by John Farris
A recent study illustrates why it's best to validate containment capabilities by understanding the quantities, point of origin and patterns through which contamination is spread
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A report was published recently by the American Journal of Health System Pharmacists (Ref.1) that identified the presence of antineoplastic contamination on surfaces in pharmacies in six cancer treatment centers in the United States and Canada. The engineering controls used in all of the studies were Class II biological safety cabinets.
These reports are instrumental in confirming a significant problem of occupational exposure of healthcare workers to antineoplastic compounds, which are potentially carcinogenic, mutagenic and teratogenic.
Industrial hygienists routinely develop sampling plans to validate environmental and personnel contamination levels. This study used the services of a team of experienced industrial hygiene professionals to design and implement procedures that would capture data during the three routine operations used to prepare antineoplastic drugs in hospitals. Design of the study included the development of protocols that defined measurement equipment, sampling locations, sampling duration, validated recovery and analytical methods.
The purpose was to understand not only the quantities, but also the point of origin and patterns by which the contamination source is spread in order to validate the containment capabilities of the positive-pressure mobile-isolation chamber.
The study set out to establish the quantity of contamination released during the three routine operations as well as worst-case contamination levels that could be experienced outside the barrier isolation chamber. It also compares contamination levels of surrogate testing material when using a chamber to the acceptable occupational exposure limit (OEL) levels of selected antineoplastic agents.
The study design provided an opportunity to confirm the phase change in aqueous naproxen sodium from liquid to vapor. The mobile isolation chamber used in the evaluation was proved to be vapor or gas tight by testing with an ammonia gas testing technique. During this test, ammonia is released inside the enclosure and is then checked for leaks with a pH- sensitive cloth. Detection of vapors and micro-aerosols requires sampling of the gas with methods specifically used for gasses—one method is to capture the gas and use a HPLC analyzer. Gasses pass through HEPA filters and cannot be detected with traditional air- or surface-monitoring methods.
Three operations
The study included three operations in which detectable levels of a drug could escape into the surrounding environment during preparation in the pharmacy.
The operations were as follows: (1) Surrogate product was withdrawn from a vial using a syringe and needle; (2) Product was then injected using a syringe and needle into a piggyback bag; (3) The product was then discharged from the syringe and needle into an open container within the barrier isolator to simulate poor technique or a spill.
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To evaluate the potential variability within each operation and provide an adequate sampling duration, each operation was performed multiple times by both trained and untrained personnel. Because it emulates the physical characteristics of a number of antineoplastic agents, aqueous naproxen sodium at a concentration of 165 mg/ml was used as the surrogate test material. Ten vials filled with 10 ml of 165-mg/ml naproxen sodium were used in both operation 1 and 2. Both operations were performed five times, resulting in a 50-vial sample for each operation. Operation 3 was conducted using three groups of ten syringes, which were held approximately six inches from an open beaker and discharged into the beaker
Aqueous naproxen sodium is safe to handle at the concentration levels used in the study. The material can generate both a vapor and micro-aerosol when dispensed through a needle and easily precipitates from solution at the 165 mg per ml level used in the study. A 21-gauge needle was used on the syringe to produce more pressure than normal when discharging the solution. One nanogram of naproxen sodium can be detected and measured using the standard industrial hygiene methods for sampling.
Sampling methods
The study was designed to collect personnel and environmental samples using both air- and surface-sampling techniques. Standard industrial hygiene air-monitoring data-collection procedures were employed using portable air monitoring pumps (Mine Safety Appliance Company Escort Elf Pumps and Ametek Alpha-1 Air Samplers, operating at calibrated flow rates between two and four liters per minute).
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Airborne powder (naproxen sodium) was collected on glass fiber filters (Gelman Laboratory Type A/E Glass Fiber Filter 37-mm P/N 61652), housed in 37-mm cassettes (Omega Specialty Instrument Company 37-mm filter cassettes), using standard industrial-hygiene techniques for potent compound monitoring. Air samples were collected at seven locations with airflow rates ranging from 2.39 to 3.8 liters per minute. After samples were collected, the filters were removed from the sampling pumps and stored in clean glass containers until they were sent for analysis. Surface samples were collected at eight locations using wipe sampling techniques described in Occupational Safety and Health Administration, OSHA Technical Manual (Ref. 3).
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Analytical methods for naproxen sodium were provided and validated by SafeBridge Consultants Inc., reference methods SB023-A (air) and SB023 (surface). Because aqueous naproxen sodium has the ability to change phase from solution to vapor or micro-aerosol to solid, it could be captured using surface sampling in the HEPA filter housing. This phase change from vapor or gas back to a solid is created by a pressure differential force when the vapor or micro-aerosol is forced through the HEPA filters and the air stream passes through the blower of the recirculating air-handling system of the barrier isolator.
Sampling points
Air-sampling points on the isolation chamber included two locations inside the main chamber, inside the air lock, outside the area of the closed transfer ports for sharps and trash and the top of the cabinet in the area of the blower fan. The breathing zone of the person conducting the study was sampled by attaching the collection filter to his collar. Another collection filter was positioned at the exit of the room ten feet from the person conducting the study.
Surface sampling locations on the chamber included inside the main chamber to the left and right of the operation, the airlock, the stainless-steel surface on the front, the front viewing area and inside the HEPA filter housings of both the supply and return sides of the air-handling system.
Implementation
The vials containing the solution of the surrogate product were intentionally contaminated on the outside in order for the product to be seen on a number of the containers.
Vials as well as supporting components of syringe, needles and alcohol wipes were introduced into the airlock of the barrier isolator using a technique developed in conjunction with the Rapid City Regional Cancer Center (Ref. 4). The technique was developed to reduce the potential of contamination migrating outside the containment unit on packaging being sent to the patient administration area.
The technique involves using a large primary zip-lock bag, which was placed over the tray used to transfer the materials into the isolator. Labels and secondary transport bags used to transport the finished product to the administration area were placed inside the large primary zip-lock bag on the tray surface.
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Vials, syringes, needles and other disposables were placed on top of the sealed primary zip lock bag. The enclosed tray was then taken into the main chamber of the isolator and 10 ml of the naproxen sodium solution was withdrawn from the vial using a syringe and needle. After the syringe was prepared, the label and bag used to transport the syringe to the administration area were removed from inside the primary bag. The syringe was labeled and placed in the secondary transport bag for removal from the isolator. The contaminated materials, including the primary bag and used disposables, were removed using the closed trash system of the isolator. This technique helps to minimize the surface contamination to the carrier bag and syringe.
Five groups of ten syringes with support materials were moved into and out of the barrier isolator for each operation. Operator 1, a pharmacist trained in preparation of sterile products, conducted the first series of transfers. The sample duration was 168 minutes.
Unit operation air concentrations and wipe sample concentrations are shown in Tables 1 and 2, respectively. Area air concentrations of drug are shown in Table 3. Eight-hour time weighted average (TWA) exposure concentrations calculated for the operators are shown in Table 4.
Injecting surrogate product
This operation involved transferring the contents of the filled syringes to the piggyback bag. Operator 2, who had no previous experience in the preparation of sterile products, did the series of transfers. The 50 piggybacks were prepared with sample duration of 64 minutes.
After the completion of operation 1, a glove change was performed without cleaning the inside of the unit. During this glove change of the chamber, the unit was intentionally left running to determine the impact of such a mistake in actual operation. This resulted in an unintended background concentration of drug from this operation that influenced the results of operation 2. Air concentrations have been adjusted based on background samples to reflect the actual exposure potential more closely.
Discharging product
This operation involved discharging the contents of 30 10-ml syringes into an open 400-ml beaker from approximately six inches above the opening of the beaker. A 21-gauge needle was used instead of an 18-gauge needle in order to create more aerosolization of the solution. Operator 2 conducted this operation with a sample duration of 23 minutes.
Results
Concentration of naproxen sodium in the breathing zone of operators did not exceed the exposure level of any of the cytotoxic agents shown in Table 5 for any of the operations performed.
Concentrations of naproxen sodium found in surface samples outside the isolator were less than the occupational exposure limits of any cytotoxic agent shown in Table 5. The TWA shown in Table 4 was less than 2 nanograms of naproxen sodium per cubic meter of air for operations 1, 2 and 3.
The method
Historically, the pharmaceutical industry has used surrogate materials in place of hazardous drugs in experiments to determine the patterns of contamination that may result from certain manipulations of those materials. This method gives valuable insight into contamination exposure levels faced by healthcare professionals in the preparation of hazardous drugs.
Selection of the proper surrogate, which displays physical characteristics similar to the hazardous drug, provides a means of gathering useful information about the potential for environmental and personnel contamination when the actual hazardous drug is used in similar manipulations. After careful review, naproxen sodium was determined by the industrial hygiene consultants to be the best candidate for this study.
To achieve a valid interpretation of results, a target air concentration that defines a goal or set point should be established. The measurement of the amount of potent compounds present in air and the ability of a system to contain these materials is compared to the OEL for the given compound.
Measuring the effect the containment device has on reducing the airborne concentration of the potent compound is accomplished by comparing levels found inside the containment device to levels found in the breathing zone of workers. To assure protection of their employees, pharmaceutical companies develop OELs, which define the level to which a worker can be repeatedly exposed eight hours daily for 40 hours weekly without experiencing an adverse health effect from the exposure (see Table 5) (Refs. 5 & 6).
Sampling of air concentrations of surrogate materials provides an indicator of the capability of the containment device. The amount of surrogate material is measured in terms of concentration per cubic meter of air to determine the amount that potentially could be adsorbed through inhalation. Surface concentrations are an indicator of potential adsorption through the dermal route of entry into the body.
The study data suggests that vapors and micro-aerosols can penetrate HEPA filters. In order for the naproxen sodium to penetrate the HEPA filter the test material must change from a liquid to a vapor or micro-aerosol. The change of state of the matter from liquid to a vapor or micro-aerosol requires energy.
The basis of this phase change is that matter exists in a certain form that can be modified only by pressure, time and/or temperature. The first law of thermodynamics governs how changes in each of these parameters determine the state of matter. An equal amount of energy is required to revert to the original state of solid, liquid or gas. This was demonstrated in the study by the naproxen sodium being captured in the wipe sample inside of the sealed filter housing.
The pressure resulting from pushing the material through the needle caused some liquid to change to a vapor or micro-aerosol, and the force required to push the vapor or micro-aerosol through the HEPA filter reversed the process. Additional energy was applied to the vapor or micro-aerosol by pushing the air stream through the fan. This was demonstrated by the finding of a higher concentration of naproxen sodium captured on the wipe sample of the inlet HEPA filter housing compared to the concentration found on the return HEPA filter housing.
Once a compound has converted from aqueous form to vapor form, an equal force is required to convert it back to its aqueous form. In the absence of an equal force created by changes in temperature or pressure, it is likely that the compound will remain in the vapor phase for an extended period of time. Surface sampling techniques would not detect the compound although it could be present in the breathing zone of personnel working in the area and only removed by the room exhaust system.
Conclusions
This study demonstrates that the preparation of parenteral products in a pharmacy has the potential to generate airborne concentrations exceeding the OEL of some of the antineoplastic agents routinely prepared. Product contamination of the environment in a pharmacy has the potential to be spread from several sources, including vials with contamination on the outside. Environmental contamination may also occur during the transfer of the product to the patient delivery system.
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The amount of contamination is a function of the amount of product and the frequency of preparation as well as the exposure controls and procedures employed by workers during product preparation. Products can form micro-aerosols or vapors that are capable of passing through HEPA filters, as demonstrated by the placebo materials found in swab testing of the inside of the filter box. Any device that vents significant quantities of air back into the pharmacy and is designed with an open face where surface contamination can be carried out on arms and hands, such as a Class II biological safety cabinet, increases the potential for airborne and surface contamination.
Preparing parenteral products in an isolator reduced personnel exposure risk to a level of less than 2.0 nanograms per cubic meter of airborne concentration measured as an eight-hour TWA.
John Farris is the leader of SafeBridge Consultants, a professional technical firm of scientific and engineering consultants providing environmental health and safety services to pharmaceutical, chemical and biotechnology industries. His expertise includes executive management, industrial hygiene, laboratory safety, control of potent pharmaceutical compounds and environmental protection.
References:
- Connor, TL, Anderson, RW, Sessink PJ, Broadfield, I, Power, LA, “Surface contamination with antineoplastic agents in six cancer centers in Canada and the United States.” Am J Health Syst Pharm. 1999 Jul 15;56(14):1427-32.
- Containment Technologies Group, Inc.—10329 Vandergriff Road, Indianapolis, IN 46239.
- OSHA Instruction CPL 2-2.20B/Technical Manual-Sect II: Chapter 2 Pgs 1-17.
- Tacket, B, “Procedure for handling trays containing cytotoxic compounds for the MIC workstation.” Rapid City Regional Medical Center Operating Procedures, 1999; Rapid City, South Dakota.
- Sargent, E. V. and G. D. Kirk: “Establishing airborne exposure control limits in the pharmaceutical industry.” Am. Ind. Hyg. Assoc. J. 49:309-313 (1988).
- Nauman, B. D., et al.: “Performance-based exposure control limits for pharmaceutical active ingredients.” Am. Ind. Hyg. Assoc. J. 57:33-42 (1996).