Pharmacy Practice News - Special Edition June 2021

The 2021 Annual Compendium of Compounding

Don’t Be Afraid of Contamination Testing The CSTD cost equation TJC still eyeing USP compliance 10 new building blocks of compounding safety 503A vs. 503B: What’s best amid COVID-19?

Supplement to Pharmacy Practice News

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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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References: 1. Cabasso VJ, Loofbourow JC, Roby RE, Anuskiewicz W. Rabies immune globulin of human origin: preparation and dosage determination in non-exposed volunteer subjects.

Bull World Health Organ. 1971;45(3):303-315. 2. Aoki FY, Rubin ME, Fast MV. Rabies neutralizing antibody in serum of children compared to adults following post-exposure prophylaxis.

Biologicals. 1992;20(4):283-287. 3. Kuwert EK, Werner J, Marcus I, Cabasso VJ. Immunization against rabies with rabies immune globulin, human (RIGH) and a human diploid cell strain (HDCS) rabies vaccine. J Biol Stand. 1978;6(3):211-219. 4. Aoki FY, Rubin ME, Friesen AD, Bowman JM, Saunders JR. Intravenous human rabies immunoglobulin for post-exposure prophylaxis: serum rabies neutralizing antibody concentrations and side-effects. J Biol Stand. 1989;17(1):91-104. 5. Data on file, Grifols.

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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 injectionsite 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.

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-----------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

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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

TABLE OF 6

CONTENTS

USP Compliance Remains A Focus of TJC Surveyors

22 The ‘Gemba’ Walk To Compounding Compliance

10 Don’t Be Afraid of Contamination Testing

26 Navigating 503A and 503B Rules Not for the Faint of Heart

15 The Cost Equation for CSTDs 28 Amid COVID-19, the Challenge Of DIY 503B Continues

16 95% USP Adherence at Ascension Is a Team Effort 18 Kienle’s 10 New Building Blocks Of Compounding Safety

32 6 Steps to an ‘A’ Grade in Sterile Compounding

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USP Compliance Remains a Focus Of TJC Surveyors L ike most things in 2021, this year’s r’s Jo Joint oint veys w ill Commission compounding pharmacy surveys will tiice c ce take a different tack, based in part on the pract practice nts ar re a re pressures of COVID-19. The main developments are pdatess tto o continued delay in enforcement of recent updates ous dr rug USP’s chapters on compounding and hazardous drug dancee ffor or or handling and a pandemic-related interim guidance compounding pharmacies.

For pharmacies that scrambled to obtain funding to build cleanrooms and update existing segregated compounding areas (SCAs) to meet requirements for the 2019 revision of USP General Chapter <797> guidance on sterile compounding, USP’s decision to consider stakeholder appeals for more expert deliberation on the new revision was reassuring. “The organizations that were not able to get the funding for such significant projects can breathe a sigh of relief that their current setup is adequate to keep them in compliance with USP <797>,” said Susan Reed, RPh, a pharmacy consultant at Steve Hirsch and Associates, in Fountain Valley, Calif.

In contrast, organizations that had upgraded their facilities to comply with the 2019 revision will likely meet or exceed the 2008 version from a structural perspective, Ms. Reed noted during the virtual ASHP 2020 Midyear Clinical Meeting and Exhibition, while in her former role as a consultant at Joint Commission Resources Inc. One of the more stringent rules in the 2019 USP <797> revision is a requirement that anterooms and buffer rooms be supplied with HEPA-filtered air through outlets located at the ceiling level, with returns placed low on the walls, Ms. Reed noted. In addition, unlike the 2008 revision of USP <797>, which only permits low-risk nonhazardous compounding in SCAs, the latest revision allows hazardous drug compounding in SCAs, assuming facilities are upgraded, she said.

“The two revisions address sterile product compounding differently,” Ms. Reed explained. Whereas the 2008 revision categorized sterile products by the number and type of ingredients used in the preparation, the 2019 revision still under expert review categorizes compounded sterile products by the location in which products are prepared.

USP Chapter <800> Organizations that have geared up to comply with USP <800> can continue with early adoption and ask

6

Technicians at Massachusetts General Hospital prepare daily compounded sterile preparations.

surveyors to assess their adherence to this chapter, according to Ms. Reed. She stressed, however, that they should expect scrutiny of everything from staff training and competencies to receipt of product, through to compounding preparation and appropriate use of personal protective equipment (PPE).

One detail that surveyors will want to see in place for organizations requesting assessment for USP <800> compliance is that an individual has been designated to oversee hazardous medication compounding, Ms. Reed noted.

“This individual needs to ensure that staff that handle and prepare hazardous medications receive appropriate training, including [on] the appropriate use of PPE for their role,” she said.

“The individual needs to work with a multidisciplinary team to perform an assessment of risk for hazardous medications and to determine proper handling, including PPE for receipt and storage, product preparation, disposal, and decontamination and cleaning requirements,” Ms. Reed added.

USP Interim Guidance During Pandemic USP has made exceptions to some rules during the COVID-19 pandemic. For example, to help with management of drug shortages, pharmacies may perform mediumrisk compounding in SCAs until the public health emergency is declared over, Ms. Reed noted. “However, if you’re

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see TJC SURVEYORS, page 8

TJC SURVEYORS continued from page 6

following this interim guidance, make sure that when the pandemic has cleared, you return to the 2008 revision of USP <797>,” she cautioned.

Interim guidance issued by USP during the pandemic includes these other allowances: • For as long as the public health emergency continues, institutions may extend beyond-use dating for lowand medium-risk, nonhazardous compounded sterile preparations that have been prepared in an SCA to 12 hours at a controlled room temperature, or 24 hours when refrigerated (bit.ly/3958yjq).

• If there are PPE shortages, organizations may conserve PPE by storing garb in a way that minimizes contamination, maintain garb within the perimeter of the SCA, or use other measures that USP has outlined (bit.ly/3165IX3).

• Pandemic-era interim guidance also allows organizations to delay recertification of primary and secondary engineering controls as long as these controls are being continuously monitored, and assuming the time between certifications does not exceed 12 months.

• If there is a shortage of sterile 70% isopropyl alcohol, institutions may compound the product in-house.

“USP understood that organizations have really been challenged in maintaining compounded sterile areas and coping with limited product,” Ms. Reed said, urging facilities to increase the frequency of personnel monitoring to every six months while adhering to interim guidance to ensure they are maintaining standards of performance.

With the exceptions listed, organizations need to comply with all the usual USP rules, she reminded meeting attendees. This year, surveyors will be looking to make sure: • there is standardized training in place for staff who prepare and verify compounded sterile preparations; • annual assessments for donning and doffing garb are done; • gloved fingertip sampling is performed; and • media-fill challenges and didactic assessments are conducted.

Training on Surveyors’ Radar Surveyors will want to see that staff members who perform surface cleaning are adequately trained and have documented competency in this task, and that they clean surfaces in the correct sequence using only products approved by the organization, Ms. Reed added.

Another aspect of compounding compliance that surveyors will be placing emphasis on this year is ensuring prior certification reports have been reviewed for completeness, and that positive culture results from air and surface sampling have been addressed.

“Perhaps the most common area of noncompliance with regard to engineering controls is staff or pharmacy

8

leadership not knowing how to read certification reports and not acting on the results,” Ms. Reed said. Remediation strategies need to be documented, and contaminated surfaces and air samples should be retested, she stressed.

Although the Joint Commission has found that organizations do a “really good job training staff and assessing their competencies, some have been challenged in documenting [such efforts],” she noted. For example, “organizations that still use paper documents in particular tend to have a problem if they group their papers by date rather than individual, because it makes it difficult to retrieve the information in a timely manner. By filing paper-based competencies by individual, all tasks completed can be found in a single record and location.”

USP Compliance at MGH Paul Baker, PharmD, the compounding compliance coordinator at Massachusetts General Hospital, in Boston, said he and his colleagues are making sure they have all the proper documentation for compliance in place this year.

This is particularly important given that some surveys are being conducted virtually, he noted, and this shifts surveyor attention away from direct observation and toward checking documents.

“We’ve gotten everything in order by conducting internal audits of our documentation pertaining to certifications, environmental monitoring, scheduled tasks, cleaning logs and other items,” Dr. Baker told Pharmacy Practice News.

Monthly Meetings To be certain his facility is complying with USP requirements, Dr. Baker and his team hold monthly meetings to review documentation and results of reports and update standard operating procedures (SOPs). “Each of our five compounding pharmacies’ managers of record, their lead technicians, the quality compliance team and the chief pharmacy officer have a seat at the table.”

Another strategy that the team uses to increase the likelihood of full compliance with USP standards ahead of a survey is auditing reports that have been issued by vendors’ engineering control certifiers. The team is making sure this equipment is being tested to current standards and is properly calibrated, Dr. Baker said.

“For our environmental monitoring, too, we work with a third-party vendor to ensure that sampling frequency, selection of sites and media use, for example, meet or exceed the USP standard and follow SOPs,” he noted.

Mock quarterly audits, in which a member of the compliance team observes personnel to see if SOPs are being followed as written, also have been useful in identifying potential issues with compliance, Dr. Baker said. “These [drills] have helped us to ensure that what is written in procedures is practiced by staff.”

—David Wild The sources reported no relevant financial disclosures.

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Don’t Be Afraid Of Contamination Testing B

ridget Gegorski, PharmD, was convinced her hospital system had done an outstanding job preparing for the implementation of USP General Chapter <800>.

“Particularly for [NIOSH] Table 1 drugs and chemotherapy, we had implemented a number of processes that significantly cut down on hazardous drug contamination,” Dr. Gegorski, the medication safety officer at University Hospitals Health System, in Cleveland, told Pharmacy Practice News. These steps included both administrative controls, such as staff training, limiting access to areas containing hazardous drugs (HDs) and good housekeeping practices, as well as engineering controls such as biological safety cabinets, proper ventilation and negative pressure rooms.

But surface contamination testing told her those steps had not been sufficient. “When we conducted surface contamination testing, we were still getting at least low positives in the environment, in places where we wouldn’t expect it—areas where we know the operators are doing things correctly and probably are even more cautious than I am about processes, so we didn’t expect to find contamination there,” said Dr. Gegorski, who spoke with Pharmacy Practice News in advance of a presentation on challenges in surface contamination testing at the 2021 virtual annual meeting of the National Home Infusion Association (NHIA).

Studies have documented the importance of wipe sampling programs for identifying the sources of surface contamination in facilities that manage HDs. In 2019, researchers from the University of North Carolina retrospectively analyzed 5,842 individual surface wipe samples from 338 pharmacies over six years. Depending on the location and surface tested, 3.94% to 25.96% of samples had high levels of HD contamination, and the researchers concluded the highest levels of contamination were in preparation areas.

Repeated wipe sampling lowered overall HD contamination: 45.24% of samples detected HDs with the first wipe compared with 31.64% for subsequent wipes (Am J Health Syst Pharm 2019;76[9]:591-598).

After the first round of surface wipe sampling in December 2018 detected contamination in several areas, University Hospitals engaged in all the recommended steps that should follow a finding of HD contamination, including: • cleaning the location with a deactivation/decontamination agent; • evaluating proper use of closed system drug-transfer devices; • observing work practice controls and the use of personal protective equipment (PPE); • revisiting PPE doffing procedures; • evaluating cleaning procedures and the cleaning and decontamination agents used; and

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The number of colony-forming units on this cleanroom sample exceeded the action level and mold was recovered. These results prompted an investigation into the source of the contamination and remediation efforts to prevent recurrence.

• assessing the appropriateness of cleaning frequency.

“We did all that, and we were still finding positives, so we were trying to figure out where we were having particles escape,” Dr. Gegorski said. “Finally, we realized that HD particles found on the outside of vials from our wholesaler could be a significant source of contamination.”

Several recent studies demonstrated that shipments of HDs can come into hospital pharmacies with existing surface contamination. For example, a 2020 literature review of 24 articles from 11 countries concluded that the majority of antineoplastic vials have surface contamination when they arrive (Eur J Hosp Pharm 2020;27[5]:313-314). So University Hospitals added a new step to its HD mitigation processes.

“While USP <800> does not require this, our wholesaler has consented to labeling totes that contain HDs,” Dr. Gegorski said. “Those totes are immediately taken to a receiving area within the HD cleanroom where we store all oncology products. We don’t open the tote until we are in that area and then we wipe down all the container surfaces.”

Pharmacy leadership may fear implementing a surface wipe contamination testing plan because they don’t want to find positives. “USP <800> says that you should do this testing, not that you must do it,” she noted. “But if you start testing and you find positives—and you’re almost certainly going to find positives—then ‘should’ becomes ‘must.’ You have to mitigate, document your action and then retest.

People may not be too keen on that, but fortunately at our institution, our leaders supported our implementation of the process. Having leadership support is key.”

Staff education is vital to a good sampling program, Dr. Gegorski said. “After our first round of sampling in December 2018, we realized that there was a lot of confusion and misinformation. We created education to explain the benefits of testing for HD contamination, the controls that are currently in place to prevent occupational exposure,

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how to reduce HD contamination in everyday practices, and next steps to take if a positive result is found.”

A town hall, held in early 2019, offered an open forum to staff to ask questions related to HD surface sampling.

University Hospitals’ second round of HD sampling took place in February 2019. “We got better results at some of our sites that had been struggling during that round, and we realized that a lot of the December bad samples had come from older compounding facilities,” Dr. Gegorski said. “We conducted a refresh on our compounding areas and now just about every one of our sites has a sterile compounding suite that is, if not brand new, at least refurbished, including deep cleaning of older hoods that was able to cut contamination back.”

Her key message is don’t be afraid of surface contamination testing. “People are afraid of what they’ll find if they start testing, so they don’t do it,” she said. “That’s misguided. I actually think it should be required, not optional. This is an essential thing we need to do to protect our employees, to identify where we’re having problems and do focused improvement.”

Microbial Sampling Sampling in the cleanroom isn’t just for HD contamination.

The 2019 version of USP Chapter <797> lays out requirements for air and surface sampling programs for viable microbial contamination (bioburden) in sterile compounding facilities.

Although it is more specific about certain elements of the program, such as air sample volumes, having a diagram of sampling locations and specifying collection procedures for those locations, “the requirements in the chapter still don’t go into enough detail,” said Abby Roth, the senior director of business operations for CriticalPoint. “It tells you what you need to do, but not how to clearly do it. However, in 2020, the Controlled Environmental Testing Association (CETA) updated its testing guide, ‘CAG-009 Viable Environmental Monitoring for Sterile Compounding Facilities,’ and it provides best practices recommendations to close the gaps in the chapters. It’s a great reference to help you ensure you have a good sampling program.” (The document is available to CETA members; membership costs $245 annually.)

The testing guide provides a list of all the documentation you should have after conducting a sampling session, she said. “That’s really where pharmacies tend to not have all the pieces to put the whole story together,” Ms. Roth told Pharmacy Practice News. For example: “Have you captured the purpose of the sampling session? Is it routine monthly sampling or is it investigational due to environmental excursions? If you do an investigational sampling and that’s not marked on the report, surveyors will ask what this is about,” she said. “It also addresses things such as controls for your media, how to ship the sampling plates to a lab, and how to interpret reports that you receive.”

Another key element of a good microbial sampling program that many institutions neglect, Ms. Roth said, is the

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Documenting the sampling session is essential. This information can yield clues in the event of a microbial excursion or hazardous drug contamination.

control plate. “People often fail to understand what the purpose of control plates would be and why they should use them. They tend to use ‘negative controls,’ sending unused media to the lab to be incubated with the samples, hoping nothing grows. But you never know what happens as your packages go through shipping. If you send an additional ‘positive sample’ to the lab, which is an unused plate the lab will purposely inoculate with organisms, you have a mechanism to know that the media is still good.”

Depending on what your viable sampling report yields, Ms. Roth advised doing a methodical investigation and only addressing one variable at a time to identify the root cause if environmental excursions exceed the action levels described in the chapter. “You don’t want to attack every possible source of the contamination at once because then you won’t be able to pinpoint where the actual source of contamination is coming from.”

In a presentation at the NHIA meeting, Ms. Roth advised pharmacies to have a standard operating procedure for postsampling investigations. “Go in with an open mind as to the source of the contamination. Let the identification of the recovered microorganisms point to where you need to spend your time investigating,” she said. “You can start with lowhanging fruit, such as garbing, and then move on to something like material handling. Make those adjustments and then resample and see what comes back. If you continue to have persistent contamination, then you’re looking at other things like environmental concerns. Is there a facility issue? Is something not sealed properly and you’re getting ambient outside air into the cleanroom?”

The type of organism identified in your sterile compounding environment will be key and will provide clues to identifying the point sources of air and surface microbial contamination, although some identified microorganisms may provide more specific direction than others. “We tend not to see a lot of gram-negatives in the cleanroom suite, so if you see something like Pseudomonas, which tends to breed in damp areas, there’s a good chance you have a problem with your sink,” Ms. Roth said. “On the other hand, something like Bacillus is an ‘everywhere organism,’ so ubiquitous that it is probably going to take multiple attempts to figure out where it is coming from.”

—Gina Shaw The sources reported no relevant financial disclosures.

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The First and Only Antiemetic Approved for Rescue Treatment of PONV Despite Prophylaxis • Barhemsys is a selective dopamine-2 and dopamine-3 receptor

antagonist, offering a pharmacological option with demonstrated XFKJY^ FSI JK‫ ܪ‬HFH^ FY YMJ ITXJX FUUWT[JI KTW 543; RFSFLJRJSY1

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Scan for additional information or visit Barhemsys.com

Packaging and vial shown are not actual size.

Indications

Barhemsys is a selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist indicated in adults for: • UWJ[JSYNTS TK UTXYTUJWFYN[J SFZXJF FSI [TRNYNSL 543; JNYMJW FQTSJ TW NS HTRGNSFYNTS \NYM FS FSYNJRJYNH TK F INKKJWJSY HQFXX • YWJFYRJSY TK 543; NS UFYNJSYX \MT MF[J WJHJN[JI FSYNJRJYNH UWTUM^QF]NX \NYM FS FLJSY TK F INKKJWJSY HQFXX TW MF[J STY WJHJN[JI UWTUM^QF]NX

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Please see Brief Summary of Prescribing Information for Barhemsys on next page.

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Delivers when it matters most

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Delivers when it matters most

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Brief Summary of Prescribing Information for Barhemsys® (amisulpride) Injection See package insert for full Prescribing Information Indications: Barhemsys is a selective dopamine-2 (D2) and dopamine-3 (D3) receptor antagonist indicated in adults for: • prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class • treatment of PONV in patients who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis Dosage & Administration: The recommended adult dosage of Barhemsys: • Prevention of PONV, either alone or in combination with another antiemetic: 5 mg as a single intravenous dose infused over 1 to 2 minutes at the time of induction of anesthesia.

• Treatment of PONV: 10 mg as a single intravenous dose infused over 1 to 2 minutes in the event of nausea and/or vomiting after a surgical procedure.

Protect from light. Barhemsys is subject to photodegradation. Administer Barhemsys within 12 hours of removal of the vial from the protective carton. See full prescribing information for preparation and administration instructions.

Dosage Forms and Strength: Injection: 5 mg/2 mL (2.5 mg/mL) or 10 mg/4 mL (2.5 mg/mL) as a clear, colorless sterile solution in a single-dose vial.

Contraindication: Barhemsys is contraindicated in patients with known hypersensitivity to amisulpride.

QT Prolongation: Barhemsys causes dose- and concentration-dependent prolongation of the QT interval. The recommended dosage is 5 mg or 10 mg as a single intravenous (IV) dose infused over 1 to 2 minutes. Avoid Barhemsys in patients with congenital long QT syndrome and in patients taking droperidol. Electrocardiogram (ECG) monitoring is recommended in patients with pre-existing arrhythmias/cardiac conduction disorders, electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, and in patients taking other medicinal products (e.g., ondansetron) or with other medical conditions known to prolong the QT interval.

Adverse Reactions: Common adverse reactions reported in ≥ 2% of adult patients who received Barhemsys 5 mg (N=748) and at a higher rate than placebo (N=741) in clinical trials for the prevention of PONV were: chills (4% vs. 3%), hypokalemia (4% vs. 2%), procedural hypotension (3% vs. 2%), and abdominal distention (2% vs. 1%). Serum prolactin concentrations were measured in one prophylaxis study where 5% (9/176) of Barhemsys-treated patients had increased blood prolactin reported as an adverse reaction compared with 1% (1/166) of placebo-treated patients. The most common adverse reaction, reported in ≥ 2% of adult patients who received Barhemsys 10 mg (N=418) and at a higher rate than placebo (N=416), in clinical trials for the treatment of PONV was infusion site pain (6% vs. 4%).

Drug Interactions: • Barhemsys causes dose- and concentration-dependent QT prolongation. To avoid potential additive effects, avoid use of Barhemsys in patients taking droperidol.

• ECG monitoring is recommended in patients taking other drugs known to prolong the QT interval (e.g., ondansetron).

• Reciprocal antagonism of effects occurs between dopamine agonists (e.g., levodopa) and Barhemsys. Avoid using levodopa with Barhemsys.

Postmarketing Experience: The following adverse reactions have been identified during postapproval chronic oral use of amisulpride outside of the United States (Barhemsys is not approved for oral dosing or chronic use). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Blood and Lymphatic System Disorders: agranulocytosis; Cardiac Disorders: bradycardia, torsades de pointes, ventricular tachycardia, prolonged QT by electrocardiogram; General Disorders: neuroleptic malignant syndrome; Immune System Disorders: angioedema, hypersensitivity, urticaria; Hepatic Disorders: increased hepatic enzymes; Nervous System Disorders: agitation, anxiety, dystonia, extrapyramidal disorder, seizure; Psychiatric Disorders: confusional state, insomnia, somnolence; Vascular Disorders: hypotension.

Use in Specific Populations: Pregnancy—Risk Summary: Available data with amisulpride use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, there were no adverse developmental effects observed with oral administration of amisulpride in rats and rabbits during the period of organogenesis at exposures about 43 and 645 times, respectively, the exposure delivered by the highest recommended human dose (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%

to 4% and 15% to 20%, respectively. Data—Animal Data: Reproduction studies of amisulpride were conducted in pregnant rats administered oral doses up to 160 mg/ kg/day (43 times the exposure based on area under the curve (AUC) at the highest recommended dose of 10 mg) throughout the period of organogenesis. No adverse embryo-fetal developmental effects were observed at any dose level. Maternal animals exhibited a dose-related decrease in overall mean body weight gain. In rabbits administered amisulpride throughout the period of organogenesis, oral doses up to 210 mg/kg/day (645 times the exposure based on AUC at the highest recommended dose of 10 mg) had no adverse developmental effects on the fetus.

Maternal animals exhibited reduced mean body weight gain at doses of 100 and 210 mg/kg/day and reduced food intake was observed at 210 mg/kg/day. The pre- and post-natal developmental effects of amisulpride were assessed in rats administered oral doses of 60, 100 or 160 mg/kg/day during the periods of organogenesis and lactation. At 160 mg/kg/day (43 times the exposure based on AUC at the highest recommended dose of 10 mg), maternal animals exhibited a reduction in mean body weight gain and decrease in food intake during lactation. Amisulpride had no effect on maternal pregnancy parameters, litter survival or pup growth, development or maturation at any dose tested. Lactation—Risk Summary: Based on case reports in published literature, amisulpride is present in human milk at concentrations that are 11- to 20-fold higher than human plasma in patients taking multiple oral doses of amisulpride (200 to 400 mg/day). The estimated infant daily dose ranged from 5% to 11% of the maternal dose. There are ways to minimize drug exposure to a breastfed infant (see Clinical Considerations). There are no reports of adverse effects on the breastfed child and no information on the effects of amisulpride on milk production. The pharmacological action of amisulpride, a dopamine-2 (D2) receptor antagonist, may result in an increase in serum prolactin levels, which may lead to a reversible increase in maternal milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Barhemsys and any potential adverse effects on the breastfed child from Barhemsys or from the underlying maternal condition. Clinical Considerations: A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 48 hours after Barhemsys administration to minimize drug exposure to a breastfed infant. Females and Males of Reproductive Potential—Infertility: In animal fertility studies, administration of repeated doses of amisulpride over a 10-day period to female rats resulted in infertility that was reversible. Pediatric Use—Safety and effectiveness in pediatric patients have not been established. Geriatric Use—No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment—Avoid Barhemsys in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2). The pharmacokinetics of amisulpride in patients with severe renal impairment have not been adequately studied in clinical trials.

Amisulpride is known to be substantially excreted by the kidneys, and patients with severe renal impairment may have increased systemic exposure and an increased risk of adverse reactions. No dosage adjustment is necessary in patients with mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2).

Overdosage: Doses of oral amisulpride (Barhemsys is not approved for oral dosing) above 1200 mg/day have been associated with adverse reactions related to dopamine-2 (D2) antagonism, in particular: • cardiovascular adverse reactions (e.g., prolongation of the QT interval, torsades de pointes, bradycardia and hypotension).

• neuropsychiatric adverse reactions (e.g., sedation, coma, seizures, and dystonic and extrapyramidal reactions).

There is no specific antidote for amisulpride overdose. Management includes cardiac monitoring and treatment of severe extrapyramidal symptoms. Since amisulpride is weakly dialyzed, hemodialysis should not be used to eliminate the drug.

How Supplied/Storage and Handling: Barhemsys is supplied as follows: • NDC 71390-125-20: Package of 10 cartons. Each carton (NDC 71390-125-21) contains one single-dose vial of Barhemsys (amisulpride) injection, 5 mg in 2 mL (2.5 mg/mL).

• NDC 71390-125-50: Package of 10 cartons. Each carton (NDC 71390-125-51) contains one single-dose vial of Barhemsys (amisulpride) injection, 10 mg in 4 mL (2.5 mg/mL).

Store vials at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

Patient Counseling Information: QT Prolongation—Instruct patients to contact their healthcare provider immediately if they perceive a change in their heart rate, if they feel lightheaded, or if they have a syncopal episode. Drug Interactions—Advise patients to report to their healthcare provider if they are taking drugs which prolong the QT interval.

Lactation—Women may consider reducing infant exposure through pumping and discarding breastmilk for 48 hours after Barhemsys administration.

BAR HCP BS 10/2020

Barhemsys® is a registered trademark of Acacia Pharma Limited. © 2021 Acacia Pharma Inc. All rights reserved. PP-BAR-1929 04/2021 Acacia Pharma Limited and Acacia Pharma Inc. are wholly owned subsidiaries of Acacia Pharma Group Plc.

The Cost Equation for CSTDs C

an a hospital make a sound economic evaluation when it comes to purchasing a closed system drug-transfer device (CSTD)?

A group of Canadian researchers say no. They claim the literature addressing the economic impact of CSTDs is sparse, and the evidence in the handful of studies that do tackle the issue lacks robustness (Eur J Hosp Pharm 2020;27[6]:361-366).

But Patricia C. Kienle, RPh, MPA, BCSCP, the director of accreditation and medication safety at Cardinal Health, said she has some issues with the study. First, it was done by Canadian researchers and published in a European journal. That’s a problem, she noted, because the way health systems get paid in this country is far different than payment approaches in Europe or Canada. Moreover, most health systems rate safety and efficacy above cost when assessing CSTDs. Still, all three factors—the “big triad” of purchase decision making—need to be addressed during any evaluation of CSTDs, Ms. Kienle stressed. “It’s the same trio that pharmacists use to assess formulary drugs,” she noted.

Safety may be the easiest aspect to evaluate, Ms. Kienle said. “There are plenty of studies in the literature that say these devices absolutely work to protect personnel against contamination of chemotherapy when used correctly” (J Oncol Pharm Pract 2019;25[5]:1160-1166).

On the question of cost, Ms. Kienle ticked off three key determinants in weighing whether a purchase makes sense: the price of the device itself; the available reimbursement; and the cost of antineoplastic drugs—a big-budget item that some health systems have tried to moderate by using CSTDs to optimize the value of single-dose drug vials through beyond-use dating (BUD).

Unlike in Europe and Canada, she said, in the United States, medical device cost “is largely driven by which group purchasing organization the hospital uses. And sadly,” Ms. Kienle added, “the decision is often made solely by materials management personnel looking at which device is cheapest, without involving pharmacy and nursing to see which one works best in their organization. That’s a problem from a cost perspective.”

However the cost calculus is conducted, it is a critical one to perform, Ms. Kienle stressed, “because cost is the biggest barrier to adopting CSTDs.”

‘Safety, Quality and Accuracy’ At Cone Health, in Winston-Salem, N.C., Andre Harvin, PharmD, the director of Pharmacy, Oncology Services, said that although cost was a consideration in deciding on a CSTD upgrade, “it was never from a ‘hey, this is going to save us money’ perspective.

“It is a big pill to swallow,” Dr. Harvin conceded, referring to the cost of CSTDs, “but what we look at is the potential for preventing exposure to our technicians and nursing staff and reducing spills around the hood.”

Last year in the midst of COVID-19, he said, “we did look at the cost per component to find ways we could save money.”

But the savings, he added, were “nothing earth-shattering.”

He drew a parallel between the benefits of CSTDs and Cone Health’s automated robotic compounding technology. The latter, he said, “is a multimillion-dollar system that provides gravimetrics for anything drawn up by hand. That’s a hard return on investment [ROI] to talk about. We justify it by safety and reducing low-level exposure for technicians. It’s safety, it’s quality, it’s accuracy that we’re really looking for.” The same standard applies to CSTDs, he said.

“I never get the argument of why you have to bring an ROI to the table for some of these [technologies]. Either you invest in quality and safety, or you don’t.”

Drug Vial Optimization The use of CSTDs for drug vial optimization (DVO) could help to offset part of the devices’ acquisition costs. But the practice remains controversial. It requires elaborate safety testing to prove the drugs remain stable and uncontaminated as a result of CSTD use. The tests are complex and remain beyond the reach of most hospitals. Ms. Kienle said accrediting organizations have been citing hospitals throughout the country for using the devices to extend vial BUD unless they have performed the required tests. see COST EQUATION, page 24

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95% USP Adherence at Ascension Is a Team Effort C omplying with compounding guidance is an onerous task for any institution, but rolling out a standardized compounding compliance program across 146 health systems and achieving 95% adherence is Herculean— and a feat that Ascension can claim to have achieved.

According to Shewan Aziz, RPh, PhD, the vice president of pharmacy at Ascension Texas, in Austin, the key to his facility’s success has been implementing standardized system-level guidance while also meeting the needs of individual hospitals.

The path to near-perfect USP compliance at Ascension started in 2012, when the organization created a compounding subcommittee. The committee, which consisted of compounding experts from individual Ascension hospitals, scoured existing compounding guidance documents, literature and best practices issued not only by USP but also by the National Institute for Occupational Safety and Health, the Occupational Safety and Health Administration, and state boards of pharmacy, Dr. Aziz said. Using these sources, the task force developed two Ascensionspecific guidelines: one for nonhazardous compounds and one for hazardous compounds.

The guidelines outline best practices for everything from IV room contamination management to use of compounding robotics, IV workflow systems and standardized closed system drug-transfer devices for chemotherapy, Dr. Aziz noted.

The subcommittee also created documents that include compliance tips and “pearls,” he added, and they developed standardized policies and procedures that individual hospitals could implement, as well as training and competency assessment modules they could use for their staff.

When it came to procuring funds for capital projects, the national team also provided this to each hospital, helping them design and build USP-compliant IV rooms.

To further enhance the safety of compounded drug management, the national compounding subcommittee even created auxiliary warning labels with handling instructions for all IV hazardous drug preparations, and they built in hazardous drug alerts for automated dispensing cabinets and electronic medication administration systems, Dr. Aziz said.

Finally, the team developed key performance indicators and compounding metrics to help individual hospitals ensure they are complying with the national-level guidance.

“In 2012, before we undertook this standardization initiative, we had 55% compliance with USP <797>, and that’s gone up to 95% today,” said Dr. Aziz, noting that the outlying 5% of hospitals are expected to be compliant with the Ascension compounding guidance by August 2021.

Dr. Aziz said he expected the system to be prepared for USP General Chapter <800> compliance and any additional

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TJC’s Top Reasons For USP Noncompliance

T

he reasons for noncompliance with USP compounding standards change from year to year, ranging from inadequate competency assessments to incomplete environmental testing. But “one thing we continue to see that hasn’t changed since day one is that those responsible for compounding are not taking the time to fully review their testing certification reports,” said Robert Campbell, PharmD, the director of clinical standards interpretation for hospital and ambulatory programs at the Joint Commission, in Oakbrook Terrace, Ill. “Too often, facilities getting the testing done do not hand the results to leadership, or pharmacy leadership takes a look at the front page of a report and does not look at the nuts and bolts of the report’s findings,” Dr. Campbell said at the ASHP 2020 Midyear Clinical Meeting and Exhibition.

Dr. Campbell pointed to several top reasons for noncompliance, including: • Personnel: a lack of competency assessments completed, a lack of didactic testing scoring and incomplete initial competency assessments.

• Products: drug shortages leading to changes in compounding products that are not accompanied by necessary changes to environment and beyond-use dating, and a lack of proper labeling.

• Environmental standards: incomplete testing and certification reports and improper resolution of these report results.

—D.W.

changes that might be contained in the revised USP <795> and <797> chapters once they are finalized and made official. “Given all the work and effort that has gone on at our hospitals to adhere to our own compounding guidances, we will be ready to meet all compounding standards when the USP appeals are resolved,” Dr. Aziz explained at the ASHP 2020 Midyear Clinical Meeting and Exhibition. “Our

P H A R M AC Y P R AC T I C E N E WS CO M P O U N D I N G S P E C I A L E D I T I O N • 2 0 2 1

see USP ADHERENCE, page 20

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Kienle’s 10 New Building Blocks of Compounding Safety Each year, Patricia Kienle, RPh, MPA, the director of accreditation and medication safety at Cardinal Health, shares 10 points that she believes pharmacists need to consider to ensure compounding safety and compliance with USP, state boards of pharmacy and other regulatory bodies.

Get up to speed on USP compounding-related chapters and state regulations. USP remanded the long-anticipated revised USP General Chapters <795> and <797> on March 12, 2020, and USP <800> on hazardous drugs is not yet compendially applicable, because it ties its federal enforceability to approval of the 2019 revisions of <795> and <797>. The appeals of the USP chapters were all about beyond-use dates (BUDs) and the ability to extend them. The USP Committee isn’t finished with discussions about the new revisions, but it’s unlikely that content related to facilities, methods of environmental monitoring and other important aspects of compounding, will change.

So, the information added to the remanded Chapter <797>— particularly information in the boxes in the remanded chapter—is valuable to incorporate into policies. To keep up to date, institutions should subscribe to the USP Compounding Compendium (www.usp.org/products/usp-compounding-compendium) and follow the USP compounding page (www.usp.org/compounding).

Regarding state regulations, in some cases, they are more stringent than USP standards, and some states already have incorporated aspects of the revised but remanded USP chapters into their state regulations. For example, although USP <825>, the chapter concerning radiopharmaceuticals, has been official since Dec. 1, 2020, it has the same federal delay in enforceability as <800>, but some states have announced they will consider <825> enforceable in their states. Because of ongoing confusion about which standards to adhere to—USP or state regulations—especially around BUD and

frequency of personnel requalification, pharmacies should follow the more stringent regulations, which may be on the state side.

Be aware of allowances and restrictions when unusual circumstances occur. The COVID-19 pandemic created situations no one anticipated. USP, ASHP, Institute for Safe Medication Practices (ISMP), CDC and FDA developed documents with allowances during the public health emergency. These included adjustments for BUDs, garb and personal protective equipment, as well as other components of compounding regulations and best practices, assuming appropriate oversight. As the situation has evolved, these documents have been updated.

Given these frequent changes, compounding pharmacists should monitor key sources of information: ASHP Connect, USP compounding pages, ISMP’s website and newsletters, CDC, as well as FDA guidance pages. It’s important to remember that these allowances are usually only meant for the duration of the public health emergency and are not intended to be permanent policies.

States also have issued alerts concerning their compounding expectations during the public health emergency, and many state health-system pharmacy societies provided summaries and notices to their members. So, it’s critically important to keep current with state-level changes by monitoring your state’s board of pharmacy website.

USP General Chapter <797> now includes strengthened recommendations for performing “at least monthly” surface wipe sampling for bacterial contamination in all classified areas and pass-through chambers. Photo credit: CriticalPoint Center for Training and Research

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‘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 [certification] reports, and take action based on the results.’

—Patricia Kienle, RPh, MPA Be familiar with the expectations of your health system’s accreditation organization.

The four hospital accreditation organizations deemed by the Centers for Medicare & Medicaid Services include the Joint Commission (TJC), DNV Healthcare, HFAP and the Center for Improvement in Healthcare Quality. All of these organizations are focusing on sterile compounding as they survey facilities.

TJC’s most recent information discussed at the ASHP 2020 Midyear Clinical Meeting (see “USP Compliance Remains a Focus of TJC,” page 6) identifies several problem areas they have found during surveys: competency assessments (including establishing a passing score for any tests), changes in BUDs when product preparations are changed, and response to certification and environmental monitoring reports. Make sure you have these items addressed before these organizations visit your site. Whatever accreditation organization you use, be sure to stay current with its guidance.

Benchmark your practices. Much of USP’s guidance focuses on existing best practices in compounding, including their requirements for 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. Review those procedural aspects and explanations and incorporate them into your own policies and procedures. To ensure that your practices meet the USP minimum standards as well as changes that evolve as practices mature, conduct gap analyses at least annually. Gap analysis tools are available at the ASHP Compounding Resource Center (www.ashp.org/Pharmacy-Practice/Resource-Centers/Compounding), CriticalPoint (www.criticalpoint.info) and other sources.

Work toward full compliance with USP <800>.

Although it is not yet federally enforceable, USP <800> is designed to protect health care workers, so work toward full compliance with the chapter. One piece of guidance in the chapter is to make sure your Assessment of Risk reflects best practice as well as how you handle hazardous drugs used in your institution. This requires a team-based, interprofessional effort to make sure your practices are appropriate throughout the health system.

Other important components of the chapter include evaluation of use of closed system drug-transfer devices

in the compounding and administration of antineoplastic agents, and implementation of wipe sampling for hazardous drug contamination.

Update staff training and requalification. The remanded 2019 revision of USP <797> includes a specific list of core competencies to meet current compounding requirements. Institutions can use information from these core competencies to guide staff training and requalification efforts and policies and procedures. Be sure that all pharmacy compounding staff have documented competency, and remember that part-time or PRN pharmacists who are responsible for occasional coverage in the IV suite need to do more than just check a drug name with a label; they need to be aware of all the requirements to oversee operations occurring as they sign off on compounded sterile products.

Be sure to include nurses and others, in addition to compounding personnel, in appropriate training and in-servicing. For example, nuclear medicine technologists who handle radiopharmaceuticals now have specific requirements laid out in USP <825>, and USP <797> also may apply if they prepare nonradiopharmaceutical sterile products. Environmental Services personnel who clean the compounding areas need to be made aware of the hazardous drug risks they might encounter, and they must have documented cleaning competency.

Consider advanced training. A Designated Person is defined in the proposed USP Chapter <795>, proposed <797> and official <800> as someone with a higher level of responsibility for oversight of compounding. It’s up to the organization to choose who that individual is, but there has to be someone who is the point person on compounding issues and who coordinates and monitors related activities. Most organizations have a pharmacist in this role, and some states require that, but the Designated Person also can be a highly trained technician. They don’t have to be a supervisor, and they can be responsible for multiple sites.

Pharmacists and pharmacy technicians now can attain advanced compounding certifications. For the pharmacist, Board Certified Sterile Compounding Pharmacist (BCSCP) certificates can be obtained through the Board of Pharmacy Specialties, while the Pharmacy Technician Certification Board awards Certified Compounded Sterile Preparation Technician (CSPT) certifications. Although passing a didactic test does not guarantee competency in mixing, it is a credential that demonstrates knowledge of compounding requirements. see BUILDING BLOCKS, page 20

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BUILDING BLOCKS continued from page 19

providing the same level of service as you would be if you were doing the compounding in-house. CMS’s Hospital Conditions of Participation—as well as its accreditation standards—require pharmacies to obtain sign-off from hospital leadership to use the external compounding companies and also require that written agreements be in place with the outsourcing compounders. These agreements should establish expectations and set out a plan for monitoring to make sure these expectations are met. What I suggest institutions do is develop reasonable expectations, including at least one operational and one clinical expectation. Make sure you look through FDA assessments for any outsourcing compounder you’re thinking of contracting with (bit.ly/2PvYeKq).

Evaluate certification reports and environmental monitoring program, procedures and results. Surveyors and state board inspectors often tell me that when they ask for the most recent certification and environmental monitoring reports, they find that the person supervising compounding operations hasn’t even reviewed 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.

Record temperature, humidity and pressure differentials at least daily; make sure your certification reports summarize all the key required elements; and have your certifier review the areas that pass, fail or need attention after their evaluation. Be sure you receive a written report within a few days of the surveyor’s visit, and schedule the return visit within six months to be sure you will have the certification completed before six months elapses, per USP requirements. In addition, design your microbial environmental monitoring program to detect excursions, incorporate wipe sampling for the detection of hazardous drugs that have escaped containment, and update your training and policies based on these results.

Use the FDA as a resource. Be sure to monitor the FDA website (bit.ly/2PzWbow) for new and revised compounding-related documents. The FDA issues compounding-related guidance documents, such as those related to insanitary conditions (bit.ly/2PvYQQe), which were updated in November 2020. Other documents concern repackaging, hospital and health-system compounding, and compounding from bulk substances. These documents may be in draft or final form, so be vigilant and make sure you have the most recent revision.

Evaluate outsourcing. The way Centers for Medicare & Medicaid Services (CMS) sees it, contracting with an external compounding facility means you feel that facility is

Ms. Kienle is an employee of Cardinal Health and a member of the USP Compounding Expert Committee. The comments in this article are her own.

USP ADHERENCE continued from page 16

experience shows that if you want to implement best practices and improve care, you can do it.”

Still Some Confusion Ascension’s success doesn’t mean there isn’t work to be done regarding USP compounding compliance. With the appeals process for USP Chapters <795> and <797> now over and the chapters remanded, and with <800> currently informational, health-system pharmacies may be confused about which protocols and procedures they should be implementing.

“None of us know what the future will hold” with regard to changes to these chapters, Robert Campbell, PharmD, the director of clinical standards interpretation for hospital and ambulatory programs at the Joint Commission, in Oakbrook Terrace, Ill., said at the ASHP Midyear meeting.

For the time being, Brian Serumaga, PhD, RPh, a scientific liaison at USP, in Rockville, Md., said his organization “has continued to emphasize through stakeholder engagement and webpage updates that due to the remand of the 2019 revisions of <795> and<797>, the currently official versions of <795> and <797> are those last revised in 2014 and 2008, respectively.”

Although the appeals focused on the framework for establishing beyond-use dates (BUDs) for sterile and nonsterile

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compounded preparations, and for extending BUDs beyond the defaults in the chapters, “the Compounding Expert Committee may consider additional changes,” Dr. Serumaga said.

“In March 2020, the USP appeals panel remanded the chapters to the compounding expert committee, with a recommendation that the committee carry out further stakeholder engagement on the issues touched on in the appeals,” added Dr. Serumaga, who spoke at the ASHP meeting.

In regard to USP <800>, Dr. Serumaga said USP considers it informational only, but the organization “encourages” early adoption of the chapter, and “regulatory bodies and oversight organizations may make their own determinations regarding the applicability and enforceability of <800> for entities within their jurisdiction.”

Indeed, for early USP <800> adopters, Dr. Campbell said the Joint Commission surveyors will be surveying according to criteria from that chapter, and <800> guidelines will supersede the 2008 version of <797> when the two chapters conflict. “For example, the 2008 version of USP <797> states that you cannot compound hazardous drugs in a segregated compounding area, whereas <800> allows for compounding these preparations in a contained segregated compounding area,” he said. “If you want to adopt <800>, you need to meet all the requirements for a contained area.”

—David Wild The sources reported no relevant financial disclosures.

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The ‘Gemba’ Walk to Compliance

D

oes your hospital pharmacy have a designated specialist assigned to walk through your sterile compounding space every single day, looking for what the FDA deems “insanitary conditions,” such as rust or paint chips, signs of water leakage, or visible microbial contamination? That’s what they’re doing at the Moses Cone Memorial Hospital, in Greensboro, N.C. In 2016, the FDA issued “Insanitary Conditions at Compounding Facilities,” a draft guidance document that was revised in 2018, to provide examples of conditions that the agency deems insanitary to assist compounders in identifying similar conditions in their own operations.

“That got us thinking differently about how we are addressing these conditions,” said Kevin Hansen, PharmD, the assistant director of pharmacy. “We noticed that when you look at 503B compounding facilities and FDA inspection documentations, their observations and warning letters are almost all focused on insanitary conditions. So, even though we are not a 503B outsourcing facility and [are] operating under Current Good Manufacturing Practices, we wanted to go above and beyond the minimum standards outlined by USP <797>.”

Dr. Hansen met with Kathleen Forbis, CPhT, CSPT, and Clinton Meachum, CPhT, CSPT, to develop a strategy. Since Moses Cone had recently gone through Lean management training, they selected the “Gemba Walk.” A Japanese term, “gemba” means “the place where it happens.” Its purpose is to allow managers and leaders to observe the actual work process and identify opportunities for continuous improvement.

“We can sit at our computers and look at numbers all day, but the real bang for your buck requires you to go to the place where the work occurs and put [your] eyes on what is actually occurring,” Dr. Hansen said. “That can be challenging in the cleanroom, since you have to fully cleanse and garb, so there needs to be some intentionality of entering the cleanroom.”

Building New Career Paths Dr. Hansen said he chose specialist pharmacy technicians for the project because “we’ve focused our efforts on building new career paths for our pharmacy technicians that give them options to step into highly specialized roles. In some cases, our state board of pharmacy even recognizes

22

and allows highly qualified technicians to conduct certain verifications that a pharmacist would normally do, so this presented an opportunity to expand the roles of both our technician and pharmacist workforce simultaneously.”

To focus the Gemba safety walk, Moses Cone Memorial Hospital used the acronym CLEAN: Checklist: Construct a checklist of items to look for during the safety walk, which was adapted by the FDA insanitary conditions draft.

Look: During each shift crossover (three times per day), have staff walk the sterile and nonsterile compounding areas.

Evaluate: Staff evaluate what they found and whether there were any concerns that need to be addressed.

Address: Staff immediately address any insanitary conditions and communicate with the team.

Note: Staff notate any findings from the safety walk and use a web-based application to document remedial actions.

“We do this walkthrough every day, constantly visualizing things that might not look right. No visible particles, rust or loose ceiling tiles,” Ms. Forbis said. “If things are not running smoothly, we troubleshoot and take immediate actions.”

Cameras are mounted in each of the sterile compounding hoods, and Mr. Meachum and Ms. Forbis review video from those cameras every day to monitor the aseptic technique of each of the compounding technicians. “If we see deviations in technique, we go over that with them,” Ms. Forbis said.

“We initially were concerned that the technicians wouldn’t appreciate that, but they’ve all adapted to it very well, and we can really see them making improvements in their aseptic technique practices. When there are safety events, we can go back and see what happened, and focus on how the systems failed,” she said.

When the Gemba walks first began in January 2019, the technicians made frequent reports: dirt in this corner, rust on the bottom of this piece of equipment. “As we got ahead of things and became more consistent in maintaining good practices,” Ms. Forbis said, “reporting and necessary corrective actions began to decline.”

—Gina Shaw Dr. Hansen and Ms. Forbis reported no relevant financial disclosures. The Moses Cone initiative was presented as a poster (4-158) at the ASHP 2019 Midyear Clinical Meeting.

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“I really want this extended BUD to work, and I’ve been saying this for years,” Ms. Kienle said. “I want to save drug and I want to save money. But I wouldn’t do it at the expense of not knowing the safety to the patient.” (For more on DVO and BUD, see sidebar.)

The Oncology Perspective Dmitry Walker, PharmD, the assistant director of Oncology, Infusion and Investigational Drug Services at West Virginia University (WVU) Medicine, in Morgantown, said the use of CSTDs for DVO would “[allow] hospitals to extend dating and realize cost savings by reducing the amount of wasted drug left over in each vial after compounding patient-specific doses.”

‘I never get the argument of why you have to bring an ROI to the table for some of these [technologies]. Either you invest in quality and safety, or you don’t.’

—Andre Harvin, PharmD

But the challenge, he said, is performing the BUD stability studies required for every drug and concentration. “I would like to be able to do that here at WVU Medicine for a lot of our monoclonal antibodies because of their high cost.

He cited examples of “drugs we were interested in pursuing”: polatuzumab vedotin-piiq (Polivy, Genentech), nivolumab (Opdivo, Bristol Myers Squibb), trastuzumab (Herceptin, Genentech), paclitaxel protein-bound particles (Abraxane, Bristol Myers Squibb) and applicable biosimilars.

“The issue we’re running into is that they are large-molecule drugs and [it’s] not as easy as doing stability studies for regular molecule drugs like chemo,” Dr. Walker said.

“The molecules are so large they require more sophisticated technology, and that is very expensive and very difficult to do for a health system. So, that’s the main barrier of being able to show the financial value of using CSTDs for the new agents that make up the large percentage of the drug spend at oncology centers nationwide.”

—Bruce Buckley Kienle is a member of the USP Compounding Expert Committee, but her comments in this article are her own and not those of USP or Cardinal Health, her employer. Drs. Harvin and Walker reported no relevant financial disclosures.

More on Drug Vial Optimization

T

he issue of using closed system drug-transfer devices (CSTDs) for drug vial optimization (DVO) remains a topic of debate, acknowledged Jim Jorgenson, RPh, MS, the CEO of Visante Inc. “But with continued drug shortages and a renewed focus on drug costs and waste,” the practice “is receiving more attention,” Mr. Jorgenson told Pharmacy Practice News.

Unfortunately, that attention isn’t always reflected in studies examining the cost of discarded drugs from singledose vials. He cited, as an example, a recent report from the National Academies of Sciences, Engineering, and Medicine that sought to quantify those added costs to the Medicare Part B program and other payors (JAMA 2021 Feb 25. doi:10.1001/jama.2021.2414). Although the report questioned some of the methods for calculating the financial impact of drug waste, it acknowledged the problem was severe enough to warrant action. The report suggested several steps, including rebates from manufacturers and the creation of policies that would allow for delivery of medication to multiple patients from a single vial in a safe manner.

“What the authors didn’t mention was [DVO],” Mr. Jorgenson said—an omission he addressed in a comment to the report posted online (bit.ly/38TpPMD). “One of my points was that USP standards mandate a six-hour expiration for single-use vials if the vial is entered and maintained in ISO [International Organization for Standardization] 5 air condition,” he said. “Using a CSTD, compounding pharmacists can

24

maintain sterility beyond that six-hour time frame.”

CSTDs can do so safety because the devices “create a closed environment that prevents the escape of hazardous medications like cytotoxics,” he explained. “However, at the same time they prevent egress of hazardous medications, they also prevent ingress of contaminants into the vial.”

Mr. Jorgenson said there is “a growing body of evidence” to support the safety and efficacy of DVO as a means for reducing waste from single-dose drug vials. “Studies by University of North Carolina, Indiana University Health, MD Anderson and The James Cancer Center at The Ohio State University have all demonstrated the ability to use CSTDs to maintain sterility of single-use vials beyond the six-hour rule from point of entry,” and save significant health care dollars in the process, he said (bit.ly/3sDW1Lu). “There is also growing international acceptance of DVO, with Japan and parts of the European Union now allowing the use of CSTDs for DVO programs.”

There also are significant cost savings to be had, as evidenced by the millions of dollars some large oncology centers are saving by using CSTDs for DVO (bit.ly/2P2N4gA).

But “more work needs to be done on this,” Mr. Jorgenson stressed. “USP really is the final arbiter on DVO and BUD. It’s up to them to develop standards for CSTDs to be used to extend the six-hour BUD of single-dose vials, as Visante has noted in comments” to USP.

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Navigating 503A and 503B Rules Not for the Faint of Heart D uring the Visante Business of Pharmacy Virtual Forum 2020, a topic that stirred considerable discussion was how to stay clear of the financial and regulatory pitfalls of sterile compounding. Whether a health care system operates as a traditional 503A compounder, focusing solely on patient-specific prescriptions, or is considering a 503B build-out to serve multiple facilities within its network, major variables need to be considered.

One looming policy roadblock that came up is the question of when the FDA will implement its draft 1-mile radius provision, which allows 503A hospital pharmacies to distribute its compounded sterile products (CSPs) to owned and controlled health care facilities, as long as they are located within a 1-mile radius.

that DIY approach is not for the faint of heart. Ryan Stice, PharmD, the vice president of pharmacy at Sutter Health, headquartered in Sacramento, Calif., noted that, given the pressures of drug shortages, quality assurance and steadily rising costs, “it’s harder to sell not doing something versus taking action.” To that end, he and his colleagues did some research, and “it looked like we had a great 503B opportunity. But then we did a deeper dive and realized that it only made sense to insource about 10 CSPs, and so we decided it just wasn’t a smart move, based on volume and value.”

The question of value can be difficult to answer, noted one forum participant from a health system that submitted an application to be an FDA-registered 503B facility in May 2019. “If we had approached this simply from a cost-

‘For health systems that handle CSPs in ways that may be perceived as blurring the line between [503A and 503B] compounding, … [the 1-mile rule] puts them at risk of heightened scrutiny by regulatory agencies.’

—Fred Massoomi, PharmD

The “1-mile rule,” as it’s known, was first released in draft form as part of the FDA’s 2016 compounding guidance.

The provision is based on the reasoning that a centralized hospital pharmacy sending compounded drugs beyond a 1-mile radius would be operating like a 503B pharmacy but not regulated as one.

In an April 2020 guidance establishing temporary policies on the compounding of certain drugs during the COVID-19 pandemic, the FDA made it clear that the 1-mile rule was still in draft form and would not be enforced yet.

Fred Massoomi, PharmD, a senior director at Visante and a facilitator at the forum, said he had expected a final version of the 1-mile rule to come out by the end of the 2020, but as of May 2021, the rule had not been finalized. Regardless of how that process plays out, he emphasized that health systems need to consider how the provision might affect their compounding operations. Indeed, “some states already have incorporated similar limitations into their statutes,” Dr. Massoomi said. “For health systems that handle CSPs in ways that may be perceived as blurring the line between the two compounding models, [the 1-mile rule] puts them at risk of heightened scrutiny by regulatory agencies.”

Still Scary: DIY 503B Building your own 503B facility is another fraught sterile compounding topic that came up during the forum. Based on comments made by several forum participants, taking

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justification basis—we invested about $10 million—there is no way this would have been a viable operation,” said the forum participant, a chief pharmacy officer, who requested anonymity due to corporate communication policy. “We had to build other services into our centralized service center [CSC] for this to really work.”

Adding those other services “was part of our overall strategy of building a viable CSC, rather than a partial solution to 503B compounding,” the participant stressed.

“A CSC strategy that includes a 503B has an ROI [return on investment] that is much more attainable.”

John Fanikos, PharmD, the executive director of pharmacy at Brigham and Women’s Hospital, in Boston, agreed that an integrated services approach to 503B is the key to success. “Contracting and supply chain distribution initiatives, nuclear medicine consolidation, code tray fulfillment—whatever service line you need to add in order to leverage that centralized facility is the way to make the investment work,” Dr. Fanikos said.

Making the Decision Hospitals should consider a few key factors when deciding whether to build a 503B facility, noted Matthew Brown, PharmD, the pharmacy manager - compounding pharmacy at Duke University Health System Raleigh-Durham, in North Carolina. Duke is one of the few health systems to produce

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Amid COVID-19, the Challenge Of DIY 503B Continues I n retrospect, Vanderbilt University Medical Center hit “pause” on creating its own in-house 503B compounding facility at just the right time.

As 2019 drew to a close, the medical center’s Department of Pharmaceutical Services determined that, before moving forward, it would take the time to put key products through the enhanced stability testing required for meeting the extended beyond-use dating (BUD) standards that are part of the FDA’s current good manufacturing practice requirements for 503B compounding outsourcing facilities.

“We wanted to send all of our products through that level of testing just as a measure of preparedness for the future,” Deidra Dickerson, PharmD, the manager of sterile and nonsterile compounding at the Nashville, Tenn., institution, told Pharmacy Practice News. “So at the end of 2019, we made the decision to start using a 503B outsourcing facility while pulling back from our own internal program, planning to ramp back up later once the results started trickling in.”

‘In these critical [pandemic] situations, I cannot underscore enough the importance of having these [outsourcing] relationships, and even multiple relationships for redundancy.’

—Deidra Dickerson, PharmD After meeting with several outsourcing facilities, Vanderbilt settled on QuVa, which has compounding facilities in Sugar Land, Texas, and Bloomsbury, N.J., and serves more than 2,200 hospital customers with over 280 product SKUs. “We placed our first order with QuVa in January, right before the pandemic hit the United States,” Dr. Dickerson said. “By March and April, they were experiencing such demand that they were no longer able to bring on new customers because of the need to properly serve existing customers.”

Vanderbilt initially outsourced only a handful of products to QuVa, including ephedrine, epinephrine and phenylephrine syringes and phenylephrine and midazolam IV bags. But as the pandemic continued, more were added.

“Fentanyl was an item that became challenging early on, and we were having difficulties procuring any of the vials for infusion we typically get from our standard wholesaler,”

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Dr. Dickerson said. “QuVa was able to step in then, which took a stressor off of us during that time frame.”

Funds Dry Up During Pandemic Before the pandemic, many hospitals and health systems, such as Vanderbilt, were putting significant investments into pharmacy as one of their profit centers. However, with COVID-19 decimating the bottom line for many institutions, the availability of capital for major new investments, such as a 503B compounding facility, has dried up. “Of the CEOs and chief pharmacy officers I’ve spoken with, most of them say that prospectively trying to get into 503Bs probably isn’t in the works for at least another couple of years, financially speaking,” said Michael Souza, the CEO of New England Life Care (NELC), whose Advanced Compounding Solutions (ACS) 503B outsourcing facility is jointly owned by its 50-plus member hospitals (most in the Northeast).

Keith Thomasset, PharmD, ACS’s vice president of clinical solutions and chief pharmacy officer, said the company’s approach is catching on. “We are experiencing an uptick in interest based on our model, so much so that we’ve created a joint venture with another system-owned 503B facility in Minnesota, and we are combining our efforts both to market to a broader base and provide more capacity for the increased demand we’re seeing,” Dr. Thomasset said. “This is at least partially attributable to pressures from the pandemic, especially for those hospitals that were considering developing their own 503Bs. But even pre-pandemic, the capital investment and operating expenses associated with opening a 503B can get pretty scary if you’re going it alone.”

Fagron Sterile Services US, another leading 503B outsourcing company, found early in the pandemic that it had to modify its production planning. “We had a significant increase, approximately 20%, in demand from our customers, with hospitals requiring new and different products or much greater quantities of existing products for needs such as supporting high numbers of patients going on ventilators,” said Jason McGuire, who oversees the company’s operational and quality areas. “They needed

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large quantities of narcotics such as fentanyl and hydromorphone to sedate patients, and they just didn’t have the support within their facilities to provide the dosage forms and volumes they needed. Every day, there was something new that would pop up from health systems, and some of these products, quite frankly, we didn’t have immediately available,” Mr. McGuire said. “But we [were] still able to respond fairly quickly with something that would work and yet maintain a high level of quality.”

‘[It] costs, by conservative estimates, $5 [million] to $15 million and three years to open your [503B] doors. It’s not a quick fix, not just <797> on steroids.’

—Eric Kastango, MBA, BSPharm

A Pioneer Partners Up The midwestern hospital system SSM Health, which operates more than two dozen hospitals and health centers in Wisconsin, Illinois, Oklahoma and Missouri, was the first health system to register as a 503B sterile compounder in 2014, and remains one of only a handful of such systems in the country. SSM Health currently produces about nine products in-house. Because operating rooms closed to elective surgeries during the height of the pandemic, SSM Health pharmacy director Kristina Bryowsky, PharmD, said her facility shifted production toward bags for the ICU and away from OR syringes. “We saw a reduction in volume overall because of the ORs, so we shifted the days we would have produced other products to make sure we stocked up heavily on IV products for the ICUs, so we never had a shortage of those bags. That was a big relief for our ICU team,” Dr. Bryowsky said.

In December 2019, SSM Health had started its first round of testing to add fentanyl to its list of compounded products, but after the pandemic began, the system was unable to access active pharmaceutical ingredients (APIs) to complete the next two rounds of testing. Dr. Bryowsky said they will complete that testing before the end of the year, but in the meantime, to accommodate the high volume of fentanyl needed at the system’s larger hospitals, they use either an outsourcer or compound in-house under 503A’s internal <797> seven-day BUD limits.

“Some of our bigger centers had allocations with larger outsourcers, but if you didn’t have that already, you weren’t going to get it during COVID-19,” she said. “Because our ORs were closed and care had shifted to patients who were incredibly acute, the volume wasn’t as high. So we were able to spend the extra time to make internal batches of 300 bags with 2- or 5-mL vials, which is not something an outsourcer will do anyway.”

Because of the shutdown of elective surgeries in both hospital ORs and ambulatory surgery centers, compounders such as Fagron also were able to shift some of their capacity to meet hospitals’ ICU needs. “It was still a bit of a challenge, especially as it relates to narcotics—you have to go to the Drug Enforcement Administration [DEA] and request access for more than your original quote,” Mr. McGuire said. “Fortunately, the DEA was very responsive

30

and helpful, as was the FDA. For example, if there was a product that we had never created before within our facility, we might not have performed the full stability testing or validation around it. So we were permitted to leverage our partner laboratories’ data available via R&D or the published literature, and then using FDA guidance, get something out there, even though it might have more limited dating. They were really trying to find ways for outsourcing facilities to be flexible during this extraordinary time, to meet patient needs while still maintaining our responsibility for the high quality of the products we produce.”

The February closure of PharMedium, AmerisourceBergen’s compounding business, was a double whammy for hospitals in the Northeast, noted Stuart Hinchen, the co-founder and CEO of QuVa. “The initial wave of COVID hit the Northeast particularly hard, and that was also an area where PharMedium had been very strong,” Mr. Hinchen said. “So a lot of hospitals were really cut short, and we were getting four times the regular demand for certain products, particularly in critical care. We had to give preferential treatment to COVID-related products wherever we could. We looked at other inventory we had on the shelves, and where we had adequate reserves, slots that would have gone to that inventory were reallocated to COVIDrelated products. Throughout March and April, every day was a major production effort and there really was no playbook.”

Keeping up With Shifting Demand As changes in the pandemic have rippled throughout the country, along with reopenings of elective procedures, outsourcers have worked to keep up with shifting demand.

“COVID-19 became less frantic in May [2020], but then elective surgeries started to open up in June, so we went through an oscillation as the health networks were extremely keen to get those going again,” Mr. Hinchen said. “Then in the summer, COVID-19 cases spiked in the Sun Belt, and we had dual pressures of both COVID-19 and elective surgeries.”

QuVa, NELC/ACS and Fagron all have increased capacity to meet the changing demand. QuVa has added more than 100 people to its labor force this year, with more staffing planned in the immediate future. “We put on a third shift in our Sugar Land site, which handles the bulk of our

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6 Steps to an ‘A’ Grade In Sterile Compounding E stablishing 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

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A technician labels syringes at a 503B facility run by Advanced Compounding Solutions at New England Life Care, in Woburn, Mass.

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

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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

‘If you want to be better than a C student, look at what GMP practices you can adapt to your [503A] facility.’

—Brett Snow, PharmD 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 not be 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 clearance. “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.”

—Gina Shaw Drs. Snow and Siegel reported no relevant financial disclosures beyond their stated employment.

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DIY CHALLENGE continued from page 30

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

503A/B continued from page 26

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

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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 The sources reported no relevant financial disclosures beyond their stated employment.

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 financial disclosures beyond their stated employment.

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