Challenges and Innovations in the Manufacture of Hazardous Drugs

SPECIAL REPORT: SAFE HANDLING | PART THREE OF A THREE-PART SERIES

For additional information, please read Part 1 and Part 2 of the Safe Handling publication series

This article is supported by Sun Pharma.

INTRODUCTION: EXPOSURE TO HAZARDOUS DRUGS IN HEALTH CARE SETTINGS

All workers in the health care setting, including those in clinical and nonclinical roles, may be exposed to hazardous drugs while performing routine job-related tasks, such as receipt, transport, storage, compounding, administration, disposal, and cleanup of these drugs. Tasks associated with exposure to hazardous drugs are further explored in the

Figure

.¹ Health care workers may come in contact with hazardous drugs through several routes, including inhalation, dermal absorption, ingestion, and injection.² Clinical health care workers who frequently have direct exposure to hazardous drugs include nurses, pharmacists and pharmacy technicians, physicians and physician assistants, veterinarians and veterinary technicians, and operating room personnel.³ Clinical staff who prepare or administer hazardous drugs, including pharmacists, pharmacy technicians, and nurses, tend to have the highest potential for exposure to hazardous drugs in the workplace; however, other workers in drug administration areas, such as physicians (eg, oncologists), dietitians, ward aides, and volunteers, also have high rates of exposure to hazardous drugs.^4,5 Nonclinical health care staff who may be exposed to hazardous drugs include any personnel engaged in shipping, receiving, housekeeping, laundry services, maintenance, transport, and disposal of hazardous drugs.³ Additionally, patients and their caregivers, family members, secondary contacts, and any hospital visitors may be unintentionally exposed to hazardous drugs via contact with contaminated surfaces in the health care setting or with personal items soiled with excreta (eg, urine, stool, and sweat) of patients undergoing treatment with hazardous drugs.^4,6 USP General Chapter <800>, which was published by the United States Pharmacopeial Convention and updated most recently in December 2017, sets forth guidelines for the handling of hazardous drugs in the health care setting with the goal of promoting safety for patients and health care workers.¹ Routes of hazardous drug exposure and measures to control exposure, which are described in USP General Chapter <800>, were extensively detailed in the previous publications of this series.¹ The National Institute for Occupational Safety and Health (NIOSH) periodically publishes an updated list of hazardous drugs that may be encountered in health care settings, and they have also described a hierarchy of controls for exposure to hazardous drugs.^7-9 Despite the risks associated with exposure to hazardous drugs in the workplace, adherence to organizational safety practices and guidelines published by professional organizations and government agencies remains variable according to the available literature.¹⁰

CHALLENGES ASSOCIATED WITH CURRENTLY AVAILABLE COMMERCIALLY MANUFACTURED HAZARDOUS DRUG PRODUCTS

At present, most commercially available hazardous drugs in the United States arrive at health care facilities in a form that requires manipulation by pharmacists prior to administration to a patient, as evidenced by the extensive list of opportunities for exposure detailed in USP General Chapter <800>.¹ In some cases, contamination of packaging by hazardous drugs can be traced back to the manufacturer, leading to immediate exposure risks for health care workers before any manipulation of the drug product takes place.^11,12 As previously mentioned, the tasks performed by pharmacists and other pharmacy personnel may be associated with a high risk of exposure to hazardous drugs. For example, oral hazardous drugs may require counting and repackaging, whereas injectable hazardous drugs may require reconstitution, dilution, or compounding.¹ In addition to concerns surrounding hazardous drug exposure risk within the pharmacy, the general processes for preparing any drugs for administration within a hospital pharmacy may be associated with human or system errors involving the drug, dose, concentration, or labeling of a medication that will ultimately be delivered to a patient.

Current practice for containment of hazardous drugs in many health care facilities relies heavily on the use of personal protective equipment (PPE), including gloves, gowns, goggles, and respirators, in addition to administrative controls, to prevent exposure among susceptible workers.¹ These processes may be time-consuming for pharmacy staff and costly for health care facilities.¹³ In addition to these drawbacks, PPE and administrative controls are considered less effective tools for preventing hazardous drug exposure, and adherence to these measures continues to be a problem for many health systems that regularly handle hazardous drugs.^8-10 According to NIOSH’s hierarchy of controls for exposure to hazardous drugs, engineering controls are the most effective method of protecting workers and patients from exposure to hazardous drugs in cases in which alternative drugs are not available. Engineering controls include methods of isolating workers from hazardous drugs during preparation of drug products, such as biologic safety cabinets, compounding aseptic containment isolators, and closed-system drug-transfer devices (CSTDs). In most cases, these engineering controls attempt to address the problem of exposure once a drug reaches the hospital.^8,9 As an alternative to PPE, administrative controls, and engineering controls, manufacturers may better serve health systems by preventing unnecessary exposure to hazardous drugs before they reach a health system. Pharmaceutical manufacturers have begun to develop and supply selected medications in ready-to-administer (RTA) formulations, thereby reducing the likelihood of worker exposure in hospitals. Other manufacturers have focused on designing equipment to aseptically fill drug containers on a large scale. These new technologies may pave the way for safer use of hazardous drugs.

Contamination of Products and Packaging by the Manufacturer

External and internal contamination of any kind associated with drug products is a common and serious concern for health care workers and patients. Regarding external contamination, hazardous drug residues on drug vials and shipping totes pose a hazardous drug exposure risk, especially among health care workers throughout a health system.^11,14 Additionally, preserving the integrity of drug packaging is a separate but no less serious concern, as damage to vials may occur during the manufacturing process or during transit of drugs from the manufacturer.¹⁵ Internal contamination, which may result from the introduction of particulate matter or microbes into a drug package at the manufacturer, is another important consideration, as it has the potential to cause injury and even death to a susceptible exposed patient.^16,17

External Contamination

Numerous studies have documented the risk of hazardous drug contamination on the exterior surfaces of vials. In 2005, a 3-part study was published that examined external hazardous drug contamination of vials in the pharmacy setting, with the first 2 studies specifically focusing on wipe sampling to detect vial contamination. Investigators in the first study, which took place at the pharmacy department of the National Institutes of Health Clinical Center, conducted wipe sampling of lots of chemotherapy vials containing cyclophosphamide and ifosfamide over a period of several months. A total of 48 samples taken from cyclophosphamide vials revealed varying amounts of contamination, all above the level of detection (LOD), whereas just a fraction of the 48 samples taken from ifosfamide vials had amounts of contamination above the LOD. The second study, which was conducted in tandem at 3 Veterans Affairs pharmacies, conducted wipe sampling of chemotherapy vials containing cyclophosphamide and fluorouracil. Fluorouracil was detected on 4 of 54 samples (7%), whereas cyclophosphamide was detected on 48 of 54 samples (89%). The investigators concluded that cyclophosphamide contamination was widespread, whereas ifosfamide and fluorouracil contamination was less common; however, they acknowledged that the test for fluorouracil was less sensitive than the test for cyclophosphamide.¹⁸

Similarly, Canadian researchers published a study in 2008 that reported on the wipe sampling of vials of cyclophosphamide from 2 different manufacturers. Results showed that 9 of 10 vials (90%) from the first manufacturer and 4 of 10 vials (40%) from the second manufacturer contained trace amounts of cyclophosphamide.¹⁹ A short publication in 2010 shared comparable results from a study across 9 pharmacies in Germany that examined external contamination of chemotherapy vials. A total of 634 vials from 55 batches were sampled over a period of 8 years for fluorouracil, cyclophosphamide, ifosfamide, and platinum compounds. The majority of vials were found to be contaminated, including 85% of cyclophosphamide vials, 96% of ifosfamide vials, 98% of fluorouracil vials, and 100% of vials containing platinum compounds.²⁰ In 2014, Swiss researchers published results of a more extensive investigation of hazardous drug vial contamination. Investigators performed wipe sampling of 133 vials from 12 manufacturers for the presence of cytarabine, gemcitabine, cyclophosphamide, ifosfamide, methotrexate, etoposide, irinotecan, doxorubicin, epirubicin, and vincristine. Results revealed that 63% of vials were contaminated with hazardous drugs above the LOD.²¹ Because contaminated products and surfaces have been found even in pharmacies and hospitals with strict controls in place to prevent hazardous drug contamination, it has been suggested that many vials and other drug packages containing hazardous drugs arrive at hospital pharmacies already contaminated, indicating that contamination may occur at the manufacturer.^11,22 In 2003, results were published from a study conducted at a single hospital in the United Kingdom that investigated hazardous drug contamination of vials arriving from the manufacturer. Investigators performed wipe sampling of 30 randomly selected vials of each of the following drugs: cisplatin, carboplatin, cyclophosphamide, ifosfamide, and methotrexate.²² Results of this study showed varying levels of contamination above the LOD, including 3% of ifosfamide vials, 10% of cyclophosphamide vials, 13% of cisplatin vials, 40% of methotrexate vials, and 100% of carboplatin vials. In 2005, results were published from a more extensive study at a single hospital pharmacy in Sweden that measured external contamination by cyclophosphamide on drug packaging surrounding vials, the vials themselves, and blister packaging. Of the packages and vials sampled, 100% of the outer packaging, both inside and outside; vial exteriors; and blister packages were found to be contaminated with cyclophosphamide above the LOD.²³ A more recent US study at a single hospital pharmacy took the investigation into manufacturer contamination a step further by evaluating hazardous drug contamination on drug shipping totes. Ten shipping totes designated for transport of hazardous drugs by the distributor were randomly selected and sampled for fluorouracil, ifosfamide, cyclophosphamide, docetaxel, and paclitaxel. Of the 10 totes sampled, 2 had detectable levels of fluorouracil contamination, indicating that contamination of shipping totes may be a less pressing concern than direct product contamination.¹¹ Health care workers may also encounter external hazardous drug contamination due to vial breakage during shipment of hazardous drugs from the manufacturer or distributor. Although there have not been any specific studies regarding rates of hazardous drug vial breakage and subsequent contamination, many health care providers endorse additional protections and extreme care in the transport of hazardous drugs. Guidelines set forth by the International Society of Oncology Pharmacy Practitioners in 2007 and the American Society of Health-System Pharmacists (ASHP) in 2018 each address the issue of potential contamination from vial breakage during shipment from the manufacturer, recommending specialty packaging and institutional procedures to prevent vial breakage.^12,15

Internal Contamination

While external contamination of hazardous drug vials poses a risk to patients and health care workers within a hospital or health system, internal contamination of parenteral medications may pose a more significant risk for patients due to the potential for immediate harm associated with this type of contamination. Internal contamination of parenteral medications involves 2 areas of concern: particulate matter and microbes. In general, patients being treated with hazardous drugs, especially chemotherapeutic drugs, are considered to be at greatest risk from internal contamination of parenteral products because they tend to be critically ill.^16,24,25

USP General Chapter <788>, which focuses on particulates in injectable drugs, defines particulate matter as extraneous mobile undissolved particles unintentionally introduced into a vial.²⁶ Literature on the subject suggests that particulate matter has a low likelihood of causing harm among healthy patients or via low-risk routes of administration, such as subcutaneous or intramuscular injections. Patients at a higher risk of complications due to particulate contamination include those who are critically ill, immune-compromised, very young, or very old; those who receive drugs via a high-risk route of administration, such as via intrathecal, intraocular, or intravenous (IV) injection, are also at a higher risk of complications from particulate contamination.^16,25 Adverse effects associated with particulate contamination among high-risk groups include phlebitis, pulmonary sequelae or dysfunction, immune dysfunction, thromboembolic events, infection, and even death.^16,24,25 Although industry has long concentrated on visible particulates, recent data indicate that subvisible particles may actually pose a greater risk. A recent analysis of particulate generation during vial filling at the manufacturer identified several mechanisms for the generation of glass particulates, including contact friction produced by 2 vials sliding past each other, impact events, and glass delamination.¹⁶

Concern surrounding internal contamination of parenteral hazardous drugs by microbes is another serious issue for pharmaceutical manufacturers. A recent review identified numerous possible sources of microbial contamination in pharmaceutical products, including water and raw materials, processing equipment, and manufacturing personnel. Although many cases of microbial contamination are associated with minor alterations in product stability or overall quality, they may be life-threatening in other cases.¹⁷

Preparation and Compounding of Hazardous Drugs

Once hazardous drugs arrive at a hospital or health system from the manufacturer, they are typically stored within the pharmacy department prior to use. USP General Chapter <800> and ASHP provide guidance for storage of hazardous drugs prior to use. Recommendations for safe storage of hazardous drugs include keeping hazardous drugs segregated from other products to minimize personnel exposure and protecting hazardous drugs from breakage.¹ Manipulation of hazardous drugs within a hospital pharmacy may lead to further risk of contamination among health-system workers. Parenteral antineoplastic agents in particular usually need to be manipulated to some extent prior to administration, from reconstitution of lyophilized products to dilution and transfer of drugs to an infusion bag. Due to issues surrounding stability and cost, most antineoplastic agents are prepared on demand when they are needed, adding a layer of stress and expediency to the preparation process, which may lead to opportunities for both hazardous drug exposure and medication errors.^14,27,28

Risk of Exposure During Preparation

Manipulation of antineoplastic products and other hazardous drugs prior to administration may create additional occasions for hazardous drug exposure. According to USP General Chapter <800>, compounding activities for parenteral hazardous drugs that may lead to hazardous drug exposure include reconstitution, dilution, withdrawal, and transfer.¹ Because many antineoplastic drugs are supplied as lyophilized powders, they require reconstitution. Whether an antineoplastic agent is supplied as a lyophilized powder or a liquid, either formulation may require dilution and transfer prior to administration. Results published in 2003 from a US study demonstrated that standard compounding techniques using needles and syringes without environmental controls are associated with some level of contamination.²⁹ USP General Chapter <800> and ASHP each provide guidance for institutional measures to prevent environmental contamination in locations within a health system where compounding of hazardous drugs takes place.^1,12

Risk of Medication Errors During Preparation

Although medication errors are a possibility with any drug product at any step in the medication use process, medication errors with hazardous drugs in general and parenteral antineoplastic agents specifically are associated with the potential for significant harm to the patient.³⁰ An investigation in Sweden aimed to characterize medication errors involving parenteral hazardous drugs by analyzing case reports from a national error reporting system. The study focused on identifying the drugs most commonly involved in errors, the types of errors that occurred, the place in the medication use process where errors occurred, and the consequences of the errors for patients. The source of each error was classified as originating with prescribers, pharmacists, or nurses. Types of errors included wrong dose (too high or too low), wrong drug, wrong patient, or wrong pump. Sixty case reports were retrieved and included in the study, with the most commonly involved drugs being fluorouracil (9 cases), carboplatin (6 cases), and cytarabine (6 cases). Of the 60 cases examined, 25 errors (42%) originated in the pharmacy. Of the 25 errors originating in the pharmacy, more than half involved the wrong drug and approximately a quarter involved a dose of drug that was too high.³¹ A prospective observational study conducted between 2001 and 2002 at 6 hospital pharmacies in Germany, France, and the United Kingdom described medication errors occurring during preparation and administration of IV medications. The preparation of 824 medications was observed during the study: 425 in Germany, 100 in France, and 299 in the United Kingdom. The most frequent medication errors that were observed in Germany during preparation included labeling errors, which occurred in 421 of 425 (99%) cases; wrong diluent errors, which occurred in 208 of 425 (49%) cases; and failure to mix errors, which occurred during 190 of 240 (79%) observations.³² A retrospective quality assurance study conducted at a single French hospital between 2006 and 2007 also identified errors with mixing of parenteral antineoplastic agents. A total of 7382 preparations containing fluorouracil, gemcitabine, docetaxel, paclitaxel, or oxaliplatin were analyzed. Of these preparations, 646 (8.8%) were rejected because they were more than 20% above or below the target concentration.³³ A simulation study conducted in Switzerland sought to analyze the errors associated with manual drug compounding and to evaluate the effectiveness of visual inspection and gravimetric control, which are 2 control processes designed to detect and prevent errors. A total of 11 operators conducted 19 preparation sessions based on standard operating procedures from the chemotherapy production unit; ultimately, 438 syringes were accepted for analysis in the study. Although 11 safety errors occurred during the study, of which 5 were errors in the choice of reconstituted solution vial and 6 were volume errors, the operator or the control processes in place detected and corrected these errors. Overall, approximately 15% of preparations were more than 10% above or below the target concentration.³⁴ These studies of medication errors during the preparation of parenteral antineoplastic agents highlight the wide variation in types and rates of errors.

TECHNOLOGICAL ADVANCES TO IMPROVE THE SAFETY OF THE MANUFACTURING OF HAZARDOUS DRUGS

Due to many potential dangers associated with the preparation of hazardous drugs within health systems, much of the burden for addressing these issues has shifted to pharmaceutical manufacturers to develop strategies to further minimize risk to health care workers. Part of the reason for this shift in responsibility to manufacturers is likely related to a disparity in financial resources. Although individual hospitals or health systems may not to be able to afford the equipment needed to fully protect employees from exposure to hazardous drugs, pharmaceutical manufacturers typically already have such facilities at their disposal to support the production of hazardous drugs in the safest manner possible.¹⁴ Technological advances in the safe handling of hazardous drugs include the use of CSTDs and RTA products.

CSTDs

Traditional preparation, compounding, and administration of hazardous drugs involve the use of needles and syringes, which have been associated with drug leakage into the surrounding environment.³⁵ CSTDs, which USP General Chapter <800> classifies as supplementary engineering controls to be used during compounding of hazardous drug products, are designed to mechanically prevent the transfer of environmental contaminants into the drug product and the escape of a drug or its aerosolized particles outside the drug container.¹ CSTDs may be used at any step during the preparation, compounding, or administration of hazardous drugs, such as when they are transferred from one container to another (eg, from vial to syringe or IV bag) or when they are prepped prior to administration (eg, spiking or priming the IV bag).³⁵

Currently available CSTDs and general information about their use during the preparation and administration of hazardous drugs were discussed in the first supplement in this series, Current and Future Considerations for the Safe Handling of Hazardous Drugs, which was published in March 2018. The first CSTD, PhaSeal, was tested in Europe over 2 decades ago and entered the US market in 2000. That same year, NIOSH defined the term “CSTD” in its first publication on preventing exposure to hazardous drugs in the workplace. Other CSTDs that subsequently became available on the US market include Equashield, ChemoClave, ChemoLock, VialShield, and OnGuard with Tevadaptor (

Table 1

^36-38). USP General Chapter <800> recommends the integration of CSTDs for safe handling of hazardous drugs, encouraging their use in compounding and requiring their use for administration in situations where the dosage form allows.¹ The most recent ASHP guidelines, published in 2018, endorse the recommendations for the use of CSTDs in USP General Chapter <800> while acknowledging the need for more rigorous studies to evaluate the effectiveness of available devices.¹² Numerous studies have investigated the use of CSTDs to evaluate their potential benefits in reducing exposure to hazardous drugs. An extensive study of PhaSeal, the first CSTD marketed in the United States, took place at 22 US hospital pharmacies from 2000 to 2005. In this study, wipe sampling for cyclophosphamide, ifosfamide, and fluorouracil was performed on potentially contaminated surfaces within hospital pharmacies before and after introduction of the PhaSeal system into the pharmacy. Prior to the introduction of PhaSeal, 78% of wipe samples tested positive for cyclophosphamide, 54% for ifosfamide, and 33% for fluorouracil. Following implementation of the CSTDs, 68% of wipe samples tested positive for cyclophosphamide, 45% for ifosfamide, and 20% for fluorouracil. A significant reduction in the level of contamination was observed for cyclophosphamide (P <.0001), ifosfamide (P <.001), and fluorouracil (P <.01) after the implementation of the CSTDs.³⁹ A similar study subsequently took place at 30 US hospitals from 2004 to 2010. Unlike the previous study, wipe sampling of potentially contaminated surfaces only tested for the presence of cyclophosphamide. The percentage of surfaces contaminated by cyclophosphamide was similar before (83%) and after (80%) introduction of PhaSeal. However, a significant reduction in the level of cyclophosphamide contamination after the introduction of PhaSeal was observed, from median values of 0.22 to 0.03 ng/cm², or an 86% reduction (P <.0001).⁴⁰ A more in depth French study that took place in 2014 again focused on the potential benefits of the PhaSeal system in reducing hazardous drug contamination. The study was conducted during the first 6 months of operation of a newly opened antineoplastic drug compounding unit within a university hospital. The new unit was equipped with 2 isolators; in the first isolator, antineoplastic drugs were compounded using a traditional needle and syringe method, while in the second isolator, antineoplastic prescriptions were compounded using the PhaSeal system. During the study, monitoring was conducted via wipe sampling for cyclophosphamide, cytarabine, dacarbazine, doxorubicin, fluorouracil, ganciclovir, gemcitabine, ifosfamide, irinotecan, and methotrexate. Of the 20,097 doses compounded during the study period, more than half (12,554 doses, or 62%) were prepared using the traditional needle and syringe method. Wipe sampling for dacarbazine, doxorubicin, methotrexate and irinotecan indicated that these drugs were rarely present in either isolator. Gemcitabine, cyclophosphamide, and ifosfamide accounted for the most frequent and extensive contamination. Contamination rates in the isolator that used the PhaSeal system were consistently lower for most sampled drugs than contamination in the isolator using the traditional needle and syringe method of compounding, including rates for cyclophosphamide (12.3% lower), cytarabine (33.2% lower), fluorouracil (4.8% lower), ganciclovir (51.4% lower), gemcitabine (5.6% lower), ifosfamide (30.5% lower), and irinotecan (3.5% lower). Investigators concluded that the use of the PhaSeal system for hazardous drug compounding significantly reduced levels of contamination, but they acknowledged that the use of CSTDs did not completely eliminate contamination, most notably for gemcitabine. The investigators hypothesized that an exposure event at the beginning of the study involving gemcitabine may have accounted for the persistent gemcitabine contamination throughout the study.⁴¹

Beyond reducing hazardous drug contamination during compounding and administration, CSTDs may serve another important purpose by preventing microbial contamination of the final drug product. An early study of the susceptibility of CSTDs to microbial contamination took place in Belgium.⁴² Four CSTDs were evaluated: the Chemoprotect spike, the Clave connector, the PhaSeal system, and the Securmix device. The rubber stoppers on the drug vials in the study were purposely contaminated with 2 levels of bacteria (ie, high and low inocula), and then each CSTD was connected to a contaminated drug vial. The fractions of the high and low inocula that penetrated the vial after connection with the CSTDs were 16.0% and 14%, respectively, with the Clave connector; 6.8% with Securmix (only high inoculum tested); 4.3% and 4.3%, respectively, with the Chemoprotect spike; and 2.2% and 2.6%, respectively, with PhaSeal. The investigators attributed the difference in contamination among CSTDs to a difference in needle gauge, as PhaSeal has the thinnest needle and the Clave connector has the thickest needle. The wide variation in CSTDs observed in this study highlights that CSTDs are not equivalent or interchangeable.⁴²

A more recent investigation designed to evaluate various aspects of CSTD performance, including microbial safety, compared 2 CSTDs with one another and with a classic spike device. The CSTDs selected for this study were PhaSeal, the longest available and most frequently studied device, and VialShield/Texium, a newer, combination, needle-free device complex; the classic spike device used for comparison was SpikeSwan. No microbial growth was observed with the 2 CSTDs or SpikeSwan. Although PhaSeal was determined to be more protective than VialShield/Texium, overall satisfaction among pharmacy technicians was greater for VialShield/Texium than for PhaSeal.⁴³ Although the protection provided by CSTDs may vary, health care worker satisfaction may be an important consideration to ensure adherence to this important safety measure.

RTA Products

Although many studies and guidelines endorse the use of CSTDs to reduce exposure to hazardous drugs during compounding and administration, an adequate improvement in contamination with the use of CSTDs was not observed for all drugs.⁴¹ For this reason, alternative strategies are being explored to improve the safety of health care workers and patients who may be exposed to hazardous drugs in a hospital. One recent advance has come in the form of RTA medications, which eliminate the need for compounding, dilution, transfer, and repackaging of the finished drug products.⁴⁴ Although the number of RTA products available on the US market is limited, research supporting the development of these devices continues.

RTA medications have numerous potential benefits for health care workers and patients. They may contribute to improved pharmacy workflows by decreasing the amount of time needed to prepare medications for administration. In addition, RTA medications may improve safety for patients by reducing the number of opportunities for the introduction of microbial contamination into a finished drug product, by lessening the escape of hazardous drugs into the environment, and by lowering the risk of medication errors during preparation and compounding. Unlike traditionally packaged hazardous drugs, RTA medications may be delivered to the patient’s bedside with minimal risk of hazardous drug exposure to workers or patients.⁴⁴ Another helpful feature of RTA drugs is the placement of a bar code on the outer packaging, which adds a layer of protection for the patient. Rather than relying on labeling created within the health system to identify a medication, manufacturer-supplied barcoding provides a form of electronic verification for pharmacy and nursing personnel to ensure that the correct drug at the correct dose is being administered to the patient.⁴⁴ In addition, USP General Chapter <800> requires clear labeling for all hazardous drugs, and RTA medications are supplied with clear labeling already present to identify the contents, preventing errors in labeling, which are common among manually compounded infusions.^1,32

INTACT Technology: Developments in Sterile Manufacturing

To support the sterile manufacturing of drug products, Medinstill Development LLC has created devices and technology to facilitate sterile filling, connecting, and dispensing of pharmaceutical and cosmetic products.⁴⁵ INTACT filling technology is a closed-system filling technology that provides an automated connection to allow for the filling of pre-sterilized closed containers with sterile drug products, thereby limiting or completely eliminating many forms of external contamination from the filling process.^45,46

Advances in Dosing of Hazardous Drugs: Dose Rounding and Dose BandingDose Rounding

Traditional calculations for dosing of chemotherapeutic agents have relied on the patient’s body surface area (BSA). In an effort to standardize and simplify dosing and to reduce costs and minimize drug waste, many institutions have adopted policies for dose rounding of antineoplastics and biologics. It has become standard practice to round doses to within 5% to 10% of the target dose.⁴⁷ Recent studies have supported the hypothesis that dose rounding is associated with significant cost savings at individual institutions.^27,47 A position statement from the Hematology/Oncology Pharmacy Association (HOPA) was published in 2018. A task force of oncology pharmacists was formed to evaluate the literature and to produce a set of recommendations regarding the use of dose rounding in oncology. HOPA recommends dose rounding of biological agents and cytotoxic chemotherapy within 10% of the target dose, whether the goal of treatment is cure or palliation. As a best practice, HOPA recommends that individual institutions develop their own dose-rounding guidelines for biological agents and cytotoxic chemotherapy and that these institutional guidelines be based on collaborative consensus. Evidence demonstrates that dose rounding of biological agents and cytotoxic chemotherapy is not only more cost effective than traditional dosing but also safer because it can simplify drug preparation; in addition, dose rounding has not demonstrated increased toxicity or decreased safety for the patient.⁴⁸

Dose Banding

Dose banding is a system of dosing IV antineoplastic agents that takes the concept of dose rounding a step further. Dose banding is defined as a system in which doses of antineoplastic medications are calculated based on BSA and then rounded up or down to preset standardized doses, referred to as bands, with a variance limit of ±5%; the standardized doses are then compounded or commercially manufactured in advance based on the stability of the medications and the predicted need.^49,50 A pharmacokinetic comparison of dose banding with traditional, individualized BSA dose calculations confirmed the feasibility of implementing dose banding.⁵¹

Dose banding may rely on BSA calculations, target doses, or a logarithmic strategy to calculate individual patient doses. Logarithmic dose banding has gained the widest acceptance because it offers the broadest application. Numerous advantages of logarithmic dose banding over traditional dosing include universal application, constant proportionality, and ease of implementation with computer systems.⁵⁰ Benefits associated with dose banding for health care workers and patients include reduction in patient wait times, diminished potential for medication errors, reduced drug wastage, and prospective quality control.⁵¹

INFUGEM: AN INNOVATION IN THE MANUFACTURE OF HAZARDOUS DRUGS

Gemcitabine, a frequently prescribed antineoplastic agent identified on the NIOSH list of hazardous drugs, was first approved by the FDA in 1996 and subsequently approved for generic manufacture in 2010.^52-56 Since its initial FDA approval, gemcitabine has been used extensively in the treatment of numerous cancers, with current indications for breast cancer, ovarian cancer, pancreatic cancer, and non—small cell lung cancer.^52,53 As a prime example of the potential pitfalls of traditional formulations of hazardous drugs, gemcitabine has been historically supplied only as a lyophilized powder in sterile single-use vials, meaning that it must be reconstituted with 0.9% sodium chloride solution, diluted, and transferred to an infusion bag prior to administration. The final product can be stored at room temperature for up to 24 hours.⁵³ As described in the previous sections, each of these steps may be associated with the potential for internal and external contamination and medication errors. In light of the issues surrounding the preparation of lyophilized gemcitabine, a safer formulation of gemcitabine in RTA packaging was approved by the FDA in July 2018.⁵⁶

Infugem (gemcitabine in sodium chloride injection)

Infugem, a unique formulation of gemcitabine, is supplied as an RTA infusion that eliminates the need for reconstitution and dilution of drug prior to administration. Infugem is the first drug available on the US market as an RTA infusion.⁵⁶ The potential benefits of Infugem are many, including the prevention of internal and external contamination and medication errors associated with the compounding of hazardous drugs.⁵²

How Supplied

Infugem, which is supplied in sterile, single-dose, premixed infusion bags containing 10 mg/mL of gemcitabine in 0.9% sodium chloride, is ready to use and does not require any further preparation prior to administration. Infusion bags of Infugem range in size from 1200 mg to 2200 mg; the infusion bag closure, which is made without natural rubber latex, has an aluminum overlap and is tamper evident. Infugem should not be diluted prior to use, and medication should not be added to or removed from the bag.⁵²

DOSE SELECTION

The prescribing information for Infugem contains tables to assist in dose selection based on the patient’s BSA and indication for treatment (

Table 2

and

Table 3

).⁵² This method of dose calculation relies on the concept of dose banding, which was described in detail already, with the goal of simplifying the calculation of the patient’s dose and reducing drug manipulation and waste.⁴⁹

Storage and Handling

Unopened bags of Infugem are stable until the expiration date indicated on the package when stored at 20°C to 25°C; excursions are permitted between 15°C and 30°C. Because gemcitabine is a cytotoxic drug, special handling and disposal procedures are recommended regardless of dosage form. The safe handling of Infugem should include wearing PPE, such as gloves, and exercising general caution.⁵²

Administration

After removing the overwrap from Infugem, the infusion bag should be checked for leaks by squeezing the inner bag firmly. If leaks are found, the bag should be discarded. The infusion should also be visually inspected for any particulate matter or discoloration prior to use. If particulate matter or discoloration is found, the bag should be discarded. All doses of Infugem should be infused slowly over 30 minutes. If 2 premixed infusion bags of Infugem are required to achieve the prescribed dose, the total volume of both bags should be infused slowly over 30 minutes.⁵²

CONCLUSIONS

Exposure to hazardous drugs is common among health care workers and patients and has been associated with significant risks to susceptible parties. Although currently available administrative and engineering controls may limit the risks associated with hazardous drug exposure, these controls are not able to fully eliminate the risks. External and internal contamination of hazardous drug products at the manufacturer may contribute to risks for health care workers and patients. Preparation and compounding of hazardous drugs within a health-system pharmacy may generate further risk. Technologic advances over the past 2 decades, including CSTDs, have contributed to risk reduction among susceptible workers and patients, although they also fail to eliminate risk completely. RTA products may offer the most comprehensive elimination of risk by removing steps from the preparation and administration of hazardous drugs associated with the most significant risks. Infugem, the first RTA infusion to receive approval by the FDA, has the potential to improve safety with a commonly used and highly toxic antineoplastic medication.

Jeffrey Lombardo, PharmD, BCOP, is a research assistant professor at the Center for Integrated Global Biomedical Sciences, Translational Pharmacology Research Core, at the University at Buffalo School of Pharmacy and Pharmaceutical Sciences in New York.

REFERENCES

• United States Pharmacopeial Convention. General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeial Convention website. usp.org/compounding/general-chapter-hazardous-drugs-handling-healthcare. Published December 1, 2017. Accessed August 21, 2018.
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