Considerable Controversy Accompanies NIOSH Move Toward a Universal Protocol for Testing CSTDs
Stakeholders are concerned a universal protocol for testing closed-system transfer devices will not adequately address different systems that protect against hazardous drugs.
Concerns about chronic, low-level exposure to hazardous drugs were first noted by Falck et al in the 1970s and have been documented in more than 100 research papers since that time. Researchers have recorded increases in the risk of stillbirth and spontaneous abortion among women who handle hazardous drugs frequently, as well as an increased risk of chromosomal abnormalities associated with leukemia in health care professionals who frequently handle these medications.1,2
Closed-system transfer devices (CSTDs) are drug transfer systems that mechanically prohibit the transfer of environmental contaminants into the system and prevent the escape of hazardous drug or vapor concentrations outside the system. As part of a hazardous drug safety program, CSTDs have been shown to reduce contamination of areas near hazardous drug compounding facilities, patient care areas, nursing areas, and other working areas, and they may reduce staff exposure to hazardous drugs.
In recent years, increasing concerns about exposure to hazardous drugs in the health care setting and regulations governing the handling of hazardous drugs have led to a greater awareness and increased relevance for these devices among health care professionals.1,3-5
CSTDs are supplementary engineering controls intended to protect health care professionals from hazardous drugs and to prevent the ingress of hazardous drugs into medication vials. Since their introduction in the United States in 1998, several CSTDs have come to market. These devices are evaluated based on varying forms of evidence, so currently, there is no established universal standard for testing them.1,6-8
As a result, the National Institute for Occupational Safety and Health (NIOSH) has developed a draft protocol to evaluate the specific types of CSTDs that are mechanically closed. The other major category of CSTDs rely on an air-cleaning carbon filter to limit exposure to hazardous drugs. These air-cleaning CSTDs are not intended to be tested with the current draft NIOSH protocol.
However, in testing air-cleaning CSTDs alongside mechanically closed CSTDs, preliminary tests with the NIOSH protocol indicate that mechanically closed CSTDs offer more reliable protection against accidental release of hazardous drugs during compounding. However, these preliminary findings are controversial.6-8
In a public meeting of NIOSH on November 7, 2016, NIOSH experts, industry stakeholders, and public participants voiced comments and concerns regarding revisions to the CSTD testing protocol. Representatives of 4 major manufacturers of CSTDs—Equashield, Becton Dickinson, ICU Medical, and Teva/B. Braun—discussed their views and presented evidence for consideration.8
NIOSH is a standard setting organization formed in 1970 to ensure that all people in the United States work in safe and healthful conditions. NIOSH is distinct from the Occupational Safety and Health Administration (OSHA) in that NIOSH focuses on research, whereas OSHA is a regulatory agency. NIOSH has been working on safety standards for hazardous drugs since the mid-1980s and continues to research optimal safety controls for those dealing with these medications. As a result, the NIOSH protocol serves as a research resource, not a regulatory standard.8
Early Methods of Evaluating CSTDs
Qualitative and semiquantitative CSTD testing methods have been used to approximate the comparative efficacy of CSTD systems. These testing methods include manipulations of sealed vials containing fluorescein dye and inspection of product surfaces after transfer operations with a black light, testing pH levels on adaptor surfaces with litmus paper after drug transfer manipulations have occurred, and testing for leakage of titanium tetrachloride smoke from CSTDs. Unfortunately, none of these tests simulate the varied conditions that occur when any of the more-than-200 hazardous drugs identified by NIOSH are used with CSTDs.1,8
The NIOSH Protocol
In response to concerns raised by hospitals and other stakeholders regarding the relative efficacy of CSTDs, NIOSH developed a draft protocol released in August 2015. This protocol for testing CSTDs involves the use of a sealed test chamber, in which a tracer compound (70% isopropyl alcohol) is transferred in a series of 2 tasks that simulate medication reconstitution and production of intravenous solutions for administration to patients.
If, during these tasks, isopropyl alcohol is released from the system and increases concentrations within the system to 1 part per million or greater, the leakage will be detected using a real-time chemical detection system.1,6-8
According to D. Gayle DeBord, PhD, interim director for the Division of Applied Research and Technology, the team chose isopropyl alcohol as a challenge agent because a system that will contain it “will stop anything as far as drugs are concerned.”
Additionally, isopropyl alcohol has a high vapor pressure, is easily detected if released during manipulations involving CSTDs, and is widely available. According to DeBord, isopropyl alcohol was also chosen because it is compatible with virtually all plastics. Some alternative chemicals will damage plastics, including plastic components that make up CSTDs.8
Importantly, the earlier draft protocol was never finalized and is only intended to evaluate mechanically closed systems, as the requirements of this test were incompatible with the performance criteria of air-cleaning systems that rely on a carbon filter. In response to stakeholder concerns, the draft protocol was abandoned in favor of a universal protocol in development that will be suitable for evaluating both mechanically closed and air-cleaning systems.
However, noted DeBord, “We are nowhere close to having this second protocol . . . ready for release.” Considering that the first protocol was developed over the course of 5 years, release of the universal protocol may not occur in the near future.8 Toward a Universal Testing Protocol Given that the current draft of the protocol was abandoned, NIOSH has made progress in identifying elements of the original protocol for inclusion in a future universal protocol to enable testing of both mechanically closed CSTDs and air-cleaning CSTDs that employ a carbon filter.8,9
According to Deborah Hirst, PhD, PE, the revised protocol may include any of several chemicals of varying volatility. However, these chemicals have proven to be problematic because they may dissolve or damage plastic components of certain systems. Furthermore, because these chemicals are less volatile than isopropyl alcohol, the universal protocol would rely on a sensitive gas chromatography—mass spectrometry (GC-MS) instrument to detect leaks.
Unlike the less sensitive apparatus for detecting isopropyl alcohol levels, which provides real-time information during testing, GC-MS samples would need to be sent to a laboratory. Another detector under consideration—known as selected ion flow tube—mass spectrometry—is far more expensive than the GC-MS detector, but it would enable real-time testing.8,9
A major challenge in selecting a testing agent is the varied volatility of these products. In a table of 11 such compounds, Amos Doepke, PhD, noted that 2-phenoxyethanol is a strong contender for a challenge agent in a universal protocol because the chemical has a room-temperature vapor pressure of approximately 0.007 mm Hg, which is similar to the room-temperature vapor pressure of the most volatile hazardous drug, thiotepa, which has a vapor pressure of 0.009 mm Hg (in the solid phase).
Importantly, contrasting with proposed test solutions, none of which has a room-temperature vapor pressure exceeding 2 mm Hg, isopropyl alcohol has a vapor pressure at room temperature of nearly 44 mm Hg (Table). Notably, however, the vapor pressure of thiotepa cited by Doepke refers to thiotepa in a solid form before reconstitution. The real-world vapor pressure of reconstituted thiotepa may be far higher.8-10
Also relevant are the phase of each agent at room temperature (all are in the liquid phase), the water solubility of each agent, the logarithmic octanol/water partition coefficients of each agent, and the Henry’s constant, which is similar to the octanol/water partition coefficient, but for air and water. Having considered these compounds, Doepke simulated the leak of a mixture including all 11 compounds, and assessed recovery rates of each compound over time using GC-MS.
These experiments will help determine which challenge agents will be used in a future universal testing protocol for CSTD leaks, how much time must be allotted for sampling, and what will help elucidate the optimal conditions for testing.8,9
In the first of a series of four 10-minute comment sessions, representatives of CSTD manufacturers commented on the universal protocol in development. First to comment was vice president and general manager of ICU Medical, Alison D. Burcar, who discussed some of the CSTD pilot testing with surrogate compounds that her team has performed.
Regarding the issue of compatibility of surrogate compounds with plastics, Burcar noted, “Only propylene glycol was universally compatible with the plastics.”
All other surrogate compounds, however, led to some level of damage, mostly limited to slight clouding or crazing. None of the compounds led to damage severe enough to preclude completion of testing.8
ICU Medical requested that the future universal protocol include both a quantitative and qualitative test result. For example, noted Burcar, “Something like one-fiftieth of a droplet of fluid would be 50 nanograms per sample, and that might be a reasonable pass/fail detection method.”
Burcar also expressed concerns about including product reconstitution as part of the protocol because approximately 60% of hazardous drugs are supplied from the manufacturer in a liquid form and do not require reconstitution. Additionally, noted Burcar, as part of reconstitution, “injecting air into a vial is not required for all CSTDs.”
Burcar recommended following manufacturer instructions for each product, including manufacturer-specific instructions for vial connection and disconnection.8
Burcar was followed by Ronak Kadakia, director of marketing and business development for Equashield. Kadakia opened by introducing the Equashield brand as “a leading manufacturer of closed-system transfer devices. . .[with] over 500 accounts in the US today.”
In constant discussions with directors of pharmacy, Kadakia noted that there is persistent frustration among pharmacists regarding a lack of a standardized testing protocol.8 Kadakia emphasized that Equashield is not against the general methodology of air-cleaning systems.
“There are many applications of air-cleaning systems that work—gas masks work,” noted Kadakia, although in the context of CSTDs, there are limits to filter capacity.
“When we talk about 45 milliliters of vapor to be filtered by these air-cleaning systems,” he continued, “they seem to fail.”
In discussion with pharmacists, Equashield representatives have heard multiple reports of sweating, beading, and leaking of product from air-cleaning systems, as well as incidents of product breakage.8
Kadakia expressed frustration at the abandonment of the initial NIOSH protocol that was carefully developed over the course of 5 years: “What we find frustrating is that in a few short months, after a slew of conflict e-mails, Congressional letters, and strongly worded industry letters, that the thinking completely changed. . . .We think that NIOSH should look at a lower-risk approach and keep the corporate interests aside.”8
Even with a revised protocol, the surrogate chemicals proposed for use in the universal protocol are exclusively organic and do not necessarily represent certain types of inorganic chemotherapeutic medications, such as cisplatin.
“By definition, these carbon filters cannot capture these inorganic drugs,” noted Kadakia.
The limitations of carbon filters have been noted by multiple organizations, including the International Society of Oncology Pharmacy Practitioners (ISOPP) and the Japanese equivalent of NIOSH. Both organizations have reported that air-cleaning systems can saturate simply from exposure to humidity, either from within the vial or the outside environment.8,11
A bevy of existing data already supports the preeminence of mechanically closed systems over air-cleaning systems. Mention of thiotepa as the hazardous drug product with the highest vapor pressure may be misleading because the vapor pressure estimate is derived from the unreconstituted solid form of the medication.
Kadakia argued further than many chemotherapeutic products contain isopropyl alcohol, or another alcohol, as a solvent. Beyond considerations of vapor pressure, other properties of medications, including their tendency to adhere to membranes, syringes, and connections should also be considered. Kadakia was granted a 6-month extension of the comment period through June 7, 2017, to enable in-house testing of surrogate compounds.8
Angela Karpf, MD, corporate vice president of medical affairs at B. Braun, discussed perspectives about the protocol. In the United States, the air-cleaning system marketed by B. Braun is known as OnGuard. Karpf noted, “I spend a lot of time with pharmacists, and today there is a great deal of confusion among some pharmacists.”
With ongoing preparation to meet United States Pharmacopoeial Convention <800> requirements in pharmacies across the United States, Karpf believes there is a need for clarity on the definition of a CSTD, how they are tested, and appropriate interpretation of data. Karpf also recommends use of carefully selected contract laboratories to execute testing of CSTDs.
Concluding her comments, Karpf stated, “We support NIOSH’s decision to develop a universal protocol and recommend the use of the single surrogate applicable to all CSTDs, regardless of the CSTD technology.”8
Another representative associated with B. Braun, Penny Levin, MS, director of global regulatory intelligence and policy at Teva Pharmaceuticals, discussed surrogate selection. Regarding the decision to abandon isopropyl alcohol as a surrogate compound for CSTD testing, Levin stated, “Hazardous drugs are low-volatile substances, whereas IPA is a highly volatile solvent, and is therefore a poor choice as a surrogate.”
Levin supports the use of 2-phenoxyethanol as a surrogate, noting that “it has sufficient volatility to be easily detected.”8 Although testing results of air-cleaning systems using isopropyl alcohol have been poor, Levin and colleagues believe that the existing protocol is an overly restrictive standard.
“With too much of a safety factor, one can run into the question of the meaningfulness of the test,” she said.
In reference to the fact that isopropyl alcohol is 5 orders of magnitude more volatile than most hazardous drugs, Levin likened the situation to crash testing, calling testing with an isopropyl alcohol surrogate “like crashing a car at 10 million miles per hour in order to see how it performs when it’s crashing at a hundred miles per hour.”8
Later in the meeting, Joanne Beyer, associated director of medical affairs for BD Medical, weighed in on surrogate testing and the proposed methodology of a universal protocol. Beyer, whose company manufactures the mechanically closed CSTD Phaseal, noted, “We continue to express our support for maintaining a distinction between closed systems. . .that use a barrier technology versus air-cleansing technology.”
As mentioned previously by the representative from Equashield, ISOPP guidelines clearly state that carbon filters with a 0.22 micron diameter do not retail the vapors of cytotoxic drugs. “We do not believe that filtration or air-cleansing devices meet the definition of a CSTD as established and supported by many professional organizations,” concluded Beyer.8,11
The testing of CSTDs is a controversial issue that will directly affect the health of pharmacists, nurses, and other health care workers in the future. Although data have already been released related to testing CSTDs with isopropyl alcohol, this protocol is being abandoned in favor of a universal protocol. Many stakeholders are concerned that the universal protocol will not adequately represent the real-world characteristics and conditions created by hazardous drugs, potentially resulting in use of systems with suboptimal real-world performance characteristics.
Regardless of the outcomes of future tests, health care professionals should use all available evidence to make decisions about the appropriate systems to safeguard the health and safety of workers who handle hazardous drugs every day.
Editor’s Note: To comment on the NIOSH protocol, please visit regulations.gov/ and enter the docket ID number “CDC-2016-0090.” NIOSH will accept comments through June 7, 2017.