CSTDs and microbiological stability of cytostatics

This study evaluated the microbiological stability of cytostatics manipulated using the BD PhaSeal® system inside a biological safety cabinet, and results demonstrate PhaSeal’s clear benefits in maintaining product sterility in real practice.

Cancer is a major public health problem worldwide that has an elevated social impact due to morbidity and mortality, and which causes a serious financial burden to society.

Overall, an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occurred in 2008 worldwide.(1) Consequently, cytostatic drug compounding has become a major challenge for hospital pharmacy services.

The pharmacist is responsible for compounding sterile products of the correct ingredients, purity, strength, and sterility, and accurate labelling and dispensing in appropriate containers for the end user. The expiry date should be based on available chemical stability data and sterility considerations.(2)

Regarding microbiological stability, pharmaceutical manufacturers usually quote very short stability data, reflecting a care principle that considers the possibility of bacterial contamination and the fact that most of the drugs do not contain preservatives. In many cases, immediate use is instructed in the product information so that extended use is now a user responsibility, and this depends on the capability of implementing a proper aseptic technique.

Cytostatic compounding is a technical challenge because it is necessary to implement correct aseptic technique to maintain product sterility while minimising potential occupational and environmental exposure owing to the deleterious effects of this class of drugs.(3)

Health professionals who work in chemotherapy preparation and administration are exposed to these compounds in different ways (for example, dermal contact, inhalation, ingestion) and several observational studies have demonstrated that working surfaces and different objects (such as gloves and vials) are contaminated with antineoplastic agents regardless of the use of biological safety cabinets. Urine analysis of exposed workers in other studies has also revealed that systemic absorption of these compounds is a possibility.(4–6) The exposure could lead to harmful effects such as genotoxicity, reproductive toxicity, and carcinogenicity.(7–9)

The traditional technique of a needle and syringe to extract drugs from vials has been shown to lead to greater contamination levels due to aerosols, spills, leakages or losses across the rubber stopper of the vial.(10) The use of a closed system can improve safety greatly.

Closed system devices

A closed-system transfer device is defined as: “a drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapour concentrations outside the system. The system must be airtight and leakproof”.(11,12)

The BD PhaSeal® system (Becton Dickinson) meets this definition and has been shown in several studies to diminish the contamination of working surfaces and reduce personnel exposure.(13–15) However, less is known about the system’s capability to maintain product sterility in real practice.

The objective of this study was to evaluate the microbiological stability of products manipulated using the BD PhaSeal® system inside a biological safety cabinet. We also evaluated the system’s capability to maintain vial sterility once opened or reconstituted for an extended time and in different conditions.

Methods

The cytostatic drug elaboration process was simulated using Tryptone soya broth culture medium instead of initial drug solution. The study schedule was designed to simulate different operations along the cytostatic compounding process such as reconstitution, dosification and dilution (Figure 1). The study was performed at the end of the working day inside a class IIB cabinet (Telstar Cytostar®).

The process was repeated on different days (day 0, 1, 4 and 7) with the same vials. At the end of each batch, vials were kept outside the cabinet and the clean room. Two different storage conditions were tested (room ambient and under cooling). Microbiological stability of final products was determined by inspecting visual turbidity of the medium at the end of the study.

A total of 10 batches of eight vials were prepared by five different operators. All operators were pharmacy technicians with at least two years’ experience in sterile compounding. All operations were performed using the BD PhaSeal® system (Figure 2). Resulting syringes, bags and vials were incubated for 14 days at 25–35º. At the end of each batch incubation, Rodac contact plates of Tryptone soya agar medium were applied to the work surfaces and gloves to evaluate potential sources of contamination.

Results

A total of 740 samples were incubated, which simulated final products of the chemotherapy elaboration process (80 vials, 320 bags and 320 syringes). Another 40 contact plates from work surfaces and 40 contact plates from gloves were also incubated.

All of the 740 final product samples were negative for microbiological growth regardless of the operator, the number of manipulations or the temperature of storage. After seven days, all 80 vials remained sterile at the end of the study, even those with at least nine punctures of the BD PhaSeal® membranes.

No microbiological contamination was detected in the work surface samples. However, several samples from operators’ hands were positive, probably indicating a cutaneous contamination, because we isolated three gram-positive cocci and one gram-positive bacillus colony.

Discussion

Hospital pharmacy departments provide ready-to-use cytostatic drugs and ensure that the physicochemical stability and asepsis of the product is maintained. Our study showed that using the BD PhaSeal® system maintained the sterility of the final product for at least seven days.

Interestingly, the vials remained sterile even after several punctures of the membranes and when storage was performed outside the clean room. This evidence would suggest allowing pharmacy departments to recover the remaining amounts of drug in a vial without compromising patient safety. This practice could lead to significant economic savings.(16)

Other studies have evaluated the microbiological barrier function of the BD PhaSeal® system. De Prijck and colleagues17 compared the capability of different systems to avoid microbial ingress in experimental conditions with high microbial loads. The BD PhaSeal® system was the most resistant of the evaluated systems. However, it should be noted that, while contamination was not avoided completely, the study did not reflect real practice, where the possibility of contamination and the microorganism load are much lower. Our study was performed in real conditions and could be applied into practice.

McMichael et al18 evaluated 1328 syringes obtained from culture medium vials with the BD PhaSeal® system, and in this study only one sample was visually contaminated, thereby supporting the microbiological resistance of the system.

By contrast, it must be noted that our study result was obtained in the ‘worst case scenario’, at the end of the working day, when the possibility of contamination is greater, and also using a culture medium that promotes the growth of a broad spectra of bacteria. Microbial growth would be much more difficult in real practice as it has been proposed in some studies that antineoplastic drugs inhibit this possibility.(19,20)

An evaluation of the potential sources of contamination reveals that even the sterile gloves of an operator’s hand can be contaminated. One possible explanation is the presence of non-sterile elements inside the cabinet (for example, containers, external surfaces of vials) that could also be touched by the technician. Nevertheless, our study showed that there was no transfer of contamination to the final solution, indicating that an appropriate preparation technique could prevent final product contamination.

Conclusions

The BD PhaSeal® system allows proper aseptic technique in sterile compounding. Vials manipulated using this system remained sterile in our practice for at least one week, even after several punctures of the membranes that enable the recovery of the remaining contents within a vial, thereby leading to potentially significant economical savings. Although operators’ hands could be a potential source of contamination, this would be avoided by using an appropriate aseptic technique.

Key points

• Extending shelf-life is a user responsibility, and this depends on the capability to implement a proper aseptic technique.
• A closed-system transfer device is a drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or vapour concentrations outside the system.
• In our practice, the BD PhaSeal® system allows for proper aseptic technique in sterile compounding enabling the use of surplus amounts of vials during their physicochemical stability period.
• Significant savings could be achieved when sterility is guaranteed over time.

Authors

Javier Sánchez-Rubio Ferrández PharmD PhD
Pharmacy Department, Hospital Universitario de Getafe, Madrid, Spain
Email: [email protected]

Blanca Rodríguez Vargas PharmD
Pharmacy Department, Jimenez Díaz Foundation, Madrid, Spain

Luis Sánchez-Rubio Ferrández PharmD
María del Carmen Lozano Estevan PharmD PhD
Pharmaceutical Technology, Alfonso X University, Villanueva de la Cañada, Madrid, Spain

Irene Iglesias Peinado PharmD PhD
Videdean Faculty of Pharmacy, Complutense University, Madrid, Spain

References

1. Ferlay J et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127(12):2893–917.
2. American Society of Health System Pharmacists. ASHP guidelines on quality assurance for pharmacy-prepared sterile products. Am J Health Syst Pharm 2000;57(12):1150–69.
3. Connor TH et al. Preventing occupational exposures to antineoplastic drugs in health care settings. CA Cancer J Clin 2006;56(6):354–65.
4. Hedmer M et al. Environmental and biological monitoring of antineoplastic drugs in four workplaces in a Swedish hospital. Int Arch Occup Environ Health 2008;81(7):899–911.
5. Sessink PJ et al. Occupational exposure to antineoplastic agents at several departments in a hospital. Environmental contamination and excretion of cyclophosphamide and ifosfamide in urine of exposed workers. Int Arch Occup Environ Health 1992;64(2):105–12.
6. Connor TH et al. Surface contamination with antineoplastic agents in six cancer centers in Canada and the United States. Am J Health Syst Pharm 1999;56:1427–32.
7. McDiarmid MA et al. Chromosome 5 and 7 abnormalities in oncology personnel handling anticancer drugs. J Occup Environ Med 2010;52(10):1028–34.
8. Dranitsaris G 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.
9. Hansen J et al. Cancer morbidity among Danish female pharmacy technicians. Scand J Work Environ Health 1994;20(1):22–6.
10. Chaffee BW et al. Guidelines for the safe handling of hazardous drugs: consensus recommendations. Am J Health Syst Pharm 2010;67(18):1545–6.
11. International Society of Oncology Pharmacy Practitioners Standards Committee. ISOPP standards of practice. Safe handling of cytotoxics. J Oncol Pharm Pract 2007;13 Suppl:1–81.
12. National Institute for Occupational Safety and Health. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. NIOSH publication No 2004-165. www.cdc.gov/niosh/docs/2004-165 (accessed 25 June 2013).
13. Siderov J et al. Reducing workplace cytotoxic surface contamination using a closed-system drug transfer device. J Oncol Pharm Pract 2010;16(1):19–25.
14. Yoshida J et al. Use of a closed system device to reduce occupational contamination and exposure to antineoplastic drugs in the hospital work environment. Ann Occup Hyg 2009;53(2):153–60.
15. Vandenbroucke J et al. How to protect environment and employees against cytotoxic agents, the UZ Ghent experience. J Oncol Pharm Pract 2001;6:146–52.
16. Vandenbroucke J et al. Economic impact of the preparation scenario for cytotoxic drugs: an observational study. EJHP Pract 2008;14(5):37–42.
17. De Prijck K et al. Microbiological challenge of four protective devices for the reconstitution of cytotoxic agents. Lett Appl Microbiol 2008;47(6):543–8.
18. McMichael D et al. Utility of the PhaSeal closed system drug transfer device. Am J Pharm Benefits 2011;3(1):9–16.
19. Holmes CJ et al. Viability of microorganisms in fluorouracil and cisplatin small-volume injections. Am J Hosp Pharm 1988;45:1089–91.
20. Patel K et al. Microbial inhibitory properties and stability of topotecan hydrochloride injection. Am J Health Syst Pharm 1998;55(15):1584–7.