As drug demand surged during the early months of the pandemic, the US Food and Drug Administration (FDA) published temporary guidelines to free up a pharmaceutical drug source that seemed much more domestic: drug compounders, or specific pharmacies and outsourcing facilities that make specialized drug formulations.
So to what extent can drug compounding help with shortages? Or, is the very question indicative of a bigger problem?
Stephen W. Schondelmeyer, PharmD, PhD, co-principal of the Resilient Drug Supply Project at the University of Minnesota's Center for Infectious Disease Research and Policy, publisher of CIDRAP News, says drug compounders can be an important Band-Aid, but they are little more than a short-term solution.
"503Bs won't prevent shortages from occurring in the first place," he says, referring to the larger outsourcing facilities that can make compounded drug in bulk. "It's not a prevention or elimination strategy; it's a mitigation strategy only. We need to keep that in perspective."
503As vs 503Bs
Drug compounding, in general, has been around for centuries—think anytime a drug needed to go from tablet to liquid or vice versa, or if a child needed a smaller dose—and 503As have been around since 1997. 503B facilities, however, were added in 2013 after a fungal meningitis outbreak causing 64 deaths and 753 illnesses was tied to bulk compounded drugs from the New England Compounding Center.
503As must have a specific patient prescription to justify their compounding, and their drugs are not for general sale. Often, hospital pharmacies operate under 503A statutes, but some 503As are stand-alone pharmaceutical operations, like the Women's International Pharmacy or Belmar Pharma Solutions, which says it is licensed in all 50 states. Others still can be part of a larger business.
503Bs, on the other hand, mass produce and can sell formulations to entities like hospitals without needing a prescription for a specific patient.
Neither 503As or 503Bs can compound drugs that aren't on a pre-approved FDA list of bulk drug substances, which is decided by FDA based on clinical need. The drugs they do compound aren't actually FDA approved, either, since the companies don't go through the same regulations as commercial manufacturers. 503As are licensed by state boards of pharmacy, and some are federal facilities, while 503Bs are registered with the FDA and must meet current good manufacturing practices (cGMPs). Unlike 503As, they do have to report adverse events to the FDA.
To help mitigate COVID drug shortages, in April 2020, the FDA's temporary guidelines stated that 503As could compound COVID-related drugs without a specific prescription, could create essential copies of drugs, but would have to report adverse events to the FDA in no more than 15 days and have a shortened beyond-use date (BUD, essentially an expiration date to minimize possible quality issues). 503Bs were also allowed to compound essential copies of COVID-related drugs, and the guidelines said they may disregard product stability testing and have greater flexibility around BUDs up to a certain quantity.
Drug compounders use many of the same supply lines as other manufacturers, but the hope was that they would have more flexibility for production to quickly address increased demand. As Scott Brunner, CAE, MPS, CEO of the Alliance for Pharmacy Compounding puts it, 503As can prepare equipment to produce small quantities of a shortage drug much faster than 503B or manufacturers can.
It's similar to how local distillers made hand sanitizer early in the pandemic, he adds. Even though the product was "sold out" at retail stores, the ingredients were available.
"In this situation, maybe the manufactured drugs weren't available in the market but the pure ingredient that 503As could use would be available on the market," he says. "No one is arguing that 503As should be able to produce medications on the same scale a [manufacturer] or 503B can—we're talking smaller quantities, under strict regulatory guardrails, in shortage."
Liz Richardson, MSc, healthcare products project director at the Pew Charitable Trusts, says that there currently aren't enough data to assess the effectiveness of the temporary FDA guidance. Overall, though, she says the guidelines struck a good balance between public health risks and the benefits of drug compounding.
Outside of a pandemic situation, drug shortages still exist. To that end, Richardson says, "Our interviews with outsourcing facilities [in a pre-COVID investigation] have underscored that they don't necessarily make a medication simply because it's on FDA's drug shortages list. … Their production decisions are driven by several factors, including the expected duration of a drug shortage, the time needed to compound an alternative product, the availability of ingredients, and ultimately, the product's profitability."
FDA guidelines helpful to a point
According to an 800-person Alliance for Pharmacy Compounding survey from March 2021, 87 503As were able to use these guidelines to help with COVID drug supplies. Brunner says this was a "healthy" number, especially because some COVID-related drugs needed sterile preparation, and not all 503As had that capability.
For one hospital, staff turned to both a 503B and in-house resources to manage drug supply and shortages.
Deidra Dickerson, PharmD, sterile and nonsterile compounding manager at Vanderbilt University Adult Hospital (VUAH) says her hospital had been on the cusp of renewing and expanding its in-house compounding when the pandemic hit. COVID, of course, put a pause to those plans, but Dickerson was thankful that the hospital had an established 503B relationship to fall back onto.
Besides dealing with personal protective equipment shortages and operational changes, the hospital needed to address many staffing disruptions. "At that point, we outsourced additional items with the 503B we were working with: norepinephrine, oxytocin, opioid epidurals—work we could take off our team that would help save us some time," she says. Fentanyl infusions and remdesivir, which also saw COVID-related surges, were also outsourced.
Dickerson says her 503B experienced some large production delays because it had to flip flop between sterile and nonsterile compounding, and she suspects the company dealt with some typical COVID issues related to potential staffing and supply chain challenges. Still, her hospital never fully ran out of drugs.
The one drug Dickerson says her team did compound in-house was methohexital for the VU Medical Center's psychiatric hospital, but that was because the hospital already had the raw materials on hand.
From a 503B perspective, CEO of IntegraDose, Craig Else, PharmD, MHSA, former president of the Minnesota Pharmacists Association and the Minnesota Society of Health-System Pharmacists, says the temporary FDA guidelines helped to a point. For example, the company was able to lean into the hydromorphone cassette-assisted delivery device it was already making. Because the stability studies had an extended initiation deadline, IntegraDose sent out its product sooner, up to 120 a day for COVID patients.
For most product opportunities, though, the FDA guidelines didn't provide enough nimbleness. Take midazolam, Else says. Hospitals began requesting midazolam for its sedated COVID patients, but the numbers didn't check out for IntegraDose. With 150 midazolam drips produced a week, within 6 weeks, the company would have hit the 1,000-unit limit that the guidelines had for stability study exemptions in sterile aqueous solutions and then would have to abruptly cut off supply.
"The No. 1 presumption was that the pandemic would last about 6 months when we initially got into it last year—6 months, 9 months, even a year," Else says. "Well, it would take us that long to start a product. So if we were going to make the business decisions to start a product, the assumption was that the pandemic would be over before the product was even available or ready. … We were very helpful, but only in those products we already have."
Shortages will persist post-COVID
To address these limitations, the Alliance for Compounding Pharmacies is advocating a bill in Congress that focuses on expanding the situations for which 503As can help with shortages.
As David Pore, JD, MA, the alliance's legislative and regulatory counsel, says, "Our goal was to take FDA's emergency guidance as it applied in the context of the pandemic and COVID and to make the point we've been telling them for many years now—that the same patient access gap exists in many contexts."
Part of the bill includes expanding the list of drugs that can be made by 503A facilities to include drugs on the shortage list from the American Society for Health-System Pharmacists (ASHPs') which is more sensitive to regional and local drug shortages than is the FDA's drug shortage list.
Drug shortage expert Erin Fox, PharmD, senior director at the University of Utah Health, agrees that referencing the ASHP list might help, as would giving compounders more lead time, but the bottom line is compounding should be used for modifying drug forms, not solving long-term drug shortages. According to Fox, FDA regulations should change for commercial manufacturers first and foremost.
"We should have access to the commercial products we need. We should not have these chronic, ongoing drug shortages. There is a systemic problem causing those," she adds.
The way FDA's statutes are set up now, healthcare providers have to source drugs from commercial manufacturers, then 503Bs, and then 503As, which makes sense based on the level of quality the FDA can oversee for each entity. At the moment, nothing in the drug industry has truly changed; it has just been disrupted by COVID. Eventually, for better or worse, the temporary guidelines will end, while chronic drug shortages are likely to remain.
"On a positive note, it's possible that the pandemic will help improve access to 'office stock' compounded drugs that hospitals and health systems often keep on hand for a range of clinical needs beyond COVID-19," the Pew's Richardson says.
"For one, the Coronavirus Aid, Relief, and Economic Security Act—enacted last year—requires drug manufacturers to give the FDA additional information about supply disruptions, including the likely severity and duration of shortages. If FDA adds such details to its drug shortages list, outsourcing facilities may decide to compound products they otherwise wouldn't."