances may be used in compounding.
What's next?
Industry stakeholders should carefully review section 503A's requirements to ensure they understand the impact that the FDA's recent removal of these substances from Category 2 has on compounding.
Further, the FDA is currently accepting comments regarding the four substances being reviewed at the October 29, 2024 PCAC meeting, which must be submitted by October 15, 2024 to be considered by PCAC. Comments received after October 15, 2024 but by October 28, 2024 will be taken into consideration by the FDA. We encourage industry stakeholders that may be affected by PCAC determinations to submit comments to the Federal Register, Docket No. FDA-2024-N-4188, as well as closely monitor the October and December meetings.
Should you have any questions regarding the FDA's recent action, or should you wish to submit a comment regarding any of the bulk drug substances being considered at the upcoming PCAC meetings, please do not hesitate to reach out to any of the authors on this alert for further discussion.
Client Alert 2024-208
This article is presented for informational purposes only and is not intended to constitute legal advice.
