Time to start thinking outside the box?

teaser

Should the pharmacy profession be reconsidering the efficacy of vertical laminar-flow hoods in cytotoxic drug reconstitution with regard to health and safety issues? Yaakov Cass puts the case

Yaakov Cass
MSc FRPharmS

Regional Pharmaceutical Officer
Israel Ministry of Health
Ramle
Israel

Much has been written on the safe handling of cytotoxics.[1,2 ]Reviewing this may let us learn from past mistakes. As part of the shift of cytotoxic reconstitution from “nurse-­oriented” to “pharmacy-oriented”, preparation shifted from ward to pharmacy. Large budgetary allocations were made by hospital managers to equip specialised pharmacy-run units. New pieces of equipment were put to use, the most basic and familiar being a purpose-designed laminar-flow hood (LFH) �” the vertical-flow laminar-flow hood (VFLH). The aim was to gain the highest possible safety level for hospital workers and the environment.

One definition of an LFH is “a carefully enclosed bench designed to prevent contamination of semiconductor wafers, biological samples, or any particle-sensitive device”.[3] LFHs were presumably derived from fume cupboards. This entry continues: “Air is drawn through a high-efficiency particle entrapment (HEPA) filter and blown in a very smooth, laminar flow. The LFH is usually made of stainless steel with no gaps or joints where spores might collect. There are many different types of LFHs with a variety of airflow patterns and acceptable uses.”

Generally, LFHs are of vertical- or horizontal-flow type.

LFH use in pharmacies came to the fore at the advent of pharmacy-prepared total parenteral nutrition, involving combining sterile ingredients using an aseptic technique. A sterile environment is critical to ensure product integrity. The emphasis was on protecting the solution under preparation from bacterial contamination, not protecting the worker.

Risks associated with handling and administering cytotoxics led to widespread use of VFLHs for preparing and dispensing these products. VFLH use has been mandatory in most pharmacies ever since, with devices usually situated in a conventional cleanroom. VFLHs are often referred to as “biological safety hoods” or “cabinets”.

A few pharmacies took an alternative approach, using isolators placed in a suitable environment. Perceived advantages were that there was no need for cleanrooms or gowning. The main disadvantage was a lack of user-friendliness.

In VFLHs the vertical downflow of air passes through a HEPA filter, then over the work surface and through vents at front and back, then is recirculated. There may be one or more filters in the recirculation and exhaust airflows. Some 30% of recirculated air is exhausted; to compensate, air is drawn in through the front opening, creating negative pressure within the cabinet. The balance between downflow and frontal inflow produces an air curtain �” the basis of the cabinet’s operator- and product-protection properties. Exhausted air may be recirculated into the room or ducted to the outside, subject to local health and safety guidance.

Based on industrial hygiene standards, other measures were put in place to protect the environment and pharmacy workers. Pharmacy reconstitution units were divided into rooms �” “clean” and “dirty” �” physically separated and with or without air-pressure differentials. Operators were given “space-suit” gowns and gloves and “cytotoxic-safe” needles and spikes. The accepted position was that when VFLHs were sited in aseptic suites using these protective measures, product and handler were protected to the highest possible level.

For years it was accepted that everything necessary had been done. However, this was incorrect. A major reason is the fact that the ISO Class 5 standard for LFHs (previously “Class 100”) relates to maximum concentration limits for particles equal to or greater than certain sizes. Microbiological contaminants (bacteria, fungi or their spores) are of known particle size, making this standard relevant to preventing microbiological contamination. But cytotoxic contaminants vary in size, may be solid, liquid or gaseous and may even be adsorbed onto the filter, making this standard irrelevant for operator protection. The UK has never had a nationally agreed guideline for VFLHs in cytotoxic reconstitution,[2] although Australian and German guidelines did attempt to overcome this.[2] In the USA, American Society of Health-System Pharmacists (ASHP) guidelines included references to “acceptable” hoods.[4] In reality, a compromise was made from the start, with an attempt to achieve a balance between operator and product protection. At the start of the millennium, quite some time after cytotoxic reconstitution had moved to pharmacies, reports emerged questioning the effectiveness of HEPA filters alone for exhaust filtration. This is of particular concern where recycling of air into the room is involved.[2] Other work clearly showed that cytotoxics were not contained inside hoods.[5]

Soon, another problem was revealed: research showed drug container exteriors were often contaminated, with particles potentially contaminating handlers outside and inside the hood, plus the hood itself.[6] It is standard practice to wipe nonsterile items with alcohol before placing them in an LFH, but this is unlikely to reduce cytotoxic contamination.

Mounting environmental-monitoring evidence showed that occupational exposure was still a reality.[7] Measurable air levels of cytotoxics inside and outside cabinets were detected. Wipe samples showed cytotoxic drugs present on workstation surfaces, with detectable levels at points distant from places of preparation and administration.[8]

A 2004 US National Institute for Occupational Safety and Health (NIOSH) alert read: “Cancer chemotherapy is hazardous to your health. There are still dangers in preparing and administering antineoplastic agents in patient care settings.” Hospitals and clinics were warned of workplace hazard from antineoplastics. The alert added: “Current measures to prevent environmental contamination and employee exposure to hazardous pharmaceuticals are inadequate.”[9] NIOSH’s important recommendations for remedying this were adopted by the ASHP and the International Society of Oncology Pharmacy Practitioners (ISOPP).[10,11]

The NIOSH report is a detailed document on the need to change the way cytotoxics are handled when reconstituting. The best-publicised recommendation was making “closed systems” mandatory �” making it seem that the prime culprit for leakage of cytotoxic particles was “open” as opposed to “closed” transfer devices. Incidentally, using closed systems also solved the problem of needlestick injury. But unanswered questions remain. If vials are contaminated, why did NIOSH not suggest drug firms be made to solve the problem rather than just warn healthcare providers? Why was no recommendation made for an obligatory standard for level of contamination on packaging and vials? This would have addressed the issue more fully.

Another question: why was so little attention paid to VFLHs’ “failure”, despite mounting evidence of their unsuitability with cytotoxics? Even taking into account the fact that droplets are released when using open systems, how much drug could be released into the hood and escape from there? If contamination levels are as high as reported, it is hard to understand what protection VFLHs give. They may stop microbiological contamination but it seems VFLHs protect neither environment nor worker from carcinogens.

The NIOSH report covers procedures for choosing the right VFLH. But maybe we should re-evaluate VFLHs in cytotoxic reconstitution. Are they useful? Or dare we suggest they are a hindrance? Can we envisage a future where reconstitution is done using closed systems without VFLHs? Research data back such a move.[1]2 Is it rational to demand VFLH installation in countries where their use has never been accepted? Will robotics make VFLHs obsolete?[13]

Most of us would balk at discarding VFLHs where they are already in use. But even in countries where VFLHs are taken for granted, in some situations their use is impractical or impossible �” for instance, using unstable chemotherapeutic agents in theatre at some point in an intricate operation; in rare cases where chemotherapy needs to be prepared in A&E during unsocial hours; when urologists urgently need a cytotoxic bladder irrigation but the home institution lacks a cytotoxic pharmacy; when carers wish to inject rheumatoid arthritis patients with methotrexate, in the clinic setting (not every country has a licensed ready-to-inject methotrexate product, and the carer may have to prepare an injection twice a week). A closed system would make all these scenarios safer.

The NIOSH report was probably the most important document on safe handling of cytotoxics in 25 years. Its authors have done a great service to pharmacy, but are still thinking inside the box. Maybe the time has come to consider thinking outside of it. â–

The aid of Dr Alexander Tabachnik of Hadassah University Hospital, Jerusalem, Israel, in critically reviewing this manuscript is gratefully acknowledged.

This article was authored in a private capacity and should not be interpreted as reflecting the official position of the Israel Ministry of Health.

References
1. Cass Y. Hosp Pharm Eur 33;2007:53-4.
2. Cass Y, et al. Health and safety aspects of cytotoxic services. In: Allwood MC, et al, editors. The Cytotoxic Handbook. Oxford: Radcliffe Medical Press; 1997: 35-55.
3. Anonymous. Laminar flow cabinet. Wikipedia: the free encyclopedia. Available at: http://en.wikipedia.org/wiki/Laminar flow cabinet. April 2008.
4. Anonymous. Am J Hosp Pharm 1990;47:1033-49.
5. Kiffmeyer TK, et al. Pharm J 2002;268:331-7.
6. Favier B, et al. JOPP 2003;9(1):15-20.
7. Vandenbroucke J, Robays H. JOPP 2001;6;4:146-52.
8. Connor TH, et al. Am J Hosp Pharm 1999;56:1427-32.
9. US National Institute for Occupational Safety and Health. Preventing occupational exposure to antineoplastic and other hazardous drugs in health care settings. Washington DC: NIOSH; 2004.
10. American Society of Health-System Pharmacists. Am J Health-Syst Pharm 2006;63:1172-93.
11. International Society of Oncology Pharmacy Practitioners. J Oncol Pharm Practice 2007;Supp 13:1-81.
12. Sessink PJ, et al. Hosp Pharm 1999;34:1311-17.
13. Thompson CA. Am J Health-Syst Pharm 2008;65:14-15.