Navigating FDA Compounding Regulations: Tirzepatide's Removal From the Shortage List and Its Impact on 503A and 503B Facilities

Pharmacy Times® interviewed Martha M. Rumore, PharmD, Esq, MS, LLM, FAPhA, a pharmacist-attorney and senior counsel in Frier Levitt’s Life Sciences Department, on the complex legal and regulatory landscape surrounding the compounding of tirzepatide (Mounjaro for diabetes treatment, Zepbound for weight loss; Eli Lilly and Company), especially in light of recent FDA actions. Following the FDA's decision to remove tirzepatide from the shortage list, the Outsourcing Facilities Association (OFA) and North American Custom Laboratories (a 503B outsourcing facility) filed a lawsuit against the FDA, claiming the decision was arbitrary and failed to address ongoing shortages adequately. The FDA responded with a motion for voluntary remand, allowing it to reevaluate the decision and maintain non-enforcement for 503B facilities until November 21, 2024.

Martha M. Rumore, PharmD, Esq, MS, LLM, FAPhA, is a pharmacist-attorney and senior counsel in Frier Levitt’s Life Sciences Department.

This situation creates uncertainty for 503A and 503B compounders. Although the FDA clarified that it intends consistent enforcement discretion for all sterile compounders, 503A compounders remain uncertain about their status. The Alliance for Pharmacy Compounding (APC) has requested clarification on whether this enforcement discretion applies to them.

According to Rumore, the FDA’s may be moving toward reducing compounding for GLP-1 drugs, such as tirzepatide and semaglutide (Ozempic, Wegovy, Rybelsus; Novo Nordisk), which compounders rely on amid shortages. The manufacturer of semaglutide, for instance, filed a petition to add it to the FDA’s Difficult to Compound list, claiming safety concerns due to the drug’s complexity.

Looking forward, Rumore advises compounders to monitor tirzepatide’s status closely, as the FDA’s upcoming decision could limit compounding to specific circumstances requiring a prescriber’s justification of a significant medical need. This increased regulatory focus, combined with manufacturer litigation, underscores the need for careful documentation and adherence to FDA guidance to ensure compliant compounding practices.

Pharmacy Times: What was the decision on 503A and 503B compounding, purchasing, and dispensing tirzepatide, and what is the impact of this decision?

Martha M. Rumore, PharmD, Esq, MS, LLM, FAPhA: After FDA removed tirzepatide from the 506e shortage list, a lawsuit was filed against the FDA by the OFA and North American Custom Laboratories, LLC (see Outsourcing Facilities of America; North American Custom Laboratories, LLC DB/A Farmakeio Custom Compounding v United State Food and Drug Administration and Dr. Robert Califf, Civ. Action No. 4:24-cv953. Filed October 7, 2024 US District Court for the Northern District of Texas). OFA is a trade association representing 503B outsourcing facilities, and North American Custom Laboratories is a Texas-based 503B outsourcing facility.

The lawsuit filed is based upon claims that FDA acted in a “reckless and arbitrary” way to deprive patients of compounded tirzepatide. The lawsuit asserts that the FDA’s decision to remove tirzepatide from the 506e shortage list was note based on an appropriate evaluation of the tirzepatide shortage and supply.

Finally, the lawsuit asserts that FDA’s action was a “substantive” rule, and that FDA did not follow the procedure for substantive rules under the Administrative Procedures Act (APA). The lawsuit then asserts that the shortage of tirzepatide is not resolved, and that FDA failed to engage in meaningful inquiry and instead relied on a one-sided presentation to the agency by the manufacturer. To date, there has not been any similar lawsuit filed by 503A compounders.

On October 11, 2024, FDA submitted a Motion for Voluntary Remand and Stay for the purpose of “giving the agency the opportunity to reevaluate the decision at issue in view of the plaintiffs challenges to it” and give FDA an opportunity to cure any legal APA errors (see Case 4:24-cv-00953P. Document 27. Filed October 11, 2024).

The Motion was granted. Importantly, the FDA stated in the Motion that it will not take enforcement action against 503Bs for compounding tirzepatide as they did while the drug was on the FDA shortage list. This enforcement discretion will last until 2 weeks beyond FDA’s reconsideration of the decision, which is due by November 21, 2024. The enforcement discretion did not mention 503A compounders, leading to confusion for that group of compounders.

The APC, a trade group representing 503A compounders, submitted a written request to FDA for clarification regarding whether the enforcement discretion extends to 503A compounding as well. On October 17, 2024, FDA issued a letter to APC and then provided clarification on the FDA website essentially extending enforcement discretion to “sterile compounders” and that FDA “intends to treat compounders consistently at this time.”

Pharmacy Times: In the legal case challenging the FDA's decision, what are your thoughts on how the FDA may respond, and is there a precedent for this case that may inform a potential decision in this case?

Rumore: No one can predict how FDA will respond and there is no legal precedent. However, on October 30, 2024, FDA amended all listings for semaglutide on the 506e shortage list as “available.” This means that FDA is most likely reviewing nationwide availability and may be removing semaglutide from the shortage list sooner rather than later. It is no revelation that FDA has been trying to limit compounding of GLP-1s.

Pharmacy Times: What does the future hold for the availability of tirzepatide?

A pharmacist weighing chemicals for the purpose of compounding. Image Credit: © Kzenon - stock.adobe.com

Rumore: While FDA is reevaluating its position, both 503A compounding pharmacies and 503B outsourcing facilities may continue to compound tirzepatide as they have before the drug was removed from the shortage list. By November 21, 2024, FDA may place tirzepatide back on the shortage list as has occurred many times in the past where a drug is removed despite reports of shortages from patients and stakeholders; in these cases, the drug has often been placed back on the shortage list. If this occurrs, it would be status quo for compounding.

Compounders will likely need to check the shortage list daily as tirzepatide’s status on the list can change without notice. However, should FDA decide placing tirzepatide back on the shortage list is not warranted, additional restrictions will be placed on compounding this drug. One of the restrictions is that 503B facilities will no longer be able to compound the drug (after the 2 week enforcement discretion period followed by a 60-day grace period). 503A’s will be prohibited from compounding “essentially a copy” of the commercially available product, but there are circumstances detailed in FDA Guidance documents where compounding is permitted. This will have implications for availability for the pharmacy that will need to be mitigated.

The attack on compounding GLPs is not limited to tirzepatide. There are separate efforts to ban 503A compounding of semaglutide. A few weeks ago, the manufacturer of semaglutide, which has been on the FDA shortage list for over 2 years, filed a petition with FDA to ban compounding of that drug, arguing that it is “too complex” for pharmacies to safely make. The petition seeks to place semaglutide on the FDA’s Difficult to Compound list. FDA is considering that petition. This represents an escalation of efforts by GLP-1 manufacturers to prevent compounding of their products.

Pharmacy Times: What do pharmacy compounders need to know now about risk mitigation around compounding, purchasing, and dispensing tirzepatide?

Rumore: A compounded drug may be considered “essentially a copy of a commercially available drug product” even if it is not an “exact cop[y]” of or “nearly identical” to “a commercially available drug product.” A drug is “essentially a copy of a commercially available drug product” if (a) the compounded drug and the commercially available drug have the same active pharmaceutical ingredient (API), (b) the API has the same, a similar, or an easily substitutable dosage strength (± 10%), and (c) the commercially available drug product can be used by the same route of administration as the compounded drug. For 503A compounding, the phrase “essentially a copy of a commercially available drug product” does not include a drug product in which there is a change made for an identified individual patient, which produces for that patient a significant difference, as determined by the prescribing practitioner, between the compounded drug and the comparable commercially available drug product. (See 21 U.S.C. § 353a(b)(1)(D). Also see FDA Guidance, Compounded Drug Products that Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act and Compounded Drug Products that Are Essentially Copies of a Commercially Available Drug Product Under Section 503B of the Federal Food, Drug, and Cosmetic Act).

If a compounder intends to rely on such a significant difference statement, that determination is to be “documented on the prescription.”(Id. at 8). The determination is to be made by “a prescriber . . . for the patient for whom [the compounded drug] is prescribed.” FDA has indicated it will not question the prescriber’s determination. Once off the shortage list, only 503A compounding is still permitted under a narrow set of circumstances due to a specific patient’s medical need.

Despite this, keep in mind that the manufacturer has aggressively pursued via cease and desist and litigation allegations that now seem to go to the heart of compounding. The litigation is targeting smaller entities who would be more likely to sign settlement agreements when they cannot afford litigation, making good on cease and desist letters and targeting mixtures and oral formulations as experimental and unsafe.