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6 Steps to an ‘A’ Grade in Sterile Compounding
What 503A compounders can learn from 503Bs 6 Steps to an ‘A’ Grade In Sterile Compounding
Establishing a 503B sterile compounding facility isn’t for every hospital with a compounding pharmacy. The differences between the requirements for compounding under Section 503A of the Drug Quality and Security Act and Section 503B are fairly large.
Most hospitals have 503A compounders, which are traditional, small-batch compounding pharmacies, making shortdated preparations for specific patients per prescription or in very limited quantities. They’re governed by state board of pharmacy regulations and USP General Chapters <795> and <797>. In contrast, because 503B facilities make more complex products that are designed for longer beyonduse dating (BUD), they must comply with much stricter federal standards, dictated by the Code of Federal Regulations Title 21, which governs the FDA—specifically Part 210 on Current Good Manufacturing Practice (CGMP) guidelines.
Qualifying and maintaining a 503B facility is a big responsibility to take on. “We get a lot of questions from hospital pharmacies about starting up their own facility,” said Bret Snow, PharmD, the director of pharmacy for Advanced Compounding Solutions at New England Life Care, in Woburn, Mass. “Some people see it as a revenue generator, some as a buffer against shortages. But the startup time alone is significant. Construction might be 36 months, commissioning six months, BUD studies 12 months. It could easily take four years just to get a 503B up and running.”
Perhaps nothing exemplifies the difference between 503A and 503B facilities more than the recent delays in release and implementation of USP Chapter <797>. “For years, they’ve been trying to release the latest iteration of <797>,” Dr. Snow noted. The effective date of Dec. 19, 2019, for Chapter <797> was postponed, pending an appeal, a delay that also meant that the new Chapter <800> on handling of hazardous drugs in health care settings also remains informational only until <797> goes into effect. “You can’t act on it, because you don’t know what it’s going to be. But under CGMP, you don’t wait for anybody to tell you that something is a good idea. You’re pushing the highest quality all the time, being innovative and using technology to do so.”
Consider something as simple as purchasing sterile gloves. A 503B compounding facility can only accept materials from qualified vendors, who are pre-verified to hold the same quality standards as the facility itself. Dr. Snow’s facility has a full-time employee who dedicates three full days per week to managing incoming material, ensuring everything is from a qualified vendor and documenting that it is all in good condition with an accompanying certificate of analysis.
“Recently, with all the shortages of PPE [personal protective equipment], we were trying to get any sterile gloves that we could,” Dr. Snow said. “But we had to work with qualified vendors, and it takes time to qualify them. So we’d find these sterile gloves and told the quality department to get them and put them in quarantine. If we were able to qualify them later, we could use them, whereas with a 503A, you can get just about any garbing supplies from any vendor.”
But even though many hospitals and health systems
A technician labels syringes at a 503B facility run by Advanced Compounding Solutions at New England Life Care, in Woburn, Mass.
that ponder starting their own 503B compounding facility likely will reject the plan as impractical, Dr. Snow said there are many lessons that 503A facilities can learn from 503Bs. “The way that the regulations are evolving, GMP are seeping into <797> and will likely continue to do so,” he noted. “Consider what one of our Massachusetts Board of Pharmacy inspectors said: ‘Complying with <797> is what you do to be a C student.’ These are the minimum qualifications for your 503A cleanroom. If you want to be better than a C student, look at what GMP practices you can adapt to your facility.”
Jerry Siegel, PharmD, the managing partner at Safe Medication Management Associates and a clinical professor at The Ohio State University Wexner Medical Center, in Columbus, agreed. “Chapters <797> and <800> are minimum standards. You can exceed those, and maybe you should exceed those.”
Where should you start in your efforts to achieve better than a C grade? Here are six areas to consider: 1. Expanded environmental monitoring. 503A facilities only require environmental monitoring every six months, whereas 503B facilities require it “per production” shift in the International Organization for Standardization (ISO) 5 primary compounding areas as well as weekly audits in
the secondary compounding areas. You don’t have to go to that extent, but “if you do environmental monitoring every six months, you’re not getting an accurate picture of what’s going on in your cleanroom. You’re just ensuring that nothing catastrophic is going on during that period,” Dr. Siegel said. “If you increase the amount of testing, you can learn some lessons: where the danger zones are in your pharmacy, where bacteria is likely to grow, where you’re most likely to have excursions. Then you can focus on that.”
What you should notbe doing in your environmental monitoring is “shooting for zero,” Dr. Snow said. “If you are getting zero hits, you’re not doing environmental monitoring right. You want to find out where your risk points are because they do exist. And don’t test right after your monthly cleaning; that’s cheating. It may prove your clean is good, but it doesn’t demonstrate what the risk is on the compounding floor right before that clean.” A tenet of GMP is to take samples at the end of each batch. 2. Standardization. “It makes sure all of your technicians are doing things the same way,” Dr. Snow said. “If your practices are to do things the same way every time, you can share employees between locations. Standardization also gives you uniformity that allows you to catch errors more easily.”
3. Documentation of line clear-
ance. “When you are done with compounding that one batch you have to make in your hood per the 503A standards, clean out your line and document it,” Dr. Snow said. “You have to wipe out the hood anyway; then document that. Well, there are times when materials and doses get left behind, and an unlabeled CSP [compounded sterile preparation] is a dangerous thing. Document that at the end of compounding, this hood was empty; at the end of checking a batch, this bench was empty. That gives you a great deal of confidence in the products you’re sending out.” 4. Label control. Dr. Snow noted that when working at a 503A facility, if they were printing out labels for 30 doses of an individual CSP, they’d print an extra label or two in case one ripped or was otherwise unusable. “In the 503B model, we see every label as potentially a mistake that can find its way onto something it doesn’t belong on,” he said. “So we serialize every label as it comes out of the printer. You won’t necessarily want to do that in a 503A, but print out just what you need. If your technician says they need another label, you need to ask why.” 5. Structural considerations. “For example, USP <797> and <800> really don’t talk about pass-throughs,” Dr. Siegel said. “Do they need to be HEPA filtered? For a 503B, the answer is definitely yes, but for 503A, it’s not specified. When we install a pass-through in one of our pharmacies, it’s not only stainless steel but magnetic, so you can’t have both doors opened at the same time. I’ve seen technicians do that so they can talk from inside to outside the cleanroom because there’s no phone or intercom. Paying attention to that pass-through is a big deal because we often find them to be contaminated. If you put HEPA filtration or UV [ultraviolet] lighting in the pass-through, you could be at the top of the standard instead of the bottom.” 6. Consulting a microbiologist. “I’ve found out how much I don’t know by working with microbiologists,” Dr. Snow said. “For example, our environmental monitoring detected a bacillus that we’ve had a few times, and the microbiologist explained that we needed to be concerned about this one because it forms pseudospores that, when challenged by cleaning, cause spores to form that are resistant to cleaning and lead to proliferation of more bacillus. I never would have thought to use a spore-killing cleaning agent if a bacillus was detected, but that is our strategy for mitigation now. They’ve been immensely helpful in figuring out where things are coming from. A microbiologist costs less than a pharmacist and brings a skill set that adds a lot of value.”
—Brett Snow, PharmD
—Gina Shaw
Drs. Snow and Siegel reported no relevant fi nancial disclosures beyond their stated employment.
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compounding work, and five days a week we are running 24/7, with stopgap work over the weekend,” Mr. Hinchen said. Plans are underway to double the size of the company’s 75,000-square-foot facility in New Jersey, and a lease on a new facility in Sugar Land will double the company’s current 75,000-square-foot footprint in Texas. Similarly, NELC/ACS has added weekend shifts and filled all its hoods on the weekday second shift.
A Need to Pivot Quickly
Although NELC/ACS, like its non–hospital-owned competitors, experienced an early increase in demand for some supplies, particularly products for patients on mechanical ventilation, at the height of the pandemic, Dr. Thomasset said there was never significant concern that they would not be able to meet demand. “We tend to keep at least three to four months’ worth of API on our shelves, so API shortages that affected some hospitals were not affecting us. The FDA had also provided guidance that we could compound sterile preparations from sterile API with a small extension beyond the current USP <797> BUD without requiring studies. That gave us upwards of about a month’s worth of expiration.”
Mr. McGuire said the biggest lesson for 503B compounders from the COVID-19 pandemic has been understanding how to pivot very quickly. “You need to have a culture in your business where people are willing to do whatever it takes to meet patients’ needs,” he said. “It was amazing to see how folks rallied around each other and made sure we did everything possible to get medicine out the door to wherever the needs were.”
Vanderbilt is still in discussions about creating its own 503B facility—a conversation that Dr. Dickerson said will likely take several years—and does plenty of its own 503A compounding, with only about 10 products outsourced. But regardless of what happens with those plans, the medical center still will continue relationships with 503B compounding outsourcers. “Even aside from the pandemic, we know there are still some products that it doesn’t make financial sense for us to make in-house,” she said. “Some institutions still have fears associated with 503Bs, and frustrations with them because the consistency of product availability may not always be what people would hope. But in these critical situations, I cannot underscore enough the importance of having these [outsourcing] relationships, and even multiple relationships for redundancy.”
Dr. Bryowsky agreed. “We still have outsourcing partnerships and always will. [Outsourcers] can have a portfolio of 50 items or more, but for smaller [in-house 503B] operations like ours, it doesn’t make sense to have all those products, especially if only one or two of our sites use them or the volumes are really low. There’s a place for both.”
Eric Kastango, MBA, BSPharm, the vice president and managing partner at Kastango Consulting Group, cited cost as perhaps the biggest barrier to taking a DIY approach to 503B compounding. “[It] costs, by conservative estimates, $5 [million] to $15 million and three years to open your doors. It’s not a quick fix, not just <797> on steroids,” Mr. Kastango said.
“Most of the people I have spoken with are going to multiple sources and have created relationships with more than one 503B,” he added. “Most people can’t get by using just one 503B vendor, because they don’t all make the same products, or they are looking for supply redundancy. This pandemic has given us a new appreciation for just how important this unsexy part of pharmacy—compounding and distribution— really is.” —Gina Shaw
503A/B
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CSPs from active pharmaceutical ingredients (APIs), noted Dr. Brown, who described his system’s compounding strategies in a video interview with Pharmacy Practice News (bit. ly/3foioik). Most of Duke’s compounding is done as a 503A, but it is building a new facility that will have the capability of complying with 503B compounding requirements.
For health systems considering such an approach, “the first step is to determine the CSPs you need most, what your volumes would be, and your highest-cost items,” Dr. Brown said. “Then you need to determine how to produce those products. If it’s a simple, sterile repackage, it may be feasible to do that in a small CGMP [Current Good Manufacturing Practice] facility. If you have more complicated products (such as epidurals) that are going to require the use of APIs, it gets much more expensive, because you’ll need to build larger cleanrooms with more complex and expensive equipment.”
Dr. Brown emphasized that when going the 503B route, “every step in your compounding processes needs to be validated. The more complex the compounding process is, the more it’s going to cost for you to validate [it].”
Standard operating procedures (SOPs) are another hurdle. “There’s SOPs for syringe filling, SOPs for garbing of your compounding staff, and a host of other processbased SOPs, not to mention all of the quality assurance SOPs you’ll need to validate your compounding equipment and processes,” Dr. Brown said.
“It is a different world,” he added. “On some level, you have to forget pharmacy and learn CGMP. Clearly, this is not something that is going to make sense for every health system.” —David Bronstein
The sources reported no relevant fi nancial disclosures beyond their stated employment.
The sources reported no relevant fi nancial disclosures beyond their stated employment.
