Pharmacy Practice News Special Edition - The 2019 Annual Compendium of Compounding by McMahon Group

The 2019 Annual Compendium of Compounding

The Hunt for Hazardous Drug Residues Partnering Well With CSP Outsourcers CSTDs Should Be at Center Of Health Care Worker Safety USP Compliance Opens Door To Pharmacy Redesign Supplement to Pharmacy Practice News

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EDITOR’S O S DESK

The Road to Compounding Compliance E

ach article in this Special Edition of Pharmacy Practice News represents a snapshot in time, detailing the evolving efforts of health systems to comply with revisions to USP Chapters <797> and <800> and other compounding regulations. In early days, many health systems responded by employing well-known safety technologies such as closed system drug-transfer devices. Although CSTDs were given a strengthened recommendation in the latest USP updates (page 60), the devices are only one component of what’s needed to ensure that hazardous drugs and other potentially dangerous substances are prepared and administered safely. So as the USP’s Dec. 1 “go-live” date nears, pharmacy managers are digging deeper and reviewing every corner of their cleanrooms to detect vulnerabilities. Unfortunately, latecomers may be facing shortages of hoods, HVAC equipment and other materials needed to meet the regulation deadline (page 10). The good news is that for many health systems, having to comply—however onerous at the outset—has come with a huge bonus: the opportunity to refashion the pharmacy department into something more fit for 21st century practice. “New regulatory requirements are always a good reason to go to your administration and say, ‘We need money and space to comply,’” said Ernest R. Anderson Jr., RPh, MS, a pharmacy

CRITICAL CARE Judi Jacobi, PharmD, FCCM, Indianapolis, IN INFECTIOUS DISEASES

EDITORIAL BOARD ADMINISTRATION Robert Adamson, PharmD, Livingston, NJ

Steven J. Martin, PharmD, BCPS, FCCM Toledo, OH Jason Pogue, PharmD, Detroit, t MI

James A. Jorgenson, MS, RPh, St. Paul, l MN

INTERNAL MEDICINE

ANESTHESIOLOGY/PAIN

Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP Des Moines, IA

Melvin E. Liter, MS, PharmD, FASHP Lexington, KY

NUCLEAR PHARMACY Jeffrey Norenberg, PharmD Albuquerque, NM

David S. Craig, PharmD, BCPS, Tampa, FL Robert L. Barkin, MBA, PharmD, Chicago, IL BIOTECHNOLOGY Indu Lew, PharmD, Livingston, NJ

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EDITORIAL STAFF David Bronstein, Editorial Director davidb@mcmahonmed.com Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com James Prudden, Group Editorial Director

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SALES David Kaplan, Group Publication Director dkaplan@mcmahonmed.com

Cindy O’Bryant, PharmD, Aurora, CO Ali McBride, PharmD, MS, BCPS, Phoenix, AZ

Charles F. Caley, PharmD, Storrs, CT

Sara S. Kim, PharmD, BCOP, New York, NY

Lawrence Cohen, PharmD, FASHP, FCCP Fort Worth, TX

ORGAN TRANSPLANT Eric Tichy, PharmD, BCPS New Haven, CT

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TECHNOLOGY Thomas Van Hassel, RPh, Yuma, AZ

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CARDIOLOGY

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SPECIALTY PHARMACY JoAnn Stubbings, BSPharm, MHCA, Chicago, IL

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REIMBURSEMENT Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

ONCOLOGY

Philip E. Johnson, MS, RPh, FASHP, Tampa, FL

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—David Bronstein

Rob Sinclair, Circulation Manager

David P. Nicolau, PharmD, Hartford, CT

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

Julie A. Golembiewski, PharmD, Chicago, IL

consultant in Brockton, Mass. (page 6). “You don’t have a choice; you have to do this if you want to remain in the sterile products manufacturing business, which most hospitals need to do. As a result, health systems ... are becoming more successful at getting space and whatever else they need in terms of renovations.” Certainly, the cost of such renovations can be high: upward of millions of dollars for larger facilities (page 19). But the human cost of not taking such measures is unthinkable, given the risks uncovered by safe handling investigators. In several seminal studies, researchers have documented statistically significant increases in chromosomal damage linked to hematologic cancers and a twofold increase in spontaneous abortions, to name just two scary sequelae in exposed health care workers (page 30). As for hospitals that are still chafing against the need to meet the looming USP deadline, one veteran of several cleanroom build-outs had this to say: “Dec. 1, 2019, is not the day that drugs become hazardous; they’ve been hazardous all along” (page 21). And all along, Pharmacy Practice News has been writing about health systems that have taken that danger to heart. They‘ve embarked on the road—however potholed—to USP compliance. May their experiences, detailed in these pages, be of help during your own journey.

Sarah Rezvani, Account Manager srezvani@mcmahonmed.com Craig Wilson, Sales Associate, Classifieds d cwilson@mcmahonmed.com

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Michele McMahon Velle, MAX Graphics/ Creative Director Frank Tagarello, Senior Art Director/ Managing Director, r MAX Graphics subscription payable to Pharmacy Practice News to McMahon Publishing, 545 W. 45th St., 8th Floor, New York, NY 10036. Please allow 8 to 12 weeks for delivery of the first issue. Individual issues are $9.00 (U.S.) or $12.00 (outside U.S.). McMahon Publishing is a 47-year-old, first-generation, family-owned publishing

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MCMAHON PUBLISHING MCMAHONMED.COM Sales, Production and Editorial Offices: 545 W. 45th Street, 8th Floor, New York, NY 10036. Telephone: (212) 957-5300. Corporate Office: 83 Peaceable Street, Redding CT 06896 Copyright © 2019 McMahon Publishing, New York, NY 10036. All rights reserved. Pharmacy Practice News (ISSN 0886-988x) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Send address changes to Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036. company dedicated to providing medical professionals with essential, up-to-date news. As the second largest publisher of medical newspapers, McMahon produces Anesthesiology News, Gastroenterology & Endoscopy News, General Surgery News, Infectious Disease Special Edition, Pain Medicine News, Pharmacy Practice News, and Specialty Pharmacy Continuum.

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TABLE OF 6

CONTENTS

USP Opens Door to Pharmacy Redesign

10 Is Time Running Out on USP <800>? 12 Putting the Clean in Your New Cleanroom 14 A Snapshot Into Safer Sterile Compounding 16 10 Building Blocks of Compounding Safety

20 The Hunt for Hazardous Drug Residues 24 Contamination in Cancer Clinics 41 What FDA Is Finding During 503A Inspections 43 FDA Eyes 503A/B Compounding 45 A USP Chapter <797> Change Triggers Concern

46 Making USP <800> Less Scary 48 Team Tackles Hazardous Drug Lists 50 Partnering Well With SP Outsourcers 54 Dilutions May Destroy Your Sterile Products 58 CSTDS at Center of HCW Safety

60 CSTD Selection Tips 62 Cochrane CSTD Review Misses the Mark 64 Is Your Job Making You Sick?

PPNSE Review: 27 Safe Handling of Hazardous Drugs: Reviewing Standards for Worker Protection By Luci A. Power, MS, RPh, and Martha Polovich, PhD, RN, AOCN

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Trading spaces:

USP Compliance Opens Door to Pharmacy Redesign T he looming December 2019 deadline for compliance with the requirements of both U.S. Pharmacopeial Convention (USP) General Chapters <800> and <797> on the handling of hazardous drugs and sterile compounding is driving a wave of pharmacy redesign and expansion at hospitals and health systems across the country. For some institutions, renovations have been limited to the sterile compounding space, but in others, the new guidelines have provided an impetus to take on the entire pharmacy environment with an eye to revamping workflow, improving efficiency and adding automation. “At most organizations we work with, the age of the pharmacy’s physical plant is pretty old and the last remodel was typically in the 1970s or 1980s,” Gregory Burger, MS, RPh, FASHP, a senior vice president at Visante Inc., told Pharmacy Practice News. Visante provides consulting exper-

tise for many of these redesign projects. “This isn’t a case of minor remodeling, but major redeesign, because the workflow and technology in thee space has changed so much. The space these health h systems have might have been efficient at one time, but it doesn’t match the workflow in today’s pharmacy enviironment.” In many cases, Mr. Burger noted, new teechnology has been shoehorned into old space design that was geared to more manual processes. “Today, a lot more hospitals have gone cartless and are using automated dispen nsing cabinets on the patient care units. That can create som me inefficient layouts relative to where the physical inventory ory is is, and a lot more steps back and forth for people to fill carts.” “New regulatory requirements are always a good reason to go to your administration and say, ‘We need money and space to comply,’” said Ernest R. Anderson Jr., RPh, MS, a pharmacy consultant in Brockton, Mass. “You don’t have a choice; you have to do this if you want to remain in the sterile products manufacturing business, which most hospitals need to do. As a result, health systems and individual hospitals are becoming more successful at getting space and whatever else they need in terms of renovations.”

Mass General’s Approach

Some health systems are using modular cleanrooms designed specifically for compounding sterile hazardous drugs, such as antineoplastics or hormonal therapies, to streamline the rebuild process.

As a leader in next-generation therapies such as cellular immunotherapy, Massachusetts General Hospital (MGH), in Boston, is looking far down the line at what the space and sterility needs may be for its pharmacy. “I don’t think people are necessarily taking a step back enough and thinking about 10 years down the road,” said Christopher Fortier, PharmD, the chief pharmacy officer at MGH. “You need to be ahead of the game. Think about cellular therapies, precision dosing and novel delivery methods like live virus—how are we going to handle these things? Right now, a pharmaceutical manufacturer or some researcher in their lab is beginning clinical trials for these new therapies; it is eventually going to be commercialized and something that our pharmacies will need to prepare [for].” In the renovations that are now ongoing, Dr. Fortier secured double the space that the ambulatory oncology pharmacy had occupied. “I told the leadership of our cancer center, ‘You don’t want me coming back to you every three years and asking for more space. Give it to me the space now and I will design it as best I can, using my crystal ball to the best of my ability, to exceed anticipated regulations and make sure we’re not constantly coming back to you. That, of course, is a lot easier said than done. Many institutions are struggling to get the funds to do these renovations, and we have been lucky to be able to do it.”

Source: Terra Universal, www.terrauniversal.com/cleanrooms/usp-800-cleanrooms.php.

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‘Right now, a pharmaceutical manufacturer or some researcher in their lab is beginning clinical trials for [cellular therapies, precision dosing and other] new [treatments]; it is eventually going to be commercialized and something that our pharmacies will need to prepare [for].’ —Christopher Fortier, PharmD The current ambulatory infusion center pharmacy at MGH will double in size, but it must be shut down for a year for the renovations, so Dr. Fortier said he and other institutional leaders are playing a “chess match” to relocate functions temporarily. “We have another compounding facility that currently does batch compounding, and some of that compounding will be outsourced in a new venture, decreasing the volume there,” he explained. “We will install negative-pressure rooms in that space and move our ambulatory oncology pharmacy team in there for a year.” Once the ambulatory oncology pharmacy is renovated, the hospital’s inpatient oncology satellite—which is currently in space that cannot be successfully renovated to comply with USP Chapter <800>—will be relocated to the batch compounding space. “It will take three years before all is said and done,” Dr. Fortier said. “It’s a domino effect; you have to do this before you do that.” The improvements that MGH is making include: • Ambulatory oncology pharmacy will have one positivepressure room and two negative-pressure rooms with four hoods each and two separate anterooms. “We want redundancy in having two separate negative-pressure rooms so if something were to happen—a growth, an excursion—we could shut one side down,” Dr. Fortier said. • Inpatient pharmacy renovations include a fifth carousel for more drug space, a renovated and enlarged narcotic vault for more flexibility, and a more “open concept” design that will open up sight lines to improve efficiency.

Lahey Hospital and Medical Center, in Burlington, which serves northeastern Massachusetts and southern New Hampshire, has five facilities all gearing up for Chapters <797>/<800> at the same time, with at least two of them operating outpatient infusion centers either on or off campus. “We’re trying to maintain a consistency of drug classification and prep requirements across the system as we build out these areas,” said Nancy Huff, PharmD, the director of pharmacy services. Those efforts, she noted, thwarted what might have been a less expensive solution for one of the sites with an off-campus infusion center: simply designating all preparations as hazardous and treating them as such, mixing them all in the same negative-pressure room. “But all the other sites in the system have identified those medications as nonhazardous, and the Epic system is built for that designation,” Dr. Huff said. “So we are still working on solutions for that site, such as creating a designated compounding room for the nonhazardous preparation. Since it is an infusion center, there is no batching.” The other four sites—including the main campus in Burlington and centers in Beverly, Winchester and Peabody— will undergo major renovations, with Beverly the farthest along. “Beverly and Winchester have to renovate within the same footprint,” Dr. Huff said. “Beverly’s footprint isn’t too far off, so they don’t have to shut down for a period of time and move out. At Winchester, they’re plotting out a space for a negative-pressure room, buffer space, anteroom and workroom that meet requirements for airflows, square footage and so on. But they still need to find sufficient negative-pressure storage space.” At all three sites, the system is leaning toward the use of modular cleanrooms. “While stick-built is less expensive for the initial construction, it creates more challenges to maintain your required specifications for airflow and particle count,” Dr. Huff said. The main pharmacy at the medical center’s flagship location currently does only nonhazardous prep, but since batching is done there, full compliance is being sought. “Right now, all we have is a workroom and a cleanroom plus buffer space, but there is no anteroom,” Dr. Huff said. “We will be expanding the current space from 600 square feet to just over 1,100 square feet.” To achieve that, she noted, facilities including linen and central sterile processing, and the loading dock entrance will be “shifted over,” with all affected departmental areas maintaining current, although reconfigured, square footage. The main hospital’s infusion center pharmacy now occupies just over 300 square feet. “It is tiny,” Dr. Huff said. In that infusion center space, the cleanroom has been located at one end of the infusion center, with 24 infusion bays and nursing in the middle. “We now have to change the space to have a workroom into an anteroom connecting to negativeand positive-pressure rooms,” she said. Pharmacy will be relocated to the opposite end of the infusion center, taking space from what is currently nursing administration (IT, see REDESIGN, page 19

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Leading Compounding Innovation in 503B Outsourcing A Roadmap to Mitigating Recalls and Shortages: 503B Outsourcing Compounding Solutions Backg k round Disruptions in supply have been a source of frustration in the compounding industry as shortages and recalls prevail, but a look at recent history reveals that old issues remain part of the problem and have yet to be resolved. In 2012, the compounding industry received a “wake-up call” when an outbreak of fungal meningitis was traced to contaminated drug product produced by New England Compounding Center, r causing 60 deaths with hundreds of others becoming ill. As a result, the FDA has continued to impose strict requirements on 503B compounding outsourcing providers, especially with regards to implementing cGMP, P but the industry still has a long way to go.

What is cGMP? cGMP refers to the Current Good Manufacturing Practice regulations enforced by the FDA which states: “cGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities.”*

Challenging times: drug recalls and shortages Today, T y hospitals and health systems are dependent on 503B compounding outsourcing facilities to supply much needed drugs in times of shortage due to recalls and otherr market forces.

Recalls can be traced to a lack of testing and improper procedures, but drug recalls can also be due to a variety of other sources: poor environmental monitoring results; stability failures; contamination of other batches, equipment, facilities/cle / anrooms/hoods; and poor/ r/non-existent sterility assurance programs. Lack of adherence to strict cGMP processes is at the core of most recalls and it’s important to note that while testing is necessary, y it is only one component of the detailed process required to ensure drug safety. y

shortages continue to become the norm, the presence of compounding outsourcing facilities will remain a necessity. y So, what’s a Director of Pharmacy (DOP) or health system to do? o

Partner with a 503B supplierr that insists on an integrated cGMP Quality Management System

+ Efforts to minimize costs

+ Decisions to cease production of a particularr drug in favor of newer, r more proﬁtable drugs + Natural disasters, such as hurricanes and ﬂoods, disrupting access to raw materials When lack of sterile starting material exists, compounding facilities without the capability to produce from API are left with no alternative, but those 503B compounding outsourcing suppliers following the utmost cGMP practices, can not only provide needed product during times of shortage, they can assure their customers that those products are perhaps safer than those crafted from sterile starting material. The reality is that shortages leave patients without access to required medication. As these

Materials. Before bringing any materials into the system, the outsourcerr must do supplier qualification and testing of vendors. This ensures compliance with the FDA and that each batch sent is in accordance with specifications. Production. Sterility assurance, including clean room design, aseptic technique, operations under the hood, all the way to core building airflows.

Recalls have often led to drug shortages of late. Some reasons behind these shortages are: + Facilities limited by the number of drugs they can manufacture due to safety and sterility concerns

Validation. “This is where you’re V proving—before you start manufacturing the product— that you have the process under control,” says Hinchen.

“Establishing an Integrated Quality Management System is imperative,” says Stuart Hinchen, founder and CEO of QuVa V Pharma, a Te T xas-based sterile compounding outsourcer focused on obstetrics, OR, anesthesia, general medicine, cardiovascular, r ER, and pain management. “The key to the future success of ourr industry — and to the safety of patients — is to have a system of checks and balances in place that ensures cGMP best practices are met, no matter what complexities we face.” Hinchen cites 7 pillars of a strong integrated quality management system including: Facility sys y tems. Room certiﬁcation, maintenance, and calibration of equipment Regulatory and pharmacy. y Compliance with all relevant agencies, especially state Boards off Pharmacy and the FDA.

Quality y assurance. An independent quality unit that oversees the production system: reviewing aseptic practice, assembling documents to create a batch record, and assuring that the appropriate people are signing off on processes. Quality control. Final testing on the product for sterility, y potency, y and endotoxin is only 95%. In order to have 100% conﬁdence in your product, you have to make sure all of these other systems are integrated and doing theirr job. Y u can’t latch onto one aspect Yo of a program.

In Conclusion A qualiﬁed 503B compounding outsourcing partner, r with processes in place that reinforce the highest cGMP standards, can mitigate the impact of recalls and shortages. Identifying an outsourcing partner that operates according to an Integrated Quality Management System is a necessity for future patient safety and optimal clinical outcomes. For more information, visit www.QuVaPharma.com

888.339.0874 *https:// //www.fda.gov/D v rugs/DevelopmentApproval Process/Manufacturing/ucm169105.htm

503B Outsourcing Checklist STERILITY ASSURANCE Evaluate the sterility assurance program within the facility T Is there an EM/PM program in place that evaluates microbial activity for personnel, within all clean rooms and ISO 5 areas? T Are positive EM/PM microbial samples identified? T Is there an EM/PM program in place that evaluates microbial activity for personnel, within all clean rooms, and ISO 5 areas that represent every batch and every shift? T Is their EM sampling daily or by batch? Q Does the EM program include surface testing? Q Does the EM program include viable air testing? Q Does the EM program include non-viable air testing? T Are personnel media (to supplement PM qualifications) fills done for all compounders and clean room personnel, and at what frequency? Are three media fills completed for qualification? T Is there a complete investigation and evaluation of batch impact for failed media tests of personnel or processes? T Is there a CAPA program associated with out of specifications for environmental monitoring that performs comprehensive investigations and evaluates batch impact? T Are batch release criteria dependent on the passing results of EM/PM sampling? T Does the facility requirevalidation of new or changed facilities, equipment, processes? T Do all testing media undergo growth promotion and/or / qualifications? T When OOS samples are discovered, does the facility ID the organisms and identify source? T Is method suitability performed for sterility and testing? T Are all test methods validated to GMP and USP? Review the cleaning processes and cleaning agents. Are they monitored through the EM program? T Are SOPs and protocols in place for cleaning and disinfectants? Q Do they include sterile disinfectants for clean room and ISO 5 areas? Q Do they include contact times for spores and microbes? Q Do they include batch, daily, y weekly, y and monthly cleaning protocols? T Frequency of cleaning

REGULATORY Review licenses and registrations T Review Federal registrations (FDA, DEA) T Review state licensing is in place to ship products across state lines T Are appropriate state-controlled licenses in place for shipping controlled substances over state lines?

T Review individual pharmacist’s licenses needed for speciﬁed states T Does the facility dispense patient-speciﬁc prescriptions? Q For prescriptions, are the states appropriately licensed? Q Are the pharmacists licensed in needed states for 503B outsourcing and for dispensing prescriptions? Labeling/Packaging T Is there a robust labeling process to approve accurate labels and for changing labeling information? T Evaluate all labels to make sure they meet the 503B labeling requirements, including: Q All contents and amounts Q Needed statements such as “this is a compounded drug” and “for office use” Q Does the labeling provide total drug amount and concentration? Q Does the labeling include facility address and phone number? Q Does the labeling include cautionary statements, high alerts, and contraindicated routes of administration? Q FDA adverse reaction statement and telephone number Q Statements of preservatives T Does the facility have safety measures within the labeling to help practitioners avoid medication or dosing errors? Q ISMP required T TALL man lettering Q ASTM color coding standards Q USP chapter 7 labeling requirements

QUALITY CONTROL Review variance log and investigations T Review the variance process and if there is a state of control over variances/OOSs T Do the variances/OOS account for all batches that could be impacted from a retrospective perspective? Is the quality oversight group independent of production? T Is the quality oversight group well-staffed to effectively monitor all production and processing activities? T Does the quality group have full independence to accept or reject production batches? What are the facility’s batch-release criteria? Do they release at risk? T Is every batch quarantined for passing release testing (potency, y sterility, y and endotoxin)? Q Sterility testing (USP <71> or other validated method) Q Endotoxin (are endotoxin levels calculated for maximum dose and dosage route?) Q Potency (are methods GMP and validated)?

THE PERFECT BLEND OF QUALITY AND INNOVATION

Is every batch being tested for sterility using the representative number of units (IV, V syringes, etc.) deﬁned in USP <71>? Q Is USP <71> testing completed? Q Is Scan RDI or other sterility testing processes done? đ Assure it is validated to USP <71> đ Is every product validated on Scan RDI? T Are EM/PM results reviewed with batch release? T Does the facility have a robust recall system? Q

Evaluate all processes to assure there is control from beginning to end of the production process T Assess what is double-checked and other veriﬁcations within the batch process T Are there good documentation practices (GDP) requirements with the policy/ y procedures of the company? T Are there validated shipping methods which protect the integrity of the drug product from excessive temperatures and theft? Evaluate all facility OOSs and the investigations that result T Evidence of a robust CAPA system T Are all batches that can possibly be impacted investigated T What is the quarantine process? T Are investigations robust and comprehensive with post investigation evaluations to analyze effectiveness? Evaluate customer complaints and investigations T Does the facility have a 24-7 ADR and drug safety hotline to a pharmacist? T Review all reported ADR response and FDA reporting T Review all recalls and recall history T Review all customer complaints logs and investigations

LABORATORY Evaluate how BUD is determined; if applicable, review their testing results for BUD T Does the facility have a stability testing protocol/policy? T Does the facility rely on BUDs established by FDA or do they perform their own BUD testing? T Review BUD testing and evaluate stability indicating methods T Is the stability testing done by using validated methods? T Is there stability testing for all products? T Factors associated with stability testing include: pH, precipitation, endotoxin, sterility, y container/ r/closure

Become A QuVa Pharma Partner. To get started you can set up a proﬁle at: www.quvapharma.org/customerproﬁle

QuVaPharma.com 888-339-0874 customer.service@quvapharma.com

Product, equipment delays piling up

Time Running Out on USP <800>? W hen the U.S. Pharmacopeial Convention (USP) decided to push the go-live date for General Chapter <800> back from June 2018 to Dec. 1, 2019, many health systems decided to wait and put the expense of renovations in their 2019 budget. But that decision mayy be backfiring, according to consultants on thee front lines of compliance. “We’ve not been to one facility [in early 2019 9] 9] that’s ready for USP <800>,” said Greg Burger, MS, RPh, FASHP, a senior vice president of Visante Inc. “The majority of our clients are somewhere in process, either in the design or construction phase, and there’s still quite a few hospitals out there that probably haven’t even begun.” As a result, “they’re kind of behind the eight ball,” Mr. Burger said. With many hospitals scrambling to meet the Dec. 1 deadline, “we are seeing product delays and equipment delays of up to 13 to 14 weeks right now. If [hospitals] wait until the second half of the year, chances are they’re probably not going to be ready by December.” Adding further pressure is the lack of outside help. With more hospitals now working to fulfill the requirements, there are not enough consultants and experts knowledgeable in the area to go around, noted Ernest R. Anderson Jr., RPh, a consultant in Brockton, Mass. And taking a DIY approach may not be the best solution, because having the right specifications in your cleanroom to meet USP standards “really requires outside resources; it’s not something within the hospital that people can pull off.”

IU Health Making Progress Fortunately, some health systems have made progress in meeting the new USP <800> mandate—with some outside help. About a year ago, Indiana University (IU) Health University Hospital, in Indianapolis, started exploring how to get the medical center’s 12 pharmacies compliant. IU pharmacists formed a committee with nursing, environmental services and other groups, and began working with the facilities department, going from site to site taking care of any noncompliant areas. USP <800> provides standards for safe handling of hazardous drugs to lower exposure risk. As of this December’s go-live date, these agents must be prepared in negative pressure rooms within a particular range. The chapter also has standards for storage of hazardous agents. “Some pharmacies were pretty close to

com mpliant m in anticipation of this, but we have a lott of negative pressure spaces that are not quite within the recommended ranges, so we’re having w to o work with facilities on the air balancing quite a bit,” said Mark Barricklow, RPh, the pharmacy manager at IU Health. In some cases, the work m has been outside the scope of his facilities department expertise, so they’ve brought in outside experts to ensure the rooms will meet certification parameters. Another challenge has been finding negative pressure space to store hazardous medications, requiring some new construction to do so. With these efforts, Mr. Barricklow said he hopes to have his pharmacies ready to meet USP <800>’s standards by May 15, allowing them time to work out any kinks.

HVAC, a Heavy Lift

Kinks may be an understatement when it comes to meeting the heating, ventilation, and air conditioning (HVAC) requirements of USP <800>, which “are significantly more challenging than they seem on face value,” said Jerry Siegel, PharmD, FASHP, a vice president at Safe Medication Management Associates, in East Greenwich, R.I. The USP Chapter says hazardous compounding must be done in a 100% ventilation room that is negative pressure, but that pressure has to be between 0.01 and 0.03 water closet measurement, Dr. Siegel said. Many engineers have focused on building a negative pressure space without considering the range, making it super negative. “Super negative is really bad, because it pulls in microbials and makes the room fail environmental [testing],” he said. Ceiling tiles must be caulked in place, as well as any light fixtures or access panels, he added. Only three types of hoods are acceptable in USP <800>, Dr. Siegel said: Class II, Type B2 100% exhaust; Class II, Type A2 70% recirculated/30% exhaust; and compounding aseptic containment isolators. “All of those have to have 100% ventilation to the outside, and the ventilation has to be vertical,” he said. “If you’re in the basement and your building is 12 stories, the ventilation can be the most expensive part of building a cleanroom.” Some states, like Connecticut, require separate exhaust for the buffer room from the biologic safety cabinets to Vertical dual stacking may be needprovide additional safety for the comed to establish proper and sufficient pounding staff, he noted. These requirehazardous drug venting. ments have led to a range of solutions All images: Jerry Siegel, PharmD

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Complying with the HVAC requirements of USP <800> poses many difficulties, not the least of which is the “jigsaw puzzle” nature of fitting components into tight health-system spaces.

from hospitals, from building new facilities, to renovating the pharmacies, to installing additional variable air volume boxes to help route chilled air. The Ohio State University moved its IV prep space from the third floor of one building to the penthouse floor of another to allow for less ducting to go out, Dr. Siegel said. Kaiser Permanente is renovating more than 100 infusion pharmacies nationwide. “HVAC has been our biggest challenge,” said Corbin Bennett, PharmD, MPH, the senior director of oncology pharmacy services and outpatient infusion pharmacy services. “In most cases, we are remodeling pharmacies in current space or procuring additional space in the same footprint, identifying if we need to replace the HVAC system. That’s been a very important decision and really is one of the primary cost drivers.” In some cases, he said, engineers recommended custom HVAC units, but after further consultation they determined in most cases they didn’t need them.

Two USP <800>-accepted hood designs are a Class II, Type B2 100% exhaust, shown with external venting through a solid ceiling (left); and a Class II, Type A2 70% recirculated/30% exhaust, shown with thimble and external venting (right).

Hood selection also has been difficult, Dr. Bennett said. “I recommend that organizations consider either Type A2 and B2 hoods as they remodel. Type B2 hoods require more expertise in managing pressure adjustment, so Type A2 hoods may be a better option due to less maintenance and lower cost.” Hospitals need to keep nimble while navigating these construction projects. Mr. Anderson said he knew of one New Hampshire hospital that considered putting modular cleanrooms in its parking lot as a temporary measure while renovating its cleanrooms. Others may try to consolidate making all drugs in one location while renovating others. “Those are the kinds of gymnastics one has to do to renovate current space.” —Karen Blum Dr. Siegel reported serving as a speaker for BD and is a paid consultant to health systems working on USP compliance. The other sources reported no relevant ﬁnancial relationships.

2 Tips for Late Starters If your hospital is just getting started complying with USP <800> updates, consider these tips:

1. Partner with a multidisciplinary team. “We really needed our facilities people, our nursing colleagues, even our safety and security people because some of the response to a potential spill involves helping keep people out of an area,” said Mark Barricklow, RPh, a pharmacy manager at Indiana University Health University Hospital. “It’s too big a project for pharmacy to manage single-handedly.” Work closely with your architect and engineering teams to ensure they have a very good understanding of USP <797> and <800>, added Kaiser Permanente’s Corbin Bennett, PharmD, MPH. “Be very clear that they understand the differences between a must and a should, because that really drives costs.”

2. Read your Joint Commission certification report closely, advised Patricia C. Kienle, RPh, MPA, FASHP, the director of accreditation and medication safety for Cardinal Health Innovative Delivery Solutions. Certifiers may say your cleanroom meets USP <797>, but <800> requires tighter negative pressure. “People need to be very cognizant of that. Now’s the time to take a look.” When looking for space to relocate, consider where your oncology patients are, Ms. Kienle added. “They are often up on a top floor of a hospital, and maybe it would be appropriate to build out a negative pressure room up there. “The reason <800> exists is for our protection,” Ms. Kienle said. “It’s not only patient safety and environmental protection but for the protection of health care employees, so the quicker we get compliant with this, the safer we’re going to be from a health perspective.” —K.B.

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Renee Barker, PharmD, the IV room supervisor at Lucile Packard Children’s Hospital Stanford, in Palo Alto, Calif., keeps an eye on the construction of her hospital’s new cleanroom.

Putting the Clean In Your New Cleanroom San Diego—A successful move into a new pharmacy cleanroom requires significant design planning, construction monitoring, environmental testing and continuous communication, according to a presentation at the California Society of Health-System Pharmacists 2018 Seminar Conference. The first step—perhaps even before planning begins— is to identify the sterile compounding subject matter expert for your institution, noted Renee Barker, PharmD, the IV room supervisor at Lucile Packard Children’s Hospital Stanford, in Palo Alto, Calif. “Someone needs to know all of the requirements,” said Dr. Barker, noting the person needs a deep understanding of U.S. Pharmacopeial Convention (USP) General Chapter <797> for sterile compounding and USP <800> for handling hazardous drugs, as well as state board of pharmacy regulations and FDA guidance that address sterile compounding facilities. State regulations may have more stringent regulations than current guidance. California, for example, adopted a

major portion of USP <800> at the beginning of 2017, ahead of most of the country. The federal regulation will not be enforceable until December 2019.

Unique Requirements States can have other unique requirements that may affect the design and construction of a cleanroom. In California, state building codes require that all sinks have the ability to run hot and cold water, and that they be easily adjustable. Cleanrooms generally need warm water for handwashing. A review of room components is necessary to ensure all requirements are met, Dr. Barker said. “Be involved and discuss the design requirements with the architects,” she added, noting some critical cleanroom needs, such as smooth and impervious surfaces that can be easily cleaned and withstand cleaning agents. “And think about the design requirements for your future pharmacy.” Among the questions to consider: What is the projected workload for the new cleanroom? Will a pass-through be

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‘When building your timeline, remember to account for some bumps in the road, such as HVAC issues, equipment availability and inclement weather.’ —Gene Decaminada, RPh

useful? Are refrigerators or freezers needed? What functions will happen in the anteroom? How many hoods will be required? Further, emerging technologies—such as robotics, biologics and gene therapy—could affect what constitutes an optimal cleanroom. Understanding the future direction of the institution will help to direct the future need in the pharmacy, Dr. Barker noted. “Hospitals want to build to the regulations that are current and upcoming,” she said, adding that this means both current and upcoming requirements. USP <797>, for example, is under revision.

Timeline Tips Gene Decaminada, RPh, the manager of compounding compliance for Option Care, underscored the need to create a timeline agreeable by all parties: the pharmacy, the construction company and the state board of pharmacy. “When building your timeline, remember to account for some bumps in the road, such as HVAC issues, equipment availability and inclement weather,” said Mr. Decaminada, who was not involved in the presentation. “To achieve success in a new cleanroom build or a major remodel, you need to be involved in every aspect.” Dr. Barker’s hospital is in the process of building another cleanroom, which will open in November 2019. They are keeping an eye on revisions to General Chapter <797>, which is anticipated to be completed and published in the USP-National Formulary on June 1, 2019. The revisions to <797> will be harmonized with USP Chapter <800>, with an anticipated go-live date of December 2019 (www.usp.org/compounding/ updates-on-standards). Among the likely updates is a requirement that HEPA filters be mounted in the ceiling. Right now, the standard reads that HEPA-filtered air simply has to come into the room. “So, it’s common to have an air handler with HEPA filters providing filtered air through ducts and into the cleanroom,” Dr. Barker explained. The work continues during construction. The key is to inspect early and often, Dr. Barker noted. “If they’ll let you in there, go in,” she said. She recalled taking a lot of photos and measurements

during construction, which she then shared with staff. By doing so, they were able to catch minor issues as they emerged. For example, despite letting the construction team know that low-lint wipes rather than regular hospital paper towels are used in a cleanroom, they discovered a hospital paper towel dispenser had been mounted. “That went on our issues list,” she said, noting they also had to resolve a lack of easily adjustable hot and cold water. Then there was the odd signage. Outside the hazardous drug cleanroom, the construction team had installed a sign that read, “airborne infection room.” “I just looked at it like, really, is this happening?” Dr. Barker recalled. She further advised working with the construction team to prepare the cleanroom for commissioning. That means ensuring the environmental controls meet the pressure, temperature and air change requirements from a properly installed HVAC system. “Then it’s all about putting the ‘clean’ in cleanroom,” Dr. Barker said. “The engineering controls can all work, but it’s not a sterile cleanroom until everything is cleaned.”

Final Steps The final steps require actually cleaning everything— including applying sporicidal agents to all the new equipment—and inviting an environmental testing company to do the required validation of the hoods, cleanroom and anteroom in order to confirm they meet their respective International Organization for Standardization requirements. A passing inspection from the appropriate regulatory agency, followed by a license in some states, is the ticket to open and use your cleanroom, Dr. Barker added. Of course, after going live, issues can still emerge. Dr. Barker recommended creating and posting an issues log to allow for rapid process improvements—and, of course, keeping up-to-date with evolving regulations. “Always be prepared,” she said. —Lynne Peeples The sources reported no relevant ﬁnancial relationships.

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Tech Offers a Sna Into Safer Sterile Anaheim, Calif.—Implementing photo capture of sterile preparations within the electronic health record (EHR) could add a crucial layer of protection when dealing with high-risk medications. “You have a better guarantee that you actually prepared the right dose of the right drug for that patient,” said Barry McClain, PharmD, MS, the director of pharmacy information systems at Advocate Aurora Health Care in Milwaukee, during a presentation at the ASHP 2018 Midyear Clinical Meeting. “These are potentially deadly errors that you are preventing,” he told the audience. “I think a guarantee of accuracy is something everyone can appreciate.” The process of ordering, dispensing and administering high-risk medications includes many chances for mistakes that can put a patient’s health at risk. Traditionally, checks of a prepared sterile product involve the pharmacy technician pulling back the syringe to the volume he previously injected into the bag and then handing the syringe to a pharmacist to check. With this method, the pharmacist must simply trust that the technician accurately added the correct amount of drug to the final product—“but in reality, there’s no proof of what actually happened,” Dr. McClain said. “That’s a very old-school way of doing it.” It’s also proven to be unsafe, according to the Institute for Safe Medication Practices (ISMP). “For years, ISMP has discouraged reliance on the syringe pull-back method for verification, particularly for chemotherapy, complex electrolyte solutions, or [compounded sterile products] with other high-alert medications,” the group reported in a 2017 Medication Safety Alert! article (bit.ly/

2Ke8Omv). “The syringe pull-back method requires too great of a leap of faith ... and is now prohibited by some state boards of pharmacy. pharmacy.” Noting those risks, Dr. McClain and his team came up with an alternative strategy that does not include the pullback method: a photo, label and barcode-driven workflow system that traces a preparation from beginning of production to the final check. They use a continuous video stream so pharmacy technicians can review and focus an image before snapping a photo. For cleanliness, the photo capture is touch-less, with multiple foot pedals that take and then accept photos, as well as send photos for review. The photo-capture system allows pharmacists to review the images remotely.

‘Having a solution within the EHR reduces the administration burden and potential maintenance burden in moving this forward. You don’t have to do any interfacing between two different systems.’ —Barry McClain, PharmD, MS Dr. McClain McC noted that adding a midpoint step—forcing a pharmaccist check before actually injecting into the bag— can furtheer help prevent mistakes for high-risk or highcost medications, saving money for the hospital, although he did nott present any supportive data for those outcomes. Advocatte Aurora Health Care also developed custom label tem mplates as an additional safety barrier. When somethingg is dispensed through the integrated IV workflow systeem, an initial prep label prints with a pharmacy-specific barcode. After the preparation is complete and checked by the pharmacist, a completion label prints that complements the prep label and provides the final active barcode for the nurse to scan at administration. The added steps may slow down the process— “this by no means helps things go faster than the pull-back method,” Dr. McClain said. “You can’t beat the time. But that certainly doesn’t mean it’s appropriate.” see SNAPSHOT, page 18

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Focusing on perennial problems can help ensure success

Kienle’s 10 Building Blocks Of Compounding Safety Denver—With revised versions of the U.S. Pharmacopeial Convention’s (USP’s) General Chapter <797> and <800> set to go live on Dec. 1, 2019, compliance with both sterile and nonsterile compounding standards are foremost on pharmacists’ minds. To allay anxiety, Patricia Kienle, RPh, MPA, the director of accreditation and medication at Cardinal Health Innovative Delivery Solutions, and a member of the USP Compounding Expert Committee, shared 10 tips to help pharmacists get up to snuff. “I chose these 10 primarily because they address questions [that] individuals have fairly consistently asked me about or concerns that have arisen from the FDA, the Joint Commission or state boards of pharmacy during their site evaluations,” said Ms. Kienle, at the ASHP 2018 Summer Meetings. Ensure pharmacy staff knows the USP standards. “The best way to do this is to subscribe to the USP Compounding Compendium (www.usp.org/products/uspcompounding-compendium). It’s $150 well spent.” Know your state regulations. It’s important to become familiar with state regulations and what accreditation organizations want to see during inspections, because they can have different and possibly more stringent expectations, Ms. Kienle said. “For example, many states expect pharmacists to be compliant with USP Chapter <800> in advance of the Dec. 1, 2019 official date.” Eleven recently released Joint Commission FAQs also offer a good background on sterile compounding (bit.ly/1lzisNI), covering topics, such as urgent sterile compounding to closed-system transfer devices, hazardous medication per-

missible practices, personal cleansing, testing data and low-risk compounding. Review FDA compounding guidance documents (bit.ly/29Oi6C3). “From time to time, the FDA updates or releases final guidance documents that pertain to either 503A pharmacies or 503B outsourcing facilities. Read the 503B documents even if they don’t apply to you, since you probably buy products from these compounders occasionally and should be monitoring quality.” Read the proposed revision to USP Chapter <795>. This document is currently available for public comment (www.usp.org/compounding/general-chapter-795). “Every hospital performs nonsterile compounding,” Ms. Kienle said. One proposed standard she highlighted is that institutions use a containment ventilator enclosure (CVE) when weighing out powders. Few hospitals have such a hood as part of their nonsterile compounding devices, Ms. Kienle said, but “if I was planning a compounding space and performing nonsterile compounding, I would include one in the design of the facility.” Review the second public comment version of USP Chapter <797>. Set for release in July 2018, “compounding pharmacies absolutely have to take a look at this [document] because it will affect everybody that conducts any sterile compounding,” Ms. Kienle said. The upcoming version will include changes incorporated after “many valuable comments received from practitioners since the first public comment version was published in September 2015.”

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Make sure you pe perform an assessment of risk for hazardous drugss that you handle, considering variables such as specific dosages and formulations. Heed USP Chap pters <797> and <800> requirements for decontta amination and cleaning of sterile compounding areas. “T Th here’s a lot of fuzzy wording in the current version but bestt practices have evolved to address that vagueness. Develop a detailed protocol for decontamination, cleaning and disinfe fection, including the order in which you clean, what solution nss you use and every step involved in decontamination.” Document your environmental monitoring process. This should d include air and surface sampling procedures, frequency of monitoring, and importantly, how you interpret and resolve issues. “Don’t file the results away without addressing concerns. State boards of pharmacy and accreditation organizations are getting far savvier in evaluating what actions have been taken in light of the findings of these reports, and our patients deserve that we pay attention to these issues.” Know what’s in your certification reports. “Complex engineering-related reports can be overwhelming but you need to go through them and find the nuggets in there.” In addition to addressing items that do not meet certification requirements, institutions should identify surveyor concerns about issues trending toward noncompliance with certification requirements. “Remediate any issues in advance of noncompliance,” Ms. Kienle recommended.

Visit CriticalPoint (www. criticalpoint.info) and complete the annual survey and gap analysis for USP Chapters <797> and <800>. “I really encourage people to submit their information to this site for two important reasons,” Ms. Kienle said. “First, at the end of the survey you will g a list of what you get yyou’re re not compliant p with,, and second, it promotes the greater good because it gives everybody a baseline sense of where they are compared to other survey respondents.” —David Wild Ms. Kienle is a member of the USP compounding expert committee (but stated that the comments expressed in the article are her own). She also is a consultant for CriticalPoint LLC.

Video Exclusive For more on Patricia Kienle’s UPS tips, see our exclusive video interview at bit.ly/2XEysD7.

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SNAPSHOT continued from page 14

Some third-party vendors offer systems that photo capture preparations and interface with the EHR. Although such setups can provide some flexibility, they also require considerable record-mapping, testing and workflow development, Dr. McClain noted. They also involve a contract. “It’s not cheap and it’s not easy to do,” he stressed. “Having a solution within the EHR reduces the administration burden and potential maintenance burden in moving this forward. You don’t have to do any interfacing between two different systems. “But you do have to put some love into it,” he added. As of 2018, only 23% of health systems had IV workflow systems with photo capture—whether a do-it-yourself or a thirdparty system. “There’s a demand to have a solution like this. One of the big benefits of doing an integrated IV workflow for sterile compounding is the opportunity to use the innate abilities of the EHR itself to do barcode-enabled product checking and dispense quantity checking,” said Dr. McClain, noting that Advocate Aurora uses the Epic EHR with their do-it-yourself solution. “There’s an opportunity for other EHR vendors to work on incorporating this type of module if they don’t already do it.” For hospitals considering a similar approach, he recommended choosing a durable and easy-to-clean camera with high resolution, autofocus and zoom capabilities. The computer’s operating system should be more recent than Windows 7 and have webcam-splitting software to display what the camera is capturing.

DIY Approach Hardik Patel, PharmD, an informatics pharmacist at NorthShore University HealthSystem in Chicago, agreed that the functionality of the system presented at ASHP is “easier to use and maintain as one system rather than maintaining the EHR and a third-party system for taking pictures. The difficult part of this camera project is to find an appropriate camera that works with the EHR,” he said. He suggested that using a webcam splitter “so the technician can see a live preview at all times while they place items in front of the camera” was “ingenious.” Still, the do-it-yourself approach can be difficult without any guidance. “The features and technology exist to

Cart setup, which includes camera, workstation with EHR application and extended display that streams the camera’s field of view. Not visible are foot pedals used to capture and accept photographs. Photo credit: Barry McCain, PharmD, MS

do it, but there’s not necessarily a lot of guidance to set it up,” Dr. McClain said. “I hope our experience provides others with a place to start.” —Lynne Peeples

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The sources reported no relevant ﬁnancial relationships.

REDESIGN continued from page 7

education and administration), which will move to another floor. A new locker room will also be added.

Return on Investment Eastern Maine Medical Center (EMMC), a 400-bed tertiary care hospital with a significant oncology service and an off-site ambulatory oncology center, in Bangor, is building two new cleanrooms to bring its total to four. Located on the second floor of the main hospital, the pharmacy will be taking over additional space from an area that previously was occupied by sterile processing (that function moved to space in a newly constructed tower). “In total, we will be getting approximately 50% more square feet, and will comprise the entire second floor of an addition to our oncology center,” said Thomas Moniz, PharmD, MHA, the manager of pharmacy operations. “In the new space, we will be able to fit four or five hoods in the nonhazardous room, plus the hazardous room and our anteroom. The previous cleanroom space will probably become an oral compounding and storage area.” Like at other institutions, the pharmacy team at EMMC is considering the redesign as an opportunity to improve workflow. “We just did a week of demos for IV workflow, so we are looking at this renovation in terms of the ability to have IV automation, adding barcoding and imaging and possibly gravimetrics. Not only are there benefits from a safety standpoint, but as a 340B institution, being able to

tie a dispense ID to the [National Drug Code product] we use to make it will help us improve our 340B split rate and move a significant amount of IV products off WAC [wholesale acquisition cost] and into 340B. We are trying to think not only in terms of return on investment in compliance, but actually showing real dollars and driving down drug acquisition costs.”

The Future Is Remote

The University of Colorado Hospital, in Aurora, started the latest renovation process ahead of the game, said Adam Poust, PharmD, the outpatient oncology and infusion pharmacy manager. “When <797> first came out in 2010, we did a remodel that created an anteroom and a hazardous and nonhazardous compounding room, expanding our facility by about four times its size. But it was very small at the time, and we just needed to expand, period.” Because of foresight in the design of that expansion, Dr. Poust said, the cleanroom and preparation areas already meet Chapter <800> standards. “Now, we need to create negative-pressure areas and change workflows to accommodate the new NIOSH lists and how we’re dealing with pharmaceutical waste. We have some areas that prepare nonsterile medications that are hazardous, and for those we are putting in fume hoods and making other changes so that all areas are connected to the hazardous drug receiving areas, so that from the time they come in to the time they go to the patients, it’s all negative pressure.” Workflow and efficiency solutions that are being considered include new storage options. “Does it make sense to store drugs in a cleanroom where everyone is literally working all day, or do you store them in a negative storage area outside the cleanroom with a lot less people hat is the typical budget range for a USP Chapters <797> and <800> traffic?” Dr. Poust asked. compliance-focused pharmacy renovation? Not surprisingly, it varies

The Cost of USP Compliance

widely based on the size and scope of the remodel, and whether or not new heating, ventilation and air conditioning (HVAC) systems will be required. In a sterile compounding remodel, if the facility needs to install a new HVAC, that may well make up two-thirds of the costs, experts noted. Here’s a rough cost estimate based on the scope of expansion: • Small redesigns: $100,000 to $150,000 • Midrange redesigns: $400,000 to $800,000 • Major renovations: $1 million to $1.5 million and up “Most of the USP compliance projects we have worked on are between $400,000 and $800,000,” said Gregory Burger, MS, RPh, FASHP, a senior vice president at Visante Inc. But a renovation of the size and scope of Massachusetts General Hospital’s is expected to cost at least $8 million, according to Christopher Fortier, PharmD, the chief pharmacy officer at Massachusetts General Hospital. Eastern Maine Medical Center’s renovation cost will likely be close to $10 million, the team noted. At the University of Colorado’s 14 hospitals and cancer centers, renovation costs will total approximately $16 million. —G.S.

Remote Verification “We’re also considering having pharmacists do product verification remotely using high-resolution secured cameras,” he said. “Instead of having a pharmacist or pharmacists going into and out of a cleanroom all day long, dressing and undressing and taking trace out, what if we put cameras in and do everything remotely? It’s not going to happen right now—it will require us to completely systematize the way we do things in all 14 hospitals and cancer centers—but it’s something that’s on our short list, because we know there’s the technology to make it happen and we want to be innovative in what we do.” —Gina Shaw The sources reported no relevant ﬁnancial relationships.

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Surface wipe sampling a part of USP <800>

The Hunt for Hazardous Residues W hen an employee came to her with concerns about literature indicating that hazardous drugs (HDs) could escape from her then hospital’s closed-system drug-transfer devices (CSTDs), a red flag went up for Wendy Gaudet, PharmD, the director of pharmacy at Our Lady of the Lake Regional Wendy Gaudet, Medical Center, in Baton Rouge, La. An PharmD unpublished study on HD residue had noted a spill of 5-fluorouracil in one of their automated dispensing cabinets. Dr. Gaudet recalled knowing that something needed to be done. “My employees’ safety is number one,” she said. Without proper safe handling precautions, HDs rarely stay confined to the containers in which they are compounded or the devices through which they are administered. The resulting surface contamination can pose a health risk for both workers and patients. But a thorough plan to monitor surfaces with wipe sampling can go a long

way in mitigating potential exposures, Dr. Gaudet and other presenters noted during the ASHP 2018 Midyear Clinical Meeting. “Contamination is prevalent,” said Chun-Yip Hon, PhD, an occupational health professor at Ryerson University in Toronto, and a session speaker. Chun-Yip “It’s not isolated to the pharmacy or Hon, PhD drug administration areas. It is found throughout the entire hospital.” The extent of that contamination has been documented in several studies, including a National Institute for Occupational Safety and Health (NIOSH)-sponsored study by Connor et al, which showed significant levels of HD surface contamination in compounding and administration areas ((J Occup Environ Med d 2010;52[10]:1019-1027). Although there are no federally established occupational exposure limits, addressing surface contamination is included in the pending U.S. Pharmacopeial Convention

2 Test Processes

lthough there is no standardized wipe sampling method, Patricia Kienle, BSPharm, MPA, FASHP, the director of accreditation and medication safety for Cardinal Health Innovative Delivery Solutions, recommended two processes (J Occup Environ Hyg 2016;13[9]:658-667). The most common practice has been wiping an area— usually about 100 square centimeters on a flat surface in a predetermined pattern—and sending the wipe sample to a testing company. A report comes back a few weeks later with information on the drugs identified and their levels of detection. A new and far faster process also is available, and provides wipe sample results in less than an hour, Ms. Kienle noted. However, its limit of detection is higher than for traditional surface wipe sampling, she pointed out. And the test currently only identifies single drugs at a time. Specifically, it detects methotrexate and doxorubicin, with cyclophosphamide and 5-fluorouracil anticipated to come out next, Ms. Kienle noted. As for which test to use and when, “I’d probably use both processes in different settings,” she said, suggesting the more qualitative yet faster process might be particularly useful in areas where drugs are received or stored and in infusion units. And regardless of the type of test used, “it is important to make sure this is not a punitive process,” Ms. Kienle stressed. “You are only doing this to identify areas that need to be addressed.” Jerry Siegel, PharmD, FASHP, the vice president of Safe Medication Management Associates, in East Greenwich, R.I., agreed that both tests have their role to play in different practice settings. Dr. Siegel added that the two-drug

Tw wo types of tests are available for surface wipe samplin sampling: conventional tests that require samples to be sent out for results (example, right), and a rapid test, which yields results in less than an hour (left). panel used in the rapid test is not necessarily a drawback. “Those two drugs are so commonly used that they really do serve as very effective surrogates for your safe handling technique,” he said. “If one comes back positive, you can be reasonably assured that you’re getting leakage not only from the flagged compound but from other agents as well, and it’s time to take an honest look at your safe handling techniques.” He suggested performing the rapid qualitative wipe sampling every month and the more traditional quantitative sampling every six months. He also recommended conducting a wipe sample test before any pharmacy is torn down to construct a new one, which is something many hospitals are doing or considering to modernize and meet the new standards.

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—L.P.

Surface wipe sampling is an effective method for detecting hazardous drug residue from compounding, which can show up throughout the pharmacy and other areas in the hospital.

(USP) General Chapter <800>, which focuses primarily on protecting the environment and the safety of employees while they compound or administer HDs. It will become enforceable on Dec. 1, 2019. As that date approaches, many hospitals are in the final stages of facility design, implementation and procedure development, and are moving on to consider USP <800>’s recommendations on environmental quality and control related to routine surface wipe sampling. Dr. Hon suggested that organizations start with an understanding of exactly where HDs travel throughout their facility. “Track it and follow it through its whole path to figure out where it goes, what surfaces it contacts and who may come into contact with those surfaces,” he said. Follow-up wipe sampling, he added, can provide a sense of the baseline levels of contamination. In areas that have the highest level of contamination or where there is routine contamination, he advised implementing controls and ensuring that people who might be at risk for exposure are educated about exposure routes. To reduce risks, USP <800> discusses engineering controls

‘December 1, 2019, is not the day that drugs become hazardous; they’ve been hazardous all along.’ —Jerry Siegel, PharmD, FASHP such as hoods, CSTDs and personal protective equipment. “If you implement controls, even gradually, and get everyone up to speed with awareness and best practices, then there should be a reduction in contamination levels,” he said.

Detecting the Dangers Hazardous drug residues can end up on surfaces from spills, inadequate housekeeping and accidental transfer. see RESIDUES, page 22

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RESIDUES

big gap,” noted Dr. Siegel, who was not involved in the ASHP session. Despite wipe sampling appearing only as a recommendation in the upcoming USP guidance, Dr. Gaudet noted it has become a must at her institution. Her team has been rolling out a wipe sampling plan over the past few years and is now sending samples out for quantitative testing. They are also looking into adding the rapid qualitative test. She said the latter could be useful if there is an incident or when cleaning an area for turnover to be used by a different patient. It may also be helpful when orienting a new employee and teaching about decontamination. For other organizations looking to implement a wipe

continued from page 21

Dr. Hon listed a variety of objects around hospitals that have been found to be contaminated, including vials, IV bags, computer keyboards, linens, IV pumps, toilets and doorknobs ((J Occup Environ Hyg 2013;10[7]:374-383). Within the pharmacy, hood surfaces, floors adjacent to hoods, computers, pass-through chambers and order entry stations also are potential hubs of contamination. Skin contact is the most likely route of occupational exposure, Dr. Hon noted, and can result in both acute and chronic health effects—from skin rash and nausea to reproductive health risks and genetic damage ((Mutat Res Rev Mutat Res 2017 Aug ‘You can actually see microbes grow on 17. [Epub ahead of print]). The botplates. But you can’t see contamination tom line, he said, is “you want to get for hazardous drugs. So we need some contamination levels down to as low as is reasonably achievable.” other way of identifying how we can

Invisible But Toxic

detect if it has escaped containment.’

Patricia Kienle, BSPharm, MPA, FASHP, the director of accreditation and medication safety for Cardinal Health Innovative Delivery Solutions, noted the difference in environmental monitoring between nonhazardous drugs and HDs. “You can actually see microbes grow on plates. But you can’t see contamination for hazardous drugs. So we need some other way of identifying how we can detect if it has escaped containment. “It’s not just chemo drugs either,” Ms. Kienle added. “What had been missing is a way to identify some of these other hazards that we know are risky to employees, too, like hormones.” Wipe sampling provides a method to check practices and detect errant HDs that have escaped containment. She pointed to a 2012 report from NIOSH that found platinum in surface wipe samples, and cyclophosphamide on the pharmacy floor, on drug containers, in the treatment room, and on every surface wipe sample in the checkout area of an oncology clinic in Florida (bit.ly/2APd7xe). Two different types of wipe sampling tests—a new rapid qualitative test that yields results in less than an hour, and test kits that are sent out for results that come back in several weeks— are currently available (sidebar).

No Routine Monitoring Mandate? Jerry Siegel, PharmD, FASHP, the vice president of Safe Medication Management Associates, lamented that USP <800> does not require routine monitoring and fails to provide guidance on the meaning of “routine.” He said, “With the expenses of everything else you have to do to get ready for USP <800>, many people might opt to wait until it’s required to do wipe sampling. Also, because it’s expensive, I find that people will determine their routine as ‘not very often’—sometimes ‘once, ever.’ This leaves a

—Patricia Kienle, BSPharm, MPA, FASHP sampling program, Dr. Gaudet suggested working closely with vendors and creating an HD task force with representatives from various departments, including pharmacy, nursing, infection control, linen services, environmental services, risk management and human resources. That latter effort, she noted, helped her hospital improve the culture of awareness and obtain buy-in from senior leaders and stakeholders. Surface wipe sampling is just one of many tools health systems should be relying on to ensure worker safety, Dr. Hon stressed. He cited use of CSTDs when preparing HDs, cleaning the exterior of vials from suppliers, implementing safe handling practices, priming IV tubing centralized in the pharmacy, and proper and routine cleaning of surfaces as other effective methods for reducing surface contamination and potential exposures. Dr. Siegel singled out CSTDs as a particularly effective modality. The devices, he noted, “protect from contamination probably better than any single thing we’ve used.” He also stressed that the need for all of these safe handling measures should not have come as a surprise to any hospital, nor become a priority simply due to concerns over regulatory compliance. “December 1, 2019, is not the day that drugs become hazardous; they’ve been hazardous all along.” —Lynne Peeples Dr. Gaudet reported consulting for BD. Ms. Kienle reported she is a member of the USP compounding expert committee (but stated that the comments expressed in the article are her own). She also is a consultant for CriticalPoint LLC. Dr. Siegel reported serving as a speaker for BD. Dr. Hon reported no relevant ﬁnancial relationships.

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Cancer Clinics May Have A Contamination Problem A

lthough a variety of organizatyrosinosolvens) bloodstream infections tions, including the U.S. Phar(BSIs) were identified in patients with macopeial Convention (USP), have underlying malignancy and indwellpublished guidelines and standards ing central lines. “The only significant on compounding and handling sterrisk factor for infection was receipt of ile medications, poor adherence to saline flush from the clinic during the such standards and an absence of period September-October 2011, when formal infection control policies at the clinic had been preparing saline many outpatient oncology facilities flush from a common-source bag of have resulted in serious patient harm, saline,” noted the authors of a report according to experts speaking at a on the cases in Infection Control and recent CDC webinar. Hospital Epidemiology (2014;35[3]:300More than 80% of the 1.7 million 306). Other infection control deficienMore than h people diagnosed with cancer each cies that were identified at the clinic included suboptimal procedures for year receive treatment in a community outpatient oncology setcentral line access and preparation of ting, according to Nadine Shehab, chemotherapy. of the PharmD, MPH, a senior scientist in An outbreak of catheter-associated the CDC’s Division of Healthcare Klebsiella oxytoca and Enterobacter cloaQuality Promotion. Infection control cae BSIs in 27 patients at an oncology people diagnosed with practices—from sterile compoundchemotherapy center is another example cancer each year receive ing to safe injection practices—in ((Arch Intern Med d 2005;165[22]:2639treatment in a community such settings vary widely. The CDC, 2643). Investigators determined that a outpatient oncology setting. which has made preventing health contaminated common-source sodium Source: Nadine Shehab, PharmD, MPH care–associated infections (HAIs) in chloride solution was being used to preoncology patients a priority, recently fill multiple syringes to flush central venous catheters and a contaminated administration set being hosted the webinar titled “Outbreaks in Outpatient Oncology Settings: Lessons Learned and Key Considerations for used with these syringes, which “provided an opportunity for the BSI” in these patients. Handling Sterile Medications.” Because oncology patients often have several underlying According to the CDC, breaches in basic infection precauses of infections, there may be a delay in recognizing vention practices have resulted in a number of outbreaks of bacterial and fungal infections (e.g., syringe reuse, misan outbreak resulting from contaminated medications and handling in compounding of IV admixtures). Fifteen cases reporting risk to state health authorities, the CDC, the FDA and patients, Dr. Shehab said. of Tsukamurella (Tsukamurella pulmonis or Tsukamurella

80%

1.7 million

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Table. CDC Safe Injection Practices Never administer medications from the same syringe to more than one patient, even if the needle is changed or you are injecting through an intervening length of IV tubing. Do not enter a medication vial, bag or bottle with a used syringe or needle. Never use medications packaged as single dose or single use for more than one patient. This includes ampules, bags and bottles of IV solutions. Dedicate medications packaged as multidose or multiuse vials to a single patient whenever possible. Do not use bags or bottles of IV solution as a common source of supply for more than one patient. Always use aseptic technique when preparing and administering injections. Source: Adapted from www.cdc.gov/injectionsafety/providers/provider_faqs.http and www.cdc.gov/injectionsafety/providers.html.

Breaches in Compounding Protocols Dr. Shehab cited several examples of compounding practices where breaches have been identified in outpatient oncology settings. The noncompliant actions have included preparing multiple chemotherapy infusion bags in the morning for administration later in the day; combining multiple drugs into one bag; and preparing sterile medication vials or IV bags near an open window or sink. To reduce the incidence of HAIs, Dr. Shehab emphasized the need for each facility to implement the minimum standards for administration of medications (Table), including use of aseptic technique. It also is important that staff members in outpatient oncology settings adhere to at least the minimum standards for preparation of sterile medications. For example, “the CDC recommends that all medication preparation should be performed in a designated clean area that is not adjacent to potential contamination sources [e.g., sink, used equipment],” she said. During the webinar, Joseph Coyne, RPh, the director of field operations at the pharmacy consultancy Clinical IQ, reviewed current compounding standards and guidelines from USP and the Association for Professionals in Infection Control and Epidemiology (APIC) and noted that ASHP published updated guidelines for compounded sterile preparations (CSPs) in September 2018 (bit.ly/2QUKncd). Among its standards, USP Chapter <797> states that “opened or needle punctured single-dose containers, such as bags, bottles, syringes, and vials of sterile products and CSPs shall be used within 1 hour if opened in worse than ISO [International Organization for Standardization] Class 5 environments,” and “any remaining contents must be discarded.” USP’s rationale for the one-hour time frame is to limit the potential for microbial proliferation, as compounding in less than ISO Class 5 conditions increases the risk for microbial contamination, according to Mr. Coyne. The APIC guidelines state that outside of an ISO Class 5 environment, “spiking a bag, vial or bottle of sterile fluid with a dispensing device and leaving that device in place to withdraw medication for multiple patients increases the risk for

microbial contamination. When performed outside of an ISO Class 5 environment, the device and subsequently the fluid can become contaminated. For this reason, using a dispensing device to spike parenteral solutions outside of an ISO Class 5 environment and leaving it in place to dispense medication for multiple patients puts patients at risk for infection and must be prohibited [bit.ly/2aWtJJv].” Reviewing USP <800> standards related to hazardous drug (HD) preparation, Mr. Coyne stressed that whether a facility is high or low volume, training, assessment and documentation are crucial. “Improperly trained personnel are probably the No. 1 cause of adverse events,” he said. Training should include a review of the following: HD lists, storage and handling of HDs, proper use of equipment and personal protective equipment, procedures dealing with acute exposures to HDs, spill management, and disposal of HDs and trace-contaminated materials. In addition, if new agents or procedures are introduced, training, assessment and documentation must occur immediately, he said. Waiting until the annual reassessment is required is not acceptable. —Nikki Kean The sources reported no relevant ﬁnancial relationships.

Additional Resources

Aseptic techniques: bit.ly/1pWM3mK Preventing infections in oncology patients: bit.ly/2T79PML 503A compounding: bit.ly/2GyJZj1 Safe injection practices: www.oneandonlycampaign.org

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Safe Handling of Hazardous Drugs: Reviewing Standards for Worker Protection LUCI A. POWER, MS, RPH Senior Pharmacy Consultant Power Enterprisess San Francisco, California

MARTHA POLOVICH, PHD, RN, AOCN Assistant Professo or Byrdine F. Lewis College of Nursing and Health Professions Georgia State Uniiversity Atlanta, Georgia

n July 30, 2018, the ASHP board of directors approved the 2018 edition of the “ASHP Guidelines on Handling Hazardous Drugs.”1,2

The guidelines are harmonized with United States Pharmacopeial Convention (USP) General Chapter <800>3 and the National Institute for Occupational Safety and Health (NIOSH) 2016 hazardous drug (HD) list.4 This fifth set of guidelines from ASHP since 1983 contains updated guidance on many aspects of the safe handling of HDs and an extensive reference list (current to October 2017). The included appendices provide step-by-step guidance on many of the key tasks required in an established HD safety program. Guidance documents for safe handling of HDs have been available for decades, with the Occupational Safety and Health Administration (OSHA) publishing its earliest guidelines in 1986.5 In addition to ASHP, other professional groups in the United States, most notably the Oncology Nursing Society (ONS), have disseminated and regularly updated guidelines since the early 1980s.6,7 NIOSH published its landmark alert, “Preventing Occupational Exposure to Antineoplastic

and Other Hazardous Drugs in Health Care Settings,” in September 2004.8 Nursing staff, pharmacists, and pharmacy technicians are identified most frequently as at risk for exposure to HDs. More recent observational studies found that oncologists, ward aides, dietitians, unit clerks, and transport workers come into contact with HD-contaminated surfaces. Most of these workers are in job categories not generally thought to be exposed to HDs.9 Further study found that some of these workers had cyclophosphamide in their urine (oncologists, ward aides, dietitians, and volunteers).10 The authors concluded that workers in the drug administration setting, even those who were not responsible for administering the drugs to patients, were absorbing drugs from contaminated surfaces through unprotected skin. These findings support the expansion of the list of potentially exposed workers. Although guidance documents provide important

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information, the term guidance has made the information seem optional or discretionary, resulting in many situations where exposure that could be reduced is not. The involvement of the USP in the safe handling of HDs began in 2008, when USP General Chapter <797> “Pharmaceutical Compounding—Sterile Preparations”11 was revised to include specific precautions to be implemented when HDs are compounded. Because USP chapters under 1000 are considered standards, the best practices contained in these chapters are more likely to be followed than those provided as guidelines. USP General Chapter <800> “Hazardous Drugs—Handling in Healthcare Settings” augments the 2008 USP <797> to include best practices for administration, as well as compounding, and addresses the need for containment whenever and wherever HDs are received, stored, transported, compounded, administered, and disposed of. Because USP <800> builds on decades of research and guidance in the field of occupational exposure to HDs, few of the concepts in it are novel, but its implementation of standards for HD handling will be an important step forward for the safety of pharmacists, nurses, and other potentially exposed health care workers (HCWs). The influence of USP <800> can be seen in the numerous publications and educational programs that are available to assist practitioners in preparing for the requirements set forth in the new standard. USP <797> is being revised, and its HD section will be eliminated because of USP <800> best practices and mandates.12 However, the mandates in USP <797> still must be followed for any HDs compounded and administered as sterile preparations. USP anticipates that the USP <797> revision will be completed and become official at the same time as USP <800>, on December 1, 2019.

Guidance Not Always Followed And Workers Remain at Risk Despite long-standing and continuing efforts, evidence of workplace contamination, worker exposure, and results of work practice surveys show that even with the availability of these extensive standards and guidelines, recommendations are not always followed and worker protection has not improved much.13-23 A NIOSH-sponsored study published in 201024 reexamined risk points from a 1999 study25 and showed similar levels of HD surface contamination in both compounding and administration areas. Two studies described evidence of drug uptake and chromosomal changes in oncology workers,26,27 and a 2012 study documented increased spontaneous abortions in nurses exposed to HDs in the workplace.28 NIOSH recently sponsored an internet survey to determine current practices used to minimize chemical exposures and barriers to using recommended personal protective equipment (PPE) for a number of chemical hazards.19 This survey—the Health and Safety Practices Survey of Healthcare Workers—developed

hazard modules for specific types of chemical exposures, including compounding and administering antineoplastics and other HDs. The modules included questions on hazard-specific training; adherence to safe-handling guidelines; use of engineering controls and PPE; barriers to using PPE; and exposure monitoring and medical surveillance, if applicable. Gaps were discovered in many areas. The results of specific modules were published separately, beginning with the module related to administration of antineoplastic drugs. 20 Of the 2,069 respondents to the administration survey, 98% were nurses who worked primarily in hospitals, outpatient care centers, and physician offices. Collectively, they had administered more than 90 different antineoplastic drugs during the week before the survey. With varying frequency, respondents reported not performing activities recommended in guidelines, such as wearing PPE, because they perceived the risk for skin exposure to be minimal. Respondents noted taking home clothing that was potentially contaminated with HDs and performing activities such as touching IV pumps and doorknobs while wearing contaminated gloves. In addition, 12% of respondents who handled liquid chemotherapy drugs reported experiencing a spill or leak during administration in the past week.20 The survey results show deficiencies related to training, awareness of employer procedures, and awareness of national safe-handling guidelines. The survey results indicate that guidelines for the safe handling of HDs are not followed universally. In the compounding survey, nurses and pharmacy practitioner respondents who compounded antineoplastic drugs reported not always wearing gloves or gowns, not always using engineering controls or closed systems, and using unsafe IV priming practices.21 They also reported a lack of training, safe-handling procedures, and medical surveillance programs. The survey team discussed factors that predict adherence or nonadherence to appropriate safe-handling practices, identifying training and familiarity with guidelines for safe handling of HDs, adequate time to adhere to guidelines, and availability of PPE and certain engineering controls as major factors that influence adherence.22 Their conclusions are similar to others in reviews of HCW adherence. Survey results from British Columbia, Canada, suggest that knowledge about risks associated with HDs can be improved and that training can improve HCWs’ perceptions of the risks.23 Failure to comply with HD safe-handling precautions has been linked to exposure. A recent study identified an inverse relationship between use of protective measures and exposure, as measured by surface wipe samples and HCW urine samples.29 Numerous publications indicate that HCWs handling HDs experience exposure, and, therefore, are at risk for adverse effects (AEs). Ongoing efforts are necessary to promote HCWs’ awareness of the health risks associated with exposure and assess whether the continuing

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exposure is due to ineffective interventions or the lack of adherence to recommended precautions.

Defining HDs Many drugs that are potent and toxic in patients have the potential to cause AEs in people who are occupationally exposed to them. Although the cytotoxic potential of alkylating agents was the primary concern initially, there are multiple mechanisms by which drugs cause AEs. In 1990, ASHP attempted to define these drugs in its “ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs,”30 for the first time using the term hazardous drugs in reference to drugs that involve risks from occupational exposure. This is compatible with the OSHA Hazard Communication Standard (HCS) (CFR 1910.1200), the most recent version of which became effective on May 25, 2012.31 ASHP used terminology referring to inherent characteristics of drugs to include all classifications of drugs associated with safety concerns—not just cytotoxic agents. NIOSH revised ASHP’s HD characteristics for the 2004 Hazardous Drug Alert.8 The NIOSH characteristics of HDs are listed in Table 1.4,8 These criteria essentially form the definition of drugs that should be handled as hazardous. NIOSH has a mechanism to evaluate newly FDA-approved drugs against these criteria on a regular basis. The review process for the addition of the new listings is described in the Federal Register.32 The NIOSH HD list was updated in 2016.33 An updated list with newly approved drugs and some older drugs with new warnings was expected to be published by the end of 2018 but is not yet available on the NIOSH website. Since 2016, the NIOSH list is divided into 3 tables of HDs, one covering antineoplastic HDs; another covering non-antineoplastic drugs that meet one or more of the NIOSH criteria for an HD; and the third covering HDs that primarily pose a reproductive risk to men and women who are actively trying to conceive and women who are pregnant or breastfeeding.4 NIOSH recommends the use of standard or universal precautions when handling HDs; however, many HDs are not used in all clinical settings. Separating HDs into 3 tables helps organizations identify non-antineoplastic agents more easily. USP <800> does not define HDs, but requires entities to use the NIOSH list and the NIOSH criteria to identify HDs. USP <800> requires any health care entity handling HDs to maintain a list of HDs. The organization-specific list must include any drug on the NIOSH HD list that the entity handles. It further requires organizations to use the NIOSH criteria to determine if any new or investigational drug entering the market after publication of the current version of the NIOSH HD list should be handled as hazardous.3 USP <800> distinguishes between the types of HDs, as described in the 3 tables in the NIOSH HD list, and the risks they represent to HCWs.3 More detailed information on USP <800> requirements is available in the full version of the chapter accessible from USP (https://bit. ly/2y2TWAT) and in the current edition of the USP

Table 1. NIOSH Characteristics Of Hazardous Drugs Carcinogenicity Teratogenicity or developmental toxicity Reproductive toxicity Organ toxicity at low doses Genotoxicity Structure and toxicity profile of new drugs that mimic existing drugs determined hazardous by the above criteria NIOSH, National Institute for Occupational Safety and Health Based on references 4 and 8.

Compounding Compendium (www.usp.org/store/ products-services/usp-compounding-compendium).

Routes of Occupational Exposure HCWs may breathe contaminated air or absorb HDs through unprotected skin. Current literature provides evidence that HCW exposure to HDs primarily results from dermal absorption.34-36 Dermal exposure may occur by direct contact with the drugs (eg, during spills, handling of contaminated HD vials, or touching of HD solutions in IV bags and tubing), or by indirect contact from touching drug-contaminated surfaces.37 Standard work practices for handling injectable drugs in vials and syringes can generate powder and liquid aerosols.38,39 These drug residues may contaminate the air and surfaces in the work area.40 The outsides of generic and brand-name HD vials that are commercially distributed in the United States, Canada, Europe, and Japan have been shown to have HD residues.41-44 Certain HDs have been shown to vaporize at room temperature, which results in drug contamination of the air.45-47 Drug uptake may occur through the ingestion of contaminated food or beverages that are inappropriately located in or near drug-handling areas. The transfer of HD residue from hand to mouth also may result in the ingestion of HDs. Sharps injuries with HDcontaminated needles or cuts from glass fragments of vials or ampules may result in exposure by injection.

Guidelines and Standards For Safe Handling of HDs OSHA updated its guidance in 1995 and made it available online, as part of the OSHA Technical Manual (OTM), in 1999.48 This section of the OTM was archived in 2016. An update to the OSHA guidelines was posted to the “OSHA Safety and Health Topics: Hazardous Drugs” in May 2016.49 ASHP1,50 and ONS51-53 have published updated guidelines that are harmonized with the 2004 NIOSH Alert and USP <800>. Currently, these organizations make the same recommendations for

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handling HDs. Although the publications from these professional associations are respected, some practitioners and facilities regard them as voluntary. Possibly, HD precautions being referred to as “guidelines,” rather than “practice standards” or “rules,” promotes a lack of employer and individual worker concern. We applaud the actions of USP in publishing practice standards for HD handling to promote both employer and worker awareness of potential exposure and their responsibilities related to safe handling. ONS, the American Society of Clinical Oncology, and the Hematology/Oncology Pharmacy Association published a joint position statement addressing the safety of HCWs handling HDs in 2015.54 The statement outlines the obligations of organizations to provide appropriate policies, safety equipment, education, and training aimed at reducing exposure. The American Nurses Association released a resolution in 2012 advocating for nurses’ safety from HD exposure during pregnancy.55 In 2011, the Washington state legislature required the state Department of Labor & Industries (L&I) to set requirements to protect HCWs who handle chemotherapy drugs and other HDs. This landmark bill required L&I to adopt rules that are consistent with, but do not exceed, provisions in the 2004 NIOSH Alert related to preventing occupational exposures to antineoplastics and other HDs in health care settings. The L&I’s HD rule was adopted on January 3, 2012, and the rule took effect in stages beginning January 1, 2015.56 Similar legislation was passed in California,57 North Carolina,58 and New Jersey.59

Continuing Exposure Multiple studies have documented the presence of HD residue on wipe samples of work surfaces in all areas where HDs are handled, including receiving areas, storage areas, compounding areas, administration areas, areas located in transport routes, and areas where HD waste is stored and discarded.9,60-65 Studies examining HCWs have found HD contamination on hands,34,35,66-68 pads placed on workers,35,66,67 and in the urine of workers involved in handling HDs directly,10,29,34,39,69 and even peripherally.10 In the previously noted study of HCWs separated into 8 job categories,9 including workers not directly involved with the preparation of HDs or their administration, workers in all 8 job categories had some urinary excretion of cyclophosphamide (CP) in excess of the limit of detection, with unit clerks having the highest average level.10 A comprehensive study of CP contamination on surfaces throughout a hospital medication system looked for, and found, drug residue on box cutters, elevator buttons, pens, markers, and so forth.65 Pens used in the preparation area had the highest level of CP residue. The study did not examine gloves; however, it is reasonable to infer that the CP on pens was transferred from gloved or ungloved hands and that additional transfer was likely.65 A NIOSH-sponsored, multicenter study from 2010

detected HD contamination on surfaces in compounding and administration environments of all sites studied.24 The findings of the study included a correlation between the size and spatial design of the compounding area and the amount of surface contamination. Preliminary reports support the USP <797> design standard that requires an appropriate buffer area around the primary engineering control (PEC)11 as well as the more specific containment requirements of USP <800>. One site studied in the 2010 NIOSH study had a smaller, less delineated compounding area, and the investigators found a higher rate of surface contamination at that site.24 Surprisingly, the percentage of surfaces contaminated with HD residue in the study is almost identical to that found in a similar study published more than a decade earlier, in 1999.25 In both studies, 75% of surfaces sampled in the pharmacies were found to have residue of at least one of the marker HDs. This raises the question of whether the efforts of NIOSH and USP, to that date, had made any difference regarding HD contamination. Additional concern was generated by a substudy within the NIOSH research. In this companion study, also published in 2010, investigators at the University of Maryland, in College Park, evaluated the chromosomal effects of selected HDs in HCWs using fluorescence in situ hybridization.27 The DNA of exposed workers showed a statistically significant increased frequency of damage to chromosome 5 or 7 (P=0.01) and an increased frequency of damage to chromosome 5 alone (P=0.01). Myelodysplastic syndrome and acute myeloid leukemia are known to be associated with signature lesions in chromosomes 5, 7, and 11. These results provide additional evidence of harmful effects from occupational exposure to HDs. Although the initial data showed a pronounced effect when alkylating agent handling alone was considered, in a later publication, the investigators reported an increase in aberrations in all 3 chromosomes (5, 7, and 11), reaching statistical significance for chromosome 5, suggesting that the targeting of chromosome 5 is not limited to alkylating agents.26 A 2011 retrospective study of occupational exposures and pregnancy outcomes in 8,461 participants in the Nurses’ Health Study II found an associated 2-fold increased risk for spontaneous abortion among participants with HD exposure.28 The study authors noted that even though awareness of HD exposure has increased, protocols to reduce exposure of HCWs to these chemicals have been insufficient to eliminate the exposure.28 Other researchers have postulated other reasons for continuing HD exposure, including workers’ lack of awareness of the issue, poor facility design, a lack of vigilance in work practices, poor adherence to the use of PPE, less than supportive attitudes by supervisory personnel, and inadequate time to compound, administer, and properly care for patients.16,24,70-74 In a 2006 review of the HD safe-handling literature,

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Table 2. Comparison of NIOSH, ASHP, and USP Chapter <800> Recommendations for HD Compounding Environment

Storage environment

NIOSH

ASHP

USP Chapter <800>

• Store HDs separately from other drugs in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.

• Segregate HD inventory and store in an area with sufficient general exhaust ventilation to dilute and remove any airborne contaminants.

• Antineoplastic HDs requiring manipulation and any API HDs must be stored separately from other drugs. • Sterile and nonsterile HDs may be stored together, but HDs used for nonsterile compounding should not be stored in areas designated for sterile compounding. • Refrigerated antineoplastic HDs mustt be stored in a dedicated refrigerator in a negative-pressure area with at least 12 ACPH.

Compounding • Prepare HDs in areas devoted to that purpose alone and restricted to authorized personnel.

• HDs should be • Sterile and nonsterile HDs must be compounded in compounded within a C-PEC located in a a controlled area C-SEC. where access is • C-SEC for sterile compounding may be an limited to authorized ISO Class 7 buffer room with an ISO Class 7 personnel trained in anteroom, or an unclassified C-SCA. handling requirements.

Ventilation

• Because of the hazardous nature of these preparations, a contained environment where air pressure is negative relative to that of the surrounding areas or that is protected by an air lock or anteroom is preferred.

• Where feasible, exhaust 100% of the filtered air to the outside.

• Storage: Antineoplastic HDs and API HDs mustt be stored in an externally vented, negative-pressure room with at least 12 ACPH. • Compounding: The C-SEC used for sterile and nonsterile compounding must: -be externally vented -be physically separated -be at negative pressure relative to all adjacent areas -have an appropriate ACPH

ACPH, air changes per hour; API, active pharmaceutical ingredient; ASHP, American Society of Health-System Pharmacists; C-PEC, containment primary engineering control; C-SCA, containment segregated compounding area; C-SEC, containment secondary engineering control; HD, hazardous drug; ISO, International Organization for Standardization; NIOSH, National Institute for Occupational Safety and Health; USP, US Pharmacopeial Convention Based on references 1, 3, 4, and 8.

the study authors reported the common finding that policies and procedures for handling HDs exist but that employees who are directly involved in the preparation and administration of HDs are not compliant with them.75 Two surveys of HD safe-handling work practices showed that existing recommendations are not always followed, and have offered little improvement in protection.16,71 A 2013 study showed that failure to use protective measures in HD handling resulted in increased exposure, as measured by surface wipe samples and HCW urine samples.29 The authors used a checklist to identify compliance with 5 key safety points: safety equipment and maintenance; training and documentation; devices for safe handling; PPE; and emergency care. They found a significant reduction in environmental contamination when there was 80% compliance with the checklist. In a 2017 review, Kibby tested the correlation of surface wipe sampling and urine monitoring for the same

antineoplastic HDs.60 He identified 21 studies that concurrently measured surface contamination by antineoplastic HDs via wipe sampling and antineoplastic HD absorption via urine monitoring. Although he found no statistically significant correlation between wipe sampling and urine monitoring for antineoplastic HDs, he did find decreases in urine and wipe levels after interventions implemented to reduce exposure. Kibby noted that none of the studies found detectable antineoplastic HDs in urine for median surface levels below 0.01 ng/cm2. This is significantly less than the 1 ng/cm2 of CP surface contamination noted in USP <800> to be a measurable level that may result in uptake of the drug. NIOSH actively continues to promote awareness of this issue by maintaining their webpage “Hazardous Drug Exposures in Health Care.”76 This webpage provides references to extensive background information, the latest studies, updates on related activities, and NIOSH publications.

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Barriers Many studies document continuing HD contamination and worker exposure, and, recently, some have attempted to identify why efforts to improve worker safety have not been successful.16,19-23 Two studies of nurses sought to explain this issue.16,22 Both studies used data collected from nurses to identify predictors of the use of HD safe-handling precautions. Polovich and Clark16 found that the following factors predicted higher use of precautions: fewer patients per day per nurse, fewer barriers (eg, availability and convenience of PPE), and a better workplace safety climate (eg, training provided, supervisors’ encouragement of precaution use, and expectations that policies are followed). Silver and colleagues22 found that familiarity with safe-handling guidelines and training were associated with more PPE use and that use of closed-system drug-transfer devices (CSTDs) and perceived availability of PPE were associated with increased PPE use and fewer spills. These findings have important implications because workplace factors seem to be the most important influences on safe-handling practices.

Recommendations Recommendations for the safe handling of HDs have been available since the early 1980s. As more research has been conducted and more groups have been involved, the recommendations have been coordinated in an attempt to provide uniformity. Each group, however, has a somewhat different focus. The NIOSH Alert provides broad guidelines; the ONS “Chemotherapy and Biotherapy Guidelines” focus on administration and patient safety information; ASHP addresses pharmacists’ concerns. USP <800> provides the most comprehensive practice and quality standards available and differentiates among the HD classifications as presented by NIOSH.3,4 The 2016 HD list contains many non-antineoplastic drugs and drugs in tablet and/or capsule form. Although NIOSH advocates that HCWs take standard or universal precautions when handling HDs, it recognized that no single approach can cover the diverse potential occupational exposures to the drugs.4 USP <800> requires that drugs on the NIOSH HD list that include any HD active pharmaceutical ingredient (API) and any antineoplastic HD requiring manipulation must follow all of the containment requirements in USP <800>.3 Drugs on the NIOSH HD list that are in final dosage form and conventionally manufactured HD products that do not need any further manipulation other than counting or repackaging do not have to follow all the containment requirements of USP <800> if an assessment of risk is performed.3 The assessment of risk, which must be drug- and dosage form–specific, is performed to determine alternative containment strategies and work practices to those in USP <800>. All guidelines agree that to reduce exposure to HDs in occupational settings, each facility needs to develop a

comprehensive safety program that deals with all aspects of drug handling—from selection and receipt of the product to storage, compounding, transport within the facility, administration, spill control, and waste management. Key components of such a program are administrative, environmental engineering, and work practice controls, as well as PPE. These components are based on principles of industrial hygiene that have been successfully used to mitigate risks from other occupational exposures.77

ADMINISTRATIVE CONTROLS Administrative controls include policies, procedures, staff education and training, validation of competency, and medical surveillance. Facilities must identify all aspects of HD handling, clearly define staff performance expectations, determine methods for validating staff competency, and establish judicious processes for the ongoing monitoring of adherence to policies. USP <800> emphasizes administrative controls for the containment of HDs throughout the health care setting, mandating conditions that protect HCWs and other personnel from receipt to disposal.3 Additional requirements include extensive training of all personnel involved in the handling and disposal of these drugs. USP <800> reinforces the OSHA and NIOSH recommendations by requiring initial training of HCWs—before they assume responsibility for the preparation or handling of HDs—and by mandating that the effectiveness of training be verified. USP training requirements are consistent with the HCS training mandates.3,31 Ongoing training must be documented at least annually. The components of the training program are specified to include didactic overview of HDs and their mutagenic, teratogenic, and carcinogenic properties. The training program must address each new HD that enters the workplace. Training in work practices also must include the following: aseptic manipulation; negative-pressure technique; correct use of safety equipment; containment, cleanup, and disposal procedures for breakages and spills; and treatment of personnel for contact and inhalation exposure. OSHA, NIOSH, ASHP and USP <800> all recommend medical surveillance as a part of a comprehensive HD safety program. Medical surveillance involves collecting and interpreting data to detect changes in the health status of working populations potentially exposed to hazardous substances. In 2012, NIOSH released an updated publication that provides directions for establishing such a program and lists the elements that should be included.78 Only 3 specific elements of medical surveillance in USP <800> are required; the rest are best practices. The first requirement is that all workers who are potentially exposed to HDs with reproductive capability confirm in writing that they understand the risks associated with handling HDs.3 Organizations must provide information about HD exposure related to pregnancy and develop a mechanism for employees

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Table 3. Comparison of NIOSH, ASHP, and USP Chapter <800> Recommendations for Primary Engineering Controls

VECs

NIOSH

ASHP

USP Chapter <800>

• Aseptic containment ventilation ISO Class 5 air is needed for sterile compounding • Class II BSC (type B2 preferred) • Class III BSC or CACI

• VEC with ISO Class 5 air needed for sterile compounding • Class II BSC (type B2 preferred) • Total exhaust is needed if HD is known to be volatile • Class III BSC or CACI

• Sterile and nonsterile HDs mustt be compounded within a C-PEC located in a C-SEC • C-PEC for nonsterile HD compounding may be a VEC, Class I or II BSC, or CACI • C-PEC for sterile compounding must provide ISO Class 5 or better air quality and must be externally vented • Class II BSC (type A2, B1, or B2), Class III BSC, or CACI are acceptable • Class II BSC type B2 typically reserved for volatile HDs

Ventilation • Do not use a venti• Without special design lated cabinet that considerations, Class II recirculates air inside BSCs not recommended the cabinet or exhausts in traditional, positiveair back into the room pressure cleanrooms environment if drug is volatile

• C-PECs for nonsterile compounding must be either externally vented (preferred) or exhausted through redundant-HEPA filters in series • C-PECs used for manipulation of sterile HDs mustt be vented externally

ASHP, American Society of Health-System Pharmacists; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; C-PEC, containment primary engineering control; C-SEC, containment secondary engineering control; HD, hazardous drug; HEPA, high-efficiency particulate air; ISO, International Organization for Standardization; NIOSH, National Institute for Occupational Safety and Health; USP, US Pharmacopeial Convention; VEC, ventilated engineering control Based on references 1, 3, 4, and 8.

to acknowledge the risk. The second requirement is for immediate evaluation of personnel who clean up HD spills or have direct skin or eye contact with HDs. Organizations must develop a mechanism for this evaluation to occur and to make sure employees know where to be evaluated. The third requirement is compliance with an OSHA regulation concerning employee access to exposure and medical records. The other standards, including a pre-placement health appraisal, periodic monitoring, and an exit examination, are recommendations. One of the new standards from USP <800> involves environmental quality monitoring for HD contamination. Despite the lack of standardized procedures for surface wipe sampling for HDs, routine monitoring— defined as occurring at least every 6 months—is recommended.3 Connor and colleagues describe surface wipe sampling as part of a comprehensive safe-handling program and provide a summary of recommendations for methods.79 Positive wipe samples should be used to evaluate the effectiveness of HD containment efforts. Kibby’s report on studies that looked at surface wipe sampling and concurrent urine testing for several antineoplastic HDs showed substantial knowledge gaps in correlating the data acquired from the 2 methods in the health care environment.60 Kibby provided a number of recommendations for further research that may improve the ability to correlate these 2 important data points.

ENVIRONMENTAL

AND

ENGINEERING CONTROLS

USP <800> contains extensive mandates to improve the environment in which HDs are handled.3 These, along with the directives of USP <797>,11 are designed to increase patient safety by reducing the potential for the microbial contamination of sterile dosage forms, and to improve worker safety by addressing design concerns in traditional, positive-pressure compounding environments. The USP <797> revision proposes a number of changes to engineering controls and practitioners should monitor its progress. It does not appear that this revision will affect USP <800>. The NIOSH, ASHP, and USP <800> best practices for the HD compounding environment and ventilated engineering controls are compared in Tables 2 and 3.1,3,4,8 HDs should be stored separately from other inventory to prevent contamination and exposure of personnel. USP <800> requires that antineoplastic HDs needing manipulation other than counting or repackaging of final dosage forms and any HD API must be stored separately from non-HDs in a manner that prevents contamination and personnel exposure. Because of concerns about volatilization at room temperature, it is preferable to store these drugs within a containment area, such as a negative-pressure room with exhaust ventilation to dilute and remove airborne contaminants. USP <800> requires that antineoplastic HDs needing manipulation and any HD API must be stored in an externally ventilated, negative-pressure

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room with at least 12 air changes per hour (ACPH).3 USP <800> has clarified the terminology of the engineering controls used with HDs to emphasize containment. The new terms include containment primary engineering controll (C-PEC), the cabinet in which the HD is compounded; containment secondary engineering controll (C-SEC), the room in which the C-PEC is located; and containment supplemental engineering controls, which include CSTDs.3 An International Organization for Standardization (ISO) Class 5 C-PEC is required for sterile HD compounding to prevent microbial contamination of sterile preparations and to protect workers and the environment by preventing the escape of HD aerosols or residue. Appropriate C-PECs for compounding sterile HD preparations include Class II biological safety cabinets (BSCs) and compounding aseptic containment isolators (CACIs). To meet the criteria of USP <797>, a CACI must provide isolation from the room and maintain ISO Class 5 air quality within the cabinet during dynamic operating conditions. The CACI air quality must be documented by particle counts during compounding operations and during transfer of material into and out of the isolator. Recovery time to ISO Class 5 air in the main chamber must be documented after material is transferred into and out of the main chamber. The Controlled Environment Testing Association has established standards for testing and use of compounding isolators.80,81 Work practices must be developed to reduce disruption of the air quality in the CACI and to minimize recovery time. A Class II BSC has an open front and depends on an air barrier to prevent HD contamination from escaping the cabinet.82 This air barrier can be compromised by worker technique, allowing escape of the contaminated air.83 The design of this type of cabinet may be problematic for product protection because the air barrier is composed of air coming from the C-SEC around the BSC. As air is pulled into the BSC, poor air quality in the C-SEC may compromise the ISO Class 5 compounding environment within the Class II BSC. USP <800> requires that sterile and nonsterile HDs are compounded inside a C-PEC that is located within a C-SEC and that all C-PECs used for manipulation of sterile HDs be externally vented.3 The C-SEC used for HD compounding must be physically separated from other preparation areas; be externally vented and have a negative pressure to all adjacent areas; and have appropriate ventilation measured as ACPH.3 USP <800> has established 2 types of C-SEC: an ISO Class 7 buffer room with an ISO Class 7 anteroom (preferred) and an unclassified containment segregated compounding area (C-SCA).3 The beyond-use date of all sterile preparations compounded in a C-SCA, however, must be limited as described in USP <797>.

WORK PRACTICE CONTROLS Work practices must be designed to minimize the

generation of HD contamination and maximize the containment of inadvertent contamination that occurs during routine handling or in the event of a spill. The compounding techniques described by Wilson and Solimando continue to be the standard for any procedure in which needles and syringes are used to manipulate sterile dosage forms of HDs.84 These techniques, when performed accurately, minimize the escape of drugs from vials and ampules. Many work practice controls are specifically designed to reduce environmental contamination and worker exposure when engineering controls are not available, such as during HD administration. Some of these include priming IV tubing with nondrug solution, not touching equipment with HD-contaminated gloves, carefully removing PPE, handwashing with soap and water after HD handling activities, and regularly decontaminating potentially contaminated surfaces.52

CONTAINMENT SUPPLEMENTAL ENGINEERING CONTROLS Containment supplemental engineering controls are defined in USP <800> as adjunct controls that offer workers additional levels of protection, especially when they are handling HDs outside of PECs and SECs (eg, during administration).3 The most noteworthy device in this category is the CSTD, which is defined by NIOSH as a drug-transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of HDs or vapor concentrations outside the system.8 Numerous studies using marker HDs have demonstrated the effectiveness of primarily one CSTD in reducing HD contamination in the workplace.39,40,61,63,64,85-87 Other studies comparing the performance of various devices marketed as CSTDs have demonstrated differing results in their ability to contain challenge agents.88,89 At clinical practice sites with various types of inpatient and outpatient compounding and administration, the implementation of a CSTD reduced surface contamination significantly compared with standard practice.39,61,64 Some CSTDs have not been tested in peer-reviewed studies, and the configurations of available CSTDs may differ from that of the device reported in the literature. Any device marketed as a CSTD should be clinically tested. CSTD components should lock into place during compounding and administration to reduce the potential for leakage. CSTDs provide protection during the administration of IV push and IV infusion HD doses that previously had not been available. CSTDs are designated by the FDA as Class II medical devices not requiring premarket approval.90 The FDA uses the 510(k) process to clear these devices for market; however, the 510(k) process neither establishes independent performance standards for devices submitted as “substantially equivalent” nor tests or approves these devices. Based on a successful review of the manufacturer’s 510(k) submission, the

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Table 4. NIOSH-Recommended PPE and Engineering Controls For Working With HDs in Health Care Settings Protective Gown

Eye Protection

Respiratory Protection

VEC

Single pair

N/A

Cutting, crushing, or otherwise manipulating tablets or capsules

Double gloves

Yes

Yes, if not done in a VEC

Yesb

Tablets or capsules

Administration

Double gloves

Yes

Yes, if powder generated

N/A

Oral liquid drug

Compounding

Double gloves

Yes

Yes, if not done in a VEC

Yesb

Administration

Double gloves

Yes

Noc

N/A

Topical drug

Compounding

Double gloves

Yes

Yes, if not done in a VEC

Yesb

Topical drug

Administration

Double gloves

Yes

Yes, if liquid that could splashc

Yes, if inhalation potential

N/A

Ampule

Opening

Double gloves

Yes

Yes, if not done in a VEC

Yes, BSC or CACI if sterile

SC, IM injection

Preparation (withdrawing from vial or ampule)

Double gloves

Yes

Yes, if not done in a VEC

Yes, BSC or CACI if sterile

SC, IM injection

Administration from prepared syringe

Double gloves

Yes

Yes, if liquid that could splashc

Yes, if inhalation potentialc

N/A

IV solution

Compounding

Double gloves

Yes

Yes, if not done in a VEC

Yes, BSC or CACI if sterile; recommend use of CSTD

IV solution

Administration of prepared solutiond

Double gloves

Yes

Yes, if liquid that could splashc

Yes, if inhalation potentialc

N/A

Solution for irrigation

Compounding

Double gloves

Yes

Yes, if not done in a VEC

Yes, BSC or CACI if sterile; recommend use of CSTD

Solution for irrigation

Administration (bladder, HIPEC, limb perfusion, etc)

Double gloves

Yes

N/A

Powder/ solution for inhalation

Inhalation

Double gloves

Yes

Yes, when applicable

Drug Formulation

Activity

ASTMa Gloves

Intact tablet or capsule

Administration from unit-dose package

Tablets or capsules

ASTM, American Society for Testing and Materials; BSC, biological safety cabinet; CACI, compounding aseptic containment isolator; CSTD, closed-system drug-transfer device; HDs, hazardous drugs; HIPEC, hyperthermic intraperitoneal chemoperfusion; IM, intramuscular; N/A, not applicable; PPE, personal protective equipment; SC, subcutaneous; VEC, ventilated engineering control a

ASTM D 6978-05 (2013); b Select VEC per type of activity; c Required if patient may resist (infant, unruly patient, veterinary patient) or if administered by feeding tube; d IV tubing already attached and primed Adapted from reference 4.

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FDA “clears” (not approves) the new device for sale in the United States.90 Many devices marketed for IV compounding or administration have been cleared by the FDA 510(k) process under various product codes. Many devices marketed and used for HD compounding are not CSTDs by definition and may not be appropriate for HD use. The FDA created a product code, ONB, specifically for a closed, antineoplastic and HD reconstitution and transfer system.91 As with other product codes, the FDA does not independently test applications under ONB; the application process is, however, more stringent for the manufacturer. Products that are marketed as CSTDs but have not been cleared by the FDA under the product code ONB should not be considered CSTDs. USP <800> notes that there is no certainty that all CSTDs will perform adequately, and, until a published universal performance standard for evaluating CSTD containment is available, users should carefully evaluate the performance claims by the various manufacturers.3 In the absence of a performance standard, NIOSH is attempting to develop a universal protocol to test the containment performance of both the physical barrier type of CSTD and those designed to operate using air-cleaning technologies.92,93 Difficulties encountered in this attempt include the selection of a surrogate and the method to capture and analyze the surrogate. The NIOSH protocol is a positive step in evaluating these devices. As other products become available, they should meet the definition of CSTDs established by NIOSH8 and should be required to demonstrate their effectiveness in independent studies.3 A CSTD must not be used as a substitute for a C-PEC when compounding. USP <800> states that CSTDs should be used for compounding HDs when the dosage form allows and the CSTD is known to be physically and chemically compatible with a specific HD.3 In addition, CSTDs mustt be used when administering antineoplastic HDs when the dosage form allows and the CSTD is known to be physically and chemically compatible with a specific HD.3 ASHP’s 2018 HD guidelines agree with USP <800> as to CSTD usage.1 The utility of CSTDs recently was questioned in a Cochrane systematic review.94 In response to a request for proposals from the UK Oncology Nursing Society, Gurusamy et al attempted to apply methodology generally used to assess interventions in patients to the performance of a medical device used in compounding and administering HD IV therapy.94 The authors concluded that “there is currently no evidence to support or refute the routine use of [CSTDs] in addition to safe handling of infusional hazardous drugs.” The review authors stated, “We also disagree with any guidelines or recommendations that CSTD should be used routinely whenever possible.” Although there are a number of flaws in their review, a key issue is the selection of studies that failed to differentiate effective CSTDs from ineffective ones. They included studies that did not identify the actual CSTDs

used, or reported “varied” devices or that the device in use was “not stated.” In addition, the limited number of studies ultimately selected for the review predominantly assessed compounding activities by pharmacy personnel. The authors considered oncology nurses, pharmacists, and pharmacy technicians who handled HDs to be a “homogeneous” population of exposed workers. The tasks assigned and, therefore, the levels of HD exposure to a pharmacy technician do not approach the exposure levels of oncology nurses who may compound HDs in a safety cabinet but administer them with nothing but PPE and good technique as their protection. HD handling activities and, thus, exposure opportunities vary considerably by type of personnel. USP <800> mandates CSTDs during administration of antineoplastic HDs due to the increased risk of exposure to oncology nurses. A recent study reported on HD surface contamination in US cancer centers.95 This study selected wipe sampling locations in the administration areas designed to measure the effectiveness of the CSTD as an intervention. Sampling the armrest of the infusion chair and the floor below the infusion pump for existing HD contamination produced a higher percentage of positive samples and greater amounts of measured HD residue than reported in previous studies of counters, waste containers, and door handles in patient care areas. Underreporting of surface contamination in HD administration areas effectively underestimates the exposure risk of nurses. The use of effective CSTDs in antineoplastic HD administration reduces that risk, a risk that was not properly assessed by Gurusamy et al. 94 For more information about the limitations of the Cochrane review, go to www. pharmacypracticenews.com/Clinical/Article/09-18/ Cochrane-Review-on-CSTDs-Misses-the-Mark/52639.

PERSONAL PROTECTIVE EQUIPMENT In addition to environmental and engineering controls, PPE is required to provide a barrier between the HCW and HDs during episodes of potential contact. PPE is especially important during HD administration, spill management, handling of drug waste, and handling of contaminated patient waste, because no C-PECs can be used for these activities. PPE includes gloves, gowns, eye and face protection when splashing is possible, and respiratory protection, when needed. All PPE should be selected for effectiveness. Workers must wear gloves whenever they handle HDs or are in an area where HDs are handled. A recent Canadian study found dermal contamination of workers compounding and checking HDs and having contact with surfaces in HD work areas. Workers’ hands were wiped with a premoistened tissue, and the tissues were analyzed for marker drugs. Of 18 wipes tested, 28% had measurable levels of CP and methotrexate,96 supporting the need for gloves. Glove materials should be capable of withstanding permeation by a variety

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of HDs.97-99 Several HDs require nonaqueous diluents for patient use and may permeate PPE more readily than others. The American Society for Testing and Materials (ASTM) has developed a standard for testing chemotherapy gloves (D 6978-05) (2013) that is specific to a battery of chemotherapy drugs and duration of exposure.100 Although thicker gloves, in general, provide greater protection from permeation,101 several chemotherapy-tested gloves that prevent permeation for over 240 minutes are 6 mils (approximately 0.15 mm) or less in thickness. NIOSH recommends wearing double gloves for all HD handling (except when administering a single, intact, unit-dose oral HD).4 Some practitioners question the need for double gloves when wearing thick gloves; however, the double-gloving recommendation is not made to reduce the chance of permeation. Wearing 2 gloves prevents the transfer of contamination from the outer surface of a used glove to the hand. Transfer of fluorescent lotion as a surrogate for contamination occurred during removal of gloves 52.9% of the time in a recent study.102 When 2 gloves are worn, the hands are protected by the inner glove. ASHP and NIOSH recommend coated gowns for use with HDs.1,6,50 This recommendation was emphasized recently in an Institute for Safe Medication Practices Medication Error Safety Brieff that reported on a “chemo” gown being used for preparing a dose of iron dextran injection.103 The drug was accidentally sprayed onto the gown and penetrated it. A follow-up report noted that the FDA considers gowns to be medical devices.104 Companies that do not claim a gown has been tested for use with HDs and who do not describe it as a surgical gown are exempt from the requirement for 510(k) submission. It is important that in the absence of a standard, PPE be selected according to the criteria developed by ASHP and NIOSH based on several peer-reviewed studies.97-99 There is no such standard for gowns or gowning materials to be tested for permeation by sample chemotherapy or other HDs. ASTM F739-12e1 is a test method for permeation by liquids and gases through protective clothing materials under conditions of continuous contact.105 This ASTM standard neither specifies drugs or concentrations to be tested nor has a performance standard for an acceptable resistance to permeation. Using provisions of both ASTM standards may be an appropriate testing method for gowns or gowning material, but that has not been determined. Careful removal of gowns is necessary to prevent the transfer of contamination from the gown to clothing, which has been shown to occur 37.8% of the time in simulations.102 During sterile compounding, barrier garments must be worn to prevent the shedding of human skin and hair cells and the deposition of mucus or respiratory residue into the compounding area. USP <797> specifies that compounding garb must include the following: dedicated shoes or shoe covers, face masks, head and facial hair covers (eg, beard covers in addition to face masks),

a nonshedding gown with sleeves that fit snugly around the wrists and is enclosed at the neck, and sterile powder-free gloves.11 Powdered gloves are now banned for use in health care in the United States.106 USP <800> provides additional practice standards for PPE.3 Appropriate PPE still must be worn when the sterile compounding of HDs is performed in a BSC or CACI and when CSTDs are used. For sterile compounding of HDs, PPE includes coated gowns, masks or respirators (depending on the use of a C-PEC), eye and face protection, hair covers, shoe covers, and double gloving with sterile HD-tested gloves (Table 4).4

Conclusion Despite continuing reports of HD workplace contamination and worker exposure, there are indications of progress. NIOSH is working with OSHA and the Joint Commission to promote employer and employee awareness of safety. USP <800> has elevated many of the NIOSH recommendations to standards, fostering compliance with a broad segment of safety program controls. Although hazard communication, education, training, and competency validation are necessary to reduce HD exposure of HCWs, they are insufficient. Handlers of HDs generally work as employees in a health care organization, such as a hospital, clinic, or pharmacy. Circumstances in the workplace, such as the workload, availability of safety equipment, presence of policies and procedures, and expectations for compliance with policies, affect safety. These factors influence employees’ use of HD precautions.16 Friese et al proposed that strengthening the culture of safety in health care settings—usually thought of in terms of patient safety—is likely to affect worker safety.18 There will not be significant progress in reducing occupational HD exposure until there is universal acceptance and application of current safe-handling best practices.

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100. American Society for Testing and Materials. D 6978-05(2013) standard practice for assessment of resistance of medical gloves to permeation by chemotherapy drugs. www.astm.org/Standards/D6978.htm. Accessed September 20, 2018. 101. Landeck L, Gonzalez E, Koch O. Handling chemotherapy drugs – do medical gloves really protect? Int J Cancer. 2014;137(8):1800-1805. 102. Tomas ME, Kundrapu S, Thota P, et al. Contamination of health care personnel during removal of personal protective equipment. JAMA Intern Med. 2015;175(12):1904-1910. 103. Institute for Safe Medication Practices. Safety Brief: Caution! ChemoPlus gown may not afford worker protection. ISMP Medical Safety Alert!! June 14, 2012. www.ismp.org/newsletters/ acutecare/issue.asp?dt=20120614. Accessed December 31, 2017. 104. Thompson C. With protective gowns, look beyond brand name. Am J Health Syst Pharm. 2012;69(15):1270-1272. 105. American Society for Testing and Materials. ASTM F739-12e1. Standard test method for permeation of liquids and gases through protective clothing materials under conditions of continuous contact. www.astm.org/Standards/F739.htm. Accessed September 20, 2018. 106. FDA. Banned devices; powdered surgeon gloves, powdered patient examination gloves, and absorbable powder for lubricating a surgeon’s glove. Fed Regist. December 19, 2016. www.federalregister.gov/documents/2016/12/19/2016-30382/ banned-devices-powdered-surgeons-gloves-powderedpatient-examination-gloves-and-absorbable-powder. Accessed September 20, 2018.

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What FDA Is Finding During 503A Inspections Phoenix—A comprehensive review of 483 forms identified some of the most common observations made by FDA inspectors of 503A compounding pharmacies. Issues with drug quality, stability and sterility, as well as maintaining a controlled sterile environment, were at the top of the list, according to a poster (abstract 1) presented at the 2018 National Home Infusion Association Annual Conference. “You can be guaranteed that when inspectors come in, they’ll be looking for the same things,” said Ernest R. Anderson Jr., MS, FASHP, FMSHP, a pharmacy consultant in Brockton, Mass., who was not involved in the poster. “The FDA is very interested in reining in how people are compounding sterile products throughout the country.” The FDA began stepping up its oversight of compounding pharmacies in response to a 2012 fungal meningitis outbreak that sickened more than 750 people and resulted in more than 60 deaths. The culprit was an injectable sterile drug product, which had been compounded by the New England Compounding Center (NECC) and distributed across the country. Later, in August 2016, the FDA issued a draft guidance that included conditions at compounding facilities that could cause a drug to become contaminated and harm patients (bit.ly/2s4YxgN). Although 503A compounding pharmacies are supposed to be inspected by boards of pharmacy in each state, the FDA has the authority to and has become proactive in conducting its own inspections and, when necessary, taking enforcement actions to protect public health. During an inspection, the FDA will note on a Form 483 any observations of issues that may endanger patients. To gain greater insight into just what the FDA is looking for during these inspections, the research team from

Option Care in Wood Dale, Ill., analyzed 185 Form 483s issued to 503A compounding pharmacies and posted between January 2016 and December 2017. They excluded forms issued to outsourcing facilities or drug manufacturers. All forms were available on the FDA’s website. The team then sorted the total of 1,032 observations into three main categories: issues related to the compounding process or compounder (46%), issues related to the compounding area or equipment (44%), and administrative issues (10%). Within those categories, they created subcategories—more specific issues including lack of sterility, mislabeling or procedural problems.

Garbing, Aseptic Technique Cited The team found that the majority of observations made during the inspections were related to potential contamination from improper garbing or the use of nonsterile garbing, improper aseptic technique, visible contaminations in the compounding area, and failure to monitor the environment to ensure the compounding area is maintained at a pressure, temperature and airflow that is safe and appropriate for compounding a sterile drug product. The FDA findings exemplify the importance for compounding pharmacies to establish and follow policies and procedures that consistently provide high-quality product and ensure patient safety, the Option Care team suggested. Mr. Anderson noted that lumping inspections into these three main categories could be a useful tool to focus efforts in the right areas when addressing issues. “You need to tell the FDA how you are going to remedy what’s on the 483,” he said. see 503A INSPECTIONS, page 42

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Sterile Compounding Culprits ✔ Improper garbing or the use of nonsterile garbing

✔ Improper aseptic technique ✔ Visible contaminations in the compounding area

✔ Failure to monitor the environment to ensure proper pressure, temperature and airflow Source: Option Care

503A INSPECTIONS

crepancies: Under CGMP, absolutely no skin is allowed to show, while USP <797> is looser regarding garb. “When the FDA inspector comes in, that may be one thing they cite that a state board might not cite,” he said. “If insanitary conditions are not corrected, the facility and the individuals who compound the sterile medications Bret Snow, PharmD, the regional director of pharmacy at may face escalating regulatory actions that can include New England Life Care, has firsthand experience, having a warning letter, a seizure of product or an injunction,” experienced an FDA inspector visit his 503A compounding added Eric Bauer, RPh, a senior consultant with Central pharmacy. “An FDA audit is a lengthy process, often taking the better part of a week to complete,” he said. Admixture Pharmacy Services (CAPS), who also was not involved in the poster. “The FDA may also recommend that Dr. Snow advised compounding pharmacies to underthe facility initiate a recall of some or all of its drugs. stand their certification reports and environmental moni“The trends identified in this poster are consistent with toring program. “It is not enough to have a certified cleanroom and certified hoods. ‘Be prepared to accept criticism and Understand the data that allow you to be certified,” he said. “Also recommendations. Understand that [an consider the small things. DesigFDA inspection] will likely bring about nate a place away from the normal hustle and bustle of the pharmacy changes that will improve the quality of to allow inspectors to review the your compounding operation, which has records that they will request.” Also, designating a scribe to an obvious benefit to your patients.’ accompany the FDA through the inspection and a runner to make —Bret Snow, PharmD copies of documents, he added, can further facilitate the process. many of the objectionable findings that the agency is telling sterile compounding pharmacies to correct,” said Mr. Bauer, “Be prepared to accept criticism and recommendations,” referencing the FDA’s August 2016 guidance, triggered in Dr. Snow added. “Understand that this process will likely bring about changes that will improve the quality of your part by the NECC outbreak. compounding operation, which has an obvious benefit to Although the FDA observations generally align with U.S. Pharmacopeial Convention (USP) General Chapyour patients.” —Lynne Peeples ter <797>/<800> standards imposed by state boards of pharmacy, they can be superseded by the FDA’s more rigorous Current Good Manufacturing Practice (CGMP) The sources reported no relevant ﬁnancial relationships. standards. Mr. Anderson noted one example of such discontinued from page 41

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Raising safety standards

FDA Eyes 503A/B Compounding 5

according to several sources who spoke with Pharmacy 03A and 503B facilities, beware: The FDA is watching Practice you. That was the message of FDA Commissioner Scott News. Gottlieb, MD, and Deputy Commissioner Anna Abram “The updated guidance has provided 503B compounding when the agency released new guidance about Current pharmacies with greater detail and insight into the FDA’s Good Manufacturing Practices (CGMPs) late last year. expectations,” said Matthew Brown, PharmD, MLS(ASCP), the pharmacy manager, Compounding Pharmacy (a 503A “We’re especially focused on the importance of ensuring compounded product quality. Through enforcement facility), Duke University Health System, in Durham, N.C. actions, we’ve been addressing insanitary conditions and A Tale of Two Categories manufacturing quality issues at compounders’ facilities across the country,” they wrote. “And we’ve stepped up our The Federal Food, Drug, and Cosmetic Act separates collaborative work with the Department of Justice.” facilities that compound drugs into two categories: 503A The new guidance raises safety standards for outsourcand 503B. 503A facilities, which come under the purview ing facilities and clarifies the requirements. It also encourof state boards of pharmacy, compound products accordages 503A facilities, which may be acting as 503B outsourcing to prescriptions specific to particular patients. 503B ing facilities, to register as 503B. outsourcing facilities are permitted Some 503A facilities, such as central to manufacture large quantities of fill facilities that distribute to hospitals medications from bulk active pharmamore than 1 mile away, probably should ceutical ingredients (APIs) without a be registered as 503B facilities. “I think prescription and must meet a higher some people are actually doing 503B regulatory standard by maintaining but aren’t registered and being held compliance with CGMPs, which is to CGMP,” said Kristina N. Bryowsky, enforced by the FDA. PharmD, MBA, BCPS, the director of The new guidance “is intended to As of Sept. 9, 2018, pharmacy at SSM Health St. Clare Hosprovide clarity on quality assurance, pital, in Fenton, Mo., which operates a maintaining suitable facilities, steril503B facility. ity, stability testing, and beyond-use outsourcers or expiration dates for products that This could be a move by the FDA to were registered as 503B don’t go through the FDA approval get more facilities under the 503B—and facilities. the FDA’s—umbrella. process,” Dr. Gottlieb and Ms. Abram explained. In addition, the new guidSource: FDA (bit.ly/2XtkF5x). Transparency Welcomed ance attempts to recognize the differences between outsourcing facilities “The more clarity that the FDA can provide around how they view specific elements, I think is and conventional drug manufacturers. better for everyone,” said Jim Jorgenson, MS, RPh, FASHP, The FDA “has learned through inspections how to apply the CEO and chair of Visante. “I think it is great that they CGMPs with 503B to ensure the right balance of compliare continuing to expand their guidance documents. ance to ensure manufacturing of a safe and effective prod“I also think that we got more perspective in that Gottlieb uct for the consumer,” and as a result, “this version of the statement,” which he called pretty telling. “Clearly, the FDA document provides much more detail in the expectations wants to be more proactive, and they want to prevent probof the agency than the original vague version,” said Stuart lems before they put patient safety at risk,” Mr. Jorgenson Hinchen, the founder and CEO of QuVa Pharma, a 503B explained. “But they want to do that through an enhanced outsourcing facility. focus on enforcement actions.” The clarity is welcome, according to Dr. Bryowsky. “I think this is a decent document, and I’m glad to have it,” The FDA said being proactive is a key objective to protect consumers, and the goal of the new guidance is to outline she said. best practices in the form of CGMPs. The guidance docuDr. Brown said some of the updates reduce the burden ment revision includes changes or clarifications to a numassociated with CGMP compounding. “For example, they ber of areas, such as quality assurance activities, air quality provide guidance regarding the use of a certificate of standards, sterility testing and beyond-use dating (BUD). analysis from bulk API [active pharmaceutical ingredient] The more clarity the FDA provides on CGMPs, the easier suppliers for component acceptance, as well as the ability it is for compounding facilities to hit key compliance goals. to perform limited stability studies.” The FDA document certainly moves in that direction, see 503A/B, page 44

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503A/B continued from page 43

But QuVa thought this new guidance provides more requirements for testing. “This version provides requirements for nonsterile products [which] the original version did not address. The additional reporting requirement with Annual Product Reviews will be a significant adjustment for 503B businesses, which is evidence of the agency’s continuous increasing requirements with CGMPs,” Mr. Hinchen said.

‘There is no way the average hospital can come even close to what is required by this document.’ —Jim Jorgenson, MS, RPh, FASHP “It reduces the sterility testing if you meet certain criteria, but as a 503B producing larger batches, we won’t benefit from those changes,” Dr. Bryowsky explained.

Registering as a 503B The new guidance encourages 503A compounding pharmacies to register as outsourcing facilities, and these would be the facilities that would likely benefit from changes in sterility testing. “The update is much more detailed and evidence that the FDA wants to make 503B registration accessible for more sterile compounding pharmacies,” Dr. Brown said. “The FDA acknowledged concerns regarding smaller pharmacies that may not have the production volume to justify the expense required to use bulk API for compounding. Prior testing required full testing of each shipment of bulk API; the new guidance provides a path to limited testing if acceptable documentation is obtained from the supplier.” The new guidance also allows for more limited stability testing as long as certain BUD and production limits are met. “The default BUD may be nice for some places doing 503A,” Dr. Bryowsky said.

Mr. Jorgenson said many of the requirements, such as a dedicated quality control unit that is independent from all other activities, would be difficult for smaller operations to accomplish. “There is no way the average hospital can come even close to what is required by this document,” he said. Just as SSM Health did, some health systems are weighing the feasibility of opening their own 503B facility, and although this document might make some areas a little easier for them now, the outsourcing environment is more highly regulated than the hospital pharmacy. “Hospitals looking to build a 503B pharmacy still need to carefully consider their goals and financial tolerance; the batch size limits and default beyond-use dates mean desired storage and extended expiration may not be achieved without performing more expensive and robust stability studies,” Dr. Brown said. “The increased detail in this draft will be vital for health-system leaders analyzing the practicality of building an outsourcing pharmacy.”

Expanded Oversight and Control Regardless of whether hospitals register as 503B facilities or not, they should seriously look at these moves by the FDA, said Mr. Jorgenson, to prepare for the future, because he thinks the FDA is looking more closely at all compounding. “This clearly signals that the FDA is taking an expanded interest in compounding in general, and I think the agency wants to expand its capabilities for oversight and control, whether it is 503A or 503B,” Mr. Jorgenson said. He suggested that as hospitals move to be in compliance with U.S. Pharmacopeial Convention General Chapters <797> and <800>, they should also consider how closely future rules will move toward CGMPs and the best ways to “future proof ” what they are building. “QuVa believes this new release is the continued evolution of the agency defining the CGMPs that are applied to 503B facilities. QuVa expects the agency enforcement of these CGMPs will exponentially increase as the evolution continues,” Mr. Hinchen said. —Marie Rosenthal The sources reported no relevant ﬁnancial relationships beyond their stated employment.

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A boost in immediate-use prep time cited

<797> Change Triggers Concern T

he final USP General Chapter <797> released in June contains few surprises for anyone who has paid close attention to the sterile compounding document’s revisions and comment periods over the past few years. But one change jumps out: It increases the time allowed to administer immediate-use preparations (from one hour to four hours), meaning those that are compounded using aseptic techniques but outside a classified cleanroom environment or segregated compounding area. The clock was adjusted, said Patricia C. Kienle, RPh, MPA, the director of accreditation and medication safety at Cardinal Health Innovative Delivery Solutions, mainly to accommodate the needs of practitioners outside the hospital setting, including physicians’ offices. Ms. Kienle expressed concern about the potential effect of the extended timeline. “The one-hour rule has worked well for 11 years,” Ms. Kienle told Pharmacy Practice News. “Every time I speak, I make a personal plea to say that it doesn’t need to be changed in a hospital setting. I hope people won’t change it because I think they would lose control of the whole patient safety issue if they did.” That’s not the only change that stands out, Ms. Kienle noted. A new rule requires “at least monthly” surface sampling for bacterial contamination in all classified areas and pass-through chambers. It replaces the “periodic” surface monitoring schedule called for in the older <797>. “People were all over the board on that,” she said. “Some were doing it monthly, others every year. Most people probably had their certifier doing it every six months.” Ms. Kienle said there were “plenty of public comments” on the new monthly directive, many of them supportive. “The reason it was changed,” she added, was “the need to make sure that those areas remain in a state of control. And monitoring every six months or a year didn’t provide enough data points to be able to tell.” The new surface sampling schedule will require additional resources. “People are going to need supplies, and they’re going to need incubation space,” Ms. Kienle explained. “And they’re going to need more knowledge, because they can’t just depend on their certifier to do it.” The hospital’s infection control practitioner can be one resource for acquiring knowledge, she noted. And if sampling plates reveal colony-forming units exceeding specific <797> action levels, “they’re going to need a microbiologist to iden-

tify the organism and take appropriate actions to remedy it.” Ms. Kienle pointed to other <797> measures of which pharmacists need to be aware. One is ensuring that compounding personnel’s aseptic procedures remain at peak performance. A new rule increases the frequency of visual observations of compounding personnel’s hand hygiene and garbing procedures. “It used to be annually,” she noted. “Now it’s every six months.”

Media Fill Test The requalifying aseptic competency test involves performing a media fill test that simulates the most challenging compounding procedures a compounder is likely to encounter, followed by the performance of three gloved fingertip and thumb samplings inside an International Organization for Standardization Class 5 primary engineering control. Additionally, the initial visual observation and subsequent six-month retesting have to be documented and the documentation maintained to provide a record of personnel competency. Ms. Kienle also said the Chapter <797> update also cleared up a point in the 2008 version that conflicted with a USP Chapter <800> rule requiring hazardous drug (HD) preparation to be done under negative pressure. The earlier <797> document, she explained, allowed small quantities of, say, antineoplastic drugs to be compounded in a chemotherapy hood located in a positive pressure room. The 2019 revision of <797> now specifies that all HD compounding must comply with the Chapter <800> standard specifying negative pressure preparation. The <797> revision also states that radiopharmaceutical compounding is subject to <825> rules. The final Chapter <797> revision is slated to go live and become federally enforceable on Dec. 1, along with Chapter <800>, a revised Chapter <795> covering nonsterile compounding, and the new Chapter <825> on radiopharmaceuticals. But scrutiny by federal regulators, state boards of pharmacy and health, and accrediting organizations may not kick in immediately as these agencies work to update their standards. Nevertheless, Ms. Kienle said, “I think people are aware of what they need to do. Many were waiting for the final wording of <797>. But I hope their existing processes allow them to make small adjustments for what they may need from a documentation perspective. The only thing I think is going to be a big difference is that monthly surface sampling.” She added: “The one thing I keep trying to make sure see <797> CHANGE, page 52

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Making USP <800> Less Scary Las Vegas—Not all hazardous drugs need to be handled according to the full gamut of measures specified in USP General Chapter <800>, an expert reminded attendees of the 2019 MHA Business Summit. “A lot of people think they need to treat everything using all the strict requirements of USP <800>, but this can be really burdensome if all these measures are not necessary based on the risk,” said Joseph Coyne, RPh, the director of field operations at Clinical IQ LLC, a pharmacy consulting firm based in Florham Park, N.J. USP <800> requires pharmacies to follow all of the chapter’s risk containment strategies for antineoplastic drugs that are manipulated, as well as for active pharmaceutical ingredients of any type. However, there is greater flexibility when handling antineoplastics that only need to be packaged or counted as well as for handling hazardous non-antineoplastic drugs and agents that pose reproductive hazards only.

“If a pharmacy is only counting antineoplastics, for example, [then] using appropriate gloves and decontaminating a dedicated counting tray and spatula after use can be adequate containment measures,” Mr. Coyne said. Other examples of alternative work practices include marking lidded automated dispensing cabinet bins with appropriate precautions, removing vials of certain hazardous medications from unit stock, packaging partial tablets in the pharmacy using a manual system, and preparing all liquid doses in patient-specific oral syringes. Mr. Coyne said developing alternative containment strategies and work practices according to the USP <800> Assessment of Risk provision depends on five elements: drug, dosage form, packaging, risk for exposure, and how a pharmacy will be manipulating the drug. Different strategies also can be applied at different points of contact, he noted. “For example, the receiving clerk has a lower level of risk if the product they are handling is sealed by the manufacturer than the pharmacist who is manipulating the drug,” he said.

Provide Documentation As part of the Assessment of Risk, pharmacies need to provide documentation detailing the alternative contain-

ment strategies and work practices they will use to handle a given agent. They also need to provide information on the drug, dosage form, risk for exposure, packaging, and how it is being manipulated. Although tailoring containment strategies for each agent may seem onerous, Mr. Coyne said pharmacy and therapeutics or medication safety committees can integrate this activity into their routine meeting agendas. “You don’t need to create a separate committee to deal with risk containment strategies,” he said. “It doesn’t need to be a mystical approach.”

Can I Just Not Report? Many health systems assume they don’t need to throw the kitchen sink of containment measures at every NIOSH-listed drug. That’s why many of them consider not naming drugs they deem low risk as hazardous in their USP <800> reporting. This certainly was an attitude that Patricia Kienle, RPh, MPA, the director of accreditation and medication safety at Cardinal Health Innovative Delivery Solutions, based in Dublin, Ohio, encountered after USP <800> was released. However, she stressed that skipping the reports is not an option under current USP guidelines. In fact, “all hazardous drugs on the NIOSH list need to be identified, and you need to state how you’re going to contain risk of exposure,” said Ms. Kienle, a member of the USP Compounding Expert Committee. Still, there is some leeway in selected cases. For example, although the active pharmaceutical ingredient of any drug on the NIOSH list or any Table 1 antineoplastic agent that needs to be manipulated requires all the containment strategies and work practices defined in USP <800>, dosage forms of other drugs on the NIOSH list can be considered for the pharmacy’s assessment of risk, Ms. Kienle explained. Further, like Mr. Coyne, she said many drugs on NIOSH Tables 2 and 3 may be able to be managed with easyto-implement measures, such as wearing chemotherapy gloves, using identifiable lidded bins for storage, decontaminating containers and surfaces, and similar methods of containment.

Free Resources Resources to help pharmacies assess risk and develop containment strategies are available online. For example, ASHP offers a free activity on this topic (bit.ly/2UfihcJ). —David Wild Mr. Coyne disclosed no relevant ﬁnancial relationships. Ms. Kienle is a member of the USP compounding expert committee (but stated that the comments expressed in the article are her own). She also is a consultant for CriticalPoint LLC.

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It Takes a Team to Build Better Hazardous Drug Lists Anaheim, Calif.—A systemwide approach can facilitate a smooth process to help entities within health systems create hazardous drug (HD) lists and procedures required by the updated U.S. Pharmacopeial Convention (USP) General Chapter <800> standard. During the Safety & Quality Pearls session at the ASHP 2018 Midyear Clinical Meeting, Bridget Gegorski, PharmD, MS, a medication safety officer, described such an approach used at University Hospitals (UH) Health System, a large health system in northeastern Ohio with multiple sites including a large academic medical center and 11 community hospitals. Dr. Gegorski discussed the process that she and others in a systemwide multidisciplinary committee used to create entity-specific HD lists from an assessment of risk (AoR) compendium for the health system. The first step in this process is “identifying what hazardous drugs you have in your house,” Dr. Gegorski said. “Start by looking at the NIOSH [National Institute for Occupational Safety and Health] list and glean from that which drugs … to consider for the hazardous drugs list.” Broader than the pharmacy standard, the new standard requires consideration of “the entire life cycle” of an HD, including receiving, transporting, storage, mixing, administering and disposal, Dr. Gegorski said. Eliminating the risk entirely is obviously the strongest control, she said, “but we need to be able to administer these drugs to our patients, … so we must rely mainly on our personal protective equipment [PPE], administrative controls, etc. to minimize risk” (Figure). In addition, she stressed, employees, including those in receiving and transport, as well as pharmacy technicians, pharmacists, nurses, physicians, and medical office and procedural personnel “need to know when to apply these” protections.

Dr. Gegorski noted that USP <800> requires a full containment strategy for any active pharmaceutical ingredient (bulk powders for compounding) listed in Tables 1 (antineoplastics), 2 (nonantineoplastics) and 3 (reproductive-only hazards) of the NIOSH list as well as all drugs listed in Table 1 that require manipulation. (The tables are available at bit.ly/2GTNX67.) The chapter delineates PPE requirements for all aspects of handling, as noted in NIOSH Table 5, and requires that receiving/unpacking occur in a negative or neutral pressure area and that storage occurs in a negative pressure area with at least 12 air changes per hour. The full containment strategy in USP <800> also describes some new work practices designed to minimize exposure and discusses requirements related to equipment and areas for handling HDs.

Alternative Strategies Given that it can be impractical or impossible to handle every drug on the NIOSH list in every dosage form with all the containment strategies and work practices listed in USP <800>, the standard allows facilities to perform an AoR to determine alternative containment strategies for some qualified drugs and dosage forms. The AoR entails review of the type of HD, dosage form, risk for exposure, packaging, type of manipulation performed to render the final product, and the specific alternative containment strategy and/or work practices that will be used to lower the risk for exposure. For the AoR at UH, the team opted to evaluate medications from NIOSH Tables 2 and 3 as well as those from Table 1 that would not be manipulated (i.e., they require only counting and/or packaging). They also evaluated biologicals, drugs that previously were handled as HDs but were removed from the NIOSH list, and new drugs added to the formulary. The multidisciplinary team, which included representa-

Table. USP <800> HD Handling In Health Care Settingsa • Standard designed to protect employees from exposure to HDs • Requires maintenance of an HD list based on Joint Commission MM.01.01.01 and NIOSH listb • Alternate handling strategy allowed with assessment of risk • Becomes official Dec. 1, 2019 a

<800> Hazardous drugs – handling in healthcare settings. In: USP Compounding Compendium. Rockville, MD: U.S. Pharmacopeial Convention; 2016:85-103. Department of Health and Human Services. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016. www.cdc.gov/niosh/ docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB2016161.

HD, hazardous drug; NIOSH, National Institute for Occupational Safety and Health; USP, U.S. Pharmacopeial Convention

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Most effective

Hierarchy of Controls Physically remove the hazard

Replace the hazard

Isolate people from the hazard

Change the way people work

Protect the worker Least effective

Figure. CDC and NIOSH recommended controls. NIOSH, National Institute for Occupational Safety and Health; PPE, personal protective equipment Source: CDC.gov. Hierarchy of controls. www.cdc.gov/niosh/topics/hierarchy.

tives from the nursing, pharmacy and safety departments, used a shared website to centrally collect relevant documents and conducted weekly conference calls. Based on their evaluation of 157 drugs (227 dosage forms), the team compiled an HD compendium spreadsheet and drafted an HD handling policy for the health system. The compendium includes 206 HDs for the overall health system. All UH sites used the compendium to standardize containment strategy information across the health system. But, as required by USP <800>, each facility’s HD list was developed based on the products used at that facility using site-level purchasing and stocking data. The individual sites are required to use the compendium and “pare it down to just what they have in their sites, so they can eliminate the extra noise of those drugs that the infusion center pharmacies stock but the community hospital pharmacies may not,” Dr. Gegorski said. She added that using a multidisciplinary group to complete the AoRs and develop such policies allows hospitals to avoid some USP <800> requirements, such as drug storage facility constraints, for HDs associated with a low risk for employee exposure.

Color-Coded HD Chart Christine Roussel, PharmD, BCOP, the director of pharmacy at Doylestown Hospital, in Pennsylvania, noted that at her hospital they use a simple, color-coded chart to organize and label HDs, with colors corresponding to different risk

levels and the PPE and other controls required. Copies of the chart (available in pharmacy and nursing versions) are placed in medication rooms and on the hospital’s intranet so staff can access it at any time. “Nurses and pharmacy staff need to know to protect themselves,” Dr. Roussel said. (To acccess the chart, see the online version of this article at www.pharmacypracticenews.com). In an interview with Pharmacy Practice News, she stressed the importance of having this information readily available to staff, so that, for example, staff members who are pregnant can “self-identify and protect themselves without having to inform managers” about their pregnancy before they are ready to share that information. Dr. Roussel also noted that when patients come into the emergency department or to the hospital for an admission, they often bring their medications from home, “some of which are not on formulary at a hospital and could be hazardous.” For example, the increasing use of oral chemotherapy has resulted in more patients bringing in specialty oncology drugs that are not on a hospital’s formulary. Given the potential for these nonformulary agents to be brought into the hospital, Dr. Roussel underscored the need to include these drugs on the HD lists. She also recommended that staff wear gloves before handling any medication a patient brings from home. —Sarah Tilyou Dr. Gegorski reported no relevant ﬁnancial relationships. Dr. Roussel reported a ﬁnancial relationship with UCB Medical.

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What to ask your vendor

Partnering Well With Sterile Product Outsourcers W

ith the FDA now urging hospitals to acquire all their outsourced compounded sterile products (CSPs) from facilities registered with the agency under Section 503B of the Food, Drug, and Cosmetic Act, it may be tempting to assume that all FDA-designated 503B compounders are created equal. After all, the section requires that these facilities must observe Current Good Manufacturing Practices (CGMPs) and provide the FDA with certain information about the products they compound; they’re also subject to regular FDA inspection according to a risk-based schedule. But there are no easy, one-step ways to choose a sterile compounding facility. “Generally, the 503B industry is not steeped in CGMP,” said Stuart Hinchen, the founder and CEO of QuVa Pharma, a Sugar Land, Texas–based sterile compounding outsourcer focused on anesthesia, general medicine, cardiovascular, operating room (OR), ER, pain management and obstetrics. “They came into it late, after the Drug Quality and Security Act [DQSA] was passed in 2013. Simply being a 503B facility is not enough.” It’s also not enough to review the Form 483 reports—the notices from the FDA of their observations after inspect-

ing a compounding facility. “Honestly, I don’t get terrified when I see that a compounder has had a 483, because pretty much everybody is going to get something,” g said Patricia Kienle, RPh, MPA, FASHP, the director of accreditation and medication safety at Cardinal Health. “What I do get concerned with is the egregiousness of the issues, repeat violations and how the company has responded to the FDA.” After a Form 483 is issued, the FDA may also issue a Warning Letter, which indicates that higher level agency officials have reviewed the observations and that a serious violation may exist. If the sterile compounding partner being considered has a warning letter (or letters), it should be a cue to look even more closely. “A Warning Letter is a red flag, although not necessarily a disqualifier,” said James Hussey, the executive vice president of Athenex Pharmaceuticals, a 503B manufacturer of specialty and generic products with U.S. headquarters in Buffalo, N.Y. “Read the Warning Letters carefully. In a number of cases, you’ll see that the FDA has recommended that the company hire a consultant to help them develop CGMP. That tells you that the compounder does not even have the internal expertise

‘Honestly, I don’t get terrified when I see that a compounder has had a 483, because pretty much everybody is going to get something. What I do get concerned with is the egregiousness of the issues, repeat violations and how the company has responded to the FDA.’ —Patricia Kienle, RPh, MPA, FASHP

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to get to CGMP—and if you see that, I’d recommend that you walk away.” Similar to Form 483s, recalls can be informative but also should not necessarily eliminate a compounder from consideration. “There are certain matters outside of the control of a production facility,” said Jason McGuire, the vice president for quality and regulatory affairs at Fagron North America (JCB Labs/Fagron Sterile Services), an FDA-registered 503B compounding outsourcer based in Wichita, Kan., that specializes in ophthalmology, corticosteroids, OR syringes, and other high- and mediumrisk pharmaceutical preparations. “Examples may include adverse events related to poor hygienic practices or facility protocols not being followed by the end users. When a customer complaint is made, the production facility may not have all the information related to the clinical facility. However, out of extreme caution, it may be decided to initiate a recall instead of risking potential patient harm.” “Even in Big Pharma, we see recalls. It’s not possible to eliminate 100% of that risk,” agreed Paul Yamamoto, RPh, the corporate pharmacist and general manager at California- and Colorado-based Leiters, a 503B outsourcing facility focused on ophthalmology and hospital-based products. “But it is important that your outsourcing facility quarantines and holds product, and does not rationalize releasing a product when the data suggest otherwise.” (See the sidebar for additional considerations in choosing an outsourcer.)

It’s All in the Documents To be in compliance with CGMPs, Mr. Hussey said, all sterile compounders should provide a Certificate of Analysis with every batch that includes the following items: • sterility testing • potency testing • bacterial endotoxin testing • testing for visible particulates • visual inspection for container integrity “This must be signed and dated by a registered pharmacist,” he said. “Ask to see these in writing and check to ensure that the batch number and lot number match. In some cases, a compounder will do a mockup C of A, but when you look, the lot number doesn’t match the product shipped. That means they did it one time, but not on every batch.” The compounder also should be able to show data confirming that the basic formulation of every product they’re compounding will remain stable for 90 days, he added. An outsourcer’s quality assurance unit should have clear independence from the rest of the operation, Mr. Yamamoto said. “They must be given the responsibility of approving and rejecting all products. I’ve seen several 483s that say the quality entity was not given the authority to do this. Releasing product is not a decision that should be left in the hands of pharmacists—sorry, pharmacists. You need a variety of quality employees. Your chemists don’t do the microbiology methods; your microbiologists don’t review see PARTNERING, page 52

A Health System’s ‘Mission’ For Vetting 503B Outsourcers

ver the past year, Mission Health, a six-hospital health system serving western North Carolina, has evaluated three potential 503B sterile compounding outsourcers. Of the three potential vendors, only one was ultimately chosen. “As with many other institutions facing significant drug shortages, we’re trying to find partners who can meet our needs,” Josh Powell, PharmD, Mission’s pharmacy operations manager, told Pharmacy Practice News. Dr. Powell’s tips for 503B vendor review: Start with the FDA. Analyze the information available on the FDA’s website, including 483 reports and recalls. Dr. Powell agrees that 483 reports alone are not a red flag against a particular outsourcer, and concurs with the recommendation to steer clear of companies that have been warned by the FDA to seek a consultant’s help with Current Good Manufacturing Practices. “If you’re searching for a consultant after the fact, that means you missed something pretty significant to begin with.” Check the catalog. After identifying promising outsourcers, determine whether the company can provide the drugs you need. “These facilities often want to know that you’re going to remain with them if that particular drug shortage or shortages are resolved,” Dr. Powell said. “Sometimes they may say that they can’t support you unless you’re willing to open up to more items in their catalog.” Request documentation. Now it’s time for the paperwork. Dr. Powell always asks for items such as quality reports, FDA registration and state licensures, and Certificates of Analysis. Never skip the site visit. But only schedule one after thoroughly vetting the company. “Multiple site visits can be burdensome in terms of cost as well as time of your pharmacy staff,” he said. “We gather all our documentation and only visit the facilities that we know we would approve contingent on a good site visit.” Don’t let them see you coming. Many compounders will offer to pay for your travel expenses and arrange the visit. “We want to see the pharmacy when they’re not ready for us,” Dr. Powell said. Rely on ASHP. “After we’ve collected our data and conducted our site visit, we use the ASHP outsourcing assessment tool to round out our discussion,” Dr. Powell said. He cautioned that some facilities already have the tool filled out for their customers. “It’s important to use the tool yourself first and then compare it to the facility’s answers.” —Gina Shaw

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PARTNERING continued from page 51

the chemistry data. There are many roles within the quality segment, and everyone there should be trained in CGMP.”

Multistep Process Ensuring a supplier has an integrated system is itself a multistep process. It should start, if at all possible, with on-site audits. “You need to see the facility and validate with your own eyes what is going on,” Mr. Yamamoto said. “You should interact with the leaders in quality, production, pharmacy and compliance, and view their documentation. We’ve had customers ask us to complete paper-based surveys, but they don’t come close to giving you the information that you really need.” Before the site visit, prepare by reviewing the FDA’s 483 reports on the supplier. “They are the best independent arbiter of what a supplier is doing. Look at what elements the 483 addresses,” Mr. Hinchen said. “Is there a problem with room certification, with the facility showing weakness? Is there an issue with aseptic practice, pointing to the production system? On your site visit, you can then ask focused questions about room certifications, about the calibration program, about whatever the 483s have identified.” The company should be able to provide a written explanation to the pharmacist—the potential partner—as to what is being done to address any issues raised in the 483s, Ms.

Kienle said. “If they have an explanation and a clear plan of action for correction, then [they shouldn’t be eliminated] from consideration. But if they say they don’t think that the 483 accurately represents what they’re doing, then I would be more concerned.” There isn’t a single compounder in operation today that hasn’t had a recall or a 483 report, the experts reiterated. But most of the time, when there’s a breakdown in one of the pillars of a good sterile compounding operation, the other pillars should act as checks and balances on that one. “An integrated process means that you have controls all the way through, and that’s what you need to look for,” Mr. Hinchen said. “Don’t rely on glossy brochures.” Mr. McGuire compared the integrated quality components of good sterile compounding to those that maintain human homeostasis. “The human body has 11 different support systems designed to maintain optimum physiological function. If any of those support systems malfunctions, it’s an indicator that you may not be 100% healthy. Similarly, the quality of a compounded sterile product is tied to the quality systems built into the entire process, and each part must be monitored, reviewed and found in working order prior to the product release.” —Gina Shaw The sources reported no relevant ﬁnancial relationships other than their stated employment.

USP <797> CHANGE continued from page 45

people realize from a <797> perspective is that it’s a patient safety issue. We need to be doing the right thing, and we need to be able to monitor. We want patients to know that the areas in which our sterile preparations are being made are clean.”

Pressure Has Been Building Administrators of health care institutions should be familiar with compounding standards required under USP due to the increased pressures being applied by accreditation bodies, the Centers for Medicare & Medicaid Services, state regulatory bodies and the FDA, noted Fred Massoomi, PharmD, the senior director of hospital & health-system pharmacy services at Visante. “Modifications to the compounding practices in the United States change frequently, and health systems should include within budget forecasts the ability to anticipate the changes and plan for them,” Dr. Massoomi said. “USP publishes anticipated changes to standards at least a year in advance of the expected compliance date for the public to review the modifications and comment. “Standards and regulations often drive compliance. The Pew Institute monitors published examples of where compounding practices have failed, leading to patient harm and death. Hospitals are not immune from these unfortunate

USP 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.

events and thus should continually strive towards excellence when preparing medications for their patients.” —Bruce Buckley Ms. Kienle reported that she is a member of the USP Compounding Expert Committee, but her comments are her own and neither afﬁliated with nor endorsed by USP. Dr. Massoomi does consulting work on USP <800> compliance. He has also done lectures for BD, Equashield and ICU Medical.

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The Sterile Products Dilution Problem Judith Jacobi, PharmD, FCCP, MCCM, BCCCP a Senior Consultant Visante, Inc. St. Paul, Minnesota

Maureen Burger, RN, MSN, CPHQ, FACHE Chief Nursing Officer Visante, Inc St. Paul, Minnesota

ou spend a lot of time being compliant with US Pharmacopeial Convention (USP) General Chapter <797> during preparation of sterile products, but do you know how syringes are prepared on nursing units? Does your pharmacy purchase ready-to-administer, prefilled syringes, only to find that nurses are transferring the contents to a prefilled saline flush syringe or some other vehicle? If you answer “yes” or “I don’t know” to any or all of these questions, there is cause for real concern.

IV Push Medication Errors IV push medication preparation and administration are highrisk processes due to the fast onset of action and narrow therapeutic index of many IV drugs and the limited ways to reverse their effects. Nearly two-thirds of harmful drug errors involve injectable medications,1,2 and the number of errors with injectable medications is higher than with any other dosage form. Numerous measures have improved the safety of pharmacyprepared medications, but almost half of harmful errors occur during the medication administration phase, which typically is not under the direct supervision of pharmacists.3,4 Some factors contributing to IV push medication errors include: • multiple manipulations required to prepare the drug

(eg, vial-to-syringe transfer, syringe-to-syringe transfer, dilution, use of a filter); • preparation of the drug in clinical areas instead of the pharmacy, under conditions that are not compliant with USP <797> and with limited or sometimes absent labeling of the product; and • nonstandard practices and lack of training.5 The Institute for Safe Medication Practices (ISMP) identified widespread dilution of IV push medications, including dilution of medications from prepared syringes, as an unnecessary practice leading to unlabeled or mislabeled syringes, potential contamination of sterile IV medications, dosing errors, and other types of drug administration errors.6 All 5 factors listed above are risks inherent to the process of diluting IV push medications.

How Widespread Is Dilution Of IV Push Drugs? In 2012, ISMP surveyed nurses about Carpuject prefilled cartridges as a follow-up to a safety alert from Pfizer about potential overfill in the cartridges.7 The survey revealed that nurses were not concerned about the risk for overfill because they were using the cartridges as single- or multiple-dose vials rather than a prefilled delivery system. Nurses were discarding the needleless adapter and puncturing the rubber diaphragm with a needle and syringe. Nurses noted that they expected overfill, and would remove the amount needed from the cartridge and waste the remaining drug or use it for a subsequent dose. The nurses continued the practice despite acknowledging safety concerns, including potential contamination, mislabeled or unlabeled syringes, dosing errors, needlestick injuries, and drug diversion. A follow-up study revealed that 83% of nurses routinely dilute IV push medications prior to administration.6 The nurses diluted drugs in single-use vials or ampules most often, with 77% responding that they did so “sometimes,” “often,” or “always.” About half responded that they diluted

Table. Why Nurses Prefer to Dilute IV Push Drugs Anticipated discomfort at the injection site during injection Vesicant or irritant nature of the medicationa High risk for extravasation with the medication or drug delivery device (eg, butterfly) Need to administer a medication very slowly via IV push, because rapid administration causes adverse effects Viscosity of the medication (eg, LORazepam)a Difficulty in measuring a very small dose of medication a

Consistent Co s ste t with w t package pac age insert. se t

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Based ased on o reference e e e ce 7.

An ISMP survey of nursing practices found:

77% of respondents diluted single-use vials or ampules

49% diluted multidose vials

43% diluted prefilled syringes

20% diluted pharmacy-prepared syringes Based on reference 6.

multidose vials (49%) or prefilled syringes (43%), and 20% diluted pharmacy-prepared syringes (prepared in patientspecific doses). The drugs most frequently diluted were opioids followed by antianxiety drugs and antipsychotics. A study published in 2018 revealed even more objective evidence of the scope of dilution by nurses.8 Trained observers watched nurses prepare and administer IV push drugs using either a vial plus a syringe, prefilled cartridges, or manufactured prefilled syringes. Of note, 64 of 65 observations showed that prefilled cartridges were used as vials, and 21 of 102 observations showed that the nurses withdrew the drug from manufactured prefilled syringes and further diluted the drug. The study found that the observed nurses diluted at least half of diphenhydramine, famotidine, hydromorphone, hydralazine, ketorolac, labetalol, lorazepam, metoclopramide, and promethazine doses. Several of these drugs do not require dilution for safe administration. Many sources recommend the use of manufactured prefilled syringes to reduce the risks for IV push drug errors. However, this study confirms the previous survey findings and presents a new risk for misuse of manufactured prefilled syringes.

Why Do Nurses Dilute? Nurses dilute IV push drugs for many reasons, with little or no evidence to support the practice. In the 2012 ISMP survey, nurses reported several reasons for diluting IV push drugs, including the potential for discomfort at the injection site, difficulty measuring small doses, and possible extravasation (Table).7 Nurses also noted that the type of vascular access device influences the decision to dilute. For example, nurses are more likely to dilute IV push drugs given via a saline lock (intermittent device) than those given a continuous infusion, and are less likely to dilute if administering via a central venous line. Conversely, some nurses will dilute all IV push drugs into a 10-mL syringe when the drugs are given via central venous access. This practice may be a misunderstanding about the need to use

a 10-mL–diameter syringe to flush a central line after insertion. Once line patency has been confirmed, a smaller diameter syringe can be used to administer a medication.9 However, the saline flush after the medication should again be a 10-mL syringe. Nurses also diluted IV push drugs because they thought it was safer to dilute all medications before IV push administration. Reasons for dilution included the ability to administer the dose slowly, to minimize discomfort, or to have time to observe the response.9 Generally, nurses were trying to practice in a manner they hoped would increase patient safety.

Expert Opinion or Outdated Thinking? Tertiary references abound in nursing that direct nurses to dilute IV push drugs. These statements are not referenced and do not reflect current thinking about the hazards of manipulating IV drugs, nor do they reflect the new product forms that are designed to reduce the risks related to unlabeled or mislabeled syringes and contamination. Procedure manuals are silent on the steps to safely dilute IV push drugs, and many nurses routinely dilute IV drugs into prefilled saline flush syringes, which are not FDA approved for use as a diluent. These well-meaning, but potentially dangerous, procedures are passed down during orientation by preceptors and rarely are questioned or reviewed. The need to evaluate local practices and adopt evidence-based practice is a focus of translational science. The University of Iowa Hospitals and Clinics recognized that many nursing practices were not evidence-based. In response, the hospital developed a program to improve the quality of nursing care by eliminating “sacred cow” practices.10 It is one of many examples of performance improvement programs that, although not specific to IV medication practices, are focused specifically on nursing. The authors suggest that such programs should summarize the evidence, audit organizational standards, survey actual practice, grade baseline performance (via a grading rubric), set priorities and an action plan, and then see DILUTION PROBLEM, page 56

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DILUTION PROBLEM continued from page 55

implement changes and measure the results.10 Efforts to incorporate new technology amid outmoded practices should ideally include a failure mode and effects analysis. Unfortunately, drug shortages and limited product availability have forced adoption of new devices and medication delivery tools with minimal planning. Thus, periodic evaluation of practices related to these new products is an important performance improvement step. Various templates are available to assist practitioners. ISMP developed a quality initiative focusing on IV push medications, and the 2015 Safe Practice Guidelines for Adult IV Push Medications summarizes best practices from a summit meeting.11 To reduce the risk for drug errors during the preparation and administration of IV push drugs, the guidelines clearly recommend against dilution and/or other unnecessary manipulation of IV push drugs. If the manufacturer requires dilution, ideally it should be done in the pharmacy under the best conditions as required by USP <797>. If dilution must be done at the point of care, then nurses need to know and follow the guidelines for immediate-use sterile products. USP <797> applies to all practitioners, including nurses, and all sites in which sterile injectables are compounded, including nursing units. Imagine all the effort that pharmacists put into protecting patients from contaminated sterile products, and how unnecessary dilution is undermining your safety goals for your patients. Orders for drugs that require dilution, such as lorazepam, should include specific directions that are visible to nurses. Similarly, prefilled and ready-to-use syringes could have a statement “do not dilute” in the product comments. The National Health System (NHS) in the United Kingdom has commented on appropriate use of ready-to-administer medications within their tool to promote safer use of injectable medications.12 This 2007 NHS Safety statement defined readyto-use and ready-to-administer products as those requiring no additional dilution or reconstitution prior to administration. Similar criteria were published in the US in 2017, which notes that ready-to-administer products require no manipulation (e.g., no need for further dilution).13 The pharmacy department at the Ohio State University developed a template for performance improvement to assess compliance with Medication Management Standards of the Joint Commission, using tracer methodology.14 Projects like this have led the Joint Commission Resources to develop a tool for evaluation of injectable medication management.15 This tool directs practitioners to evaluate major aspects of medication management, such as patient safety/regulatory compliance, pharmacy practices for drug acquisition and dispensing, nursing unit practices, and anesthesia practices. This detailed tracer tool considers the preparation type—whether frozen, ready to use, 503B-compounded, or locally prepared— for a variety of common medications. The tool covers the use of automated dispensing cabinets, ordering and order verifi-

cation processes, and IV room compounding practices. Individual facilities can customize this very detailed performance improvement tool based on their needs. As drug delivery technology becomes more sophisticated and novel, our patients stand to benefit from enhanced safety systems, such as prefilled and ready-to-use syringes, if we allow them to be used to their greatest capacity. Pharmacists should lead their multiprofessional teams in optimal use of these products.

References 1. Taxis K, Barber N. Ethnographic study of the incidence and severity of intravenous drug errors. Br Med J. 2003;326(7391):684-687. 2. Cousins DH, Sabatier B, Begue D, et al. Medication errors in intravenous medicine preparation and administration: a multicentre audit in the UK, Germany and France. Qual Saf Health Care. 2005;14(3):190-195. 3. Bates D, Spell N, Cullen DJ, et al. The cost of adverse events in hospitalized patients. JAMA. 1997;277(4):307-311. 4. Bates DW, Cullen DJ, Laird N. Incidence of adverse drug events and potential adverse drug events: implications for prevention. JAMA. 1995;274(1):29-34. 5. Institute for Safe Medication Practices. Errors with injectable medications: unlabeled syringes are surprisingly common! Acute Care—ISMP Medication Safety Alert! www.ismp.org/Newsletters/acutecare/articles/20071115.asp. November 15, 2007. Accessed March 7, 2018. 6. Institute for Safe Medication Practices. Some IV medications are diluted unnecessarily in patient care areas, creating undue risk. Acute Care—ISMP Medication Safety Alert! www.ismp.org/newsletters/acutecare/showarticle.aspx?id=82. June 19, 2014. Accessed March 7, 2018. 7.

Institute for Safe Medication Practices. ISMP survey reveals user issues with Carpuject prefilled syringes. Acute Care—ISMP Medication Safety Alert! www.ismp.org/newsletters/acutecare/showarticle.aspx?id=28. August 9, 2012. Accessed March 7, 2018.

8. Hertig JB, Degnan DD, Scott CR, et al. A comparison of error rates between intravenous push methods: a prospective, multisite, observational study. J Patient Saff 2018;14(1):60-65. 9. Gorski L, Hadaway L, Hagle ME, et al. Infusion Nursing Standards of Practice, Standard 45. Flushing and Locking. J Infusion Nurs. 2016;39(1 suppl):s77-s81. 10. Hanrahan K, Wagner M, Matthews G, et al. Sacred cow gone to pasture: a systematic evaluation and integration of evidence-based practice. Worldviews Evid Based Nurs. 2015;12(1):3-11. 11. Institute for Safe Medication Practices. ISMP Safe Practices Guidelines for Adult IV Push Medications. www.ismp.org/Tools/guidelines/ IVSummitPush/IVPushMedGuidelines.pdf. f Accessed March 7, 2018. 12. National Health System. National Patient Safety Agency. Patient safety alert. Promoting safer use of injectable medicines. npsa.nhs.uk/EasySiteWeb/GatewayLink.aspx?alId=2269. March 28, 2007. Accessed March 7, 2018. 13. Fanikos J, Burger M, Canada, T, et al. An assessment of currently available i.v. push medication delivery systems. Am J Health-Syst Pharm. 2017; 74:e230-5 14. Hendrick EC, Montanya KR, Griffith N. Medication tracers: a system approach to medication safety. Hosp Pharm. 2007;42:916-920; doi:10.1310/hpj4210-916. 15. Joint Commission. Ready to Administer Injectable Medication Safety Tracer Tool. Oak Brook, IL: Joint Commission Resources. In press. a

At the time of writing, Dr. Jacobi was a critical care pharmacist at Indiana University Health Methodist Hospital, in Indianapolis. Dr. Jacobi reported a ﬁnancial relationship with Fresenius Kabi. Visante has worked with Fresenius Kabi on safe use of readyto-use injectables. Dr. Massoomi has done lectures for BD, Equashield and ICU Medical.

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Best practices in automation, informatics and patient safety

New data show pharmacists, nurses at risk

CSTDs Should Be at Center Of Health Care Worker Safety W ith the recent announcement from the U.S. Pharmacopeial Convention that it will push the go-live date of USP Chapter <800> to 2019, health care institutions have gained more time to plan for implementation of the chapter’s requirements.

hallways.” Although the contamination “is pretty widespread,” Dr. Connor noted, “it’s concentrated in pharmacy and treatment areas, and we know from the literature that people are picking this up through dermal contact; our nurses and pharmacists are being exposed.”

chemotherapy infusion centers included in NCI wipe sampling study of centers found to have hazardous drug residue under IV pole and on arm of an infusion chair. of centers tested positive after simulated use of CSTD during chemo prep. Source: Poster (No. 79) presented at the 2017 annual meeting of the Oncology Nursing Society, in Denver.

However, experts in workplace contamination say health systems should not delay complying with one of those new requirements: the use of closed-system drug-transfer devices (CSTDs) to protect health care workers (HCWs) from hazardous exposures. Their urging is based in part on new wipe sampling data showing significant contamination in chemotherapy administration areas. Such findings are not surprising to Thomas H. Connor, PhD, a research biologist at the CDC. “Dozens and dozens of studies in the United States and around the world— probably over 100 now—demonstrate surface contamination with hazardous drugs,” he said. “These studies have primarily been done with a few of the more than 100 antineoplastic agents in use, and wherever you look, you find them: in pharmacy areas, where the drugs are prepared; in nursing areas, where the drugs are administered; and even outside those areas, like on elevator buttons and in

Occupational health expert Chun-Yip Hon, PhD, an associate professor in the School of Occupational and Public Health at Ryerson University, in Toronto, led several of these studies. “We have found contamination throughout the facilities, and no institution is immune. Some facilities where the drug preparation area is immediately adjacent to the nursing area have less spread of contamination throughout the facility, but nursing and pharmacy areas consistently have significant contamination.” These “leaks” in administration areas can permit drugs to find their way into the bodies of nurses, pharmacists and other HCWs who do not deal with the drugs directly but are working in the area. In a 2015 study, Dr. Hon’s group found that 55% of Canadian HCWs had nonmetabolized cyclophosphamide in urine samples that was above the level of detection, with workers who had a duty to handle antineoplastic drugs showing

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‘Some facilities where drug preparation [is done] immediately adjacent to the nursing area have less … contamination throughout the facility, but nursing and pharmacy areas consistently have significant contamination.’ —Chun-Yip Hon, PhD higher concentrations ((Int Arch Occup Environ Health 2015;88[7]:933-941). A new multisite study, presented at the 2017 annual meeting of the Oncology Nursing Society, demonstrated the ability of CSTDs to reduce surface contamination and HCW exposure in chemotherapy administration areas. The study, funded by the National Cancer Institute, was conducted in 17 cancer centers to evaluate the performance of a new CSTD during a protocol designed to challenge the administration process. Before and after use of the CSTD, wipe samples were taken from three administration locations: two on the floor under the IV pole and one on the arm of the infusion chair. Hazardous drug residue at or above the level of detection was found in 74% of the baseline wipe samples; after simulated administration of antineoplastic agents (cyclophosphamide and 5-fluorouracil) with a CSTD, only 2% of wipe samples were at or slightly above the level of detection ((P<0.001). “In this study, the researchers specifically looked at wipe sampling in chemotherapy administration areas, selecting sampling locations that were directly impacted by CSTDs, as opposed to areas such as counters and trash cans that have been sampled in other studies,” said Luci A. Power, MS, RPh, a senior pharmacy consultant at Power Enterprises, who was involved with the study. “The existing contamination at these specific sampling locations was higher than reported in the literature for miscellaneous locations in the chemo administration area, and the use of the CSTD at these sites in simulated administration with real chemo drugs showed a significant improvement in all 17 sites.” Kristin Rupp, RN, BSN, OCN, a lead treatment nurse at the Comprehensive Cancer Center at Desert Regional Medical Center in Palm Springs, Calif., presented the study results at ONS. “Only a few previous studies have reported on contamination specific to the infusion areas,” she told Pharmacy Prac-

tice News. “Infusion sampling sites have not been determined by administration tasks, and no previous studies have looked at reduced contamination by CSTDs in administration. These findings were consistent across study sites, and demonstrate both the presence of contamination in chemotherapy administration areas as well as the effectiveness of the device.”

High Cost May Be Barrier Institutions may balk at the cost of these systems. “Depending on the type of system and how many pieces you have to use, it can cost between $15 and $20 for a full dose of a drug that’s compounded in the pharmacy, with $5 to $7 a dose extra for the nursing pieces, so a total of $20 to $27 if you’re looking at the full system,” Ms. Power said. “At an institution like MD Anderson, that means you’re looking at $2 million a year, every single year.” But it’s an expense that must be borne and should not be delayed, noted Dr. Connor, who works at the National Institute for Occupational Safety and Health, Division of Applied Research and Technology, in Cincinnati. “We have good enough [data] to show that CSTDs, in addition to engineering controls and personal protective equipment, are an important tool to help reduce worker exposure. You wouldn’t say, ‘I’m going to save money by not buying gloves for workers,’ would you? That’s another cost that adds up enormously. You have a proven technology that every agency recommends, that is known to reduce exposure. Why not put it in place as soon as possible?” —Gina Shaw Ms. Power disclosed that she is an independent consultant with primary expertise in the safe handling of HDs. She is currently a paid consultant to Corvida Medical and has received speaker honoraria from BD, Equashield and ICU Medical. She is a nonpaid member of the USP Compounding with Hazardous Drugs Expert Panel but does not represent USP. Dr. Hon, Dr. Connor and Ms. Rupp reported no relevant ﬁnancial relationships.

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CSTD Selection Tips:

Matching Right Device to Right Hospital Anaheim, Calif.—Selecting a closed-system drug-transfer device (CSTD) that works best to protect pharmacists, technicians and nurses from hazardous drug exposure can be a challenge for health systems faced with tight budgets and razor-thin operating margins. “The dilemma facing hospitals and infusion centers with aggressive cancer treatment programs is the necessary additional expenses for safety with no incremental increase in revenue for those expenses,” said Fred Massoomi, PharmD, FASHP, a senior director of hospital and healthsystem pharmacy services at Visante Inc. It can take months to come to a decision on a CSTD. At the University of Wisconsin Health (UW Health) in Madison, for example, the evaluation of potential devices began in July 2017 and didn’t conclude until last June. At the 2018 ASHP Midyear Clinical Meeting, Jevon Oliver, PharmD, MS, currently the pharmacy manager of perioperative services at Massachusetts General Hospital in Boston, and until June a master’s degree candidate at UW Health, described a year of vigorous discussions, negotiations and testing that led to the final choice. The year began, he said, with the formation of a multidisciplinary workgroup tasked with seeing the project through from the initial evaluation of available FDAcleared systems, to a pilot phase involving two CSTDs that survived the initial appraisal, to the final implemen-

tation of the winning device. Two weeklong pilot tests carried out in the pediatric oncology infusion unit were key to the decision. Team members judged how well the devices performed within the pharmacy and nursing workflow. They compared surface

With USP Chapter <800> due to become final this December, health systems with infusion centers have stepped up their adoption of CSTD systems to comply with its stipulation that the devices ‘must’ be used to administer hazardous drugs and ‘should’ be used for compounding. wipe samples and found that both devices left no hazardous drug traces. They also had “some lively discussions” about paying for the device. Dr. Oliver said the payment decision was resolved when pharmacy and nursing agreed to share the cost, based on the level of use by the various units. The team also looked at CSTDs for drug vial optimization. A pharmacy analysis showed that eliminating single-

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Table. Drug Vial Optimization: An Opportunity for CSTD Savings

In the end, Dr. Oliver reported, the successful CSTD was adopted for nursing administration but delayed for compounding, pending further analysis.

USP Chapter <800> Looming

Drug

4-Week Cost of Waste for Single-Use Vials, $

Rituximab

17,679

Pegaspargase

11,516

Trastuzumab

6,556

Pembrolizumab

4,648

Ipilimumab

4,304

Cetuximab

4,172

Cyclophosphamide

3,260

Carfilzomib

2,574

Busulfan

2,482

Panitumumab

2,460

Nivolumab

2,358

Daratumumab

2,029

Arsenic trioxide

1,824

Bevacizumab

1,749

GAMMAGARD S/D

1,580

Bortezomib

1,491

Bezlotoxumab

1,235

Reslizumab

878

Fosphenytoin

648

With the U.S. Pharmacopeial Convention’s General Chapter <800> due to become final this December, health systems and hospitals with infusion centers have stepped up their adoption of CSTD systems to comply with its stipulation that the devices “must” be used to administer hazardous drugs and “should” be used for compounding. Competition among CSTD manufacturers has been lively. Dr. Massoomi noted that the U.S. market right now “is fairly rich with options in the CSTD realm, and folks should really explore what works best for their pharmacy and nursing staffs.” He said it was important to note that although all currently marketed devices have received FDA 510(k) clearance, the ONB product codes describing their functionality can vary considerably in addition to their proprietary mechanisms. “One may prevent bacterial ingress over a certain amount of time,” he pointed out, whereas another states it “mechanically prohibits the transfer of environmental contaminants into the system and the escape of drug or vapor contractions outside the system.” But what the decision finally comes down to, Dr. Massoomi added, is how well the devices work within the workflow of the institution or clinic site, and how they interface with compounding and administration devices used at the facility. Dr. Massoomi emphasized that CSTDs were the only devices cleared by the FDA for both compounding and administration. The use of needle and syringe and luer connectors “have never been cleared for that purpose,” he noted. “I would hope at some point,” he added, “we would all realize that while we pay pennies for these [earlier] devices, they were never cleared for compounding and administration. That’s probably why we have the problems we have. They were never designed to do that appropriately.” —Bruce Buckley

Source: 2018 UW Health Waste Analy Analysis ysis for DVO.

vial waste of 19 hazardous drugs listed by the National Institute for Occupational Safety and Health had the potential to save UW Health $1.4 million a year (Table). The finding, however, played no part in the decision, Dr. Oliver said. Originally, he told Pharmacy Practice News, the team leaned toward one of the CSTDs based on its history and what people had said about it. But after conducting the pilot tests, he said, “we decided to go with the other product.” For one thing, while both CSTDs increased technicians’ compounding time from the baseline of 5.2 minutes per preparation, the winning device took an average of 6.2 minutes compared with 8.4 minutes for the other product. There also was greater nursing and pharmacy satisfaction with the winning device.

Dr. Oliver reported no relevant ﬁnancial relationships. Dr. Massoomi is a senior director at Visante Inc., which does consulting work on USP <800> compliance. He has also done lectures for BD, Equashield and ICU Medical in the past year.

Video Exclusive For Dr. Massoomi’s views on sterile compounding and patient safety, see our exclusive videos at www.pharmacypracticenews.com/multimedia.

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Review on CSTDs Misses the Mark Luci A. Power, MS, RPh Senior Pharmacy Consultant, Power Enterprises, San Francisco, California

Martha Polovich, PhD, RN, AOCN Assistant Professor, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, Georgia

Melissa A. McDiarmid, MD, MPH, DABT Professor of Medicine and Epidemiology & Public Health, Director, Division of Occupational and Environmental Medicine, University of Maryland School of Medicine, Baltimore, Maryland

Patricia C. Kienle, RPh, MPA, FASHP Director, Accreditation and Medication Safety, Cardinal Health Innovative Delivery Solutions, Wilkes-Barre, Pennsylvania

recently released Cochrane Review1 questioning the utility of closed-system drug-transfer devices (CSTDs) has triggered considerable debate among safe handling stakeholders in pharmacy. The review, by Gurusamy et al, concluded that “there is currently no evidence to support or refute the routine use of [CSTDs] in addition to safe handling of infusional hazardous drugs [HD], [because] there is no evidence of differences in exposure or financial benefits between CSTD plus safe handling versus safe handling alone.” The authors further concluded that none of the studies included in their review adequately documented health benefits. The six review authors stated, “We also disagree with any guidelines or recommendations that CSTD should be used routinely whenever possible.” Unfortunately, the Gurusamy review has many flaws that influence its conclusions. The major shortcoming in this review is the violation of one of the principles of the Cochrane approach—that is, the need to demonstrate the homogeneity of the data to be synthesized.2 For example, the authors did not determine performance criteria for CSTDs and selected studies that had the term CSTD in the title or abstract but no verification that the CSTD in use was effective. Moreover, the authors made no attempt to validate the “safe handling” parameters in use in any of their selected studies, and they lumped together pharmacists, pharmacy technicians, and oncology nurses as “participants,” regardless of their potential for exposure. The review authors’ questioning of CSTDs also contradicts a history of support for the devices from some of the leading safe handling experts. In the United States, for example, guidance documents on the safe handling of HDs that recommend CSTDs have existed for decades and were developed by agencies that advocate for the protection of all workers. They include governmental agencies, such as the National Institute for Occupational Safety and Health (NIOSH)3 and the Occupational Safety and Health Administration (OSHA).4 Professional societies that represent health care workers, such as the ASHP5 and the Oncology Nursing Society (ONS),6 which have developed recommendations that are considered best practices to ensure the safety of

their members, also see the value of CSTDs. The United States Pharmacopeial Convention (USP) is another organization that has underscored the value of CSTDs in protecting worker safety. USP published General Chapter <800> “Hazardous Drugs—Handling in Healthcare Settings,” in 2016.7 These safety standards require the use of CSTDs for antineoplastic drug administration whenever the dosage form allows. This new mandate—an official standard—will take effect in December 2019 and likely prompted the Cochrane Review. The review authors state their objectives are “to assess the effects of closed-system drug-transfer of infusional hazardous drugs plus safe handling versus safe handling alone for reducing staff exposure to infusional hazardous drugs and risk of staff contamination.” They provide a definition of CSTD that is similar, but not identical, to that created by NIOSH in 2004,3 which states that “a closed-system drug-transfer device is an apparatus that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapour outside the system.”

Flawed Device Identification The review authors have failed to grasp the differences among devices marketed as CSTDs in the United States and elsewhere. In fact, the authors state, “We considered interventions as similar when it was clear that the system was a [CSTD].”1 However, they offer no evidence of what made it “clear” that the devices were all CSTDs, and in the review they appear unable to actually identify the device in 7 of 23 studies. Not all devices marketed as CSTDs function as defined by NIOSH, and many best-practice documents note that a performance standard is sorely needed to differentiate between effective and ineffective devices.5,7 Yet the review failed to determine if the devices in the selected studies actually performed as CSTDs. Additionally, the review included studies that did not identify the specific devices and included a study of a device that has no administration adaptor and, thus, does not meet even the simple NIOSH definition of a CSTD.8 There is another flawed definition in the review that compromises its conclusions. Despite decades of concern about workplace HD exposure resulting in thousands of pages of guidance on the safe handling of HDs,3-7 the review authors chose a simplistic definition of safe handlingg as “including protective clothing, gloves, and biological safety cabinets” and made no attempt to validate that any of these criteria were in effect in the selected studies. This definition is biased toward compounding exposure while ignoring HD administration tasks. In a detailed description of the studies, the review authors note that they screened the titles and abstracts of 7,587 records (identifying 7,321 unique references); obtained full texts for 83 potentially eligible studies; excluded 56 references; and included 23 studies (27 references). They also state that studies that

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‘Acceptance of the authors’ blanket rejection of all CSTDs, regardless of effectiveness, will continue decades of avoidable exposure to HDs.’ did not mention CSTD in the title or abstract are likely to show no evidence of benefit of CSTD. Note that 8 of the 23 included studies do not mention CSTDs in the title.

Validity of Worker Groups Another significant failure in this review, admitted by the authors, is that they considered study populations to be similar simply if those populations were workers exposed to HDs. As a result, they considered oncology nurses, pharmacists, and pharmacy technicians who handled HDs as a “homogeneous” population when, at least in the United States, this is not true. The levels of potential HD exposure to a pharmacy technician do not approach those of oncology nurses, who may compound HDs in a safety cabinet but administer them with nothing but personal protective equipment (PPE) and good technique as their protection. It has been well documented that HD handling activities, and, thus, exposure opportunities, vary considerably by type of personnel. Yet the study personnel included in the review consisted primarily of pharmacists and pharmacy technicians; only two studies involved nurses, and the numbers of nurses were small. The importance of proper study and subject selection is underscored in a recent examination of surface contamination in US cancer centers.9 The study used wipe sample locations designed to measure the effectiveness of the CSTD as an intervention during administration of HDs. Sampling the armrest of the infusion chair and the floor below the infusion pump, rather than counters, waste containers, and door handles in patient care areas produced a higher percentage of positive samples and greater amounts of measured HD residue. This study found that surface contamination in HD administration areas has been underreported in other studies, thereby underestimating the exposure risk of nurses.9 This bias toward compounding activities and personnel may explain the authors’ cavalier attitude toward the use of CSTDs in the administration of HDs, concluding that “CSTDs provide no protection when used for HD administration.” This conclusion is nott shared by ONS, ASHP, and USP.5-7

Questionable Use of Outcomes In their conclusions, the review authors include “exposure to an appropriate selection of [HDs] used in the hospitals” as an outcome, yet they fail to define appropriate HDs or to correlate the included studies by iden-

tifying the selection of HDs in the studies. The authors also identify “health benefits” as an outcome, yet none of the 23 studies examined health outcomes. Urine sampling of exposed workers may provide evidence of exposure, although not health outcomes. Cyclophosphamide is commonly reported in assays of surface sampling and urine sampling. There are no levels of cyclophosphamide (a Group 1 carcinogen by the International Agency for Research on Cancer [or IARC]10) that are acceptable in the urine of health care workers, although this, too, is not a health outcome. In a review of studies with concurrent surface wipe sampling and urine monitoring for the same HD, Kibby found no statistically significant correlation between wipe sampling and urine monitoring for HDs; however, decreases in urine and wipe levels following interventions to reduce exposure were noted.11 The outcomes measured in the Gurusamy review overreached the studies they assessed by looking for health outcomes in studies that only measured surface contamination. Health outcomes of exposure to HDs have already been examined in 2 systematic reviews/meta-analysis and 1 additional meta-analysis that provide a much better assessment of the subject than that produced by Gurusamy et al.12-14 Based on decades of studies documenting continued exposure to HD residue from contaminated work environments,15,16 USP, NIOSH, ASHP, and ONS recommend the use of CSTDs as part of an extensive HD safety program to reduce HD surface contamination, and thereby, reduce health care worker exposures.3,5-7 Recognizing the increased risk to nurses, USP has mandated CSTDs for administering antineoplastic HDs whenever the dosage form allows.7 These groups recognize that the CSTD does not and cannot eliminate all sources of HD exposure, including residue from HD packaging and vials that arrive at the health care facility already contaminated. In addition, CSTDs are no guarantee against HD cleaning methods that are not totally effective. Furthermore, the devices cannot protect against HD exposure that is unrelated to compounding and administration, such as handling contaminated body fluids from treated patients. However, adding CSTDs, especially during administration tasks where engineering controls are not available, provides protection that is superior to exclusively using PPE, which is the least effective intervention in NIOSH’s Hierarchy of Controls.17 see MISSING THE MARK, page 66

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Is Your Job Making You Sick? How to protect yourself from hazardous drugs Anaheim, Calif.—In 2010, after mixing chemotherapy drugs for 23 years, pharmacist Sue Crump died at age 55 due to pancreatic cancer. Before her death, Ms. Crump spoke to the media extensively about how she believed her occupational exposures had contributed to her disease. Many pharmacists know the job poses some risk, particularly to those who work in compounding and oncology. But every pharmacist, even those bottling pressed powder tablets in ambulatory pharmacies, can have occupational exposures to toxic medicines—with potentially dangerous effects. In every pharmacy around the world, there are traces of dust from pharmaceuticals—it may be on door handles, work surfaces, keyboards, elevator buttons and even food areas far from where medications are handled. Some of the dust comes from relatively harmless products, but many pharmacists are exposed to dust from toxic medications, such as methotrexate, cyclosporine, tacrolimus and compounds known to cause secondary cancers in patients, including cyclophosphamide and melphalan. An analysis of urine from health care workers (HCWs)—including some pharmacists and pharmacy technicians who were not directly involved with compounding—found that nearly two in five urine samples had traces of cyclophosphamide, and one in five had ifosfamide, which the workers hadn’t prepared in three weeks (Am ( J Health Syst Pharm 2003;60[22]:2314-2320). Relative to the general

population, occupationally exposed HCWs are more likely to show signs of DNA damage ((Mutat Res Rev Mutat Res 2017 Aug 24. [Epub ahead of print]) and experience reproductive issues ((J Occup Environ Med d 2014;56[9]:901-910). Most troubling, some studies have shown HCWs have a higher rate of mortality from some cancers, including leukemia ((Am J Ind Med d 1999;36[1]:159-165). When Christine Roussel, PharmD, BCOP, presents this information to a group of pharmacists—including recently at the ASHP 2018 Midyear Clinical Meeting—they are often really surprised, she told Pharmacy Practice News. “The looks on people’s faces is somewhere between shock and horror. And they start thinking about what they may have been exposed to in the past and the risk they may have incurred.” Knowing your risks is important, and taking the time to protect yourself is crucial, stressed Dr. Roussel, the director of pharmacy at Doylestown Health, in Pennsylvania. “Health care providers are very good at caring for their patients, and continually focusing on their patients’ safety, but health care workers are often not very good at caring for themselves,” she said. So, Dr. Roussel has made it her mission to educate her colleagues about the risks they face, and what they can do about it. There are many factors that cannot be controlled that can cause damage to human DNA—from the sun to environmental chemicals—but workplace exposure can be decreased, she said, adding, “You only have one body; you should take care of it.”

Powder Everywhere

Figures 1 and 2. Images showing how powder can linger during counting and filling. Courtesy of Christine Roussel, PharmD.

Since earning a bachelor’s degree in toxicology and starting to work as an oncology pharmacist in 2007, Dr. Roussel has been interested in the dangers associated with certain medications. “I spent the first couple of months as an oncology pharmacist worried about my patients’ exposures to toxic therapies, then thought: ‘Do I need to protect myself?’” At the time, she couldn’t find much research about occupational exposures in pharmacists, so she decided to search on her own. She reached out to Thomas Connor, PhD, a consultant for the National Institute for Occupational Safety and Health (NIOSH), who has written extensively on safe handling of hazardous drugs. Working with Dr. Connor, Dr. Roussel learned that nearly every pharmacist is exposed to potentially dangerous products. By simply counting uncoated, pressed powder tablets, methotrexate and similar compounds can be liberated into the personal breathing space of the person counting the tablets and onto the surfaces of the work environment (Figures 1 and 2). The same issue arises for cyclophosphamide, which is packaged in uncoated, pressed powder tablets. Over time, many pharmacists are inhaling low doses of these and other toxic agents. “I personally think the danger

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of inhalation of drug particulates in a retail pharmacy is underrated,” Dr. Roussel said. Numerous studies have documented this risk in multiple practice sites. A 2013 paper found that the vast majority of surfaces in a hospital pharmacy—the areas in and around biological safety cabinets and pharmacy countertops—contained traces of cyclophosphamide ((Hosp Pharm 2013;48[3]:204-212). In 2013, NIOSH released a report examining exposures at an outpatient pharmacy, which found active pharmaceutical ingredients in the air, and lactose (which acts as a proxy for drug ingredients) on surfaces around the pharmacy and in the air for an hour or more after handling activities (Health Hazard Evaluation Program 2010-0078-3177; bit.ly/2XiFeP7).

DNA on Drugs There is evidence that long-term exposure to these toxic products can have an effect. In 2017, Drs. Roussel and Connor published a meta-analysis examining the risk for chromosomal damage among pharmacists and other HCWs who had been exposed to antineoplastic drugs during their workday ((Mutat Res Rev Mutat Res 2017 Aug 24. [Epub ahead of print]). The results were stark: Among 17 studies, HCWs were significantly more likely to have chromosomal aberrations than controls. A study of female workers at a Danish pharmaceutical plant showed they had a higher risk for breast cancer ((Int J Epidemiol 1994;23[5]:891-898) and a 1999 study showed that white female pharmacists living in 24 U.S. states had higher rates of breast and ovarian cancers, as well as myeloid leukemia ((Am J Ind Med d 1999;36[1]:159-165). Occupational exposures also can pose a reproductive risk to pharmacists, including reduced fertility, problems in a developing fetus and even health problems in children (J ( Occup Environ Med 2014;56[9]:901-910). But it’s not just a concern for female pharmacists, according to Melissa A. McDiarmid, MD, MPH, the director of the Division of Occupational and Environmental Medicine at the University of Maryland School of Medicine, in Baltimore, who also spoke during the ASHP session. Evidence shows that some drugs can cause infertility in exposed men and possibly male-mediated fetal abnormalities, she said.

Pregnancy Risks The Occupational Safety and Health Administration requires that workers are informed about the hazardous chemicals they handle and receive regular training about the potential health outcomes (www.osha.gov/SLTC/hazardousdrugs/standards.html). Pharmacists—men and women—should obtain information about potential reproductive hazards, as well as a written policy about how their workplace plans to protect them, before they seek an accommodation because they are pregnant, breastfeeding, or trying to conceive, Dr. McDiarmid told Pharmacy Practice News. Of course, these are not always easy conversations to have, Dr. McDiarmid admitted. Workers at larger pharmacies should contact a representative of employee health to

Resources on Safety for Workers Handling Hazardous Drugs • CDC. NIOSH. Workplace Solutions. Medical surveillance for health care workers exposed to hazardous drugs. www.cdc.gov/niosh/docs/ wp-solutions/2013-103/pdfs/2013-103.pdf. • Power LA, Coyne JW. ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2018;75(24):1996-2031. • Power LA, Polovich M. Safe handling of hazardous drugs: reviewing standards for worker protection. Pharmacy Practice News. 2019 Jan 17. www.pharmacypracticenews. com/Review-Articles/Article/02-19/ Safe-Handling-of-Hazardous-Drugs/53875. • Roussel C, Connor TH. Chemotherapy: biomarkers of exposure, effect, reproductive hazards, and cancer. Oncol Pharm. 2014;7(1):1, 10-13, 18. • Roussel C, Connor TH. Chemotherapy: current and emerging issues in safe handling of antineoplastic and other hazardous drugs. Oncol Pharm. 2014;7(3):1, 8-11. • Roussel C, Connor TH. Chemotherapy: every step you take, every move you make. Oncol Pharm. 2013;6(4):1, 8-12.

find a new role with less risk, but at smaller facilities with less ability to swap employees, that’s more difficult. “I’ve received phone calls from pharmacists who know they are putting their reproductive health at risk, but their only option is quitting their job, losing income and even their health insurance,” Dr. McDiarmid said. “It’s a Catch-22.”

Reproductive Toxicants Dr. McDiarmid added that she understands why employers may think they can’t afford to set up alternative duty or some other system to protect workers of reproductive age, but they have to do something. Some of these drugs “are no-holdsbarred human reproductive toxicants. In no other industrial sector in this country would people be able to handle these chemicals with no safe handling policy,” she said. The first step of prevention is education, ensuring that see JOB SICK, page 66

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MISSING THE MARK continued from page 63

Gurusamy et al1 frequently mention the “very low quality” of the studies, which has resulted in a low-quality assessment. It is not clear how such strong conclusions of absolute certainty that CSTDs are of no value can be made from such “very low quality” and “biased” studies. Perhaps these studies were not appropriate for such a review? In our opinion, acceptance of the authors’ blanket rejection of alll CSTDs, regardless of effectiveness, will continue decades of avoidable exposure to HDs.

References 1. Gurusamy KS, Best LMJ, Tanguay C, et al. Cochrane Database Syst Rev. 2018;3:CD012860. 2. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 (updated March 2011). Higgins JPT, Green S, eds. The Cochrane Collaboration; 2011. www.handbook.cochrane.org. http://handbook-5-1. cochrane.org. Accessed August 22, 2018. 3. National Institute for Occupational Safety and Health. NIOSH alert: preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. www.cdc.gov/niosh/docs/2004-165. Accessed August 22, 2018. 4. Occupational Safety and Health Administration. Controlling occupational exposure to hazardous drugs. www.osha.gov/SLTC/hazardousdrugs/ controlling_occex_hazardousdrugs.html. Accessed August 22, 2018. 5. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2018. In press. bit. ly/2QmqECF. Accessed August 22, 2018. 6. Polovich M, Olsen M. Safe Handling of Hazardous Drugs. 3rd ed. Pittsburgh, PA: Oncology Nursing Society; 2017.

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schools and workplaces teach pharmacists and pharmacy technicians about the dangers of occupational exposures, Dr. Roussel said. “Once people understand what the risk is, it incentivizes them to take precautions.” These precautions should be adapted to the needs of the specific environment. Doylestown Hospital, where Dr. Roussel works, has created a separate storage room for hazardous drugs, and has disseminated a chart with a detailed guide on how to handle various drugs. Such prevention efforts can work. In the previously mentioned study in which researchers detected cyclophosphamide and ifosfamide in health care workers’ urine, when the researchers tested the workers after they used a closed system drug-transfer device to prepare chemotherapy, no employees tested positive for either drug ((Am J Health Syst Pharm 2003;60[22]:2314-2320). Time and finances are always a concern, but that’s no excuse to skip necessary precautions, Dr. McDiarmid said. “We know how to do this safely. We can do this. We just have to commit to it.”

Hazardous drugs—handling in healthcare settings (general information chapter 800). In: The United States Pharmacopeia, 39th rev., and The National Formulary, 34th ed. First supplement. Rockville, MD: United States Pharmacopeial Convention; 2016.

8. Forges F, Simoens X, Chauvin F. J Oncol Pharm Pract. 2011;17(1):61-67. 9. Bartel S, Tyler T, Power L. Am J Health Syst Pharm. 2018;75(4):199-211. 10. International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans. Pharmaceuticals. Volume 100A. Lyon, France: 2012 http://monographs.iarc.fr/ENG/Monographs/ vol100A/index.php. Accessed August 22, 2018. 11. Kibby T. J Occup Environ Hyg. 2017;14(3):159-174. 12. Sakhvidi MJZ, Hajaghazadeh M, Mostaghaci M, et al. Int J Occup Environ Health. 2016;22(1):52-67. 13. Villarini M, Gianfredi V, Levorato S, et al. Mutat Res/Rev Mutat Res. 2016;770:35-45. 14. Roussel C, Witt KL, Shaw PB, et al. Mutat Res/Rev Mutat Res. 2017. In press. 15. NIOSH Safety and Health Topics: Hazardous drug exposures in healthcare: antineoplastic agents. www.cdc.gov/niosh/topics/hazdrug/antineoplastic.html. Accessed August 22, 2018. 16. NIOSH Safety and Health Topics: Occupational exposure to antineoplastic agents and other hazardous drugs: effects of occupational exposure. www.cdc.gov/niosh/topics/hazdrug/effects.html. Accessed August 22, 2018. 17. NIOSH Workplace Safety and Health Topics: Hierarchy of controls. www.cdc.gov/niosh/topics/hierarchy. Accessed August 22, 2018.

Ms. Kienle is a member of the USP Compounding Expert Committee, but these comments are her own and not those of USP. Dr. McDiarmid reported no relevant ﬁnancial relationships. Ms. Polovich has received speaker fees and travel expenses from BD in the past year; she is a consultant to USP, but these comments are her own and not those of USP. Ms. Power is an independent pharmacy consultant and has worked with Corvida Medical in the past year.

Beyond the standard resources and recommendations (see box), Dr. Roussel said she believes pharmacists should feel free to take any extra precautions they think make sense—such as wearing gloves when touching all drugs and drug containers, which may be contaminated, and handling all pressed powder antineoplastics inside a biological safety cabinet. “It’s important for pharmacists to take an extra few minutes to put on the appropriate protective gear.” They also should clean regularly, using agents such as HDClean (ChemoGlo), Surface Safe cleaner (Cardinal Health) and even bleach. Learning about the risks associated with handling medicines can be scary, but Dr. Roussel tries to reassure pharmacists that the one unfortunate exposure that haunts their memory is likely not going to cause a problem— they’re more at risk from regular, low-level exposures. “There is definitely something to be concerned about, but the number one thing they can do is to start protecting themselves today.” —Alison McCook

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Dr. Roussel is on the speakers bureau of ICU Medical.

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