Closed-System Transfer Devices, USP , and the NIOSH Protocol

To the Editor,In the article below, it was previously stated that “The OnGuard/Tevadaptor system is not considered a closed-system transfer device (CSTD) in its country of manufacture (Israel), and its sale was banned in Sweden as the result of a court ruling.” Since it is incorrect and was taken from a source¹ that did not provide attribution for its statements it has been removed.Based on correspondence from the manufacturer of Tevadaptor, Teva Pharmaceutical Industries, Tevadaptor is approved in Israel as a “closed drug reconstitution and transfer system.” In addition, Tevadaptor has never been banned in Sweden by a court ruling or otherwise.To add further context to the tests performed by Fred Massoomi, PharmD, FASHP, of Nebraska Methodist Hospital Pharmacy,² the reader should note that the tests evaluated CSTDs using isopropyl alcohol (IPA) as a surrogate for hazardous drugs (HDs), which was part of NIOSH’s 2015 draft protocol.³ However, NIOSH no longer considers IPA an appropriate HD tracer compound because HDs are low-volatile substances, whereas IPA is a highly volatile solvent. NIOSH has modified the protocol to reflect selection of surrogates whose properties are more representative of currently known HDs.⁴One of the articles⁵ indicates that use of 2-phenoxyethanol as a tracer compound may not fully represent the performance of CSTDs. However, 2-phenoxyethanol is one of the surrogate compounds under consideration in the NIOSH modified protocol.⁴The study⁶ by Dr. Igal Bar-Ilan cited in “Closed-System Transfer Devices: What Do They Offer?” used titanium tetrachloride to evaluate the integrity of several CSTDs. Of note, titanium tetrachloride is not among the surrogate compounds under consideration in the NIOSH 2016 Protocol.⁴

Sincerely,

Michael R. Page, PharmD, RPh

REFERENCES

• Dash TA. Comment on the Centers for Disease Control and Prevention Notice: a vapor containment performance protocol for closed system transfer devices used during pharmacy compounding and administration of hazardous drugs. Regulations.gov website. regulations.gov/document?D=CDC-2015-0075-0026. Published March 9, 2016. Accessed October 5, 2017.
• Massoomi F. Comment on the Centers for Disease Control and Prevention Notice: a vapor containment performance protocol for closed system transfer devices used during pharmacy compounding and administration of hazardous drugs. Regulations.gov website. regulations.gov/document?D=CDC-2015-0075-0027. Published March 9, 2016. Accessed October 5, 2017.
• National Institute for Occupational Safety and Health. A vapor containment performance protocol for closed system transfer devices used during pharmacy compounding and administration of hazardous drugs. Fed Regist. 2015;80(173):53802-53803. federalregister.gov/documents/2015/09/08/2015-22525/a-vapor-containment- performance-protocol-for-closed-system-transfer-devices-used-during-pharmacy. Published September 8, 2015. Accessed October 5, 2017.
• NIOSH. A performance test protocol for closed system transfer devices used during pharmacy compounding and administration of hazardous drugs. Centers for Disease Control and Prevention website. cdc. gov/niosh/docket/review/docket288a/pdfs/APerformanceTestProtocolforClosedSystemTransferDevices.pdf. Accessed October 5, 2017.
• Page MR. Closed-system transfer devices: important considerations for pharmacists. Pharmacy Times Health-System Edition. 2017;6(5):24.
• Bar-Ilan I. Comparative study of vapor containment efficiency of hazardous drug transfer devices. Equashield website. equashield.com/wp-content/uploads/2015/12/008-Equashield-Closed-System-Transfer-Device- CSTD.pdf. Accessed October 5, 2017.

An estimated 8 million health care workers in the United States are exposed to hazardous drugs (HDs) each year, according to the National Institute for Occupational Safety and Health (NIOSH). Many studies show that this exposure to HDs may be associated with an increased risk of genetic damage, which may lead to neoplasms, reproductive toxicity, and teratogenicity. In recognition of these risks, standards-setting organization such as the United States Pharmacopeial Convention and NIOSH have developed guidelines and standards to help protect health care professionals and evaluate the efficacy of devices to reduce HD exposure, such as closed-system transfer devices (CSTDs).^1,2

It is important to recognize that concerns related to HD exposure in people of reproductive age are based on a large body of evidence. Studies evaluating reproductive risk associated with HD exposure include the following:

• A study of more than 7000 nurses exposed to antineoplastic medications revealed twice the risk of spontaneous abortion in association with regular handling of HDs.³
• A retrospective study of nearly 3000 nursing and pharmacy staff showed a 40% increase in the risk of spontaneous abortion and stillbirth compared with a control group of about 4000 women who were not exposed to HDs.⁴
• A meta-analysis identified a 46% increase in the risk of spontaneous abortion among female health care workers handling cytotoxic drugs.⁵

In addition to reproductive risk, genetic changes characteristic of some forms of leukemia have been found to occur at a greater frequency in health care workers with higher HD exposure levels. McDairmid et al measured rates of chromosome 5 and 7 abnormalities in blood samples of 109 health care workers with varying levels of exposure to HDs. In a high-exposure group, the study authors identified significantly more structural chromosomal abnormalities (0.18/ person vs 0.02/person; P = .04), a significantly higher risk of chromosome 5 abnormalities (P = .01), and a significantly higher risk of chromosome 5 or 7 abnormalities (P = .01).⁶

To address these potential risks, NIOSH publishes and regularly updates a list of HDs. As of 2016, the updated HD list comprised more than 100 medications, including drugs that are carcinogenic, teratogenic, genotoxic, toxic to reproductive capacity, or organotoxic at low doses. As an additional measure of safety, the list also includes new medications that are structurally similar to existing HDs. This list of HDs is important in implementing a new set of regulations known as USP <800>.^2,7

USP <800> REGULATIONS

Regulations governing the handling of HDs in health care settings were published by the United States Pharmacopeial Convention in 2016. These standards, known as USP General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings, are a legally enforceable set of guidelines that apply to the transport, storage, handling, and administration of HDs.^2,7 Important provisions of USP <800> relevant to pharmacy operation include ensuring proper training in HD handling, storage of HDs in an area separate from nonhazardous drugs, as well as storage and preparation of HDs in a segregated negative-pressure area with a separate refrigerator.^2,7

In handling HDs, USP <800> requires use of 3 types of engineering controls classified as primary, secondary, or supplemental. Primary engineering controls include the work area (eg, hood) where HDs are prepared, whereas the secondary engineering control is the negative-pressure room containing the primary engineering control. CSTDs are an example of supplemental engineering controls.^2,7

Although USP <800> recommends the use of CSTDs during compounding of HDs in the pharmacy area, USP <800> requires CSTDs for nurses administering HDs to patients. It is important to note, however, that CSTDs are not usable for the administration of all types of HDs. For instance, CSTDs cannot be used with medications that are incompatible with CSTD materials (eg, bendamustine). They also cannot be used for the administration of intrathecal dosage forms, irrigations, ophthalmic medications, or topical creams, ointments, or gels.^2,7

As a result of the important role of CSTDs in USP <800>, all medical facilities in the United States will ultimately gain access to these devices. Given the expanding use of these devices, it is critical that health care professionals and decision-makers have access to clear evidence of the relative protective efficacy of these devices. One such protocol for testing CSTDs has been developed by NIOSH.^2,7

Although CSTDs are cleared by the FDA, these clearances are based on an evaluation of substantial equivalence to predicate devices. Therefore, FDA clearance of CSTDs does not guarantee protective efficacy. NIOSH has designed a draft protocol for the evaluation of CSTDs to enable an analysis of systems through a single standardized method.^2,7

THE NIOSH PROTOCOL

The NIOSH protocol is intended to test systems that contain HD vapors and prevent microbial ingress into sterile medication vials and administration systems. Although the first CSTD was approved in 1998, it was not until 2012 that the FDA developed a special designation for CSTDs, known as an ONB code. This designation indicates that devices are appropriate for compounding hazardous drugs, including antineoplastic drugs.^8-12

Importantly, CSTD technologies vary by manufacturer, with some systems relying on a physical barrier to prevent escape or ingress of HDs, while other systems rely on carbon filters to contain hazardous drugs and protect medications from potential microbial contamination.^8-12 Although the NIOSH performance protocol is intended to enable unbiased comparison of CSTDs, and provides some basis for choosing a product based on its comparative efficacy with other systems, this protocol is not applicable to CSTDs that employ a carbon filter. Only mechanically closed CSTDs can be evaluated.^8-12

In the past, several attempts to assess CSTDs have included the use of the inorganic tracer gas sulfur hexafluoride, lactose powder, and fluorescent compounds. Although each of these testing substances has strengths and weaknesses, NIOSH settled upon 70% isopropyl alcohol (IPA) as a tracer compound. The selection of IPA was based on its propensity to generate vapor at room temperature, its ubiquity, and the availability of equipment to reliably measure concentrations of IPA within a test environment using a gas analyzer (the Miran SapphIRe detector, which reports IPA concentrations in parts per million once per second).^8-12

Per the NIOSH protocol, the detector continuously measures IPA concentrations in a sealed environmental test chamber (Secador Techni-dome 360 Large VacuumDesiccator) where CSTD manipulations occur. Furthermore, the CSTD protocol specifies testing for several types of connections made with CSTDs, including connection of the CSTD with several types of adapters.^8-12

These may include adaptors that connect with vials, ports, Y-sites, and intravenous bags. IPA detectors have an important limitation: they cannot establish that zero IPA has escaped from a CSTD. However, they can establish that IPA is not present at concentrations above a lower limit of detection, below which the detector cannot reliably establish IPA levels.^8-12

For the Miran SapphIRe detector, this limit of quantification is 1 part per million—an astonishingly low concentration, equivalent to 1 teaspoon of water in a 5000-liter tank. According to NIOSH, this setup offers assurance that, “CSTD performance was as good as could possibly be measured using the particular instrument within the evaluation protocol.”8-12

In response to the NIOSH protocol document, Fred Massoomi, PharmD, FASHP, CSTD expert and pharmacy operations coordinator for Nebraska Methodist Hospital Pharmacy, published a series of studies available as attachments to the NIOSH protocol. These attachments include a study utilizing the NIOSH protocol to evaluate all available qualifying CSTDs on the market, a leakage test using 5-fluorouracil, and a further study evaluating filter-based (air-cleansing systems) CSTDs.^8-12

Massoomi and colleagues tested 6 systems: Equashield, PhaSeal, ChemoClave, ChemoLock, VialShield, and OnGuard/Tevadaptor. Consistent with the NIOSH protocol, researchers used the Secador Techni-Dome 360 Desiccator to contain the CSTD during manipulations of 70% IPA, and the Miran SapphIRe analyzer to detect any leakage of IPA. Throughout manipulations, 4 pharmacists and technicians continuously monitored the Miran analyzer to determine which manipulations of CSTDs led to leaks.^8-12

Manipulations performed in the study included 2 tasks: task 1 and task 2.^8-12

• Task 1 simulated reconstitution of a vial and preparation of an intravenous bag. Investigators first withdrew 45-mL of IPA from a vial, and injected 45-mL of IPA into a second vial, bringing the total volume of the second vial to 90-mL. Then, two 45-mL aliquots of IPA were drawn from the second vial and injected into a 500- mL 0.9% saline intravenous bag.
• Task 2 simulated reconstitution of a vial and injection of the reconstituted medication into an intravenous bag at bedside. As in the first task, researchers first withdrew 45-mL of IPA from a vial and transferred the contents to a second vial, bringing the total volume of the second vial to 90-mL of IPA. Then, two 45-mL aliquots of IPA were transferred from the second vial into the Y-site of intravenous tubing.

Of the 6 brands tested, no change in the concentration of IPA occurred for 2 systems: Equashield and PhaSeal (table1²).^8-12

LIMITS OF THE NIOSH PROTOCOL

Since the publication of the NIOSH protocol, industry stakeholders have expressed concerns about the fairness of the test. During a March 2016 meeting, Teva/B. Braun, the maker of a filter-based system known as OnGuard/ Tevadaptor, recommended the use of a different detector system capable of measuring even lower concentrations of alcohol, and recommended using 1% IPA as a tracer compound, rather than 70% IPA.^12,13

The use of 1% IPA may reflect the fact that the carbon filter in the OnGuard/Tevadaptor product is mainly intended to filter chemotherapeutic medications, which are mainly aqueous, with a very small proportion of organic molecules in solution. As a result, concentrated 70% IPA—composed predominantly of organic molecules&mdash;may not be representative of the filtering efficacy of the OnGuard/Tevadaptor device in filtering chemotherapeutic medications, which are primarily aqueous. Due to these concerns, NIOSH extended review of its protocol and ultimately abandoned the standard.^12,13

Despite abandonment of the NIOSH protocol, it is worth noting that filter-based products were previously barred from being called CSTDs in other countries. For instance, filter-based systems are not classified as CSTDs by International Society of Oncology Pharmacy Practitioners (ISOPP) guidelines.^8-13

It is also worth noting that even after the NIOSH protocol is amended and approved, the implementation and use of the NIOSH protocol will be voluntary. NIOSH does not have the authority to enforce standards for CSTD testing, and as a result, the NIOSH protocol is mainly intended as a standardized test that manufacturers or individual hospitals can perform to evaluate a system.^8-13

Although larger institutions may use the NIOSH protocol to decide which CSTD system to purchase, the expense of testing largely excludes smaller hospitals and health systems. As a result, CSTD testing using the NIOSH protocol is feasible only for regulatory bodies and larger institutions. Ultimately, incorporation of the NIOSH protocol into requirements for FDA ONB product clearance might be its most appropriate application.^12,13

CONCLUSIONS

The review and approval of the NIOSH protocol and an official FDA evaluation of CSTDs for efficacy using a single, standardized test will be an important factor for institutions to determine which specific CSTD technology they will adopt. Although preliminary data generated using the draft NIOSH protocol offer some indication of the comparative efficacy of these systems, ultimately, individual health care professionals must decide which product is most appropriate for their health care system.

References

1. NIOSH. Hazardous Drug Exposures in Health Care. www.cdc.gov/niosh/topics/hazdrug/. Accessed February 2017.

2. Tocco A. The Future Impact of USP 800 in the Health Care Setting. www.michiganpharmacists.org/Portals/0/education/cearticles/usp800012015.pdf. Accessed February 2017.

3. Lawson CC, Rocheleau CM, Whelan EA, et al. Occupational exposures among nurses and risk of spontaneous abortion. Am J Obstet Gynecol. 2012;206(4):327-328.

4. Valanis B, Vollmer WM, Steele P. Occupational exposure to antineoplastic agents: self-reported miscarriages and stillbirths among nurses and pharmacists. J Occup Environ Med. 1999;41(8):632-638.

5. Dranitsaris G, Johnston M, Poirier S, et al. Are health care providers who work with cancer drugs at an increased risk for toxic events? A systematic review and meta-analysis of the literature. J Oncol Pharm Pract. 2005;11(2):69-78.

6. McDiarmid MA, Oliver MS, Roth TS, Rogers B, Escalante C. Chromosome 5 and 7 abnormalities in oncology personnel handling anticancer drugs. J Occup Environ Med. 2010;52(10):1028-1034.

7. Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeial Convention website. usp.org/sites/default/files/usp_pdf/EN/m7808.pdf. Accessed February 2017.

8. Page MR. Independent Tests Show Key Differences in Protective Efficacy of CSTDs, with Important Implications for Pharmacists. www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2016/july-2016/independent-tests-show-key-differences-in-protective-efficacy-of-cstds-with-important-implications-for-pharmacists/P-1/. Accessed February 2017.

9. Page MR. Selection of Closed-System Transfer Devices: Tips for Engaging Nursing and Pharmacy Stakeholders in Purchasing Decisions. www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2015/october-2015/selection-of-closed-system-transfer-devices-tips-for-engaging-nursing-and-pharmacy-stakeholders-in-purchasing-decisions. Accessed February 2017.

10. Page MR. In Selecting Closed-System Transfer Devices, Anticompetitive Bundling Practices Put Health Care Professionals at Risk. www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2016/september-2016/in-selecting-closed-system-transfer-devices-anticompetitive-bundling-practices-put-health-care-professionals-at-risk/. Accessed February 2017.

11. NIOSH. A Vapor Containment Performance Protocol for Closed System Transfer Devices Used During Pharmacy Compounding and Administration of Hazardous Drugs. CDC website. http://www.cdc.gov/niosh/docket/review/docket288/default.html. Accessed February 2017.

12. Regulations.gov. A Vapor Containment Performance Protocol for Closed System Transfer Devices Used During Pharmacy Compounding and Administration of Hazardous Drugs. https://www.regulations.gov/docket?D=CDC-2015-0075. Accessed February 2017.

13. NIOSH. A Performance Test Protocol for Closed System Transfer Devices Used During Pharmacy Compounding and Administration of Hazardous Drugs. https://www.cdc.gov/niosh/docket/review/docket288a/default.html. Accessed February 2017.