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Published on 9 June 2010

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Microbiological integrity of transfer devices

teaserRecent research shows that closed system transfer devices used for preparation of cytotoxic injections vary in susceptibility to microbial contamination and this has implications for practice

Johan Vandenbroucke
PharmD
Central Pharmacy
Ghent University
Hospital
Belgium

teaserRecent research shows that closed system transfer devices used for preparation of cytotoxic injections vary in susceptibility to microbial contamination and this has implications for practice

Johan Vandenbroucke
PharmD
Central Pharmacy
Ghent University
Hospital
Belgium

Traditional aseptic procedures emphasised the importance of minimising the possibility of contamination of the product with microorganisms. However, over the past 15 years there has been a growing understanding of the importance of protecting the operators from exposure to hazardous drugs, including cytotoxic agents, when they are compounded as injections. Guidelines from NIOSH,[1] ISOPP[2] and ASHP[3] have stipulated the use of closed system transfer devices to minimise the risks of occupational exposure to hazardous drugs for staff involved in the preparation of injectable doses. We have seen the introduction of a number of products claiming to fulfil this purpose.

Aseptic operating procedures were developed when the main mode of preparation involved the use of needles and syringes. The methods used include no-touch technique, working in a laminar-flow hood in sterile air and rigorous surface decontamination. In addition, clean room facilities and validated procedures and staff are mandatory.

For the most part it has been assumed that sterile transfer devices pose no greater microbiological risks than traditional systems and so they have simply replaced the syringe and needle systems.

One transfer device (PhaSeal) has been studied extensively and several studies have confirmed its protective capacity and ability to prevent leakage of fluids, aerosols and vapours.[4-11] However, until recently, there were few (if any) published data concerning the ability of transfer devices to protect the products from accidental microbiological contamination. In view of this gap in knowledge and the potential for these devices to be used in the preparation of injections for immediate use in certain situations, researchers in Belgium undertook a study of four protective devices.[12]

The study was designed to compare microbiological contamination with four transfer devices and the traditional needle and syringe system, using simulated transfers and connections (See Table 1).

Rubber stoppers and connections were artificially contaminated using known quantities of Pseudomonas aeruginosa. Both high- and low-challenge inocula were used, designed to give 4 x 10[5] cells and 4 x 103 cells on the stopper surface, respectively. In order to simulate the in-use situation, as the first step in the procedure, rubber stoppers were contaminated and the transfer device was put in place. The vial, containing sodium chloride 0.9% as the acceptor medium, was turned upside down to allow maximum contact of the acceptor medium with the spike/needle that had pierced the rubber stopper. Each procedure was carried out ten times. After the connection of the transfer device the vial contents were examined by solid phase cytometry (SPC) in order to determine the numbers of viable organisms transferred to the ‘drug’ solution.

To do so, the vial content is filtered over a black coated filter which is then incubated for 30 minutes on a pad impregnated with ChemChrome V6.The principle of this analytical method is that only metabolically active cells are able to take up the substrate which is cleaved by intracellular enzymes into a fluorescent part and a non-fluorescent part. The fluorescence is measured by argon laser scanning. The advantages of this method are:
1. Speed: results are known in less than one hour after the beginning of the test.
2. Accuracy: it is possible to measure down to one single viable microorganism.
3.Reliability: consistency of results with repeated measurements has been demonstrated with quantified control samples.

The second phase of the test procedure was the coupling of the syringe to a contaminated transfer device or multiple puncture with a needle through the rubber stopper to mimic continuous repeated use of the transfer device/vial. The acceptor medium of the vial was transferred into the syringe and afterwards analysed by SPC. The results showed that PhaSeal afforded the lowest level of transfer of microorganisms during both ‘dopping’ (the procedure connecting the actual protective device to the drug vial) and connection, that is, coupling of the injector to protector (for PhaSeal) or sterile syringe for the other products. The quantity of microorganisms transferred into the acceptor medium was one-two log cycles lower using PhaSeal compared with the other transfer devices or the traditional needle and syringe technique.

The second objective of this study was to compare the efficiency of a number of disinfection procedures for rubber stoppers and this involved spraying and swabbing with a range of agents before connecting the PhaSeal device. Four main categories of procedure were used – (i) single swabbing, (ii) consecutive use of two different swabs, (iii) spraying and (iv) the combined use of spraying and swabbing.

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Once again, the vial stoppers were artificially contaminated with an overnight culture of one of the four test organisms: Pseudomonas aeruginosa (10[8] cfu), Staphylococcus aureus  (10[9] cfu), Candida albicans (10[7] cfu) and Aspergillus niger (10[6] cfu).

The numbers of viable organisms transferred to the  ‘acceptance’ solution were determined with or without a disinfection procedure of the rubber stopper and following on the dopping of the PhaSeal device.

An interval of up to 100 minutes was left between inoculation of the micro organism and the disinfection procedure and/or connecting the PhaSeal device. Each procedure was performed five times. Three procedures turned out to be effective. They were:
1. Spraying with 0.5% (w⁄v) chlorhexidine in 60% (v⁄v) isopropanol (wait of 15 seconds), followed by threefold swabbing with isopropanol.
2. Spraying with 2% (w⁄v) chlorhexidine (15s) in 70% (v⁄v) isopropanol, followed by single swabbing with isopropanol.
3. Spraying with 2% (w⁄v) chlorhexidine in 70% (v⁄v) isopropanol (closed box, 6min), followed by swabbing with isopropanol.

Neither spraying alone nor swabbing alone provided effective disinfection.

Discussion
PhaSeal has the thinnest needle of the devices tested and therefore causes less damage to the rubber stopper. In addition, the double membrane technology used in PhaSeal connectors provides further protection for the product. These two factors probably contribute to the low rate of transfer of microorganisms that was observed in this study.

An extremely high level of inoculum was used in the study and it is unlikely that this level of contamination would occur in a real life situation, taking into account the fact that this work is normally undertaken in a clean room under a laminar flow hood. Unfortunately, in some countries, both in and outside Europe, cytotoxic doses are not prepared in protected conditions but at the bedside or on a countertop.

Only four transfer devices were tested because these were the only four that were available at the time. Clearly it would be interesting to repeat the experiment with newer devices such as the Tevadaptor (Teva) and Genius (ICU medical).

Two important messages emerge from this work.  First, the importance of having an effective and validated disinfection procedure. Disinfection, that is, the reduction of the microbiological burden, has always been one of the cornerstones of good aseptic practice and the results of this study reinforce its importance. Second, transfer devices vary in their susceptibility to microbial contamination and this should be taken into account when considering prolonged use of vials.

References
1. NIOSH Alert: DHHS (NIOSH) Pub No. 2004-165, September 2004.
2. ISOPP Standards of Practice. J Oncol Pharm Practice 2007;Suppl 13,1–81.
3. American Society of Health-System Pharmacists. Am J of Health-Syst Pharm 2006;63:1172–1193.
4. Connor TH, et al. Am J Health Syst Pharm 1999;56:1427–1432.
5. Connor TH, et al. Am J Health Syst Pharm 2002:59,68–72.
6. Sessink PJM, et al. Hosp Pharm 1999;34:1311–1317.
7. Vandenbroucke J, et al. J Oncol Pharm Pract 2001;6:46–152.
8. Spivey S, et al. Hosp Pharm 2003;38:135–139.
9.  Wick C, et al. Am J Health Syst Pharm 2003;60:2314–2320.
10. Poirier S, et al. J Oncol Pharm Pract 2004;10:81.
11. Tans B, et al. J Oncol Pharm Pract 2004;10:217–223.
12. De Prijck K, et al. Letters in Applied Microbiology 2008;47:543–548.



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