Evaluation of the chemical tightness of CSTDs

This study presents the evaluation of the chemical tightness of closed system transfer devices (CSTDs) as unintended exposure of healthcare professionals to hazardous drugs by a fluorescence-based test method.

Chemical contamination by hazardous drugs is a potential health risk, especially to pharmacists, nurses, physicians and other healthcare workers dealing with the preparation, transport, administration and disposal of these agents and infusion system components every day. According to the National Institute for Occupational Safety and Health (NIOSH), a hazardous drug is defined as any drug characterised by at least one of the following criteria:¹

• Carcinogenicity
• Teratogenicity or developmental toxicity
• Reproductive toxicity in humans
• Organ toxicity at low doses in humans or animals
• Genotoxicity
• New drugs that mimic existing hazardous drugs in structure or toxicity.

Exposure to hazardous drugs can occur at numerous points in the treatment chain. Two major scenarios have been described to lead to chemical contamination. The dermal contamination route is defined by direct contact of skin with fluids or the contaminated surfaces, for example, vials, drug boxes, body fluids, spills and primed intravenous sets, syringes or open ampoules.^1–5

The second way of contamination is by aerosols that originate from the preparation and administration procedures of drugs. However, both potential contamination routes imply the risk of uncontrolled and recurrent uptake of potentially harmful drugs by the user.

The amount of drug that is finally absorbed during handling contaminated devices is difficult to assess, as are the biological health effects on each individual.

Depending on the frequency, uptake level and nature of the hazardous drugs, the health consequences can be seen in either short-term by acute symptoms, such as skin rashes or nausea⁶ or after recurrent uptake in chronic symptoms as dermatitis,⁷ hypersensitivity,⁸ nephrotoxicity,^9,10 chronic liver damage and fibrosis¹¹ or even infertility,12 miscarriage,^12–14 birth defects¹⁵ or leukaemia and other cancers.¹⁶

However, the retraceability of those symptoms to the primary cause is often difficult, or even virtually impossible.

Besides direct health consequences for the affected healthcare workers, financial consequences for healthcare institutions cannot be disregarded. In cases of chemical contamination, guidelines require a strict procedure for the treatment of the exposed area, leading to reduced productivity and increased hardware and medication costs for acute symptoms such as rashes or diarrhoea.

In addition, the sick leave or forced changes of occupation also lead to reduced productivity with a significant cost factor. Additional costs also occur for special training of the substituting healthcare staff working with respective infusion system components. Finally, in retraceable contamination-related health cases, the respective healthcare institutions have to deal with expensive legal consequences.

To minimise the risk of such chemical contaminations and related health risks, the implementation of preventive strategies are recommended by national bodies (NIOSH, Centers for Disease Control and Prevention (CDC), International Society of Pharmacovigilance (ISOP), German Society for Oncology Pharmacy (DGOP), Swedish Work Environment Authority (AFS)).

The primary focus in achieving a reduced risk is a reduction of exposure and prevention of contamination during handling of hazardous drugs. In addition, the use of specially designed ‘protective devices’ is recommended, which help to prevent the release of toxic contaminants by aerosol formation or drip contamination.

However, additional regular controls, such as blood tests for healthcare workers are recommended in order to monitor exposure levels.¹⁷

Aim of this study

The scope of the test is to prove that defined parts of a system for reconstitution, dilution or administration of hazardous drugs prevents the escape of drugs or drug aerosols outside the system. The main objective of this study was to evaluate the chemical tightness of the connection of B. Braun’s Cyto-Set and Cyto-Set Mix during administration. The Cyto-Set and Cyto-Set Mix closed system is utilised for the preparation and administration of cytotoxic drugs.

Fluorescence-based chemical tightness test

To investigate the chemical tightness of closed system transfer devices, a fluorescence-based method was used due to its high detection sensitivity. Sodium fluorescein was chosen for its high recovery rate due to its fluorescence properties.

The detection threshold of sodium fluorescein in water is approximately 10–15mg/ml. The sodium fluorescein was used as a tracer substance for the simulation of an administered drug substance and the quantitative determination of the chemical tightness/release of the valve-protected connections of Cyto-Set and Cyto-Set Mix.

Test procedure

All products were tested according to the instructions for use.

A Cyto-Set Mix was connected to one intravenous solution container Ecoflac® plus (100ml 0.9% NaCl solution). Then, the line was primed with 0.9% NaCl solution and the clamp was closed afterwards. The Ecoflac® plus was then filled with 10ml fluorescein solution (30g/l). This procedure was performed for three other Cyto-Set Mix-Ecoflac® plus combinations.

The main line of the Cyto-Set was inserted into a 1000ml Ecoflac® plus 0.9% NaCl solution and then primed. The four Cyto-Set Mix-Ecoflac® plus combinations were then connected to the Cyto-Set (Figures 1 and 2). The system was placed in a water basin (30l water volume) in such a way that the valve-protected connections of Cyto-Set and Cyto-Set Mix were underwater.

The main line led out of the water basin (Figures 3 and 4). The roller clamp of the first Cyto-Set Mix was opened (~4 drops/sec) until the Ecoflac® plus bottle was empty. Subsequently, the main line was flushed with 50ml out of the main Ecoflac® plus. The procedure was repeated with the other three connected Ecoflac® plus bottles.

At time point t0, and directly after administration of all four Ecoflac® plus/fluorescein solutions, water samples were analysed for released sodium fluorescein. A Cyto-Set with an artificially introduced leakage for a forced release of sodium fluorescein in water was used as a positive control.

To detect the traces of released sodium, each water sample was transferred as eight-fold replicate (300µl each) into a 96-well microplate. The plate was then optically analysed by a fluorescence reader (Synergy MX, BioTek Instruments) using fluorescent light (485nm absorption, 514nm emission).

For analysis and evaluation, a calibration curve was recorded prior to the analytical work. Background extinction signal from water was subtracted from the data.

All tests were performed five times with new materials for each single experiment. The average results of all five experiments are reported.

Results 

Figure 5 shows that no fluorescence tracer was released through the valve-protected connections of Cyto-Set and Cyto-Set Mix into the surrounding water during four consecutive administrations of 100ml Ecoflac® plus containers filled with 10ml sodium fluorescein solution through the Cyto-Set–Cyto-Set Mix system.

As a positive control, a Cyto-Set with an artificially introduced leakage for a forced release of sodium fluorescein in water was used. Due to the high signal of the positive control, the positive control was diluted by a factor of 10.

The extinction units for Cyto-Set and Cyto-Set Mix connections are in the margin of error.

Discussion and conclusions

Many hazardous and cytotoxic drugs are used in the treatment of patients and pose a clear danger to human health, especially to pharmacists, nurses, physicians and other healthcare workers in daily hospital routine. Here, the recurrent potential exposure to those hazardous agents can lead to severe health consequences.

Chemical contamination was routinely found inside used isolators but only rarely on the outside, indicating a protection during preparation. However, contamination was found on the surfaces of infusion bags and gloves in contact with infusion bags filled with cytotoxic drugs.¹⁸ Thus, additional protective equipment is still recommended during the manipulation and administration of the drugs because of potentially contaminated vials and infusion components.

Therefore, the development and implementation of drug admixture and infusion system components minimising or even preventing the exposure of hazardous drugs to workers involved in drug therapy is an important improvement. The investigated Cyto-Set in combination with the Cyto-Set Mix is one integrated admixture and infusion system components in the treatment of cancer patients.

The presented method is based on the fluorescence dye fluorescein as tracer substance administered through the investigated system components. This setup was chosen for the evaluation of chemical tightness of closed system components as it simulates a worst-case scenario.

The detection limit in the used setup is approximately 10nl fluorescein tracer in the used 30l water basin. Thus, the used test setup is extremely sensitive to detect released chemical components through the connections of the infusion system.

By means of the used test method, the tested Cyto-Set and Cyto-Set Mix demonstrated chemical tightness, providing they are applied according to the instructions for use.

The results confirm that the valve-protected connections of Cyto-Set and Cyto-Set Mix are a closed system according to NIOSH definition,^1,19 as it prevents the escape of hazardous contaminants into the adjacent environment.

Author

Jörg Brünke
QualityLabs BT GmbH
90411 Nuremberg, Germany

Conflict of interest

The experiments were carried out on behalf of B. Braun Melsungen. The company did not have any influence on the evaluation of the test results.

References

1. National Institute for Occupational Safety and Health. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings. U.S. Department of Health and Human Services, Public Health Service, Centers form Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) 2004. Publication No. 2004-165.
2. Mason HJ et al. Cytotoxic drug contamination on the outside of vials delivered to a hospital pharmacy. Ann Occup Hyg 2003;47(8):681–5.
3. Schmaus G, Schierl R, Funck S. Monitoring surface contamination by anti-neoplastic drugs using gas chromatography-mass spectrometry and voltammetry. Am J Health Syst Pharm 2002;59:956–61.
4. Fransman W, Vermeulen R, Kromhout H. Occupational dermal exposure to cyclophosphamide in Dutch hospitals: a pilot study. Ann Occup Hyg 2004;48(3):237–44.
5. Kromhout H et al. Postulating a dermal pathway for exposure to antineoplastic drugs among hospital workers. Applying a conceptual model to the results of three workplace surveys. Ann Occup Hyg 2000;44(7):551–60.
6. McDiarmid MA, Egan T. Acute occupational exposure to antineoplastic agents. J Occup Med 1988;30(12):984–7.
7. Gielen K, Goossens A. Occupational allergic contact dermatitis from drugs in healthcare workers. Contact Dermatitis 2001;45:273–9.
8. AFS 1999 11. Cytostatics and other drugs with enduring toxic effects.
9. Sessink PJM et al. Environmental contamination and assessment of exposure to antineoplastic agents by determination of cyclophosphamide in urine of exposed pharmacy technicians: is skin absorption an important exposure route? Arch Environ Health 1994;49(3):165–9.
10. Lassila O, Toivanen A, Nordman E. Immune function in nurses handling cytostatic drugs. Lancet 1980;2(8192):482.
11. Sotaniemi EA et al. Liver damage in nurses handling cytostatic agents. Acta Med Scand 1983;214:181–9.
12. 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):632–8.
13. Selevan SG et al. A study of occupational exposure to antineoplastic drugs and fetal loss in nurses. N Engl J Med 1985;313(19):1173–8.
14. Stücker I et al. Risk of spontaneous abortion among nurses handling antineoplastic drugs. Scand J Work Environ Health 1990;16:102–7.
15. Hemminki K, Kyyrönen P, Lindbohm M-L. Spontaneous abortions and malformation in the offspring of nurses exposed to anaesthetic gases, cytostatic drugs, and other potential hazards in hospitals, based on registered information of outcome. J Epidemiol Community Health 1985;39:141–7.
16. Skov T et al. Leukaemia and reproductive outcome among nurses handling antineoplastic drugs. Br J Ind Med 1992;49:855–61.
17. Quapo S3 Quality Standard for the Oncology Pharmacy Service with Commentary. Institute for Applied Healthcare Sciences (IFAHS e.V.) for the German Society of Oncology Pharmacy (DGOP e.V.). 2003.
18. Crauste-Manciet S et al. Environmental contamination with cytotoxic drugs in healthcare using positive air pressure isolators. Ann Occup Hyg 2005;49(7):619–28.
19. Nygren O, Olofsson E, Johannson L. NIOSH definition of a closed system transfer device (Letter to the Editor). Ann Occup Hyg 2009;53:549.