What is compounding?
Compounding is the creation of a custom drug for an individual patient based on a physician’s prescription. A compounding pharmacist mixes (“formulates”) an active ingredient (an “API” active pharmaceutical ingredient) with other inactive ingredients (“excipients”) to create a final product. Excipients can be colorants used to make the final product an appealing color; binders used to hold all the ingredients together; preservatives to keep the product stable for longer or other ingredients that aid in manufacturing or administration.
Compounding has historically been used — and is still used — by many healthcare providers in two situations. First, compounding is used when a patient is allergic to one or more of the excipients used in an FDA-approved product (such as peanut oil in the case of Prometrium®, a progesterone product). Second, when available FDA-approved products don’t offer a certain dosage level of a medication (e.g., 50 mg desired and 100 mg tablets are the lowest dose available), a compounded product can meet this need.
Although we mostly hear about compounded therapies with respect to menopausal hormone therapy, many other drugs are also compounded. Clinicians may prescribe a compounded medication when there is no FDA-approved product available. An example would be testosterone for women. The only FDA-approved testosterone products are for men and the concentration is too high for women. The use of testosterone in women for low desire (HSDD) is called “off-label” as it has not been approved for this indication (i.e., symptom) by the FDA. However, the International Menopause Society released guidelines supporting its use in 2019.
What does bioidentical mean?
“Bioidentical” is a term used to indicate that a product is made to be chemically identical to the hormone your body produces. However, the ingredients of a bioidentical product, whether in a compounded version or an FDA-approved product, are all manufactured in a lab. The idea of bioidentical products being more natural has long been associated with compounded products but it is a misconception.
Read more about bioidentical here.
How are compounded products different from FDA-approved products?
There are two dimensions on which an FDA-approved product and a compounded product differ. One has to do with proof of safety and effectiveness and the other has to do with the manufacturing process.
1. Proof of safety and effectiveness
In order to become FDA-approved, there are several hurdles a potential therapy/product has to clear to prove its safety and effectiveness. There are two types of pharmacy (503A or 503B) that can produce a compounded product. Each has a different level of requirements as noted in the label below.
Required Steps |
FDA-Approved |
Compounded
|
Compounded
|
|---|---|---|---|
|
1. Three trials in humans to ensure the safety and effectiveness of a specified combination of active and inactive ingredients versus a placebo or another product. A first trial (Phase I) to verify safety, learn about side effects of different doses and how much of the drug is in your bloodstream over time; A second trial (Phase II) to make sure the drug works as intended and to assess side effects in a larger group; A third trial (Phase III) to test the drug against another drug or a placebo, to verify benefit and further assess safety in a third population.
|
YES | NO | NO |
|
2. Labeling/Package insert (on the package and included with the product). A list of all of the active and inactive ingredients. Alerts for the patient about possible side effects, precautions related to interactions with other drugs, and any “black box warnings”* associated with the product – often potential cancer risks. More here.
|
YES | NO | Yes, some. Not as extensive as FDA.1 No black box warnings.* |
|
3. Post-marketing surveillance, sometimes called (Phase IV), is the requirement that all adverse events (AEs) experienced by patients are reported to a centralized database to continue learning about product safety.
|
YES | NO | YES |
2. The manufacturing process
FDA-approved products are made in batches according to a specified manufacturing process. This ensures the product is made exactly the same way with the same proportion of ingredients every time.
Here is way more detail than you need (don’t bother reading), but a quick glance at the following paragraph will convey how much is specified about the way an FDA-approved product is made:
A list of all components used in the manufacture of the drug product (regardless of whether they appear in the drug product) and a statement of the composition of the drug product; the specifications for each component; the name and address of each manufacturer of the drug product; a description of the manufacturing and packaging procedures and in-process controls for the drug product; the specifications necessary to ensure the identity, strength, quality, purity, potency, and bioavailability of the drug product, including, for example, tests, analytical procedures, and acceptance criteria relating to sterility, dissolution rate, container closure systems; and stability data with proposed expiration dating.1
In contrast, most compounded products, those that are made by 503A pharmacies, are designed to be “one-offs” meaning that they are made to a specific prescription for a specific patient. A compounding pharmacist takes the active ingredient as specified by the prescription and mixes it with inactive ingredients. The precision of the process relies on the skill and expertise of that pharmacist. The products made by a 503B pharmacy are made in batches, but not by an FDA-approved process with required manufacturing specifications as listed above.
So, are compounded products unsafe?
It’s not compounding in and of itself that presents risk, rather the risk is in the lack of regulation and therefore the lack of assurance you get that a compounded product has certain, safe ratios of ingredients and that it’s made in a sterile process without contaminants.
Here are the risks with compounded HT products:
- Exact ingredient ratios: It’s important that you are getting enough progestogen (either progesterone or a progestin) with your estrogen to protect your uterus from cancerous overgrowth. Therefore, your assurance that there is a precise combination of ingredients is important.
- All ingredients FDA-approved: Some frequently prescribed compounded products have ingredients that have not been FDA-approved as safe.
- Sterile products: The contamination of methylprednisolone acetate injections made at the New England Compounding Center in 2012 resulted in fatalities that raised concerns about compounding safety in general. However, those products were injectable and MHT is usually compounded as a cream or gel.
There are compounding pharmacies and pharmacists that follow their own and industry-established guidelines to ensure the safety of their products. However, as a consumer without the assurance of FDA approval and a regulated manufacturing process and with products that contain multiple ingredients, it’s really hard to know what is safe.
In July 2020 The National Academy of Sciences, Engineering, and Medicine (NASEM) convened a panel to assess the safety and effectiveness of compounded hormone therapy also referred to as compounded bioidentical hormone therapy (cBHT). More on “bioidentical” here (link). The committee concluded:
There is not sufficient evidence for the safety and effectiveness of compounded bioidentical hormone therapy (cBHT) to warrant its use, except for dosage and allergy, in light of two factors:
- There are FDA-approved forms of bioidentical hormones (estrogen and progesterone) that have been extensively studied for safety and efficacy.
- There is little research about the safety and effectiveness of compounded bioidentical hormone therapy (cBHT). More is needed.
The final report: The Clinical Utility of Compounded Bioidentical Hormone Therapy; A Review of Safety, Effectiveness, and Use National Academies of Sciences, Engineering, and Medicine. 2020. Washington, DC: The National Academies Press.
In February of 2018 the FDA asked The Board on Health Sciences Policy within the National Academies of Sciences, Engineering, and Medicine (NASEM) to form a committee to investigate the use of compounded hormone therapy.
The twelve-person committee was made up of experts from many backgrounds including, “drug research and development, pharmacology, toxicology, endocrinology, epidemiology, health literacy, pharmaceutical compounding and manufacturing, health risk mitigation, and health policy.”1
1. Recommendations by The Board on Health Sciences Policy within the National Academies of Sciences, Engineering, and Medicine, 1. p.245. Download available here.
What is the National Academy of Science (NASEM)?
The National Academy of Science was founded by a congressional charter in 1863 during Abraham Lincoln’s presidency. “Each year, thousands of the world’s leading experts serve pro bono (i.e., for free) on study committees that address some of society’s toughest challenges. Our rigorous process produces independent, objective reports that present the evidence-based consensus on these issues.
The committee searched national and international libraries to identify scientific articles about the safety and effectiveness of compounded hormone therapy products. They interviewed people from the compounding industry including compounding pharmacists and prescribers of compounded hormone therapy products. Importantly, they also heard testimony from women who used compounded bioidentical hormone (cBHT) products.
More on compounding pharmacies
What are the other differences between a 503A and a 503B pharmacy?
503A pharmacies are smaller organizations that can only create a product when they have a specific prescription for a specific patient. 503B pharmacies can both create a product for a specific prescription and can also create large amounts of common prescriptions and store them for later sale. The 503B organizations, often called “outsourcing facilities,” are also permitted to sell across state lines, 503As are not. To become a 503B, a pharmacy voluntarily registers annually with the FDA and undergoes inspections on a risk-based schedule, and must report adverse events (see table above). 503A organizations are subject to the regulation of their own state’s boards of pharmacy and those regulations vary from state to state. As of February 2020, only 73 pharmacies in the US were registered as 503Bs.1 This link lists each 503B organization when their last inspection was and whether they’ve been issued any warnings.
Recommendations by The Board on Health Sciences Policy within the National Academies of Sciences, Engineering, and Medicine 3. p. 57 (download is available here.)
So, are products from 503B pharmacies FDA-approved?
No, and this is an important distinction. When a pharmacy registers as a 503B organization, the FDA inspects the facility. This allows 503B organizations to make batches of products and sell them beyond state lines. Some sellers then use the phrase “made in an FDA-approved facility” and this is a true statement. However, products from a 503B pharmacy have not undergone the rigorous testing required to become an FDA-approved product (refer to the table above).
- These products lack testing for safety and effectiveness.
- They lack a precise understanding of how long the active ingredients stay in your body.
- These products don’t have the same labeling requirements.
- They are not required to include black box warnings about cancer-causing ingredients.
As you look back at the differences in the table above, you’ll see that there are considerably fewer safety assurances with a compounded product — from either type of organization — than with an FDA-approved one.
What about the third-party certifications that some compounding pharmacies mention on their websites?
Within the compounding industry, there are two third-party certifications a pharmacy can get to demonstrate compliance with a set of safety protocols and standards related to manufacturing. They are called The Pharmacy Compounding Accreditation Board (PCAB) and The Joint Commission Medication Compounding Certification (MCC). Most pharmacies list these accreditations if they have them.