In a major expansion of its temporary policy on compounding, the FDA has announced it will permit outsourcing facilities working with hospitals to compound a substantially larger number of drug products to deal with emerging shortages of essential products used to treat patients with COVID-19.
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Executive IQ Brief
- How things work now: Pharmaceutical compounders generally make customized drugs for individual patients. However, they are generally prohibited from making copies of FDA-approved drugs unless that product is specifically permitted, or if the product is on a drug shortage list.
- What’s New: The FDA now says it will permit pharmaceutical compounders registered as “outsourcing facilities” to make copies of 13 types of drugs—mostly painkillers, muscle relaxants and anesthetics—in the hopes of alleviating emerging shortages. The policy will only allow the facilities to sell directly to hospitals, and only if those hospitals have been unable to purchase FDA-approved equivalents of the drugs. Other requirements will apply to the compounded drugs as well.
- Impact: There is reason to believe the impact of the policy will be limited. There are just 76 outsourcing facilities in the US, and many of those facilities have had problems during FDA inspections. Deficient compounding practices could cause significant harm to patients receiving the drugs, especially those intended to be sterile and injected into patients for intubation.
The FDA defines drug compounding as the practice of a licensed professional combining, mixing or altering ingredients of a drug to create a medication tailored to the needs of an individual patient.
Compounded drugs are intended to be used by individual patients for which there is special need not otherwise met by a manufactured drug product. For example, a patient with an allergy might require a specific medication without a certain dye, or a patient with trouble swallowing might need a liquid formulation of a drug only manufactured as a tablet. Typically, providers write individual prescriptions for patients that need a compounded drug, which is filled in a pharmacy.
Pharmaceutical compounding differs from traditional drug manufacturing in three crucial respects: compounded drugs are manufactured for different types of patients, in different type of facilities and overseen by different regulatory authorities.
Compounded drugs are not individually approved by the FDA. The FDA does not verify the safety, effectiveness or quality of individual compounded drugs. As a result, compounded drug products generally lack the same safety, quality and effectiveness assurances as approved drugs.
Following a major safety event caused by a compounded product, Congress created a modified regulatory framework for compounding pharmacies. The Drug Quality and Security Act (DQSA) of 2013 established a new regulatory approach based on the scope, scale and intended use of compounding. Notably, it established two different types of compounders under federal law, each with varying regulatory requirements.
Compounding Pharmacies, also known as 503A compounders, produce products exempt from labeling, approval and current good manufacturing practices (cGMPs). These compounders are licensed by state Boards of Pharmacy or other regulatory bodies instead of the FDA. Compounding is conducted based on the compounder’s receipt of a valid prescription for an individual patient.
Outsourcing Facilities, also known as 503B compounding pharmacies, produce large quantities of drug products. Unlike 503A pharmacies, these facilities are allowed to ship products across state lines and are also permitted to compound limited quantities of products before the receipt of an individual prescription (based on the facility’s expectation that it will receive those prescriptions). These facilities are exempt from labeling and approval requirements but are required to register with the FDA annually, meet cGMP requirements under 21 CFR 210-211 and are subject to FDA inspections.
Compounding pharmacies are limited in the types of drugs they can make. For example, under ordinary circumstances they cannot make a product that is “essentially a copy” of an already-approved substance. Further, they are unable to make specific products deemed by the FDA to be “difficult to copy,” and are also prohibited from using certain bulk substances contained on its “Bulks List.”
However, there is one legal avenue which permits compounding pharmacies to make “copies” of already-approved drugs.
Under Section 503(B)(a)(2)(ii) of the Federal Food, Drug and Cosmetic Act, a facility may make products in bulk if “the drug compounded from such bulk drug substance appears on the drug shortage list” maintained by the FDA.
As the FDA has endeavored to help physicians and clinicians confront COVID-19, shortages of needed drug substances are becoming more common. On the supply side, some manufacturing facilities may be shut down due to staff members with COVID-19, while other countries may have restricted the export of medications deemed to be essential. On the demand side, an influx of patients using specific medications (such as painkillers needed to ventilate patients or substances used for dialysis) are causing both local and national shortages of some products.
The FDA has already looked to pharmaceutical compounders to help alleviate previous shortages during the COVID-19 crisis. For example, it has announced two separate policies that would respectively allow compounders to make hydroxychloroquine and hand sanitizer.
But now the FDA says that “additional flexibility is temporarily needed to ensure that treatment options are available when hospitals are unable to obtain FDA-approved drugs used for hospitalized patients with COVID-19.”
The problem, the FDA said in an immediately-in-effect guidance document, is that the shortages list generally only captures products already in shortage, which makes it difficult for the agency to take action where shortages are likely to occur in the future.
Under ordinary circumstances, the FDA works with companies proactively to try to alleviate shortages, but generally keeps this information secret to ensure that facilities don’t stockpile the drug in anticipation of a shortage and exacerbate the very problem they were trying to avoid.
In some cases, an individual hospital may find it difficult to obtain a drug, even if that product isn’t yet on a national shortage list.
To solve for this, the FDA said it would enact a new policy of enforcement discretion meant to allow outsourcing facilities to make copies of products using substances not included on its bulks list.
However, products can only be compounded if they meet four main requirements.
- The product must be one of the 13 listed by the FDA in its guidance document. That list includes many painkiller products used to help put patients on ventilators.
- The product must be provided directly to a hospital, and orders for the drug must come from the hospital, which has also made attempts to first obtain legally-marketed equivalents of the drug.
- The bulk drug substances used must be made at registered outsourcing facilities and otherwise comply with US Pharmacopeia monograph standards.
- The facility must comply with stability testing and expiration date requirements. For example, for products compounded in an aqueous sterile solution for injection, the facility should use a default beyond-use date (BUD) of less than 28 days (at room temperature) or 42 days (refrigerated). The FDA says it will require “limited stability testing” for sterile products made in aggregate batch sizes larger than 1,000 units, and non-sterile products in batches larger than 5,000 units.
The drugs included in the FDA’s policy includes Cisatracurium besylate (a muscle relaxant), Dexmedetomidine hydrochloride (a sedative), Etomidate (a short-acting anesthetic), Fentanyl citrate (a painkiller), Furosemide (a diuretic), Hydromorphone hydrochloride (a painkiller), Ketamine hydrochloride (an anesthetic), Lorazepam (anti-anxiety), Midazolam hydrochloride (anti-anxiety, sedative), Norepinephrine bitartrate (blood pressure), Rocuronium bromide (muscle relaxant), Vancomycin hydrochloride (antibiotic), Vecuronium bromide (muscle relaxant).
This is the third time the FDA has loosened its bulk compounding requirements, indicating that the agency is likely to continue to leverage its compounding authorities in the future.
The latest policy is perhaps most notable in that some of the products are intended to be sterile injectables, which are substantially more dangerous from a risk perspective.
Quality problems at facilities are considerably more likely to cause debilitating illnesses in patients, many of whom are already in poor health.
While the policy makes clear that this only applies to bulk compounding facilities, which the FDA does have the authority to inspect (unlike 503A facilities), the FDA has indicated it is unable to conduct most domestic inspections right now due to COVID-19-related social distancing measures.
The policy seems most likely to be able to help hospital facilities solve spot shortage issues, rather than persistent national ones. There are currently only 76 outsourcing facilities registered in the US, and its unlikely that all of those facilities would have the expertise or capacity to make the drugs on the FDA’s list. Many, for example, have been issued FDA Form 483s, which generally indicates that major issues were observed at a facility.
The FDA’s policy will also be for naught if the raw chemicals used to manufacture the drugs are in short supply. Some shortages could be caused by a lack of active pharmaceutical ingredients (APIs), which could serve to further limit the availability of those products.