ChemoLock Needlefree Closed System Transfer Device

ChemoLock Needlefree Closed System Transfer Device Clinical Evidence Table of Contents Pg Number Studies Evaluating Environmental Contamination ph Liquid Integrity Test of FDA-Approved ONB Closed-System Transfer Devices Carolyn Pfeifer, Pharm.D.; Patrick Fuller, Pharm.D., University of Nebraska Medical Center, Omaha, NE Michael Koraleski, Pharm.D.; Firouzan Fred Massoomi, Pharm.D., Nebraska Methodist Hospital, Omaha, NE... 2 Evaluation of FDA-Approved ONB Closed-System Transfer Devices Utilizing Cyclophosphamide as a Marker Michael Koraleski, Pharm.D*, Firouzan Fred Massoomi, Pharm.D*, Matt Zock+ *Nebraska Methodist Hospital, Omaha, Nebraska ; +RJ Lee Group, Inc., Monroeville, PA... 4 Studies Evaluating Mechanically & Microbiologically Closed Systems Microbial Ingress Study for ChemoLock Devices...6

STUDY SUMMARY ph Liquid Integrity Test of FDA-Approved ONB Closed-System Transfer Devices Carolyn Pfeifer, Pharm.D.; Patrick Fuller, Pharm.D., University of Nebraska Medical Center, Omaha, NE Michael Koraleski, Pharm.D.; Firouzan Fred Massoomi, Pharm.D., Nebraska Methodist Hospital, Omaha, NE BACKGROUND Healthcare workers who handle hazardous drugs are at risk for occupational exposures resulting in adverse events including skin rashes, stillbirths, spontaneous abortions, and certain cancers. 1 Closed-System Transfer Devices (CSTDs) are specifically designed to reduce this risk. 2 Since 1999, six CSTDs have received FDA 510(k) approval. In 2012, the FDA established a new category for CSTDs under an ONB code to better categorize products that are intended to be used for safe handling. Today, only two CSTDs have received FDA approval for the new ONB code: PhaSeal (Becton, Dickinson and Company, Franklin Lakes, NJ) and the newly 2013 approved ChemoLock (ICU Medical, Inc, San Clemente, CA) systems. HISTORY OF LITMUS TESTS AND CSTD S 2007 Leakproof Connection Integrity Test For Devices Intended for Handling Hazardous Drugs. 3 > > Spiros & Clave by ICU Medical Inc., B. Braun OnGuard Vial Adaptor & Syringe Adaptor by Teva Medical Ltd., Alaris SmartSite Vented Vial Access Device & Texium Male Luer by Cardinal Health, and PhaSeal Protector & Injector Luer Lock by Carmel Pharma. > > Results: PhaSeal was the only system with no leakage observed after 10 manipulations. Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. 4 > > Showed that personnel exposure to cyclophosphamide (CP) and ifosfamide (IF) decreased after 6 months of implementation of PhaSeal. 24-hour urine samples were collected from 8 employees including pharmacists, pharmacy technicians, and nurses working full-time in a chemotherapy drug infusion center and pharmacy. 6 of 8 had positive urine samples for CP and 2 of 8 were positive for IF before implementation. 0 of 8 were positive after 6 months of implementation. The FDA ONB Code (last updated November 1, 2013) > > Definition: Reconstitute and transfer antineoplastic and other hazardous drugs in healthcare setting indicated to reduce exposure of healthcare personnel to chemotherapy agents in healthcare setting. > > Three criteria must be met: 1) no escape of hazardous drug or vapor concentration, 2) no transfer of environmental contaminants, and 3) prevention of microbial ingress. WHAT IS CHEMOLOCK? CSTD approved in 2013 > > Needlefree system that passively aids in both needlestick injuries and exposure to cytotoxic chemicals Photo 1. ChemoLock system > > One-step connection process with an audible click that sounds when syringe successfully connects to the vial > > Air pocket chamber located inside drug vial that collects any air vapor that may escape WHAT IS PHASEAL? First CSTD, approved in 1999 > > Contains enclosed needle within syringe connector > > Three-step connection process: Push, Turn, Push > > Large air pocket chamber alongside vial adaptor that collects any air vapor that may escape Photo 2. PhaSeal system

OBJECTIVES To evaluate the liquid containment of the two FDA ONB code-approved CSTDs, PhaSeal and ChemoLock, in comparison to the traditional needle and syringe method for drug transfers at varying ph s. To mimic the full-scale ph of hazardous drugs by using the following ph buffers as a substitute for active drug: ph 4.0, ph 7.0, and ph 10.0. Hazardous Drug Bleomycin 4.5-6.0 Carboplatin 5.0-7.0 Cytarabine 7.6 Davarbazine 3.0-4.0 Epirubicin 3.0 Fludarabine 7.2-8.2 Irinotecan 3.5 Methotraxate 8.5 METHODS ph from MSDS For each ONB CSTD and needle and syringe method: Ten 1 ml transfer manipulations with each of the three ph buffers. > > Disconnected vial and syringe after each manipulation and tested both connection endpoints with litmus paper. > > Connection endpoints were cleaned and allowed to dry with sterile alcohol if previous manipulation resulted in litmus paper color change. > > Each syringe connector and vial adaptor was used in ten consecutive manipulations without being changed, in accordance with the FDA-approved limitations of the devices. > > The test was performed in duplicate by pharmacy residents from The Nebraska Medical Center and from Nebraska Methodist Hospital in Omaha, Nebraska. Photo 3. Litmus paper results for needle and syringe method RESULTS Visible leakage occurred with 1.7% of PhaSeal System and 43% with traditional needle and syringe method. (Table 1). No leakage was observed with the ChemoLock system by ICU Medical. PhaSeal ChemoLock Needle and Syringe ph 4.0 ph 7.0 ph 10.0 ph 4.0 ph 7.0 ph 10.0 ph 4.0 ph 7.0 ph 10.0 Total Color Changes 1 1 0 0 0 0 22 17 13 Total Manipulations 20 20 20 20 20 20 20 20 20 Percent of Litmus Tests with Leakage 1.7% (2 of 120) 0% (0 of 120) 43% (52 of 120) CONCLUSION The data suggests that CSTDs are necessary for safe preparation of hazardous drugs as the needle and syringe method failed to contain all three ph solutions within the transfer process. The PhaSeal product improved solution containment but had two failed manipulations in a relatively small sample size. The ChemoLock product had no litmus paper color changes and no visible droplets evident during manipulations. The currently FDA-approved ONB CSTD systems demonstrated containment of acid, base, and neutral solutions when compared to the traditional needle and syringe method. References 1. Powers, Luci A. Closed-System Transfer Devices For Safe Handling of Injectable Hazardous Drugs. Pharmacy Practice News. June 2013; 1-16. 2. National Institute for Occupational Safety and Health. NIOSH alert: preventing occupational exposure to anti-neoplastic and other hazardous drugs in healthcare settings. www.cdc.gov/niosh/docs/2004-165/ 3. Jorgenson, JA. Leakproof Connection Integrity Test for Devices Intended for Handling Hazardous Drugs. The University of Utah. 2007. 4. Wick C, Slawson MH, et al. Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. Am J Health-Syst Pharm. 2003; 60:2314-2320. * Texium/SmartSite is marketed as a closed system, not a CSTD. 2013 ICU Medical Inc. M1-1456 Rev. 01

STUDY SUMMARY Evaluation of FDA-Approved ONB Closed-System Transfer Devices Utilizing Cyclophosphamide as a Marker Michael Koraleski, Pharm.D*, Firouzan Fred Massoomi, Pharm.D*, Matt Zock+ *Nebraska Methodist Hospital, Omaha, Nebraska ; +RJ Lee Group, Inc., Monroeville, PA PURPOSE Healthcare workers who handle hazardous drugs are at risk of occupational exposure. Closed-System Transfer Devices (CSTDs) are specifically designed to minimize this risk. Since their 1999 introduction, it s estimated that less than 45% of facilities use a CSTD. In 2012, the FDA established a new category of CSTDs under a new ONB code that categorizes products to be used for safe handling. Only two CSTDs have received FDA approval for the ONB code: PhaSeal (Becton, Dickinson and Company, Franklin Lakes, NJ) and the newly approved ChemoLock (ICU Medical, Inc, San Clemente, CA). This study examines the containment potential during the drug transfer process using cyclophosphamide (CP) as a marker for the ONB devices. METHODS Decontamination procedures were used to minimize CP contamination on vials and surfaces prior to the study. Based on published studies, four common surface sampling zones within and around the biological safety cabinet workbench that were suspected to be the most likely contaminated surfaces were selected and demarcated using colored tape. Each CSTD system consists of a vial access device, syringe adaptor, and intravenous bag spike. The systems were used according to the FDA-approved package insert by a certified pharmacy technician. For the assessment, three trials, which included three individual transfers of 16 ml of drug from each of four vials, followed by disconnecting and reconnecting from vial to IV bag, occurred. A total of 72 individual compounding transfers were completed for the study. Wipe samples were taken by an independent certified industrial hygienist from the four sampling zones and from the compounder s gloves after each trail was complete. Between each device, the sample zones were decontaminated to prevent potential cross-contamination bias between devices. Samples were prepared and analyzed by a credentialed laboratory specializing in chemical analysis using a liquid chromatograph that was equipped with dual mass spectrometers (LC-MSMS) with a lower limit quantitation of 2.00 nanograms (ng) CP. TABLE 1. SUMMARY OF ICU MEDICAL CHEMOLOCK TRIALS Sample ID Surface Area, cm 2 CP, ng CP conc., ng/cm 2 Comments 5296061 Field blank na nd na 5296062 Workbench left 400 nd <0.00500 5296063 Workbench right 400 3.33 0.00833 5296016 Grill 400 nd <0.00500 5296017 Airfoil 400 nd <0.00500 5296018 Gloves na nd na 5296019 Workbench left 400 nd <0.00500 5296020 Workbench right 400 nd <0.00500 5296021 Grill 400 nd <0.00500 5296022 Airfoil 400 nd <0.00500 5296023 Gloves na nd na 5296040 Workbench left 400 nd <0.00500 5296041 Workbench right 400 nd <0.00500 5296042 Grill 400 nd <0.00500 5296043 Airfoil 400 nd <0.00500 5296044 Gloves na nd na 5296045 Workbench left 400 nd <0.00500 5296046 Workbench right 400 nd <0.00500 5296047 Grill 400 nd <0.00500 Decontamination ChemoLock, Trial 1 ChemoLock, Trial 2 ChemoLock, Trial 3 Photo 1. ICU Medical ChemoLock system, vial access. 5296108 Airfoil 400 nd <0.00500 na not applicable nd not detected (<2.00 ng/sample) Photo 2. PhaSeal system, vial access.

TABLE 2. SUMMARY OF PHASEAL TRIALS Sample ID Surface Area, cm 2 CP, ng CP conc., ng/cm 2 Comments 5296038 Field blank na nd na 5296039 Workbench left 400 nd <0.00500 5296000 Workbench right 400 nd <0.00500 5296001 Grill 400 nd <0.00500 Decontamination 5296002 Airfoil 400 nd <0.00500 5296003 Gloves na nd na 5296004 Workbench left 400 nd <0.00500 5296005 Workbench right 400 nd <0.00500 5296007 Grill 400 nd <0.00500 PhaSeal, Trial 1 5296064 Airfoil 400 nd <0.00500 5296065 Gloves na nd na 5296066 Workbench left 400 nd <0.00500 5296067 Workbench right 400 89.1 0.223 5296068 Grill 400 nd <0.00500 PhaSeal, Trial 2 5296069 Airfoil 400 nd <0.00500 5296080 Gloves na nd na 5296081 Workbench left 400 nd <0.00500 5296082 Workbench right 400 8.56 0.0214 5296083 Grill 400 nd <0.00500 PhaSeal, Trial 3 5296084 Airfoil 400 nd <0.00500 na not applicable nd not detected (<2.00 ng/sample) RESULTS Wipe samples collected from vials following the initial decontamination procedure and prior to use in the study were free of detectable CP. CP was detected on one surface prior to the ChemoLock trial and no detectable CP was found on surfaces prior to the PhaSeal trial. For the ChemoLock system, no CP was detected on working surfaces or the compounders gloves. For the PhaSeal system, CP was detected on the biological safety workbench following trials 2 and 3 and no CP was detected on the technician s gloves. On one occasion during trial 2 of the PhaSeal system, the internal needle of the product became unintentionally exposed with a fluid droplet observed on the needle tip. Photo 3. ICU Medical ChemoLock system, IV bag access. Photo 4. PhaSeal system, IV bag access. CONCLUSION The results of this study suggest that the ChemoLock system was effective in preventing detectable surface contamination during three separate trials of simulated compounding activities with known amounts of cyclophosphamide. It appeared that the PhaSeal system was effective in preventing detectable contamination when the product functioned as designed. The ONB FDA-approved devices demonstrate minimization of contamination to the work environment for CP. Photo 5. PhaSeal Protector with unintentionally exposed needle and visible fluid droplet. Photo 6. Wipe sample collected from BSC workbench (left). Surface Wipe Study Funded by ICU Medical Inc. 2013 ICU Medical Inc. M1-1455 Rev. 01

STUDY SUMMARY Microbial Ingress Study for ChemoLock Devices Report of a study commissioned by ICU and conducted by AAIPharma Services PURPOSE The purpose of this study was to evaluate microbial ingress on ChemoLock devices following multiple activations. METHODS A protocol was developed and executed by AAIPharma Services using four bacterial strains: > > Staphylococcus aureaus, ATCC #6538 > > Staphylococcus epidermidis, ATCC #12228 > > Klebsiella pneumonia, ATCC #4352 > > Pseudomonas aeruginosa, ATCC #9027 Microbial Recovery Studies > > The device was inoculated in duplicate with an appropriate volume of inoculum to yield 1-5 x 103 colony forming units (CFU). > > The device was allowed to dry for 1 minute. After drying, the device was placed in 10 ml of sterile 0.9% saline and vortexed. > > The positive control was prepared by inoculating a 10 ml volume 0.9% saline with the same inoculum used to inoculate the device. > > 1 ml aliquots were plated to Trypticase Soy Agar (TSA) and incubated at 30-35 C for 1-2 days. > > Acceptance Criteria: Percent recovery should be greater than 70%. Microbial Ingress Procedure > > Six devices for each organism were inoculated with an appropriate volume of inoculum to yield 1-5 x 103 colony forming units (CFU). > > The devices were allowed to dry for 1 minute. > > The septa was wiped vigorously in a circular motion for not less than 3 seconds with a 70% IPA prep pad and allowed to dry. > > The device was activated using a syringe with 10 cc saline. The fluid was collected in a filter funnel and filtered through a 0.45 micron cellulose nitrate filter. The filter was rinsed with 100 ml of Fluid A. > > The filter was transferred to a solidified plate of TSA and incubated at 30-35 C for 2-3 days. > > The process was repeated ten times (ten activation) per device per organism during one 24-hour period. > > One replicate was prepared for the positive control by performing the activation and testing procedure without the 70% IPA disinfection step. > > Negative controls were performed in D-AA0397M_0_1. > > Acceptance Criteria: Report results. RESULTS The results for the Microbial Recovery Studies are shown in Table 1. Table 1. Microbial Recovery Studies Results Test Organism Device Recovery Average (CFU) Control Recovery Average (CFU) Percent Recovery Meets Criteria Staphylococcus aureus 248 264 94% Yes Pseudomonas aeruginosa 231 251 92% Yes Staphylococcus epidermidis 160 133 120% Yes Klebsiella pneumoniae 320 312 103% Yes

The results for the Microbial Ingress are shown in Tables 2-5. No growth on negative controls. For all organisms tested, the positive control reported in the data tables represents a single positive control performed as outlined in the procedure. A new sterile device was inoculated with the appropriate volume of organism (same used for testing); however, there was no alcohol wiping step. The device was activated and 10 ml sterile saline was flushed through the device. Standard inoculum counts were performed by inoculating 10 ml saline with the same amount of organism used for testing and 1 ml was plated using the pour plate method. Table 2. Klebsiella pneumoniae Microbial Ingress Results 17 Table 3. Staphylococcus aureus Microbial Ingress Results 11 Table 4. Pseudomonas aeruginosa Microbial Ingress Results 31 Table 5. Staphylococcus epidermidis Microbial Ingress Results 25 CONCLUSION Based upon the results of the microbial ingress testing as reported above, it is determined that the ChemoLock system meets established criteria for microbial recovery studies. Per the device s FDA 510(k) clearance, the ChemoLock system prevents the transfer of environmental contaminants, including bacterial and airborne contaminants into the system. 2013 ICU Medical Inc. M1-1452 Rev. 01