Pharmacy Practice News (Special Edition)

The 2020 Annual Compendium of Compounding

Sterile Compounding In the Time of COVID-19 Pandemic throws wrench into cleanroom renovations Building a ‘starship’ compounding enterprise 10 new building blocks of compounding safety

Supplement to Pharmacy Practice News

$60 M USP compliance project checks all the boxes

Introducing greater dosing convenience with a new 3-mL (900-IU) vial

When protecting your patients with HRIG

DELIVER MORE OF THE TOTAL DOSE AT THE WOUND SITE. HyperRAB® (rabies immune globulin [human]) 300 IU/mL The first and only high-potency human rabies immune globulin (HRIG) that offers:

the volume of medication administered in a total dose, potentially resulting in fewer injections the concentration of rabies antibodies per mL at the wound site

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Please see Important Safety Information and brief summary of Prescribing Information for HyperRAB on adjacent pages, or visit www.HyperRAB.com for full Prescribing Information..

HyperRAB® (rabies immune globulin [human]) is indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies.

HyperRAB is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent that can cause disease. There is also the possibility that unknown infectious agents may be present in such products.

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For more information, visit www.HyperRAB.com © 2020 Grifols

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March 2020

US-HB3-2000016

Indication and Usage HYPERRAB® (rabies immune globulin [human]) is indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies.

Limitations of Use Persons who have been previously immunized with rabies vaccine and have a confirmed adequate rabies antibody titer should receive only vaccine.

For unvaccinated persons, the combination of HYPERRAB and vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of postexposure prophylaxis.

Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred.

Important Safety Information For infiltration and intramuscular use only.

Severe hypersensitivity reactions may occur with HYPERRAB. Patients with a history of prior systemic allergic reactions to human immunoglobulin preparations are at a greater risk of developing severe hypersensitivity and anaphylactic reactions. Have epinephrine available for treatment of acute allergic symptoms, should they occur.

HYPERRAB is made from human blood and may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

The most common adverse reactions in >5% of subjects during clinical trials were injection-site pain, headache, injection-site nodule, abdominal pain, diarrhea, flatulence, nasal congestion, and oropharyngeal pain.

Do not administer repeated doses of HYPERRAB once vaccine treatment has been initiated as this could prevent the full expression of active immunity expected from the rabies vaccine.

Other antibodies in the HYPERRAB preparation may interfere with the response to live vaccines such as measles, mumps, polio, or rubella. Defer immunization with live vaccines for 4 months after HYPERRAB administration.

Please see brief summary of Prescribing Information on adjacent page or visit HyperRAB. com for full Prescribing Information.

®

HyperRAB

-----------DOSAGE FORMS AND STRENGTHS---------300 IU/mL solution for injection supplied in 1 mL, 3 mL and 5 mL single-dose vials.

HIGHLIGHTS OF PRESCRIBING INFORMATION

--------------------CONTRAINDICATIONS--------------------None.

Rabies Immune Globulin (Human) These highlights do not include all the information needed to use HYPERRAB® safely and effectively.

See full prescribing information for HYPERRAB. HYPERRAB [rabies immune globulin (human)] solution for infiltration and intramuscular injection Initial U.S. Approval: 1974 ----------------INDICATIONS AND USAGE------------------HYPERRAB is a human rabies immune globulin indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies.

Limitations of Use Persons previously immunized with rabies vaccine that have a confirmed adequate rabies antibody titer should receive only vaccine.

For unvaccinated persons, the combination of HYPERRAB and vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of postexposure prophylaxis.

Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred.

--------------DOSAGE AND ADMINISTRATION------------For infiltration and intramuscular use only.

Administer HYPERRAB within 7 days after the first dose of rabies vaccine.

Postexposure HYPERRAB • Administer as soon prophylaxis, 20 IU/kg as possible after along with body weight exposure, preferably rabies OR at the time of the first vaccine, after 0.0665 mL/kg rabies vaccine dose. suspected body weight • Infiltrate the full exposure to dose of HYPERRAB Single dose rabies thoroughly in the area around and into the wound(s), if anatomically feasible.

• Inject the remainder, if any, intramuscularly.

-------------WARNINGS AND PRECAUTIONS-------------• Severe hypersensitivity reactions, including anaphylaxis, may occur with HYPERRAB. Have epinephrine available immediately to treat any acute severe hypersensitivity reactions.

• HYPERRAB is made from human blood; it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

--------------------ADVERSE REACTIONS--------------------The most common adverse reactions in >5% of subjects in clinical trials were injection site pain, headache, injection site nodule, abdominal pain, diarrhea, flatulence, nasal congestion, and oropharyngeal pain.

To report SUSPECTED ADVERSE REACTIONS, contact Grifols Therapeutics LLC at 1-800-520-2807 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

--------------------DRUG INTERACTIONS------------------• Repeated dosing after administration of rabies vaccine may suppress the immune response to the vaccine.

• Defer live vaccine (measles, mumps, rubella) administration for 4 months.

Grifols Therapeutics LLC Research Triangle Park, NC 27709 USA U.S. License No. 1871

3054805 Revised: 11/2019

EDITOR’S DESK

Hurry Up and Wait U

SP sterile compounding compliance is hard enough, given the repeated chapter appeals, varying levels of state enforcement and the constant pressure to finance cleanroom renovations.

But when you layer on the COVID-19 pandemic, a new set of challenges unfolds, as detailed in this Special Edition.

Canceled inspections, diverted staff resources and a shortage of personal protective equipment are just a few of the disruptions brought on by the pandemic. So it’s not surprising that many institutions have put their renovation and compliance efforts on hold. But for some experts, this pause may be a rare positive in these scary, challenging times.

“The delays have given some breathing room for people who had not gotten all the necessary funding together to do renovations in their sterile products areas,” said Ernest Anderson Jr., MS (page 8). “The fact that it has been pushed back has given people the opportunity to get [financing] in place. It’s like, ‘No more excuses.’”

It all does seem to start with the money. As Renee Barker, PharmD, said, “It’s not as if you can have a bake sale!” to pay for your new state-of-the-art cleanroom (page 12).

For cash-strapped facilities tempted to “do it on the cheap,” Dr. Barker offered some words of caution. “There definitely is a danger in cutting corners; it will probably show up as a deficient [compliance area] in the future, and making changes in an existing cleanroom can cause downtime, vendor testing, etc.,” she said. “This is expensive in terms of money, time and patient care.”

Still, funding is just one of the challenges that has to be met on the road to USP compounding compliance. Another is whether to build an in-house sterile compounding practice, partner with an outsourcer or employ both strategies—a decision process experts outlined on pages 22 and 26.

And speaking of experts, we have a lot of them quoted in these pages. For example: • Patricia Kienle, RPh, MPA, offers 10 new building blocks of safe sterile compounding (page 18).

• Jerry Siegel, PharmD, outlines strategies for working around COVID-19-related disruptions (page 20).

• Gene Decaminada, RPh, gives several tips for what to expect if the FDA comes knocking on your door for a 503A facility inspection (page 10).

I hope that after reading this Special Edition, the lessons gleaned will make your own compounding journey, whether COVID-19 delayed or not, filled with fewer bumps and potholes.

Stay safe!

—David Bronstein, Editorial Director

Ernest R. Anderson Jr., MS, RPh, Boston, MA

Kristina N. Bryowsky, PharmD, MBA, BCPS, Fenton, MO

Frank Tagarello, Senior Art Director/ Managing Director MAX Graphics

LEADERSHIP Elaine Strauss, PharmD, MS, Atlanta, GA

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STERILE COMPOUNDING

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TABLE OF

CONTENTS

5

Editor’s Note

8

Amid Pandemic, USP Compliance Drags On

10 Sterile Compounding In the Time of COVID-19 14 Despite COVID-19 Cleanroom Clampdown, Lessons Learned

10

16 Remote Tech Fosters Certification 18

Kienle’s 10 New Building Blocks of Compounding Safety

14

20 5 Qs With Jerry Siegel, PharmD 22 The Science of Sterile Compounding 26 Do it Yourself or Outsource?

18

30 Scaling Back Can Make USP <800> Compliance Less Scary 32 Building a ‘Starship’ Cleanroom 33 USP Renovations Check All the Boxes 6

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503B: engineered to be accountable QuVa was purpose-built to change 503B sterile compounding for the better and we are leading the way.

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As FDA compliance becomes more stringent and demanding, our ability to reliably supply the highest-quality, ready-to-administer medicines is more valuable than ever. It allows you to spend more time on patient care and less time worried about BUDs, waste, workload inefficiencies, and compliance.

QuVa’s 503B expertise is unmatched, so whether you’re calling for a response or being called on for a solution, know that we are accountable, and in us, you will always have an answer.

Visit QuvaPharma.com

Where are we now?

The Move Toward USP <797> Compliance Drags On H ospitals and health systems that had been running behind on their USP General Chapter <797> sterile compounding compliance received a temporary reprieve when the official effectiveness date—December 2019—was postponed, pending an appeal.

The delay also meant that USP’s new General Chapter <800> “Hazardous Drugs—Handling in Healthcare Settings” remains official, but only informational until <797> also goes into effect. Experts urged institutions not to view the postponement as a reprieve, but rather to take advantage of the additional time to ensure that their sterile compounding facilities and practices are fully compliant with the new chapters.

Less than six months later, with the appeal still in process, the COVID-19 pandemic has thrown those efforts into further confusion. While many hospitals and health systems have completed renovations and other projects designed to ensure <797> and <800> compliance, others are still midprocess, and some have hit pandemic-related roadblocks in construction and certification.

“The delays have given some breathing room for people who had not gotten all the necessary funding together to do renovations in their sterile products areas,” said Ernest Anderson Jr., MS, FASHP, the president of Ernest Anderson Consulting. “It’s given them the opportunity to get all that done. In the past, many health-system pharmacies have been unsuccessful in getting their C-suites to move, but over the past year, the urgency has been met with more serious response to pharmacy needs to do the renovation. The fact that it has been pushed back has given people the opportunity to get everything in place. It’s like, ‘No more excuses.’”

But even as those projects finally got approved, the pandemic has had its effect. “Renovations that were already in process seem to have gone forward for the most part, but projects that were still in the planning process have largely been put on hold,” said Greg Burger, RPh, the senior vice president of hospital and health system services for Visante Inc.

‘A Desperate Need for a New Build-Out’ That’s been the case at Beth Israel Deaconess Hospital– Needham, in Massachusetts, a 58-bed facility that is part of a larger 12-hospital system, which had been operating for years with a very dated, space-restricted pharmacy. “We have just a glove box for our separate hazardous compounding area, and then adjacent to the pharmacy is a small compounding room,” said Joseph Giovangelo, MSPharm, the hospital’s director of pharmacy. “We had a desperate need for a new build-out.”

The hospital had planned a new 1,700-square-foot pharmacy, with hazardous and nonhazardous buffer rooms, an anteroom and a carousel. A satellite oncology infusion

8

The “clean” portion of a new anteroom for sterile compounding at Weeks Medical Center, in Lancaster, N.H. The 25-bed critical access hospital invested $500,000 over the past several years renovating its sterile compounding rooms with guidance from expert consultants.

pharmacy is also located on-site, and plans had originally called for a shared pharmacy for both, but since the infusion pharmacy is officially part of the operation of Beth Israel Deaconess in Boston, the state department of health required two separate pharmacies. The infusion pharmacy completed its renovation in the fall of 2019, but the hospital pharmacy’s renovation was still in the final stages of approvals when the pandemic hit. “The design for our new sterile compounding space was completed and submitted to the state department of public health and the board of pharmacy registration for review, but at the last meeting, the construction had to be put on hold,” Mr. Giovangelo said. “Realistically, we probably won’t get started until July at the earliest.”

Short Pauses on Construction At UMass Memorial Medical Center in Worcester, Mass., which comprises two inpatient acute care hospitals and one ambulatory/day surgery hospital, construction on new sterile compounding suites continues. Neil Gilchrist, PharmD, the senior director of pharmacy services, projects completion and full compliance with USP <797> and <800> by the end of the summer of 2020. At the end of renovations, each of the two acute care hospitals will have a primary cleanroom compounding area as well as a redundancy com-

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pounding area for a total of five International Organization for Standardization class 5 sterile compounding rooms, while the day surgery has a segregated compounding area.

“Construction and finishes of new cleanrooms have continued uninterrupted, but we have had to put short pauses on the renovation of two existing cleanrooms for the inpatient hospital, because we didn’t want to take the risk of not being ready to serve patients,” Dr. Gilchrist said. “For example, the central pharmacy compounding suites on the basement level need only minor updates for compliance, so we have postponed those until after the surge of COVID-19 patients. As soon as we feel there is no risk, then we will advance the construction project there.”

Although experts noted that larger hospitals and health systems seem to be further along with <797> and <800> compliance than smaller hospitals that are not part of larger integrated delivery networks, one exception to that rule is Weeks Medical Center in Lancaster, N.H. This 25-bed critical access hospital invested half a million dollars over the past several years renovating its sterile compounding rooms with guidance from expert consultants. “We do an enormous amount of chemotherapy for a critical access hospital,” said John Eddy, RPh, the manager of pharmacy services. “It represents about 98% to 99% of the pharmacy dollar volume. We’re like a Dana-Farber up here in rural New Hampshire. We have one full-time pharmacy technician who does nothing but that, and a pharmacist who spends a solid three days a week doing nothing but chemotherapy. So now we have a state-of-the-art sterile compounding operation, with a biologic cabinet of about 14×6 separated from a clean anteroom. We have a negative pressure room to the right and positive pressure room to the left, all isolated from the main pharmacy.”

The lessons learned through the process of preparing for

At Beth Israel Deaconess Hospital—Needham, in Massachussetts, hazardous compounding takes place in a separate 6 x 9 negative pressure room, ventilated to outside air, using a compounding aseptic isolator. To become USP compliant, the facility will need to build a negative pressure buffer room for the compounding of hazardous products.

The surfaces within the new cleanroom must be smooth, impervious, and free from cracks and crevices to allow for cleaning of the area.

compliance with <797> and <800> have been more at the C-suite level than the pharmacy level, Mr. Anderson said.

“Their sensitivity has been heightened. They realize that they really do need to spend a million dollars, or whatever it takes, to build out a new sterile compounding area.”

Need or Want?

‘The design for our new sterile compounding space was completed and submitted to the state department of public health and the board of pharmacy registration for review, but at the last meeting, the construction had to be put on hold [due to COVID-19].’

On the other hand, Mr. Burger said, his team challenges clients to think about whether they really need the extensive renovations they are planning. “For example, some places have proposed full-blown cleanrooms and negative pressure buffers, and so forth, to achieve longer beyond-use dates (BUDs)—but for infusion centers. If 99% of what you’re making will be immediately infused, do you need a fullblown cleanroom for longer BUDs, as opposed to doing segregated compounding?” he asked. “Because of the expense involved, people really need to think through how they plan to use these cleanrooms, and for what products. Building out a full-blown cleanroom also requires a lot more work to stay in compliance than segregated compounding, so you put yourself at greater risk. If you don’t need it, don’t create all this extra work for yourself.”

—Gina Shaw

—Joseph Giovangelo, MSPharm

The sources reported no relevant financial relationships.

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What to expect when the FDA comes to inspectt

Sterile Compounding In the Time of COVID-19 F

DA inspectors continue to keep a close eye on 503A compounding pharmacies, ensuring that every effort is taken to minimize the risk for drug contamination. However, the COVID-19 pandemic has added a few wrinkles, particularly as a result of shortages in personal protective equipment (PPE).

“The FDA, state board of pharmacy or accreditation body could come in at any time,” said Gene Decaminada, RPh, the manager of compounding compliance for Option Care Health.

“You need to be diligent with your cleaning processes.”

Even after the FDA issued a revised draft of their guidance on insanitary conditions in 2018, inspectors have continued to focus on many of the same safety measures, such as environmental monitoring—from air pressure differentials to humidity and temperature—as well as proper cleaning, gowning and garbing, Mr. Decaminada noted.

“There are going to be certain pieces of PPE that cleanrooms are not going to be able to obtain over the long term of this pandemic crisis,” added Eric Bauer, RPh, a senior consultant with Central Admixture Pharmacy Services.

“Without all the standard cleanroom PPE, we really need to focus on examples of insanitary conditions related to aseptic technique as well as cleaning and disinfection of the critical surfaces where sterile compounding is conducted.”

During an inspection, the FDA will note on a Form 483 any observations of issues that could endanger patients. Option Care Health continues to monitor these forms, which are reported on the FDA website, looking for anything unusual.

In that regard, “nothing has really changed in the last 12 months,” Mr. Decaminada said.

In International Organization for Standardization (ISO) class 5 compounding areas, the FDA recommends the use of sterile germicidal agents, sporicidals and sterile isopropyl alcohol (70%), Mr. Decaminada noted. Since 2018, the FDA also is focusing on the dwell time of cleaning agents, or the time the cleaning agents stay wet on surfaces.

Mr. Decaminada recommended a dwell time of 10 minutes or less. “They are specifically looking at aseptic technique as they observe our cleanroom staff during the compounding process,” he said, adding that staff should always work from the cleanest to dirtiest areas of the cleanroom.

Mr. Bauer highlighted the importance of familiarity with the insanitary conditions guidance document. “If compounding pharmacies have the occasion to be inspected by FDA, and they are not familiar with the guidance document, those pharmacies will be blindsided,” he said. “A pharmacy’s best strategy is to focus on drug quality and patient safety at all times, which, in turn, reduces the risk of inspection.”

In addition to complying with state requirements for sterile compounding, which are mostly based on USP General Chapter <797> for sterile compounding and USP <800> for handling hazardous drugs, Mr. Bauer advised that compounding pharmacies conduct periodic audits of their cleanroom operations, using applicable portions of the guidance document as a reference.

“The FDA is letting us know what inspectors hope to see,” Mr. Bauer said. “However, it is important to recognize that some of the FDA examples of insanitary conditions exceed <797> requirements. Ultimately the 503A pharmacies will have to determine what is expected in their state.”

Safety Without PPE Due to supply chain interruptions caused by COVID-19, pharmacies now are faced with a critical shortage of PPE, which includes face masks, gloves, gowns, shoe covers, head/hair covers and other garb worn during the compounding of drug products that are intended to be sterile.

Sterile masks and cleanroom gowns, in particular, are at critically low levels, because many of those items are needed by front-line health care workers who have the greatest exposure to the virus. “Because of these compliance risks,

‘Put the guidance from USP and FDA on [personal protective equipment] conservation side by side, and then create what your organization would do to conserve PPE.’ —Gene Decaminada, RPh

10

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FDA INSPECTS continued from page 10

sterile compounders should review how their state rules and requirements are temporarily adjusting to the shortage,” Mr. Bauer added.

In April, the FDA did its part by issuing a guidance loosening requirements on PPE use. The guidance noted that the agency does not intend to take enforcement action when “drugs intended or expected to be sterile are compounded without standard PPE.” But that easing of restrictions comes with a caveat: Precautions need to be taken, such as employing sterilization where standard PPE is not used, “as long as basic garbing expectations (e.g., hairnet, clean garment, non-sterile gloves, other appropriate coverings) are followed,” the guidance noted. The relaxed rules will be in place for the duration of the COVID-19 emergency situation, the agency announced (bit.ly/2zntpjf ). This temporary policy on nonstandard PPE practices applies to pharmacy compounders regulated under section 503A. It does not apply to outsourcing compounding pharmacies registered as 503B, which are subject to Current Good Manufacturing Practice requirements and under which different PPE considerations will apply. However, in a footnote, the FDA added that the agency “may issue further guidance for outsourcing facilities if warranted.”

Generally, Mr. Bauer noted, the FDA is making 503A pharmacies aware that, for the duration of the COVID-19 public health emergency, the agency is not strictly enforcing insanitary conditions related to nonstandard PPE, provided that the pharmacy follows the aforementioned precautions, along with limited beyond-use dates, more frequent disinfection and extra documentation.

USP issued a separate set of guidelines on conserving PPE in March (bit.ly/34UDDDa). However, these differ somewhat from the FDA’s guidance. “As a company, you should put the guidance from USP and FDA on PPE conservation side by side, and then create what your organization would do to conserve PPE,” Mr. Decaminada said.

Although USP discusses the reuse of gowns and hair covers and the importance of not reusing hazardous drug compounding garb, none of that is mentioned by the FDA. Both documents underscore the need to be diligent about cleaning. “The FDA talks specifically about use of sporicidal agents,” he said, adding, “Now, more than ever, safe sterile compounding will rely on the aseptic technique, as well as cleaning and disinfecting practices of well-trained cleanroom personnel.”

More Pandemic Shortages PPE isn’t the only thing in short supply as a result of the COVID-19 pandemic.

“This is a rapidly evolving response that also factors in the extreme surge in COVID-19 demand for certain compounded sterile drugs that are in short supply, such as fentanyl, propofol and midazolam,” Mr. Bauer said.

Currently, the relevant sterile IV drugs listed on the FDA

12

shortage list are drugs needed to induce or maintain sedation, neuromuscular blocking agents used for rapid intubation, and analgesia to maintain comfort for patients under mechanical ventilation, such as fentanyl citrate, midazolam, dexmedetomidine, hydromorphone, furosemide and propofol, noted Robin Smith Hoke, the president and CEO of Leiters, a 503B outsourcing provider. Ms. Smith Hoke noted that further guidance from the FDA indicates additional shortages with cisatracurium besylate, etomidate, ketamine hydrochloride, lorazepam, norepinephrine bitartrate, rocuronium bromide, vancomycin hydrochloride and vecuronium bromide.

Steve D’Amico, RPh, the vice president of product development for Leiters, noted that the company has shifted manufacturing priorities and production capabilities to manufacture the critically needed medicines. “Hospital pharmacies should reach out to 503B outsourcing facilities and determine what products they have available in inventory and production to help alleviate and address some of the market shortage issues,” he said.

Stuart Hinchen, the CEO of QuVa Pharma, agreed. In the face of an overwhelming rise in hospital admissions, he said, 503B outsourcing facilities are “a logical resource to increasing pharmacy capacity.” He added that “those hospital systems that had preexisting relationships with large and well-credentialed 503Bs find themselves in a better position to respond to patient needs.”

Mr. D’Amico noted that 503A facilities still can play a role.

“Hospital pharmacies may also contact 503A pharmacies, both in retail and in the hospital settings, for patient-specific needs based on a prescription,” he said.

Mr. Hinchen stressed that 503As should be compounding “for named patients only, and not in large quantities requiring manufacturing quality control standards. If 503As are making for anticipatory or ‘for office’ use as opposed to named patients, then they have the potential to impact more people and should register as a 503B.” Drug supplies aside, the pandemic has added other considerations for pharmacies. “You want to work with cleanroom certification vendors to ensure that they can certify your room and ISO class 5 environment appropriately,” Mr. Decaminada said. “If they can’t get to your site, you may have to push back certification dates to accommodate their schedule.”

—Lynne Peeples The sources reported no relevant financial relationships other than their stated employment.

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Despite COVID-19 delay, many successes along the way

Cleanroom Clampdown A

new compounding pharmacy cleanroom at Lucile Packard Children’s Hospital Stanford, in Palo Alto, Calif., was slated to open in November 2019. But a number of unforeseen, yet somewhat unsurprising, factors prolonged that time line—from improper plumbing to the COVID-19 pandemic.

“We’re in a holding pattern,” said Renee Barker, PharmD, the sterile products manager at the hospital.

Dr. Barker’s experience could provide lessons for others looking to build or remodel a cleanroom.

As she learned from previous builds and remodels, a successful move into a new pharmacy cleanroom requires determination and diligence in design planning, construction monitoring and environmental testing. It also necessitates ongoing communication with everyone involved in the project.

Before the COVID-19 pandemic, Dr. Barker’s team was awaiting one of the final steps: the state board of pharmacy’s inspection of the cleanroom. When that will now happen is unclear; yet Dr. Barker highlighted informative experiences over the previous several months of construction and testing of the cleanroom, which will be part of a new fifth-floor oncology unit at the main hospital building. “Awaiting final inspections, licensing and eventual opening of our newest pharmacy is our remaining challenge,” she noted. Another cleanroom is currently compounding the oncology drugs.

Dr. Barker had been involved in a previous cleanroom construction that opened in 2017, as reported in Pharmacy Practice News (bit.ly/2S5263H). The process for that original construction began almost 10 years before the actual opening, due to the magnitude and complexity of the expansion. “The regulations

14

Renee Barker, PharmD (far left) and team members who worked on a new compounding pharmacy cleanroom at Lucile Packard Children’s Hospital Stanford, in Palo Alto, Calif.

Source: Terri Lim.

A technician and intern beginning a sporicidal cleaning of a new biological safety cabinet in the new pharmacy at Lucile Packard Children’s Hospital Stanford.

Source: Terri Lim.

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le surrounding sterile re, compounding were, and continue to be, in a constant statee of A movflux,” she said. “A ulations is ing target of regulations a challenge, when architectural plans require a ‘snapshot’ of regulations to set a design in place.

Later requests to modify designs may or may not be able to be accommodated.”

The process for the new cleanroom has been smoother with fewer surprises, and she attributed much of that improvement to involving a subject matter expert (SME) in sterile compounding in all the meetings, logs and final sign-offs. The SME understood USP General Chapter <797> for sterile compounding and USP <800> for handling hazardous drugs, as well as state board of pharmacy regulations and FDA guidance that address sterile compounding facilities.

“I was also more directly involved with the key players—the architect, project managers, construction managers,” Dr. Barker said. “The pharmacist should have the ultimate sign-off.”

She underscored the value of keeping a time line with a “frequent cadence for meetings.” For her team, that meant meetings on a weekly basis. “Everyone was on the phone or met in person—back when we could,” Dr. Barker said.

“That was really helpful.”

A few challenges still emerged.

Sterile compounding regulations, building codes and occupational safety guidelines, combined with the Americans with Disabilities Act (ADA), can “start to be mutually exclusive,” Dr. Barker said. For example, the eye wash station in the anteroom lacked a sink or catch basin for the water. The scrub sink see SUCCESSES, page 16

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SUCCESSES continued from page 14

was supposed to be deep and high, for example, yet then the eye wash couldn’t go above it and still meet ADA requirements. Her team resolved the issue with a workflow solution. “But it’s not ideal,” she said.

The scrub sink itself posed another obstacle. The contractor purchased a stainless steel sink that had copper lining on the inside and edges of the basin. But when the entire room was treated with a triple sporicidal disinfectant cleaner, the copper parts of the sink corroded. “It looked like some beautiful fountain in Italy,” Dr. Barker recalled, but it had to be replaced, which added to the delays.

Even after construction is completed, there still may be further holdups. It can take a couple months after a request is filed for an initial inspection, she noted, adding that, based on the inspection, follow-up and physical changes may be needed.

Once inspectors pass the space, then the baton is passed on to licensing. Her team has found that this step also can take months. “That’s where we have got hung up in the past,” she said. “You can know you passed, but that doesn’t mean anything until it’s posted on the website.”

In the state of California, a pharmacy also has to request a second inspection from the California Department of Public Health. That agency then has 100 days from when the license posts and the request comes in to inspect. The pharmacy can only open after that final inspection has been signed off.

During all phases of a project, Dr. Barker recommended that pharmacies constantly review requirements and touch base with architects and construction managers. “Sterile compounding regulations speak to [how they are applied] in a building. So you have to evaluate whether it meets requirement at all times. That means a lot of conversations.”

It also means digging into the intricacies of which USP chapters are final, which have been challenged and how much of the guidance documents can or should be enforced (for

more details, see page 18). “Despite the many changes to regulations, we are fortunately compliant with all current structural requirements for sterile compounding,” Dr. Barker said.

What About the Cost?

As far as finding the funds for cleanroom renovations, “It’s not as if you can have a bake sale!” Dr. Barker said. “I have been fortunate that this institution is dedicated to meeting requirements. This is also part of the vision phase, to determine what is needed for compounding, and then design to meet the requirements. The costs vary tremendously depending on the location in which you are building.”

She added a note of caution: “There definitely is a danger in cutting corners; it will probably show up as a deficient [compliance area] in the future, and making changes in an existing cleanroom can cause downtime, vendor testing, etc. This is expensive in terms of money, time and patient care.”

More Construction Cues Asked to comment on strategies for successful cleanroom and pharmacy renovations, Gene Decaminada, RPh, the manager of compounding compliance for Option Care Health, highlighted a few critical construction considerations. These include installing a hands-free anteroom sink, window ledges that are slanted or flush to the wall, ledge-free floor coving that is flush with the wall, and sealed wall panels and ceiling light fixtures. He also underscored the importance of making a line of demarcation large enough in both the anteroom and negative pressure room to accommodate cleanroom staff.

—Lynne Peeples The sources reported no relevant financial relationships.

More lessons learned from cutting-edge cleanroom renovations See pages 32 and 33

Remote Tech Helps Hospital Pass Certification

J

erry Siegel, PharmD, the vice president and managing partner of Safe Medication Management Associates Inc., is consulting for a new hospital pharmacy seeking certification in Ohio. The COVID-19 pandemic, he noted, has “added some additional and unusual wrinkles to the process.”

The state board of pharmacy determined that they were not going to send an inspector before opening the new pharmacy cleanroom suites. “Instead they wanted us to send a video tour of the facility highlighting the key features to meet USP <797> and USP <800> standards,” Dr. Siegel explained.

So they created a video that showed, among other

16

fe features, interlocking sliding doors and the ability to monitor and control temperature, humidity, pressures and air exchanges from a central system in the pharmacy (image, left). It was enough to earn approval from the board.

Dr. Siegel noted an unexpected benefit: The certification company was “available at a moment’s notice,” given a reduced workload.

“The pharmacy has now passed certification and will be ready for opening,” he added. “Plans for conservation of PPE [personal protective equipment], re-sterilization of PPE with UV-C lights, and alternate plans for cleaning supplies have already been developed.”

—L.P. Dr. Siegel reported a financial relationship with BD.

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Kienle’s 10 New Building Blocks of Compounding Safety I

n 2018, Patricia Kienle, RPh, MPA, the director of accreditation and medication safety at Cardinal Health Innovative Delivery Solutions, shared with Pharmacy Practice News 10 points she believed pharmacies needed to keep in mind to ensure compounding safety (bit.ly/3f1ZCNc). At the time, USP chapters were being revised and slated for implementation in 2019. Since then, General Chapters <795> and <797> have been appealed, leaving some confusion about what standards institutions should now follow.

For an updated list of building blocks, Pharmacy Practice News reached out to Ms. Kienle to find out what she thinks are some of the most important strategies pharmacies need to keep in mind to stay safe and compliant in their compounding activities.

Know the contents and status of USP compounding–related chapters. On June 1, 2019, the revised USP

ceu<795> and <797>. USP chapter <825> on radiopharmaceuticals will be official when USP announces the date. Subww. scribe to the USP Compounding Compendium (www. ), usp.org/products/usp-compounding-compendium), and follow the USP compounding page (www.usp.org// d compounding) to keep current with chapters and related USP documents.

Know your state regulations. In some me cases, state regulations are more stringent than USP standards, so you need to know the federal standards and state expectations. Last year, many states told their licensees they expect compliance with the revised USP chapters beginning Dec. 1, 2019. Although most have since backed off, saying they would wait for USP to issue revised chapters, some states had already incorporated aspects of the revised USP chapters into their regulations. From my experience

‘Now is the time to evaluate what is being done at your institution in terms of environmental monitoring, become familiar with what’s in the reports, and take action based on the results.’

—Patricia Kienle, RPh, MPA

chapters <795> and <797> on nonsterile and sterile compounding, respectively, were published. We all went forward thinking they were going to go into effect Dec. 1, 2019, as intended.

In the meantime, both were appealed, and there’s still some confusion about which chapters to follow. For now, the 2014 version of chapter <795> and the 2008 version of chapter <797> remain official. USP chapter <800> on hazardous drugs has been official since Dec. 1, 2019, but its “compendial applicability” ties its federal enforceability to the 2019 revisions of

18

speaking with institutions, there’s some confusion about which standards to follow, especially around beyond-use dates and the frequency of personnel requalification. Pharmacies need to follow the more stringent regulations, which may be on the state side.

Know the expectations of accreditation organizations. The Joint Commission (TJC) evaluates sterile compounding using existing TJC standards, including those

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for Medication Management, Infection Control, Human Resources, Environment of Care and others. As for USP chapter <797>, TJC has given institutions the option of using either the old or new versions of the chapter, as long as they comply completely with one of them. The three other accreditation organizations have not made similar statements; however, this could change, so stay current with your accreditation organization’s guidance.

Heed USP best practices. Although these chapters haven’t been implemented, they include a lot of bestpractice guidance for a range of topics: from use of master formulation records, compounding allergenic extracts, procedures for media fill and gloved fingertip testing, procedures for air and surface sampling, cleaning procedures, evaluation of environmental monitoring excursions, and certification of facilities. Some of these procedural aspects and explanations need to be incorporated into your own policies and procedures.

Work toward full compliance. USP chapter <800> is designed to protect health care workers, so work toward full compliance—even if your state is not inspecting for this. Although this chapter is not yet federally enforceable, pharmacies should follow the chapter for two reasons: The first is that many states have incorporated it into their standards already, and the second is that these rules are there to keep health care workers safe. One important component in the chapter is to make sure your assessment of risk reflects best practice and the way the hazardous drugs you use are handled. This is a team sport, and you need to include key members of the interprofessional team to be sure your practices are appropriate throughout the health system. Another example of an important component of the chapter is the evaluation of the use of closed system drug-transfer devices in the compounding and administration of antineoplastic agents.

Revise staff training and requalification. During the current pause, take time to review this key operational area. The 2019 revision of USP chapter <797> included a specific list of core competencies that provide a contemporary view of compounding requirements. The information in these core competencies can help guide institutions in training and requalifying staff, and provides guidance in terms of what types of policies and procedures they need to have in place. In addition to training and requalification for compounding personnel, be sure to include others in appropriate training and inservicing, such as nurses, nuclear medicine technologists and others who mix immediate-use preparations, and environmental services personnel who clean the compounding areas.

Consider advanced training. Specifically, this is for the designated person who oversees compounding and handling of hazardous drugs. It’s up to the organization which person it wants in the designated person role,

but there does have to be one person who is the quarterback on compounding issues and coordinates and monitors all related activities. Most organizations have a pharmacist in this role, and some states require that, but this person can also be a highly trained technician. The person also doesn’t have to be a supervisor, and they can have responsibility for more than one site.

Evaluate your environmental monitoring program, procedures and results. Pharmacies are used to reviewing their environmental monitoring program, but they may not react to reports as well as they should. In fact, I’ve heard from a lot of surveyors and state board inspectors who ask for the most recent certification and environmental monitoring reports, only to find out the person in charge of compounding hasn’t even looked at the report. Now is the time to evaluate what is being done at your institution in terms of environmental monitoring, become familiar with what’s in the reports, and take action based on the results. In general, be sure your microbial environmental monitoring is designed to detect excursions, incorporate wipe testing for detection of hazardous drugs that have escaped containment, and update your training and policies based on these results.

Consider outsourcing. It’s also time to evaluate your use of external compounding pharmacies and outsourcing organizations. When an organization contracts with an external compounding facility, from the Center for Medicare & Medicaid Services’ (CMS’s) perspective, they are acknowledging that that facility is providing the same level of service as they would if they were performing compounding in-house. According to CMS’s Hospital Conditions of Participation, as well as accreditation organization standards, pharmacies need to have approval from hospital leadership to use the companies and have written agreements in place with the outsourcing compounders. The goal should be to lay out expectations—and then monitor them. I always advise institutions to create reasonable expectations and include at least one operational and one clinical expectation. Always do your due diligence, and review FDA assessments of the outsourcing company you’re considering (bit.ly/3aBKfYs).

Use the FDA as a resource. Be sure to monitor the FDA site (bit.ly/2W9citc) for new and revised compounding-related documents. The FDA issues compounding-related guidance documents, such as those related to unsanitary conditions, repackaging, hospital and healthsystem compounding, and compounding from bulk substances. These documents may be in draft or final form, and occasionally temporary guidance is published to deal with a specific short-term issue.

—Reported by David Wild Ms. Kienle reported that she is a member of the USP Compounding Expert Committee but that these remarks are her own.

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5 Questions for Jerry Siegel, PharmD

Coping With COVID-19, USP Delays I

f you’re bringing your cleanroom up to the new USP <797> and <800> standards, Jerry Siegel, PharmD, the vice president and managing partner of Safe Medication Management Associates Inc., is a leading expert to call. So, we asked him about where things stand as the USP chapters go live—or prepare to, given their recent delays and COVID-19-related disuptions.

December, and these setbacks are unfortunate. The indefinite extension gives facilities more time to prepare to be compliant, but the COVID-19 pandemic has made it more difficult. I do think that, overall, things are improving, however. And USP has issued a statement indicating that during the pandemic, they will support state boards and other regulators using risk1. Has the delay in based enforcement discreimplementation of USP <797>, tion related to the implemenBiosafety cabinets must have solid vents, not originally set for Dec. 1, 2019, flexible hoses. tation of USP compounding and now being reviewed by an standards. The Joint Comindependent panel, changed mission and Centers for Medicare & Medicaid Services also how health systems are preparing to comply? have given instructions to their inspectors about how to view A lot of places already were prepared to be compliant by compliance in light of the current situation.

December, and they’ve just continued on that path. Some 4. What has been the biggest challenge facilities that were behind are using the extra time to get facilities have faced? everything into place. If a facility has implemented USP Without question, it’s obtaining funding to get the physical <800>, it is expected to follow the USP <797> revised stanfacilities built. It’s not a matter of just slapping paint on the dards. If not, it will be reviewed on the USP <797> 2008 wall; it’s millions of dollars to do cleanroom suites correctly. standards. For facilities somewhere in between, it’s helpThe HVAC (heating, ventilation and air conditioning) requireful to remember just where we are with the regulations: ments, in particular, can be extremely costly. But trying to cut Since USP <800> has been implemented but USP <797> corners to save money makes for a bad cleanroom. has not, USP <800> is not compendial, and is therefore not enforceable. As for boards of pharmacy, they’re generally 5. What are the biggest mistakes you’ve seen in not inclined to enforce for full compliance, but that can developing compliant cleanrooms? vary state by state.

I’ve seen a lot of them built poorly, and they have to be 2. Has COVID-19 affected compliance efforts? redone. For example: There currently are no live inspections, but there are innova• walls painted with a water-based epoxy paint that comes tive workarounds being done. One site was due for certificaoff when you clean them with alcohol; tion and inspection this month, and their state board said they • flooring not cove-molded properly, leaving top lips that would not come in to do the inspection—instead, they asked are not compliant; the facility to videotape the inspection and send it to them. I’ve • pass-throughs that are flimsy, not interlocking and not never seen that done before! [For more details, see page 16. ] sealed properly; Still, COVID-19 is taking a toll. In another system, for example, • rooms that may have ceiling HEPA filters but don’t have they have two sites fully compliant, inspected and cleared to low air returns, so they don’t get appropriate airflow; and the new USP <797> and <800> standards for over a year now, • external ventilation and hose types that are noncompliant. but two other sites have not even started because of budgetMany of these issues stem from failing to include pharmaary issues and problems with the physical facilities. Now, they cists and nurses, as well as expert pharmacist consultants, don’t have the funds to move forward, and there are no inspecin the design of these spaces, resulting in compliance issues tions happening due to COVID-19. It’s a quandary. They have that may lead to a significant need for renovation. two of the most beautiful cleanrooms you’ve ever seen and two —Reported by David Wild in need of full renovations.

3. How is compliance preparation going?

Most people had been working very hard to be ready by

20

Dr. Siegel consults on cleanroom renovations and reported a financial relationship with BD.

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The Science of Sterile Compounding W

ith sterile compounding, there is little to no room for error. Optimizing methods to ensure the highest level of safety for patients and staff—and to fall in line with the ever-changing rules and regulations—is more critical and challenging than ever.

“We recognize that standards are always somewhat in flux, practices evolve over time, and there’s very little training available to do hands-on activities,” said Connie Sullivan, BSPharm, the vice president of research and innovation for the National Home Infusion Association.

L.R. Dillon, RPh, a consultant and accreditation surveyor based in Loveland, Colo., noted the general lack of standardization about sterile compounding techniques. Part of the problem, he said, is siloed thinking in a pharmacy, “as we keep watching each other using the same techniques over and over and assuming it’s OK because we never see anything different.”

explained. “Sending a bolus into the vascular system can create devastating effects very quickly. We can’t forget the importance of basic chemistry.”

Increased Scrutiny In response to the growing awareness of risks, the standardsetting bodies USP and the FDA are increasing their oversight of pharmacy compounding with new and updated regulations. These include USP Chapter <797> “Pharmaceutical Compounding—Sterile Preparations,” and USP Chapter <800> “Hazardous Drugs—Handling in Healthcare Settings.” USP <797> is designed to protect the patient from harm, while USP <800> is written to also prevent occupational exposure to hazardous drugs (HDs). Some components are in effect, others have been challenged, but all are designed to keep patients and providers safe and, thus, warrant attention, experts noted.

Proper wipe P i sampling li (left) (l f ) and d use off personall protective equipment (right) are cornerstones of safe sterile compounding.

Photo credit: Wipe sampling, Bureau Veritas Laboratories; PPE, Luci A. Power, MS, RPh

Given that echo chamber, what is the best way forward?

According to Ms. Sullivan, it all comes down to the science: “We want to make sure everyone understands why the standards are what they are,” she said. “What’s the [evidence] behind them? Where, for example, does the risk of contamination really come from?”

Regulations have become stricter as patients have gotten sicker. “The stakes are growing higher,” said Eric Kastango, RPh, MBA, the CEO of Clinical IQ LLC. “We have to improve our game.”

But just how to do that may not be obvious. “We don’t know what ‘right’ looks like,” he added. “This material is not taught in school.” That education gap is troubling, given that the route of administration for compounding medicines is often inherently dangerous. “Once you give an IV, you are bypassing the body’s normal immune system,” Mr. Kastango

22

Safe sterile compounding depends on several factors, including the use of personal protective equipment, closed system drug-transfer devices (CSTDs), surface wipe sampling, and other best practices.

Compounding essentially involves creating a new drug.

A new drug generally requires a New Drug Application with the FDA. But there are exceptions to that rule for 503A and 503B compounding pharmacies. A 503A pharmacy is not required to provide labeling directions or meet Current Good Manufacturing Practices (CGMP), if a licensed prescriber issues the script for an individual patient. In contrast, a 503B pharmacy needs to both label the medication with adequate directions and meet CGMP. (For more discussion of 503A and 503B distinctions, see article, page 10.)

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see SCIENCE, page 24

SCIENCE

‘When we are in a pharmacy, we keep watching each other using the same techniques over and over and assuming it’s OK because we never see anything different.’

continued from page 22

“In the past, the FDA would walk in a compounding pharmacy and they didn’t stop to really define whether it was a 503A or a 503B,” said Barbara Petroff, MS, RPh, a surveyor for the Accreditation Commission for Health Care. “They’re doing more inspections. But now they determine if it’s a 503A or 503B and that makes a difference in how they conduct the survey itself.”

Inspections Can Be Costly The outcomes of 503B compounding facility inspections can be costly, Mr. Kastango noted. An FDA Form 483 may come back with a list of things to address that requires an action plan by the compounding pharmacy. “If you don’t address the issues on the 483, you’ll pay another $16,093 when they come back to re-inspect,” he warned.

In the case of 503A pharmacies, the inspector will hand over any findings of insanitary conditions, misbranding and the like, to the local state board of pharmacy. But what the state does with that information is uncertain, Mr. Kastango said, noting the uneven regulatory landscape among states.

Customized Solutions Such discrepancies underscore why facilities should write their own policies that not only conform to existing standards, but also are customized to their own operation.

Ms. Petroff suggested hiring a consultant to evaluate the operation and offer ideas for improvements. And in those efforts, it may be worthwhile to go beyond the current letter of the law. The new USP <800> standards include a strong recommendation, but not a requirement, for compounding facilities to use CSTDs in the preparation of HDs. The device mechanically keeps environmental contaminants from entering the system and HDs or vapors from escaping the system. Many facilities are, in fact, electing to use them as a supplementary measure to prevent exposure from splashes or aerosolization that may occur during compounding, Ms. Sullivan noted.

Meanwhile, USP <800> requires the use of CSTDs when administering antineoplastic HDs—whether in the home, clinic, hospital, infusion center or physician office—to protect the health care worker from exposure to these medications.

Clean Room, Clean People The word “clean” often is used loosely. But that should never be the case for a compounding pharmacy cleanroom.

Gene Decaminada, RPh, the manager of compounding compliance for Option Care, based in Ridgefield, Conn., described why it is essential to be “diligent and specific” with cleaning practices and environmental testing. Sterile isopropyl alcohol, along with both germicidal and sporicidal agents, is required for cleaning controlled areas.

24

—L.R. Dillon, RPh Cleaning should begin from the cleanest to dirtiest areas of the cleanroom, starting from the innermost portion of the buffer room and then working out toward the anteroom, Mr. Decaminada said. A regular cleaning regimen also should include the general, noncontrolled pharmacy area.

He advised donning safety goggles to avoid eye injury from the cleaning agents, and doing regular sampling to ensure the space is truly clean.

“Environmental sampling validates that your engineering controls are working properly,” Mr. Decaminada said. “Air and surface testing also ensures your cleaning agents and cleaning techniques are adequate to achieve a state of control in your cleanroom environment.”

Rely on the Experts Many facilities will choose to do extensive remodeling or even new construction to comply with the new USP standards. If the work is being done on a cleanroom, “do not count on contractors to know the regulations,” Ms. Petroff stressed. She suggested avoiding the use of wood or other porous surfaces and, for lines of demarcation, installing separate colored tiles or using special paint that won’t chip when washed. (For more guidance on cleanroom renovations, see articles on pages 14, 32 and 33.)

Staff also should have shoes designated for use only in the facility, and they should change into scrubs in the facility instead of wearing them to work. Appropriate garb is key.

“People are all different sizes. You cannot have bare skin.

So make sure gloves and gowns are long enough and fit correctly,” Ms. Petroff said. “We see gowns all the time that don’t fit around the neck, or there’s no cuff around the wrist. I’ve gone into places where they don’t tie the gowns,” she added. “We may not put some of this detail into the documentation itself … but that’s common sense.”

Proper sterile garb can be expensive, upward of $100 per person per gowning incident, Mr. Kastango said. But it is a necessary expense. “The dirtiest thing in the cleanroom is us.”

—Lynne Peeples The sources reported no relevant financial relationships other than their stated employment.

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A compounding conundrum:

Do It Yourself or Outsource?

S hould your hospital pharmacy entrust its compounded sterile preparations (CSPs) to an external vendor, or invest the capital, resources and space to bringing those CSPs in-house? For most institutions of any size, experts say the answer is not binary: A mix of both approaches may be the best strategy.

On paper, it’s easy to see why a hospital would have concerns about sterile compounding outsourcers. Set your newsfeed to provide an alert for “sterile compounded products recall” and you’ll get pinged with alerts at least weekly.

A 2018 report from the Pew Center found that the state of the field had improved since the 2012 meningitis outbreak linked to the New England Compounding Center (NECC), but it still identified 50 reported compounding or potential errors linked to 1,227 adverse events, including 99 deaths, between 2001 and 2017 (bit.ly/2ko8s0p). And then there’s a much-cited JAMA report about a compounder that covered

“Overall, it’s a tough decision, and most hospitals are likely to adopt some sort of a hybrid approach to sterile compounding,” said Adam Poust, PharmD, the outpatient oncology and infusion pharmacy manager at the University of Colorado, in Boulder. “The key questions are obvious: What do you need to do, and how much volume are you being asked to prepare? The lower the volume, the easier it is to keep your compounding in-house and manage it closer to home. Another issue is the size and scope of your institution. We’re a hospital with a cancer center, and we have multiple facilities designed and tested to meet [USP chapter] <797> requirements. At a critical access hospital in a remote area, they almost certainly will not be able to do extended stability testing, so they will usually be limited to immediate use for on-site compounding and will need to outsource to a 503B sterile compounding facility for everything else.”

‘My organization was very quality-minded and focused on this, but if you insource, unless you do it well, you aren’t going to be able to extend your dates very much.’

—Richard Capps, PharmD

up thousands of adverse reactions and other safety issues for years (JAMA Intern Med 2019;179[11]:1461-1462).

Given all that, couldn’t your facility do its own sterile compounding with stricter attention and oversight?

That may depend on your appetite for navigating current USP policy; the group’s revised Chapter <797> includes fundamental changes that will increase the compliance burden for many hospitals. Previously, there were three categories of compounding: low, medium and high risk. The revised chapter modifies those to Category 1 and 2; many hospitals that previously conducted low- and medium-risk compounding are likely to continue as Category 2. Category 1 CSPs are compounded in an International Organization for Standardization (ISO) class 5 primary engineering control located in a segregated compounding area, whereas Category 2 CSPs must be compounded in an ISO class 5 primary engineering control located in “an ISO 7 buffer room.”

The revised chapter also has some modifications in beyonduse dating (BUD) and the option to conduct sterility testing for nonsterile compounding or to extend the BUD.

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Another factor to consider is drug shortages, Dr. Poust added. “We might want to be able to compound a drug ourselves, but we can’t get some of the product we need, whereas a lot of the 503Bs will compound from raw product.

If we can’t get that supply in and they can, that’s one of the things that tilts us toward using a 503B to do compounding.”

Ahead of the Insourcing Trend At Prisma Health, a large nonprofit health system in South Carolina formerly known as the Greenville Health System, a team led by Richard Capps, PharmD, was ahead of the curve in establishing an in-house sterile compounding pharmacy. “We felt there were several advantages, including cost savings and the ability to customize what we wanted,” Dr. Capps said. “For example, there is a specific dose of ketamine that we use in our protocols, a 10-mg dose. Most of the time when you buy ketamine, it’s a [500-mg/5-mL (100-mg/mL)] vial. We wanted to be able to make doses specific to our patients as part of a protocol, which since has been adopted in other South Carolina

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see CONUNDRUM, page 28

CONUNDRUM continued from page 26

hospitals. Also, drug shortages were an issue. With our own compounding pharmacy, if we couldn’t purchase a specific product, we could often prepare it ourselves or repackage the product to extend the supply.”

Dr. Capps and his group were developing a request for proposal and getting positive attention from the C-suite when news broke of the NECC meningitis outbreak. “That moved the project forward much more quickly.

We received funding in 2013 and the build-out took the rest of the year, so we opened to start dispensing in 2014.”

The facility included an ISO class 8 workroom, an ISO class 7 anteroom and an ISO class 7 buffer room, all built in a “building within a building.” The setup also included a materials distribution center centrally located to take advantage of the hospital’s warehouse delivery routes, and featured two RIVA robots (ARxIUM) and a 6-foot horizontal laminar flow workbench. “Prior to that, we were very traditional. We only compounded short-dated batches scheduled to begin within the next one to eight hours, and minimal advance batch compounding within the standards of <797>,” Dr. Capps said. “Afterward, we began in-house compounding for a limited number of specific items to support our system.

We prepared CSPs with extended dating and were registered with the FDA.” But even then, some items still were outsourced, such as oxytocin, which “comes in a 500-mL bag and was kind of annoying to mix in the robot,” Dr. Capps said. “By buying it from a 503B compounder, you have it easily available in [obstetrics] for when the moms are delivering. Also, consider this: It takes a lot of investment to do insourcing really well. My organization was very quality-minded and focused on this, but if you insource, unless you do it well, you aren’t going to be able to extend your dates very much.

We conducted end-product sterility testing on all of our batches and sent everything off for stability testing. Most places are not likely to invest that heavily.”

Moving Away From Outsourcing At the seven-hospital Mission Health system in North Carolina, the central fill Ridgefield Distribution Center Pharmacy does the in-house sterile compounding, primarily for the Asheville-based flagship hospital, Mission Hospital. “Historically, we had been able to strike a good balance between insourcing and outsourcing,” said Josh Powell, PharmD, Ridgefield’s pharmacy operations manager. “We have two RIVA robots from ARxIUM, which are great resources for sterile compounding. For example, with

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Prisma Health uses RIVA robots in a cleanroom “building within a building” format to expand its in-house compounding operation.

our anesthesia syringes, it’s very attractive for our anesthesiologists and certified registered nurse anesthetists to have doses prefilled, and more often than not we are able to compound those with our robots. However, there are some cases where we can get a product from outsourcing to a 503B facility that is more cost-effective with regard to dating and potential waste.”

But recently, although Mission has split its outsourcing between carefully chosen 503B facilities, the system has encountered challenges with its outsourcers. “When a 503B compounder has a 483 observation by the FDA, there is the potential for supply chain interruptions,” Dr. Powell said. “The compounding pharmacy may have to quarantine product, or stop producing product in a certain facility for a time until the 483 is met. That may mean that we have to switch to another source, but it’s not a quick shift. When you start carrying a new item from a company, they have to build up their production, and in the meantime, we have to do the compounding. But when we compound—even if it’s the same product—we are limited to <797> dating, and it’s usually going to be refrigerated, with much shorter dating, and we have to change the product out more often.

For a time, it made sense to us financially to outsource, but we can’t afford to have our supply chain interrupted such that they can’t produce our standard monthly amount, and that’s happening more and more often.”

So Mission is planning to cut back significantly on its outsourcing for sterile compounding, aided by the RIVA robot system acquired in 2010. Although adding robotics carries significant up-front costs, Dr. Powell noted, “it’s ultimately less expensive to insource than to outsource if you can manage your supply chain within the facility.”

—Gina Shaw The sources reported no relevant financial relationships.

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Scaling Back Can Make USP <800> Compliance Less Scary N

ot all hazardous drugs need to be handled according to the full gamut of measures specified in USP General Chapter <800>.

“A lot of people think they need to treat everything using all the strict requirements of USP <800>, but this can be really burdensome iff ry all these measures are not necessary yne, based on the risk,” said Joseph Coyne, ns at RPh, the director of field operations sulting Clinical IQ LLC, a pharmacy consulting firm based in Florham Park, N.J. USP <800> requires pharmacies to follow all of the chapter’s risk containment strategies for ipulated, as well antineoplastic drugs that are manipulated, dients of any type. as for active pharmaceutical ingredients ility when handling However, there is greater flexibility antineoplastics that only need to be packaged or counted as well as for handling hazardous non-antineoplastic drugs and agents that pose reproductive hazards only.

“If a pharmacy is only counting antineoplastics, for example, [then] using appropriate gloves and decontaminating a dedicated counting tray and spatula after use can be adequate containment measures,” Mr. Coyne said.

Alternative Work Practices Other examples of alternative work practices include marking lidded automated dispensing cabinet bins with the appropriate precautions, removing vials of certain hazardous medications from unit stock, packaging partial tablets in the pharmacy using a manual system, and preparing all liquid doses in patient-specific oral syringes.

Mr. Coyne said developing alternative containment strategies and work practices according to the USP <800> Assessment of Risk provision depends on five elements: drug, dosage form, packaging, risk for exposure, and how a pharmacy will be manipulating the drug. Different strategies also can be applied at different points of contact, he noted. “For example, the receiving clerk has a lower level of risk if the product they are handling is sealed by the manufacturer than the pharmacist who is manipulating the drug,” he said.

Provide Documentation As part of the Assessment of Risk, pharmacies need to provide documentation detailing the alternative containment strategies and work practices they will use to handle a given agent. They also need to provide information on the drug, dosage form, risk for exposure, packaging and how it

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is being manipulated.

Although tailoring containment strategies for each agent may seem onerous, Mr. Coyne said pharmacy and therapeutics or medication safety committees can integrate this activity into their routine meeting agendas. “You don’t need to create a separate committee to deal with risk containment strategies,” he said. “It doesn’t need to be a mystical approach.”

Can I Just Not Report?

Many health systems assume they don’t need to throw the kitchen sink of containment measures at every drug listed by

the National Institute for Occupational Safety and Health.

That’s why many of them consider not naming drugs they deem low risk as hazardous in their USP <800> reporting. However, Patricia Kienle, RPh, MPA, the director of accreditation and medication safety at Cardinal Health Innovative Delivery Solutions, based in Dublin, Ohio, stressed that skipping the reports is not an option under current USP guidelines.

In fact, “all hazardous drugs on the NIOSH list need to be identified, and you need to state how you’re going to contain risk of exposure,” said Ms. Kienle, a member of the USP Compounding Expert Committee.

Still, there is some leeway in selected cases. For example, many drugs on the NIOSH lists may be able to be managed with easy-to-implement measures, such as wearing chemotherapy gloves, using identifiable lidded bins for storage, decontaminating containers and surfaces, and similar methods of containment.

Free Resources Many resources to help pharmacies assess risk and develop containment strategies are available online, including one from ASHP, “Performing an Assessment of Risk to Comply With USP <800>” (bit.ly/2UfihcJ).

—David Wild Mr. Coyne reported no relevant financial relationships. Ms. Kienle reported that she is a member of the USP Compounding Expert Committee, but that these remarks are her own.

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Lessons learned from a once not-so-sterile enterprise

Building a ‘Starship’ Cleanroom Las Vegas—An ongoing pattern of contamination over nearly three years in a sterile compounding suite illustrates the challenges in building and maintaining a safe and efficient cleanroom. But the systematic and ultimately successful approach used to combat the problem may offer valuable lessons for other compounding pharmacies, according to a poster presented at the ASHP 2019 Midyear Clinical Meeting.

The consistent sampling excursions began shortly after the Augusta Health cleanroom in Fishersville, Va., was remodeled in late 2015. “We were frequently having to reclean, investigate causes and resample,” said investigator John Lubkowski, BSPharm, MBA, the pharmacy director at Augusta Health (abstract 8-166).

“I think that some people may believe that it’s better to quickly and covertly address issues, but we engaged everyone possible and didn’t cut corners,” Mr. Lubkowski said.

“Our mission is always, first and foremost, patient safety.”

Mr. Lubkowski developed a system to track environmental monitoring results over time by location, created an escalating action plan to address issues identified during investigations, and then engaged both internal and external subject matter experts to implement higher-level action plans.

One of the investigations, for example, revealed that the epoxy paint used on the walls had degraded over time. “So we actually shut down the IV room and utilized another IV room in the facility,” Mr. Lubkowski said. “We then repainted, reepoxied and allowed cure time—approximately two weeks— before we recleaned, recertified and resampled the room.”

Continuing incidents of contamination resulted in the cleanroom shutting down for a couple of months for a remodeling.

A particular focus was relocating the air returns right next to the facility’s incoming HEPA-filtered air on the ceilings to a position lower on the walls that ensured more optimal airflow.

“I see the improper placement of air returns a lot,” said Patricia Kienle, RPh, MPA, the director of accreditation and medication safety at Cardinal Health Innovative Delivery

The Augusta Health cleanroom remodeling included the replacement of hinged wooden doors that opened into the clean spaces with automatic glass sliding doors.

Solutions, who was not involved in the poster. Mr. Lubkowski “recognized that was an issue and had it corrected. It’s part of looking for the patterns.”

The remodeling also included the addition of fan-assisted HEPA filters, upgraded lighting, new solid surface walls and the replacement of hinged wooden doors that opened into the clean spaces with automatic glass sliding doors.

“Previously, we had signage about not opening the two doors simultaneously. Now, it’s physically impossible, unless it’s an emergency,” Mr. Lubkowski said.

The cleanroom remodeling team also eliminated anything that could be considered clutter, including compounding supplies and drug stock kept in the anteroom. They also redesigned workflows and reeducated team members on the reasons for the new changes and processes.

Involving infection control practitioners and risk managers may pay dividends when asking for the necessary funds to solve cleanroom contamination issues. “In our case, we needed to remodel a newly remodeled IV room,” Mr. Lubkowski added, noting that can be a particularly tough sell.

Ms. Kienle agreed. “Dollars can be a real stumbling block.

Even minor changes can require significant capital expenses, and it often ends up low on the priority list because the hospital doesn’t realize the implications. You need to present the case that this is best for patient care.”

Remediation Speed an Issue

Relocating the air returns from the ceilings to a position lower on the walls helped to ensure more optimal airflow.

Jerry Siegel, PharmD, the vice president of Safe Medication Management Associates Inc., applauded the systematic approach but was surprised by the length of time it took the team to resolve the repeated contamination situation. see ‘STARSHIP’ CLEANROOM, page 33

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USP Renovations Check All Boxes Las Vegas—It’s no small feat to juggle 23 USP compounding pharmacy projects, but that is exactly what Bridget Gegorski, PharmD, a medication safety officer at Cleveland’s University Hospitals, and her colleagues have been doing over the past two years. Their success to date provides a lesson in the value of leadership, structure and multidisciplinary teamwork.

Dr. Gegorski, who outlined her team’s USP compliance initiative at the ASHP 2019 Midyear Clinical Meeting (poster 4-153), said the first step her team took in 2017 when they began working toward compliance with USP General Chapters <797> and <800> was to form a systemlevel USP steering committee. That committee was chaired by the vice president of pharmacy services and included representatives from the hospital’s safety and infection control departments, nursing directors, experts on compliance, accreditation and legal, and facilities managers, she said. The team started by conducting USP <797> and <800> compliance gap analyses at the system level, dividing their

USP compliance–related renovations

by Cleveland’s University Hospitals included a positive pressure nonhazardous drugs cleanroom.

findings into compliance with facility requirements and practice requirements, Dr. Gegorski noted.

“For facilities’ compliance, we looked at things like product storage areas, cleanroom finishes and pressure monitoring ability,” she explained. “For practice compliance, we looked at whether pharmacies had standard operating procedures [SOPs] in place, cleaning practices, whether people were wearing the right garb, donning and removing garb appropriately—minute details.”

Dr. Gegorski said the results from gap analyses yielded crucial insights into what the health system needed to do to ensure compliance. Those insights also were instrumental in getting the $60 million in funding they needed to update their infrastructure.

“We were able to approach our board of directors with quantitative data noting specific percentages of compliance and provide our chief operating officers with specific examples [of deficiencies] that see USP RENOVATION, page 34

‘STARSHIP’ CLEANROOM continued from page 32

“These are things that need to be remediated in a month,” he said. “We’ve got to keep rooms clean and techniques good, while still reducing the length of time between when we start compounding and when we give it to the patient, because bacteria will multiply more rapidly than rabbits will have babies.”

Dr. Siegel also underscored the importance of having a multidisciplinary quality control committee to determine what to do with test results, and what to do when patients have received medications made under contaminated conditions.

The revised USP General Chapter <797>, which was scheduled to go into effect last December but remains indefinitely delayed, could help compounding pharmacies maintain a state of control. “It will help you reduce the microbial contamination that is very easy to introduce into cleanrooms by having standards on positive pressure, better standards on PPE [personal protective equipment], as well as better training of technicians,” Dr. Siegel added.

Since construction finished last April, Mr. Lubkowski noted that his compounding pharmacy has had only one action-level excursion in an air sample, just inside the anteroom entrance. His team also implemented monthly internal air sampling, and since last July, there have not

‘We’ve already implemented much of the new USP <797> protocols, including monthly surface sampling and our own internal air sampling. Our IV room now looks like a starship.’

—John Lubkowski, BSPharm, MBA been any further action-level findings.

“We’ve already implemented much of the new USP <797> protocols, including monthly surface sampling and our own internal air sampling,” Mr. Lubkowski said. “Our IV room now looks like a starship.”

—Lynne Peeples Ms. Kienle reported she is a member of the USP Compounding Expert Committee, but that these remarks are her own. Dr. Siegel reported a financial relationship with BD. Mr. Lubowski disclosed no relevant financial relationships.

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USP RENOVATION continued from page 33

they may not have been familiar with, since they don’t necessarily visit the pharmacies,” she said.

Given the large sum they were granted and the hospital leadership’s belief that USP compliance was an important patient safety initiative, Dr. Gegorski was asked to manage the project as her “number 1 goal,” she said. In 2018, she spearheaded the formation of an assessment of risk work group and a USP <800> task force. The two groups developed and approved new practice requirements, system policies and SOPs, she said. At the same time, the USP steering committee helped implement Simplifi 797 (Pharmacy OneSource) software, which was used to track cleaning frequencies.

The steering committee also administered annual readiness surveys using the Joint Commission Resources Tracers with AMP (store.jcrinc.com/ tracers-with-amp) to track each pharmacy’s overall compliance with USP <797> and <800>.

These results helped periodically gauge each site’s USP readiness and indicate next steps necessary to ensure compliance.

“The task force has used these insights to develop system policies and SOPs to help drive further compliance,” Dr. Gegorski said.

Site-Specific Design Plans As for cleanroom construction projects, a team of architects, engineers, and facility and pharmacy managers developed prototypes and approved site-specific design plans, Dr. Gegorski explained, noting that some prototypes did not fit into the physical pharmacy at each site. “In some cases, we had load-bearing walls that prohibited a workable cleanroom layout or very old buildings that were too small to accommodate a cleanroom and a pharmacy workroom in the designated space.”

“Handing off the project to the local site once we got to the construction phase was also challenging because they needed to figure out how to maintain safe sterile compounding activities while the pharmacy was under construction,” Dr. Gegorski added, noting that, in some cases, pharmacies have had to relocate into temporary trailers or move to another location within the hospital while construction issues were worked out.

Each site’s pharmacy managers “really owned” the projects, holding weekly construction meetings Dr. Gegorski attended only if there were compliance questions to address.

“While I and the other committee members provide support and guidance from the system level, it’s been up to the locallevel individuals to implement plans,” she said.

By early 2019, overall USP <800> compliance had risen to 76.5% from 65% in 2018, and overall compliance with USP <797> rose from 85% in 2018 to 94% in the first quarter of 2019. Dr. Gegorski said she expected full compliance in 2020, as many facility design issues will be solved once construction is complete.

Dr. Gegorski said her team had to overcome several chal-

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USP compliance–related renovations by Cleveland’s University Hospitals included a negative pressure hazardous drug cleanroom.

lenges. For example, unanticipated events such as delays in delivery of new HVAC equipment or finding asbestos in the floors have delayed construction time lines. Another potential roadblock occurred when the project leadership received pushback about some changes and temporary work practices they implemented; “communicating early and often” may have helped avert some of these tensions. “It could be that we didn’t communicate why we were making these changes with all the stakeholders, particularly those clinicians who weren’t a part of the construction meetings.”

As for other lessons learned, standardizing practice as much as possible is key to the success of a multi-site USP compliance project, Dr. Gegorski said. Her institution, for example, now uses the same cleaning products systemwide—“ones that we know work well”—and has transitioned from having environmental services clean the compounding areas to assigning this task to technical staff trained on various cleanroom work practices, she explained. “After we did this, we saw our microbial excursions and remediation needs decline significantly.”

A Structured Approach Michael Freudiger, PharmD, a sterile compounding consultant in Fresno, Calif., who was not involved with the initiative, said he has seen many health care facilities reach near 100% USP compliance in terms of infrastructure but fall short when it comes to policies and procedures, employee education, plans for medical surveillance, hazardous drug communication, and wipe testing, for example.

The structured approach, attention to detail, and ongoing compliance tracking that Dr. Gegorski and her colleagues used provide a good model for others to follow, he noted.

“This hospital was able to identify their deficiencies using a gap analysis tool and then mobilize to address those deficiencies by assigning specific responsibilities to committees, all while tracking the progress of each site.”

—David Wild The sources reported no relevant financial relationships.

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