1. BACKGROUND INFORMATION AND RATIONALE
1.1 Background
There are several routes of exposure to hazardous drugs (HD) throughout the drug-handling chain, from pharmaceutical compounding to patient dose administration. Closed System transfer devices (CSTD) are used to protect against such worker exposures to HDs. CSTDs should have the ability to function as a closed system that restricts drug mass (vapor or liquid) from crossing the system boundary and escaping into the surrounding environment [1,7]. However, in the absence of CSTD performance standards that currently apply to drug containment and given uncertain claims of protective performance, the protective efficiency of certain CSTDs remains in doubt for at least two of these routes of exposure.
- The first route of exposure occurs during the reconstitution of HDs when the diluent injection forces the venting of air saturated with drug vapor from the vial headspace to the environment. This is applicable only to vented CSTD models, the “air-cleaning systems,” designed to filter and remove aerosol or vapor contaminants from airstreams that might escape the drug transfer system [1,7]. Air-Cleaning CSTDs came to market after “barrier CSTDs,” offering significant cost savings. However, their efficacy in preventing the escape of drug vapor remains under heavy scrutiny to this date.
- The second route of exposure occurs in a syringe during and after injection of HDs, when a layer of the drug may remain due to adhesion on the inner walls of regular syringes used with air-cleaning and barrier-type CSTDs [12,13,14], Layers of drug compounds with vapor generating potential may evaporate into the environment and potentially contaminate the syringe plunger. This is applicable to all CSTDs that use regular open barrel off-the-shelf syringes.
In the absence of such worker protection standards, the users (e.g., health care facilities and pharmacies) have no worker-protection performance basis upon which to make their selection of a CSTD, and they may be inclined to select a product based solely upon acquisition costs and uncertain claims of protective performance [1]. Since 2015, The National Institute for Occupational Safety and Health (NIOSH) has been developing performance test protocols for CSTDs. NIOSH’s first “Vapor Containment, Performance Protocol” introduction in 2015 used IPA alcohol as the surrogate [1]. NIOSH continues to adhere to detecting escaped vapor concentrations of drug surrogates as the basic testing approach. In 2016 NIOSH introduced 9 surrogates (later extended to 1 1 surrogates) to be used in the “Performance Test Protocol for CSTDs [7].” While the testing methods and equipment have significantly changed over the years, these surrogates remain under current consideration, including alcohols for testing barrier-type CSTDs (NIOSH 2019) [8]. NIOSH’s surrogate selection strategy involved the selection of Thiotepa, the HD with the highest known vapor pressure as a worst-case scenario. To build in a safety factor, surrogates were considered with vapor pressures in the range, starting with Thiotepa and going up to approximately 100 times that [7], NIOSH also stated in its 2015 protocol that “A CSTD design that relies upon aerosol filtration to clean air that exits the drug transfer system is worker protective only if use of the CSTD is limited to compounding drugs that have no vapor generating potential. For drug compounds with either known or uncertain vapor generating potential, the protective selection of air-cleaning CSTDs requires specific test data for every’ drug type and formulation they will contact, since air-cleaning technologies can have varying efficiencies based upon the chemical and physical make-up of the contaminant.”[1] This study evaluates two out of nine NIOSH surrogates for their suitability as challenge agents for testing the aforementioned two routes of exposure. The evaluation shall determine whether CSTD efficiencies vary upon the chemical and physical make-up of surrogates to the degree that inefficient surrogates, including alcohol, shall be excluded or used only in combination with efficient surrogates.
1.2 Study Objectives
The purpose of the study in its first stage was to determine that each vented air-cleaning CSTD can have varying vapor containment efficiencies with varying contaminants since some vented CSTDs could contain vapor of one type of contaminants and absolutely fail with others.
In its second stage, the purpose of the study was to establish scientific evidence for vapor release from regular open-barrel syringes as a route of exposure and further to determine that varying contaminants can cause varying levels of vapor contamination from open-barrel syringes, ranging from high contamination to none.
This study tests four commercially available vented CSTDs using two out of nine hazardous drug surrogates selected by NIOSH for testing air-cleaning CSTDs and uses NIOSH equipment, thereby identifying ineffective surrogates and their alike that should be excluded from the NIOSH list of surrogates. Ineffective surrogates may lead users to make their selection of CSTDs that have no worker-protection performance.
1.3 Introduction
This was a three stages study:
- In the first stage, air was sampled by an FTIR analyzer directly in front of the vent opening of a CSTD. The analyzer detects and quantifies in real-time the vapor concentrations that are vented out of the CSTD during the injection of 50ml of water into a vial containing 3ml of surrogate. This process is identical to reconstitution.
- In the second stage, 50ml of the surrogate/water solution from the first stage was transferred to an IV bag using the same CSTD and syringe. Air was sampled by the analyzer from the open back of the syringe during the injection of the surrogate solution into the IV bag. This process is identical to standard hazardous drug transfer from vial to bag using CSTD.
- In the third stage, surrogate incompatibilities with CSTDs were excluded. All tested devices were stored for at least 72 hours, and their mechanical integrity and functionality were examined.
The first stage complies with recent NIOSH’s approach to separately test the air-cleaning feature. In its 2019 update [8], NIOSH suggested a two-stage approach to testing Air Cleaning CSTDs: “Stage 1-Air Filter Test: The CSTD via! adapter of an air-cleaning CSTD was first to he evaluated” [8];
NIOSH also suggested in its 2019 update, the use of Gasmet DX4040 FTIR analyzer for testing barrier type CSTDs with Ethanol (see test layout in Fig. 1) [8];
However, the universal DX4040 analyzer is designed to detect hundreds of various gases with very low limits of detection, including five of the nine NIOSH surrogates. This analyzer is ideal for this study as it allows for straightforward testing in real-time for vapor containment efficacy of both the Air-Cleaning feature of vented CSTDs and vapor that may be generated by regular open barrel syringes used with CSTDs for compounding and administration of hazardous drugs. This study is based on characteristics of handling Cyclophosphamide, Ifosfamide, Cytarabine and similar drugs using the same reconstitution and transfer procedures and range of dosages or concentrations [Package Inserts 9, 10, 11]. NIOSH selected its surrogates to represent undiluted Active Pharmaceutical Ingredients (API) [7], which Ifosfamide is an example. Ifosfamide is a common hazardous antineoplastic drug listed on the NIOSH List of Hazardous Drugs. Each vial contains 3 grams of Ifosfamide which is free of any excipients. Injection of diluent (e.g., SWFI) into Ifosfamide vial is required for reconstitution [Package Insert 9]. In all terms, the testing represents the actual usage of drugs and CSTDs. This study doesn’t aim to provide absolute vapor quantities, but the performance metric of interest as the maximum concentration value (in ppm) observed during each test run. 1
1.4 Methods
The methods of testing are illustrated in Figures 2 and 3, which are based upon the NIOSH approach (Fig. 1) but simplified. Figure 4 illustrates the first stage, the “Air Filter Test: The CSTD vial adapter of an air-cleaning CSTD was to first be evaluated” (NIOSH 2019) [8].
The Gasmet FTIR analyzer has a flexible air sampling tube with a 60mm diameter glass funnel attached on its end. The funnel allows for efficient air sample suction since vented gases from CSTDs may spread in all directions.
Similar to the NIOSH test layout (Fig. 1), the analyzer has attached to its air-outlet another flexible tube with a 50mm glass funnel on its end to create a loop and significantly increase sample collection efficiency. The openings of both funnels are brought in proximity and face each other. A stand with clamps is used to fixate the assembly in position.
Figure 3 illustrates the second stage: The Gasmet FTIR analyzer has a flexible tube to allow air sampling from the open syringe barrel. For simplicity, the air-outlet is not looped.
Testing methods for the first stage (filter test) are as follows:
- 100mL vials are filled with 3mL of NIOSH surrogate
- CSTD adapters are attached to an IV bag containing sterile water for injection (SWFI)
- CSTD syringe adapters are connected to regular syringes and then are connected to IV bag. The syringes are filled with 50mL of SWFI in accordance to the individual manufacturer IFU.
- CSTD vial adapter is attached to the surrogate vial, and the CSTD syringe is attached to said vial adapter.
- The vent opening of the vial adapter is placed between the two funnels, and 50mL of SWFI is injected within 12 seconds into the vial, thereby monitoring the real-time analysis data on screen.
- The analyzer runs on continuous mode and collects the vented air from CSTDs. The results are displayed every second in ppm and indicate whether or not the Air-Cleaning system is able to filter out the surrogate gas and vapor component from the vented air.
- The above steps were repeated with each of the four CSTD brands 10 times and with each of the two surrogates (4 x 10 x 2 = 80 replicates).
Testing methods for the second stage (syringe test) are as follows:
- 50mL of the surrogate solution is withdrawn into a syringe from the vial that was tested in the first stage, and the syringe is then connected to the IV bag for injection.
- The end of the sampling tube is placed in the syringe barrel’s back opening, and 50mL of the surrogate solution is injected into the IV bag, thereby monitoring the real-time analysis data on the screen.
- The analyzer runs on continuous mode and collects the vapor generated from the syringe. The results are displayed every second in ppm and indicate whether or not surrogates stick to the syringe inner walls exposed to the environment and generate vapor.
- The above steps are repeated with each of the CSTD syringes from the first stage (80 replicates).
- Positive and negative controls are performed for both first stages.
- 50mL of the surrogate solution is withdrawn into a syringe from the vial that was tested in the first stage, and the syringe is then connected to the IV bag for injection.
- The end of the sampling tube is placed in the syringe barrel’s back opening, and 50mL of the surrogate solution is injected into the IV bag, thereby monitoring the real-time analysis data on the screen.
- The analyzer runs on continuous mode and collects the vapor generated from the syringe. The results are displayed every second in ppm and indicate whether or not surrogates stick to the syringe inner walls exposed to the environment and generate vapor.
- The above steps are repeated with each of the CSTD syringes from the first stage (80 replicates).
- Positive and negative controls are performed for both first stages.
Testing methods for the third stage (surrogate compatibility validation) are as follows
- All tested devices after the first and second stage are collected and stored at room temperature for the duration of 72 hours.
- After 72 hours, the CSTD devices are checked for mechanical and visual integrity, leaks, functionality and filter blockage.
2 Description of Investigational Products
2.1 Devices
This study includes the testing of four commercially available CSTD products and a commonly used regular syringe:
2.2 Surrogates
Two surrogates for hazardous drugs were utilized to assess vapor containment. The surrogates were chosen based on preliminary testing and study development:
3 Data Collection
For purposes of the Vapor Containment Efficacy protocol, the performance metric of interest is the maximum value observed during each test run. In order to create Background (BG) adjusted test data, the maximal BG concentration must be subtracted from the maximum concentration data point (value) collected during the test run. Maximum BG concentration data shall be observed and recorded for at least five seconds prior to the start of each test. As part of the data analysis, the maximum observed BG concentration shall be then subtracted from the maximum concentration value observed during the test run to create BG adjusted test data. The final test result equals the BG adjusted maximum concentration [1], “Within the environmental sciences, where environmental data are evaluated to estimate true exposures, the rules for handling below LOD data can he complex and labor intensive. For purposes of the CSTD evaluation protocol, the performance metric of interest is the maximum value observed during the test run.”[1]
4 Testing Conditions
- No direct airflow or turbulences on testing site
- Ambient temperature 72°F – 77°F
- Keeping all materials and equipment at ambient temperature
- Regularly refreshing the room air
- Keeping undiluted vials upright to avoid contact to vial stopper
5 Study Setup
- Analyzer and laptop were wired to operate in cable mode and powered. The CalcmetPro software that operates the analyzer is specified by Gasmet and was used with the laptop.
- Following at least 45 minutes of analyzer warm-up, the zero calibration for the background was performed at the beginning of every day of testing using a nitrogen gas of 99.999% purity in accordance with the analyzer manufacturer’s instructions.
- After the calibration, the “analysis time” in Calcmet software was set to “continuous” mode, “1 second measuring time” and “pump enabled.” This setup allows for continuous air sampling (suction) with recurring 1-second-long cycles of analysis (updated results shown every second).
- The sampling tube was connected to the “sample in” port and the return air tube connected to the “sample out” port. Glass funnels were attached to the ends of the tubes and clamped to the testing stand inclined at a 45° angle (see configuration in Fig. 2),
- Empty 100mL vials were filled with 3ml of Propylene Glycol using a pipettor and were sealed with a rubber stopper and aluminum cap using the crimper device. Vials were labeled.
- The same fill process was repeated with Tetramethylurea using a new pipette.
- CSTD bag spike adapters were attached to SWFI bags, and the respective CSTD syringe connectors were attached to syringes. All syringes with the respective four types of CSTDs attached were accurately filled with 50mL of SWFI in accordance with the CSTD manufacturer’s instructions for use.