Compounding Using Hazardous Drugs

Kellie Lau
University of Oklahoma Health Science Center
College of Pharmacy
P.O. Box 26901, Oklahoma City, OK 73190

Consider using a drug-containment system.

Cancer, a heterogeneous group of diseases, arises from the mutation of a single gene. Unlike normal cells, cancer cells have an uncontrollable accelerated growth that can affect any part of the body. As devastating as it may be to the person diagnosed with cancer, there are treatments available that can increase patient survival. One such treatment is chemotherapy using antineoplastics drugs such as cyclophosphamide, ifosfamide and fluorouracil. These drugs are more effective in treating metastatic cancers; and as a result, the number of preparations using them has increased, consequently exposing more health-care workers to them. These drugs, like many other hazardous drugs, are prepared and administered daily in hospitals; oncology offices and sometimes, patients' homes. Since some of these drugs are both carcinogenic and mutagenic and target both normal and abnormal cells, long-term and repeated exposure to these and other hazardous drugs can have a profound and negative effect on the body, especially in situations in which the person is not properly protected.

PHYSICOCHEMICAL PROPERTIES

In order to learn more about compounding using cyclophosphamide, ifosfamide and fluorouracil, in addition to other hazardous drugs, a description of their physicochemical properties is essential. Also in compounding for cancer patients, the physicochemical properties of these drugs must be taken into consideration in order to minimize exposure.

Cyclophosphamide (2-(bis(2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazophosphorine-2oxide, MW 261.08, CYT) is a nitrogen-mustard derivative, an alkylating agent that causes abnormal DNA cross-linking and the subsequent inhibition of DNA replication. It occurs as a monohydrate, white, crystalline powder with the anhydrous form determining its potency.(1) It is soluble in both water and alcohol.(1) Cyclophosphamide 1% solution has a pH of 4.5.(2)

Ifosfamide (3-(2-chloroethyl)-2-((2chloroethyl)amino) tetrahydro-2H-1,3,2,- oxazaphosphorin-2-oxide), MW 261.08, NSC-109724 is an oxazaphosphorine derivative, an alkylating agent related to cyclophosphamide. It occurs as an off-white to white, crystalline powdered.(1) Because of the spatial difference of the 2-chloroethyl groups, ifosfamide has a greater aqueous solubility, slower rate of activation and more effective DNA cross-linking distance than cyclophosphamide.(1) Similar to cyclophosphamide, it is soluble in water.(1) A 5% solution has a pH of 5.5.(2)

Fluorouracil (2,4-dioxo-5-flouropyrimine, MW 130.08, 5-FU) is a fluorinated pyrimidine antagonist, an antimetabolite that acts as a false substrate during DNA synthesis. It occurs as a white to practically white, practically odorless, crystalline powder.(1) It is sparingly soluble in water and slightly soluble in alcohol.(1) It is also light sensitive and precipitates at a low temperature.(2) The pH for a commercial solution of fluorouracil is 9.(2)

CURRENT GUIDELINES

In order to protect workers who compound with hazardous drugs, the Occupational Safety and Health Administration (OSHA) has established work- practice guidelines. The following guidelines pertain only to the preparation of antineoplastics (cytotoxic) drugs.

  1. A double layer of surgical latex gloves is more effective in reducing the absorption of cytotoxic drugs than polyvinyl chloride gloves and should be worn during the entire time of drug preparation. They should be changed on a regular basis due to increased permeability with time. In addition, powdered gloves should never be worn due to the permeability of these drugs.(3)
  2. A disposable gown made of lint-free, low-permeability fabric with a closed front, long sleeves, and elastic or knit-closed cuffs should be worn. The cuffs should be tucked under the gloves to minimize exposure.(3)
  3. A biological safety cabinet must be used. A Class II, type B biological safety cabinet with high-efficiency particulate air (HEPA) filters provides better protection than a horizontal airflow laminar (LAF) hood is preferred. Type A biological safety cabinets are the minimal requirement. The blower on the vertical-LAF hood should be on at all time, with the cabinet cleaned daily with 70% alcohol. In addition, biological safety cabinets should be certified by a qualified technician every six months.(3)
  4. A plastic face shield or splash goggles should be worn. Surgical masks do not protect against the breathing of aerosols and should not be used.(3)
  5. Work should be performed on a disposable, plastic-backed paper liner inside a biological safety cabinet. In addition this paper liner should be changed after the preparation is completed.(3)
  6. Luer-Lok@ fittings should always be used during drug transfers from vials to syringes or from syringes to intravenous sets.(3)

CURRENT FINDINGS

Although many hospitals and health-care facilities have implemented these guidelines, an alarming number of workers continue to be exposed to hazardous drugs. Two studies have been reported.

In one study using technetium and platinum labeling, researchers were able to detect surface contamination by antineoplastics drugs.(4) The other study was conducted in different sites in both Canada and the United States. Samples were taken from selected areas inside the preparation room, such as biological safety cabinets, countertop, floors, chairs and tabletops in the administration areas. Samples were then tested using high- performance liquid chromatography and gas chromatography, The results showed detectable amounts of antineoplastics drugs such as cyclophosphamide, fluorouracil and ifosfamide. The amounts of contamination were highest (1) in the pharmacy area (75%), (2) in areas around and close to the biological safety cabinets where most of the preparations took place, and (3) where the highest numbers of preparations took place.(5) In addition, all of these sites used a Class II vertical-flow biological safety cabinet that supposedly protects workers from breathing aerosols.

In order to understand how this happened, a description of the different types of biological safety cabinet may be necessary. The Class II biological safety cabinet that is specified by OSHA is actually an open-front cabinet with a HEPA-filtered LAF and HEPA-filtered exhaust air.(5) In addition, Class II biological safety cabinets are further classified into different subtypes. A type A cabinet maintains a minimum calculated average inflow velocity of 75 ft/minute through the cabinet's opening and may exhaust HEPA-filtered air back into the workroom, whereas a type B2 cabinet can maintain a minimum average inflow velocity of 100 ft/minute and may exhaust 30% of the HEPA-filtered air back in the cabinet or the workroom.(5) Finally, a type B3 cabinet maintains a minimum average inflow velocity of 100 ft/minute and discharges all exhaust air to the outdoor atmosphere after HEPA filtration.(5) With these descriptions, there is a concern that this equipment may not be as reliable as it seems and there may be too much confidence placed in conventional equipment, which may not be advisable.

In order to compare the effectiveness of different types of hoods, another study was conducted.(6) After examining the urine of all personnel who handle antineoplastics drugs, researchers found that those who worked with a horizontal LAF hood had a higher mutagenicity in their urine than those who worked with vertical LAF hood.(6)

Through these studies, researchers were able to conclude that exposure is mainly through inhalation of the aerosolized drug and through percutaneous absorption. (3) With this in mind, researchers have also speculated that during drug preparation and administration, aerosols are formed when the pressure between the syringe and the drug vial is unequal, leading to the escape of drug particles into the air.(7) In many cases, these particles are too small to be captured by the HEPA filter. In order to reiterate this point, Professor K.G. Schmidt of Duisburg, Germany, used the concept of Brownian movement to explain the escape of drugs during drug manipulation. According to Schmidt, particles with a diameter greater than 0.5 pm have a tendency to move to the bottom of the biological safety cabinet due to airflow and gravity.(8) On the other hand, particles with a diameter of less than 0.003 pm will flow with the stream. (8) As a result, the smaller particles will easily transfer to the outside of the preparation area and contaminate other areas and workers; and this may also lead to percutaneous absorption. In addition, movement of objects and the techniques used by workers during drug preparation may block and disturb the airflow, causing drug particles to be transferred outside the working area.(7) Also, increasing the temperature or decreasing the partial pressure may also lead to sublimation, the transformation of a solid into a gas,(4) which can lead to further transfer of drug particles outside the biological safety cabinet. Therefore, even with the above OSHA guidelines followed, contamination and exposure can still occur.

THE NEW AND IMPROVED CONTAINMENT SYSTEM

A possible solution to this problem is the new and improved drug-containment system, PhaSeal© (Carmel Pharma, Inc., Shelton, CT). With this device, leakage of hazardous materials can possibly be controlled even without following the OSHA guidelines. PhaSeal was first developed at the Sahlgrenska University Hospital in Gothenburg, Sweden,(8) and has been shown to be more effective than the traditional pump technique inside a biological safety cabinet, which equalizes the pressure inside the drug vial by alternating pumping and withdrawing liquid and air between the vial and the syringe.(4) PhaSeal is a user-friendly device and can be used in pharmacies, cancer treatment centers, oncology office or patients' homes for either injection or infusion. It provides a completely sealed and safe environment during preparation, administration and waste disposal of hazardous drugs. Two unique features of this system are a pressure-equalizing component, which normalizes the pressure during drug transfers from the syringe to the vial; and a double membrane, which acts as a tight seal, preventing possible leakage.(9) It has been proven to be more effective even when used alone without other protective guidelines. When PhaSeal is used, it can reduce leakage volumes up to nanoliters, whereas the traditional pump technique causes leakage volumes from 150 to 250 pL. (4) In addition, PhaSeal also reduces the cost and time in maintaining other containment systems and procedures, proving it to be cost effective.(9)

An alternative method of minimizing exposure would be the use of a barrier or isolator during the preparation of hazardous drugs.(10) An isolator is actually very similar to a glove box that is used in the nuclear industry. It is more cost effective than conventional cleanrooms and provides a better sterile environment for workers. In addition, use of an isolator over a conventional cleanroom reduces (1) the need for gowning, (2) associated capital and operating costs and (3) noise level and heat load.(10) More importantly, it improves worker productivity and communications as a result of a more comfortable and safer working environment.(11)

CONCLUSION

It has been shown that even when precautions and guidelines are followed, exposure to hazardous drugs is still possible. Because many of these drugs are being prepared daily to treat a variety of diseases, it is inevitable that health-care workers will be exposed. The concern that arises now is what workers can do to minimize exposure. Perhaps the only way is through education and training. Workers must be educated about the short-and-long-term consequences of handling these drugs. Also, they must be trained in using proper techniques when preparing and administering these drugs and should consider using the PhaSeal drug-containment system. By doing so, workers may be protected against possible harm from handling hazardous drugs.

REFERENCES

  1. McEnvoy GK, Litvak K, Welsh OH (eds). AHFS Drug Information. Bethesda, MD, American Society of Health-System Pharmacists, Inc., 1998, pp 779, 824, 835.
  2. McGuigan M, Rumack B. Micromedex: Poisindex. Denver, CO, Micromex, Inc., 1998.
  3. OSHA work-practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm 1986; 43:1193-1204.
  4. Carmel Pharma. Available from the Internet: http://www.carmelpharma.se/ehtm/doc/proceedings2.html.
  5. Connor T, Anderson R, Sessink P et al. Surface contamination with antineoplastic agents in six cancer treatment centers in Canada and the United States. Am J Health-Syst Pharm 1999; 56: 1427-1432.
  6. Colvin C, Ross M. Micromedex: Drug Consults. Denver, CO, Micromedex, Inc., 1998.
  7. Rahe H. A call to arms. Clean Rooms Magazine 1999 (October); 13:12.
  8. Clark C. Occupational exposure to cytotoxic drugs. Pharm J 1999; 263: 65-67.
  9. Sessink P, Rolf M, Ryden, N. Evaluation of the PhaSeal@ hazardous drug containment system. Hosp Pharm 1999; 34: 1311 - 1371.
  10. Pilong A, Moore M. Conversion to isolators in a sterile preparation area. Am J Health-Syst Pharm 1999; 56: 1978 - 1980.
  11. Mosko P, Rahe H. Barrier isolation technology: A labor-efficient alternative to cleanrooms. Hosp Pharm 1999; 34: 834 - 838.