In an era in which weight loss drugs dominate news headlines and telehealth platforms put prescriptions just a click away, Americans are reimagining medicine’s potential—and how they access it. This has driven new interest in compounding pharmacies, which promise bespoke solutions crafted to meet individual needs and sometimes claim to deliver the chemical equivalents of cutting-edge drugs.
Despite the enthusiasm, many Americans remain unclear about the regulations governing these facilities and which agencies, if any, are responsible for ensuring the safety and efficacy of their products.
What is compounding?
The independent nonprofit U.S. Pharmacopeia Convention (USP) defines compounding as “combining, admixing, diluting, pooling, or otherwise altering a drug product or bulk drug substance to create therapies tailored to patients’ unique or specific needs.” Similarly, the Food and Drug Administration (FDA) considers compounding to occur when ingredients are combined, mixed, or altered to create a sterile or non-sterile medication “tailored to a patient’s specific needs.” The FDA further notes that compounding may be performed by a licensed pharmacist, licensed physician, or under the supervision of a licensed pharmacist, typically within pharmacies, hospitals, or clinics. As discussed below, while compounding does not generally include making exact copies of commercially available drugs, restrictions on compounding may be lifted in cases of drug shortages.
Compounded medications can be valuable options for ensuring appropriate dosing for pediatric or geriatric patients, providing alternative administration methods for those unable to swallow standard pills, or offering formulations without allergens such as preservatives or dyes. Compounding can also provide patients access to discontinued (but not formally discredited) therapies and medicines in times of specified shortage.
While compounded drugs play a crucial role in providing tailored treatments, they do not undergo the same FDA approval process as standard medications.[1] Several of the FDA’s web pages, including one on compound drug laws and policies, declare, “Compounded drugs are not FDA-approved.” Similarly, USP publications state, “USP has no role in enforcement.” Instead, compounding pharmacies are overseen by state boards of pharmacy.
Although compounded drugs may not be subject to FDA approval, the agency conducts surveillance through its Compounding Incidents Program and can act upon receipt of adverse drug reactions. In the last year, the agency alerted stakeholders, including clinicians, patients, and compounding pharmacies, of the potential risks associated with sulfite-containing compounded drugs, warned patients about possible risks associated with compounded ketamine products for the treatment of psychiatric disorders, and cautioned that differences in strength expression on product labels of compounding pharmacies and conventional manufacturers may lead to dosing errors.
Regulatory landscape
Compounding went largely unregulated until late in the last century. While the Food, Drug, & Cosmetic Act of 1938 (FD&C Act) required drug manufacturers to demonstrate the safety and efficacy of their products, the law was not intended to curtail the good faith efforts of the family doctor or corner pharmacist mixing tinctures and ointments.
Congress eventually addressed compounding in the Food and Drug Administration Modernization Act (FDAMA) of 1997, which introduced Section 503A to the FD&C. The law was designed to support individualized therapy by specifying conditions under which compounded drugs could be exempt from certain FDA requirements, including new drug approval, labeling, and compliance with Current Good Manufacturing Practice (CGMP) standards. 503A aimed to ensure that compounding remained focused on creating medications tailored to individual patient’s needs and did not cross the regulatory line into mass drug manufacturing.
Unfortunately, 503A left regulatory gaps, which were revealed by a 2012 fungal meningitis outbreak traced to contaminated steroid injections compounded by the New England Compounding Center (NECC). The Centers for Disease Control and Prevention ultimately identified over 750 cases of infection and more than 60 deaths linked to NECC products. In bringing criminal charges against the company’s co-founder and head pharmacist, the U.S. assistant attorney described the NECC facility as a “fungal zoo.”
In response to the NECC outbreak, Congress passed the Drug Quality and Security Act (DQSA) in 2013. DQSA added Section 503B to the FD&C Act and created a distinct category of compounding pharmacies known as “outsourcing facilities.” Unlike traditional compounding pharmacies, 503B facilities can produce larger quantities of compounded medications without individual patient prescriptions. They are also subject to stricter FDA oversight and must comply with CGMP standards.
To understand these distinctions, it may help to remember that a pharmacist who prepares a liquid version of a medicine prescribed for a child who can’t swallow a pill is operating under Section 503A. So, too, is an out-of-state pharmacist filling a prescription for a proprietary tretinoin cream prescribed through a telehealth visit on a digital platform. By contrast, a compounding facility preparing larger quantities of a medication for distribution through a healthcare facility without individual prescriptions operates under Section 503B. Pharmacies performing such sterile and nonsterile compounding must comply with USP <795>. Pharmacies performing sterile compounding must also comply with USP <797>.
The wide variation in state oversight of compounding pharmacies further complicates the regulatory landscape. Some state boards of pharmacy are specific in their expectations, others much less so. An FDA attempt to limit these variations ended badly. Shortly after the agency drafted a Memorandum of Understanding (MOU) for states in collaboration with the National Association of Boards of Pharmacy (NABP), seven compounding pharmacies challenged the effort in court resulting in a suspension of implementation of the MOU and continued variation between states.
Enter the GLP-1s
FDA guidance quotes federal statute that compounding should not include “what is essentially a copy of one or more approved drug products.” However, the agency allows for certain exceptions when a drug is not commercially available and, importantly, it does not consider a drug to be commercially available if the drug is listed in the agency’s Drug Shortage Database.
When shortages of critical chemotherapies or antibiotics put lives at risk, the availability of compounded equivalents provides an important safeguard. However, this regulatory exception can also lead to the proliferation of copies—or purported copies—of FDA-approved drugs during FDA-identified shortages, raising concerns about the safety and quality of compounded versions. A recent example involves glucagon-like peptide-1 (GLP-1) drugs, which have significantly reshaped discussions around obesity and weight loss.
Semaglutide, the GLP-1 active ingredient in Novo Nordisk’s Ozempic® and Wegovy®, has been listed in the shortage database several times since its debut. (As this story goes to press, the database lists “Wegovy, Injection, .25 mg/.5 mL [NDC 0169-4525-14]” in shortage due to “Demand increase for the drug” with an estimated shortage duration “TBD”).
The shortage of GLP-1s opens the door for versions from compounding pharmacies. It also comes at a time when consumer expectations for accessing prescription medications are shifting. The rise of telehealth platforms and direct-to-consumer medical advertising has fostered a demand for faster, more flexible ways to obtain these drugs. Now, apps and websites that previously offered compounded medicines for dermatologic conditions and hair loss are offering access to GLP-1s, typically at prices much lower than those of the original versions.
A KFF survey found that while most Americans who have taken GLP-1 drugs say they got them from their primary doctor or specialist, over 20% reported receiving them through an online provider or website (11%) or a medical spa or aesthetic medical center (10%).
While securing a GLP-1 prescription from a primary care provider may involve taking time off from work or school, digital platforms allow consumers to obtain prescriptions at their convenience by completing a questionnaire, uploading a photo, and providing payment information. Most do not require a real-time video encounter. However, the ease of access comes at a trade-off. In a traditional in-person visit, patients can expect a more comprehensive consultation, including discussions about alternative treatments, nutrition, diet, risks, and comorbidities.
Concerns
While compounding pharmacies offering GLP-1 products are operating within legal parameters during an FDA-identified shortage, they are facing increasing scrutiny from both regulatory bodies and pharmaceutical manufacturers. The FDA, Novo Nordisk, and Lilly have each raised concerns about the safety and integrity of compounded GLP-1 products,
Novo Nordisk has initiated at least 21 legal actions “regarding the marketing and sales of alleged ‘semaglutide’ products” and claims that there is “mounting evidence of high levels of known impurities and the presence of unknown impurities in injectable compounded products claiming to contain semaglutide.” The company has warned these impurities could result in life-threatening immunological reactions.
Similarly, Lilly, the manufacturer of Mounjaro® and Zepbound®, stated that it has received reports of compounded GLP-1 products containing bacteria and other impurities. The company said that it will pursue legal remedies against those who falsely claim their products are equivalent to or contain tirzepatide, their drugs’ active ingredient. The company notes that it “does not provide tirzepatide to compounding pharmacies, med-spas, wellness centers, online retailers, or other manufacturers.”
Concerns about compounded GLP-1s extend beyond impurities. In July, the FDA issued an alert regarding dosing errors associated with compounded injectable semaglutide products dispensed in multiple-dose vials. Adverse events associated with these dosing errors included acute pancreatitis and gallstones.
In a letter to the National Association of Boards of Pharmacy, the FDA cautioned, “Compounded drugs, including compounded semaglutide drug products, are not FDA-approved and do not receive premarketing review for safety, efficacy, and quality.” The agency continues to emphasize that it “does not review compounded versions of these drugs for safety, effectiveness, or quality.” At least four state boards of pharmacy have acted to restrict compounding of certain forms of semaglutide. Yet, as compounding pharmacies offer “GLP-1 formulations” through television, online, and social media advertising, it is not clear that the public yet appreciates the distinction between commercially available and compounded drugs, or how many are zooming in on the fine print disclaimer that, “The FDA does not review compounded products for safety, efficacy, or quality.”
The outlook for compounding
The FDA has recently moved to impose new restrictions on compounding pharmacies, leading some industry watchers to speculate if efforts to “ratchet up regulation of 503A and 503B compounding” are being taken in direct response to the compounding of semaglutide.
In March, the FDA proposed a rule that would “amend its regulations to add two lists identifying drug products or categories of drug products that present demonstrable difficulties for compounding under the FD&C Act.”
The rule proposes six criteria that would be considered to determine whether a drug product is “difficult to compound” (DDC). These include complex formulation, delivery mechanism, dosage form, bioavailability achievement complexity, compounding process complexity, and physicochemical or analytical testing complexity.
The trade associations Pharmaceutical Research and Manufacturers of America and the Association for Accessible Medicines (AAM) support the rule. In its comment letter, AAM stated, “It is imperative that FDA move more swiftly to address drugs that are currently being compounded and should not be because they are demonstrably difficult to compound.”
In opposing the rule, the National Community Pharmacist Association and the Alliance for Pharmacy Compounding have questioned whether the FDA is overstepping its statutory authority in adding categories of products to the 503A DDC list. This question of authority dates to the adoption of Section 503B in 1997, and it is reasonable to expect that compounding pharmacies will pursue the argument in court.
Comments on the proposed rule closed on June 18, 2024, and there is currently no indication when the rule will be finalized.
Government regulation has historically lagged advancements in science and technology, and in the digital age, consumer expectations may outpace both. As the FDA considers stricter regulation of compounding pharmacies, it will likely face resistance from consumers seeking convenience and from compounding pharmacies citing their role in addressing drug shortages. The primary concern must remain the safety and well-being of patients.
[1] Biological products are not eligible for the exemptions for compounded drugs under sections 503A and 503B of the FD&C Act. Federal law does not provide a legal pathway for marketing biologics prepared outside the scope of an approved biologics license application.