Today, the FDA published a Federal Register (FR) notice (here) announcing a preliminary decision regarding three bulk drug substances that it “has evaluated and is proposing not to include on the 503B Bulks List: semaglutide, tirzepatide, and liraglutide.” The notice further states that the FDA will consider comments submitted to the docket until June 30, 2026 prior to making a final decision. The 503B Bulks List includes drug substances that are permitted to be used in the compounding of drug products by 503B outsourcing facilities.
“One of the conditions that must be met for a drug product compounded by an outsourcing facility to qualify for the exemptions under section 503B of the FD&C Act is that the outsourcing facility does not compound a drug using a bulk drug substance unless: (1) the bulk drug substance appears on a list established by the Secretary of Health and Human Services identifying bulk drug substances for which there is a clinical need (the 503B Bulks List) or (2) the drug compounded from the bulk drug substance appears on the drug shortage list in effect under section 506E of the FD&C Act (21 U.S.C. 356e) at the time of compounding, distribution, and dispensing.”
The GLP-1 active pharmaceutical ingredients mentioned above have been the subject of great interest relative to compounding and have had a rather sordid history over the past few years. The FDA did permit the compounding of GLP-1 products using bulk drug substances during a period of shortage after NDA drug approvals; however, after the Agency determined that the shortages no longer existed and that manufacturers of the approved drugs were able to supply sufficient quantities to meet market demand, the FDA began enforcement actions against compounders that continued utilize the bulk drug substances to engage in compounding of these products.
The notice further states that the “FDA will only place a bulk drug substance on the 503B Bulks List when we have determined there is a clinical need for outsourcing facilities to compound drug products using the bulk drug substance. If a clinical need to compound drug products using the bulk drug substance has not been demonstrated, based on the information submitted by the nominator and any other information considered by the Agency, FDA will not place the bulk drug substance on the 503B Bulks List.”
In making its decision on which of the nominated drugs are included on the list of permitted bulk drug substances, the “FDA does not interpret supply issues, such as backorders, to be within the meaning of ‘clinical need’ for compounding with a bulk drug substance. Section 503B of the FD&C Act separately provides for compounding from a bulk drug substance under the exemptions discussed above if the drug product compounded from the bulk drug substance is on the FDA drug shortage list at the time of compounding, distribution, and dispensing. Additionally, FDA does not consider convenience in administering a particular compounded drug product (e.g., a ready-to-use form) or the cost of the compounded drug product as compared with an FDA-approved drug product when assessing ‘clinical need.’”
The notice also states that the FDA carefully reviewed the nominations it received and it did not identify sufficient evidence to include semaglutide, tirzepatide, and liraglutide on the 503B Bulks List. Determination of clinical need is based on patient safety and medical necessity under the law.
In addition, the FDA also must ensure the integrity of the drug approval process and, thus, does not permit 503B compounders to market versions of compounded products that are essentially duplicate copies of approved drug products unless there is a documented patient-specific need for an alternate form of the compounded product. The FR notice describes in detail the FDA’s decision-making process in not including the three GLP-1 active pharmaceutical ingredients on the 503B Bulks List for compounding of parenteral or oral versions of these drugs.
