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The US framework: FDA approval, the Orange Book and compounding

Drugs@FDA and the Orange Book record what FDA has approved. The 503A nomination categories, the Pharmacy Compounding Advisory Committee decisions of 2024 to 2026 and the GLP-1 shortage timeline record everything else.

Last reviewed
2026-09-22
Reviewer
editorial review pending
Revision
1
Sources
39

Summary

In the United States a medicine reaches the market through an approved application, and the record of those approvals is public. Drugs@FDA holds the applications; the Orange Book holds the approved products with their patent and exclusivity information 12. Everything outside that system, including pharmacy compounding from bulk drug substances, is governed by sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act and by FDA's interim policy and advisory-committee process. Of the ten compounds in this knowledge base, three have or have had US applications and seven do not, and the compounding record is where most of the recent movement has been.

Drugs@FDA and the Orange Book

FDA describes Drugs@FDA as containing prescription brand-name drug products, generic drug products and many therapeutic biological products, along with over-the-counter brand-name and generic drugs, with most products approved since 1939 represented and most labels, approval letters and reviews available for products approved since 1998 1. The Orange Book, formally Approved Drug Products with Therapeutic Equivalence Evaluations, "identifies drug products approved on the basis of safety and effectiveness by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (the Act) and related patent and exclusivity information" 2.

Queries against these records produced both the positive and the negative US findings recorded here. Semaglutide is approved under NDA 209637, NDA 213051, NDA 215256 and NDA 218316 3; tirzepatide under NDA 215866 and NDA 217806 4; tesamorelin acetate under BLA 022505, first approved on 10 November 2010 5. Sermorelin acetate was approved as Geref under NDA 019863 on 28 December 1990 and NDA 020443 on 26 September 1997; approval of both was withdrawn at the holder's request effective 18 June 2009, and FDA determined in 2013 that neither product was withdrawn for reasons of safety or effectiveness, keeping both in the Orange Book Discontinued Drug Product List 6789. Drugs@FDA queries returned no match for ipamorelin, retatrutide, thymosin or timbetasin 101112, and none for prezatide copper 13. For one approved product the Orange Book record was read directly: patents for Ozempic product 001 expire between 20 January 2026 and 21 June 2033, with the drug-substance patent expiring 5 December 2031 and exclusivity code I-961 running to 28 January 2028 14.

Compounding under section 503A

A bulk drug substance may be used in compounding under section 503A if it is the subject of an applicable USP or NF monograph, is a component of an FDA-approved drug product where no such monograph exists, or appears on the 503A bulks list where neither applies 15. The list itself is codified at 21 CFR 216.23; current to 17 September 2026 it names six substances, none of which is any compound covered here 16.

While it evaluates the substances nominated in 2015, FDA operates an interim policy that sorts them into three categories 15. Category 1 substances "may be eligible for inclusion on the 503A bulks list, were nominated with sufficient supporting information for FDA to evaluate them, and do not appear on any other list", and FDA "does not intend to take action against a compounder" using them provided the conditions in the guidance are met 15. Category 2 substances were also nominated with sufficient supporting information, "however, FDA has identified significant safety risks relating to the use of these substances in compounding pending further evaluation", and the agency would consider action under its general enforcement policies 15. Category 3 substances "may be eligible for inclusion on the 503A bulks list but were nominated with insufficient supporting information for FDA to evaluate them" and are outside the category 1 policy 15. FDA has since stated that it does not intend to place substances nominated on or after 7 January 2025 into these categories 15.

None of this is approval. FDA states that compounded drugs are not reviewed by the agency for safety, effectiveness or quality 17.

The safety-risk list

FDA maintains a separate page of bulk drug substances nominated for use in compounding that may present significant safety risks. Its content current as of 22 April 2026 carries ipamorelin acetate in 503B category 2, added 29 September 2023, citing immunogenicity risk for certain routes from aggregation or peptide-related impurities, unnatural amino acids adding to characterisation complexity, and a published study reporting serious adverse events including death after intravenous administration 18. The same page carries CJC-1295 among substances nominated but withdrawn, stating that available clinical data are limited and naming increased heart rate and systemic vasodilatory reaction among identified serious adverse events 19; BPC-157, with the stated risks of immunogenicity for certain routes and complexities with peptide-related impurities and active-ingredient characterisation 20; "Thymosin beta-4, fragment (LKKTETQ), also known as TB-500", citing immunogenicity risk and the absence of human exposure data 21; and "GHK-Cu (for injectable routes of administration)" 22. Tesamorelin is not named on that page 23.

The advisory committee and the 2024 to 2026 decisions

The Pharmacy Compounding Advisory Committee "provides advice on scientific, technical, and medical issues concerning drug compounding under sections 503A and 503B" of the Act and makes recommendations to the Commissioner; it consists of a core of 12 voting members including the Chair, drawn from compounding, manufacturing, pharmacy and medicine, with representation from the National Association of Boards of Pharmacy and the United States Pharmacopeia 24. FDA publishes a briefing document before each meeting, the committee votes substance by substance, and minutes follow.

Four of the compounds here have been through that process since 2024. On 29 October 2024 the committee voted 0 yes, 12 no with 1 abstention against placing ipamorelin (free base) on the 503A Bulks List, and by the same margin against ipamorelin acetate, citing a lack of information supporting safety and efficacy; both nominations had been withdrawn on 19 September 2024 and FDA continued its evaluation on its own initiative 2526. On 4 December 2024 the committee rejected all five CJC-1295-related substances: free base 0 to 13, acetate 1 to 12, DAC free base 0 to 13, DAC acetate 0 to 13 and DAC trifluoroacetate 0 to 13 2728. For the meeting of 23 and 24 July 2026, FDA's briefing document of 11 May 2026 concluded that a balancing of the criteria weighs against listing BPC-157 (free base) and BPC-157 acetate 2930, and its briefing document of 15 May 2026 proposed that TB-500 (free base) and TB-500 acetate not be included 3132. One decision is still pending: FDA's category document updated 14 May 2026 records that "GHK-Cu (except for injectable routes of administration)" will be added back to Category 1 after a nominator clarified on 5 May 2026 that it meant to withdraw only the injectable route, and that FDA intends to consult the committee before the end of February 2027 33.

The GLP-1 shortage timeline

Tirzepatide injection was added to FDA's shortage list on 15 December 2022 and removed on 2 October 2024; after litigation the decision was remanded and a declaratory order of 19 December 2024 re-determined the shortage resolved 34. Enforcement discretion for compounders then ran to 18 February 2025 under section 503A and 19 March 2025 under section 503B 35. FDA determined the semaglutide injection shortage resolved on 21 February 2025, with enforcement discretion ending on 22 April 2025 for 503A compounders and 22 May 2025 for 503B outsourcing facilities; a district court denied a preliminary injunction on 28 April 2025 36. As of the page current on 1 April 2026, neither semaglutide nor tirzepatide appears on the 503B bulks list or on the drug shortage list 36.

FDA has also addressed products sold outside the approved system. It states that it has warned companies selling unapproved semaglutide and tirzepatide falsely labelled "for research purposes" or "not for human consumption", that salt forms such as semaglutide sodium and semaglutide acetate are different active ingredients from that in the approved drugs, and that import alert 66-80 has been established for GLP-1 active pharmaceutical ingredients 1737. On 6 February 2026 the agency announced its intention to restrict GLP-1 active pharmaceutical ingredients destined for mass-marketed non-approved compounded products 38. For retatrutide the position is stated directly: it "cannot be used in compounding under federal law" and is not a component of an FDA-approved drug 39.

Questions this page answers

What do the 503A nomination categories mean?
FDA's interim policy sorts nominated bulk drug substances into three groups. Category 1 substances were nominated with sufficient supporting information for FDA to evaluate them and do not appear on any other list, and FDA does not intend to act against compounders using them if the guidance conditions are met. Category 2 substances were also sufficiently supported, but FDA has identified significant safety risks. Category 3 substances were nominated with insufficient supporting information for FDA to evaluate them.
Is a compounded preparation an FDA-approved product?
No. FDA states that compounded drugs are not reviewed by the agency for safety, effectiveness or quality. A category 1 listing is an interim enforcement position on a bulk substance, not an approval of any finished preparation, and inclusion on the 503A bulks list at 21 CFR 216.23 is likewise not an approval.
What did the Pharmacy Compounding Advisory Committee decide about these compounds?
On 29 October 2024 it voted against placing ipamorelin (free base) and ipamorelin acetate on the 503A Bulks List, 0 to 12 with 1 abstention in each case. On 4 December 2024 it rejected all five CJC-1295-related substances. For the meeting of 23 and 24 July 2026 FDA proposed not adding BPC-157 (free base), BPC-157 acetate, TB-500 (free base) or TB-500 acetate.
When did the GLP-1 shortages end?
FDA re-determined the tirzepatide injection shortage resolved on 19 December 2024 and determined the semaglutide injection shortage resolved on 21 February 2025. The associated enforcement-discretion periods ended on 18 February and 19 March 2025 for tirzepatide under sections 503A and 503B, and on 22 April and 22 May 2025 for semaglutide.
What is the Orange Book?
Approved Drug Products with Therapeutic Equivalence Evaluations. FDA describes it as identifying drug products approved on the basis of safety and effectiveness under the Federal Food, Drug, and Cosmetic Act, together with related patent and exclusivity information.

References

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For laboratory research use only. This article summarises published literature and regulatory records; it does not describe or recommend any use of a material in or on humans or animals.
Cite this page
Harvard
HelixEVO Labs (2026) The US framework: FDA approval, the Orange Book and compounding. Available at: https://helixevo.net/knowledge-base/regulatory/us-framework-approval-and-compounding (Accessed: 2026-09-25).
APA
HelixEVO Labs. (2026). The US framework: FDA approval, the Orange Book and compounding. https://helixevo.net/knowledge-base/regulatory/us-framework-approval-and-compounding
BibTeX
@misc{helixevo-2026-the-us-framework-fda-approval-the-orange,
  title = {The US framework: FDA approval, the Orange Book and compounding},
  author = {{HelixEVO Labs}},
  year = {2026},
  howpublished = {\url{https://helixevo.net/knowledge-base/regulatory/us-framework-approval-and-compounding}},
  note = {Reviewed 2026-09-22; accessed 2026-09-25}
}
Revision history
  1. r1 · 2026-09-25 · Initial import