Safe handling of cytostatic drugs: recommendations from independent science

Abstract

Objectives

Due to their mechanism of action, most classical cytostatic drugs have carcinogenic, mutagenic and/or reprotoxic properties. Therefore, occupational exposure of healthcare staff to these drugs should be prevented. Our objective was to lay out European legislation on this topic and reflect on the process of revising the European CM-directive. We summarise independent European and Dutch studies, and give a concise set of basic recommendations for safe working with cytotoxic drugs in healthcare facilities.

Methods

We were directly involved in the process of revising the CM-directive: first, through an EU commissioned workshop in the Netherlands, and after that by contributing to the pan-European stakeholder symposium. For this aim, we had to gather the relevant study data from the Netherlands and from Europe. We analysed all relevant industry-independent studies and collated a set of basic recommendations.

Results

Independent studies show that the development of measures in recent years can lead to a safe work environment. Standardising the cleaning process leads to a significant improvement in environmental contamination in the majority of hospitals. In the Netherlands, exposure of workers was shown to be well beneath the limit value of 0.74 µg cyclophosphamide per week, therefore showing that the measures taken in recent years are adequate.

Conclusions

The safety of healthcare workers is of the utmost importance. Current practice in the Netherlands show that measures taken in recent years are adequate. European legislation should be based on independent scientific research and practice. The first goal should be to bring countries with less safe working levels to a higher level instead of introducing measures that only increase healthcare budgets but not healthcare safety.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Prevention of exposure of healthcare workers to cytostatic drugs is pivotal in providing a safe working environment. How to achieve this is not regulated centrally in Europe.

WHAT THIS STUDY ADDS

• With the upcoming revision of the European legislation, data from independent science should be used to provide centralised guidance on safe handling practices. We report on the scientifically proven measures that can be taken to improve worker safety.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Decision-making on a European level can be influenced by lobbying of companies that have financial gain as their primary aim. Data from independent science presented in this paper show which mitigating strategies to improve worker safety should be taken.

Introduction

Classical cytostatic drugs are inherently toxic, due to their mechanism of action. Accordingly, almost all of these drugs are ‘CMR substances’, which means that they have carcinogenic, mutagenic, and/or reprotoxic properties. For a number of substances, the European Chemical Agency has set an occupational exposure limit (OEL), previously known as maximum allowable concentration in air at the workplace (MAC).¹ However, exposure can occur via several different routes: via ingestion, via the eye, via inhalation, and via the skin.^{2 3} OEL values only indicate limits for possible inhalation. In fact, cytostatic drugs in nursing wards are not usually administered as dry powders but as solutions in an infusion or injection, so there is only a small risk of inhalation in this setting.⁴ Pharmacy technicians, on the other hand, do handle dry powders. Hence, they should be protected from inhaling these substances by technical measures and personal protective equipment. In general, in hospital practice there is only a negligible risk of exposure via ingestion or via the eye, so exposure via the skin is considered to be the greatest risk.^{2 4} The at-risk staff in this regard are nurses, doctors, pharmacists, pharmacy technicians, and transport and cleaning staff.

The Netherlands has a long history of setting up guidance on safe handling of cytotoxic drugs. We want to share the knowledge gained and experience on this topic with a broader public, laying out practices that can be implemented elsewhere to enhance worker safety.

In this paper, we will lay-out the European legislation on this topic, summarise recent independent European and Dutch studies, and give a concise set of recommendations for safe working with cytotoxic drugs in healthcare facilities.

Methods

The European directives comprise the highest form of legislation within the European Union (EU). Member states still have national laws, but these always have to adhere to the general rules set out in the European directives. Member states are allowed to be stricter, but not less strict, than the legal framework of the centralised European directives. European directives are revised and updated periodically. With regards to the current foreseen update of the directive regarding carcinogens and mutagens, we have followed the preparations of that process closely, and have striven for improved guidance on the safety of workers that handle cytotoxic drugs. Additionally, we have learnt that currently the variance of measures in place to protect workers between member states is large.^5–7 To aid decision-making on a European level, we presented the data from independent peer reviewed literature to participants at two workshops commissioned by the EU in 2021. The first one was held in the Netherlands, and was one of five national workshops the European Parliament had ushered. For this workshop, we were asked to give an overview of the Dutch guidelines and the Dutch studies that were done by academia or independent research organisations. Hence, we performed a PubMed and Scopus search using the keywords: ‘cytotoxic’ OR ‘cytostatic’ OR ‘antineoplastic’; ‘contamination’ OR ‘exposure’ OR ‘wipe sample’; ‘Dutch’ OR ‘Netherlands’. Next, we performed the same search for the pan-European workshop without ‘Dutch’ OR ‘Netherlands’. We included only industry-independent studies, that included either an active intervention with before and after measurements, or that compared contamination levels in different hospitals that use different working procedures from Europe.

In this paper, we present the data from the literature we found, after giving an outline of the legislative framework.

Results

European legislative framework

In daily healthcare practice, ‘CMR’ is used as a handle to define the hazards of specified drugs.⁸ European legislation, however, is different. In that context, cytotoxic substances fall under the directive on the protection of workers from the risks related to exposure to carcinogens or mutagens at work,⁹ but reprotoxic substances do not. On further enquiry with the Directorate of Employment of the EU, the difference appears to derive from the assumption that reprotoxicity has a limit value beneath which exposure is safe. However, this may not be the case for carcinogenic and mutagenic substances. In the case of healthcare staff though, with a large number of young individuals, reprotoxicity is at least as important to prevent as carcinogenicity or mutagenicity.¹⁰ The directive on the protection of workers from the risks related to exposure to carcinogens or mutagens at work⁹ was drawn up 16 years ago and is now in need of revision. The directive on safety for pregnant workers and workers who have recently given birth or are breastfeeding¹¹ is even older. The guidelines in these directives do not specifically describe handling of drug products. They are based on two key principles of occupational hygiene though, that are applicable in any situation where a potential hazard is present: (1) the occupational hygiene strategy, which starts by tackling the source (if possible), followed by collective measures (eg, technical measures such as the use of special safety cabinets and the use of infusion systems fitted only with needleless connectors, centralising the preparation of cytostatic drugs in the pharmacy, and using clear hazard pictograms and labels), followed by individual measures (eg, rotation of tasks), and finally personal protective equipment such as gloves and aprons; (2) the precautionary principle—if a substance is suspected of being harmful, based only on a limited amount of scientific evidence, measures should nevertheless be taken without delay and, for safety reasons, efforts must be made to minimise any exposure.

European studies

Many related European studies were published during the period from 2000 to 2010, in particular. The literature search yielded 112 results, from which 12 met the criteria (being industry-independent, from Europe, and including an intervention to reduce contamination or exposure or comparing different settings). These studies mainly focused on environmental contamination. For example, a study group from Munich published results of 24 German hospitals participating in a wipe sampling study. They found that, overall, 60.9% of all wipes (n=375) were positive for one or more cytotoxics. When looking into work practices in the participating hospitals, a significant positive effect of the use of multi-way infusion systems was found on the amount of contamination.¹² Another German study also showed widespread surface contamination in a clinical oncology ward (116 wipe samples were tested), but found no evidence of internal exposure in urine from workers, when gloves were regularly worn.¹³ In a study from the Czech Republic (Czechia), a combination of measures aimed at standardising and improving cleaning procedures, both in the pharmacy and on the wards, resulted in effectively lowering surface contamination levels.¹⁴ Cleaning optimisation comprised three changes to the earlier routine: establishing a cleaning order from the cleanest to the dirtiest spots, cleaning the outside of incoming vials and cleaning work tables every 2 hours with 50% l-isopropanol in water.¹⁴

These were all single-centre or single-country studies though, and many studies that were published, in addition to the ones mentioned above, were excluded because they were sponsored by the manufacturers of medical devices.

As yet, it has not been possible to translate contamination of the environment and of surfaces directly into actual cancer risks for staff.¹⁵ One reason for this is that different substances have different physico-chemical properties (a substance’s ability to detach from a surface depends both on the substance itself and on the surface; furthermore some cytostatic drugs are more readily absorbed via the skin than others). Another reason is that very large-scale epidemiological studies are needed to quantify late health risks.

To conduct an independent comparative study, the European Society of Oncology Pharmacy (ESOP) has launched the MASHA (Research about Environmental Contamination by Cytotoxics and Management of Safe Handling Procedures) project. The first MASHA study spanned 15 hospitals in 11 European countries (figure 1). It involved an extensive questionnaire on the (cleaning) procedures and tools used in each hospital, in combination with standardised surface wipe sampling, and an intervention. For the purposes of this study, three series of 10 surface wipe samplings were performed per hospital (five in the pharmacy and five in a nursing ward). The first series was a baseline measurement. This was followed by a training course on risks and risk management for staff from the participating hospitals. In addition, a standardised cleaning protocol was universally implemented, consisting of daily cleaning of exposed surfaces with 70% isopropanol or ethanol and a weekly extra cleaning with an alkaline solution of 0.05 mol/L sodium hydroxide. The second series was performed immediately after this intervention, and the third series followed a year later. Environmental contamination was found in all of the participating hospitals. The level of contamination for the samples that were used in the baseline measurement was found to be 20%. This figure dropped to 14% after the intervention (figure 2), at which point 70% of the hospitals showed a statistically significant improvement in the number of positive samples as well as in the degree of contamination. The most contaminated locations were the areas of floor directly beneath infusion poles in the nursing wards. An extensive analysis of hospital variables was performed to see if there were any associations between the number of contaminated samples/degree of contamination and specific hospital characteristics and working practices. This showed that the number of chemotherapy treatments that were prepared and administered annually was not a factor. Furthermore, the use of closed-system drug-transfer devices (CSTDs) showed no statistical benefit over the use of spikes (small plastic devices that prevent aerosol formation via a built-in filter and also prevent needle prick injuries). In fact, the hospitals with the highest contamination levels were hospitals where CSTDs were used. The only variable that showed a statistically significant correlation was the use of special chemotherapy infusion sets, with needleless connectors and infusion bags that have a side line filled with a neutral solution attached.⁷ These infusion sets are mandatory in the Netherlands, where they are used by every hospital in the country. The results of the second MASHA study are currently being processed. That study, which focuses on environmental contamination in oncology nursing wards, is being carried out in cooperation with the European Society of Medical Oncology (ESMO).

Figure 1.

Hospitals participating in the MASHA (Research about Environmental Contamination by Cytotoxics and Management of Safe Handling Procedures) project. Reprinted with permission from Korczowska et al. ⁷

Figure 2.

Contamination results in the MASHA (Research about Environmental Contamination by Cytotoxics and Management of Safe Handling Procedures) project. BSC, Biological Safety Cabinet reprinted with permission from Korczowska et al ⁷.

Examples from the Netherlands

The literature search yielded 24 results, of which eight met the criteria (industry-independent and multicentric). We used these eight in the national workshop in the Netherlands.

The Netherlands was one of the first countries in Europe to start drawing up guidelines to protect health workers against exposure to cytostatic drugs. The first guideline was written in 1992 by the Netherlands Comprehensive Cancer Organisation,¹⁶ and has been periodically revised on the basis of new knowledge. The results of a study into reprotoxic effects among oncology nurses in the Netherlands were published in 1999.¹⁷ This study found that oncology nurses had a longer time to conception than nurses working in other specialisms (ie, surgery). The former were also found to have an increased rate of premature deliveries and an increased rate of newborns with a low birth weight. These findings accelerated the development and implementation of effective precautionary measures to prevent exposure by the hospitals as well as by the authorities in the years after these results were published. In 2001, the Ministry of Employment issued a Working Conditions Policy Rule under the Dutch working conditions act¹⁸ that included binding regulations for any staff who could come into contact with cytostatic drugs in hospitals. This Working Conditions Policy Rule was replaced in 2004 by a Working Conditions Covenant (a sector-wide agreement). In 2009, that covenant was replaced by the current Occupational Health and Safety Catalogues.^{19 20} Finally, in 2018, the Occupational Health and Safety Catalogues’ guidelines were translated into specific working instructions by a multidisciplinary working group. Details of these working instructions can be found at the website containing all Dutch medical guidelines called ‘richtlijnendatabase’.²¹ Based on the above mentioned 1999 study of fertility effects among nurses, a limit value has been derived for the occurrence of reprotoxicity. This value has been calculated for cyclophosphamide, a cytostatic drug in relatively common use that is known to persist in the environment for a relatively long period of time. This makes it an effective worst-case marker substance. This tentative limit value is 0.74 µg cyclophosphamide skin contamination per week.²²

Since 2000, several studies have been conducted in the Netherlands into the safe handling of cytostatic drugs. In 2009, at the request of the Dutch Association of Hospital Pharmacists (NVZA), the Netherlands Organisation for Applied Scientific Research (TNO) conducted a study into the risks associated with handling cytostatic drugs in Dutch hospital pharmacies.²³ This study showed that these drugs can be handled safely without the need for a negative air pressure cleanroom (which had previously been mandatory). However, it did report a potential risk of cytostatic drug carry-over from one room to another. This risk was subsequently investigated by analysing a database containing the results of surface wipe sampling over a 10-year period (2001–2011) at nine different hospitals. During this period, the set of safety guidelines was amended in 2004. After 2004, compounding with spikes, in a dedicated cleanroom with safety cabinets or isolators by trained staff, was mandatory. The study showed that the incidence of contamination in areas outside the preparation areas amounted to a total of 6%, and that these no longer occurred after 2008.²⁴ This shows that it is likely that the full effect of issuing guidelines only becomes visible after time for implementation is allowed, but that these guidelines were able to reduce contamination. The risk of carry-over from inside the compounding rooms to adjacent areas in the Netherlands is extremely small. Another study, performed in 2017, focused on the risk of contaminating the exterior surfaces of prepared cytostatic drug infusions. In this perspective, a study carried out in eight hospitals examined the exterior surfaces of a total of 146 5-fluorouracil infusions by means of surface wipe sampling. None of the infusion bags were found to have contamination on their external surfaces.²⁵

The largest Dutch study was carried out in six different hospitals by the Dutch Occupational Hygiene Society, in cooperation with the Dutch Association of Hospital Pharmacists in 2014. In this study, actual skin exposure to cytostatic drugs was measured in nurses, pharmacy technicians, and cleaning staff by taking hand-wash samples after these individuals had completed their routine activities. The hand-wash samples were tested for the presence of eight different cytostatic drugs. Weekly exposure to the marker substance (cyclophosphamide) was calculated. The average weekly exposure was 0.12 µg for nurses, 0.05 µg for pharmacy technicians, and 0.03 µg for cleaning staff. All of these are well below the limit value of 0.74 µg. The values -per task were also compared with those from previous studies, carried out from 2001 to 2003 (table 1). It was found that the average exposure had decreased by a factor of 10.

Table 1.

Cyclophosphamide contamination on the hands (µg/task). Reprinted with permission from van Rooij and Hilhorst²⁶

Time period	2001–2003			2013–2014
Reference	Fransman et al 37			Van Rooij et al 26
Number of hospitals	4			6
Task	n	GM	Range	n	GM	Range
Compounding cytostatics	26	0.01	0.01–0.04	10	0.004	<0.0013–0.05
Administering cytostatics	0			10	0.0008	0.00005–0.02
Decanting urine	26	0.02	0.01–0.14	0
Transporting urine	0			7	0.004	0.001–0.009
Washing chemo-patient	10	0.03	0.01–0.10	7	0.004	0.002–0.02
Changing bed linen	8	0.02	0.01–0.17	8	0.003
Cleaning of sanitary facilities	19	0.01		3	–	<0.0025–0.014

GM, geometric mean.

Average exposure is important, but so is the risk of peak exposures. Accordingly, Monte Carlo simulations were used to calculate the risk of exceeding the limit value. Here, a risk of ≤5% serves as a statistically acceptable cut-off limit. The risks of nurses and cleaning staff exceeding the limit values were 3.6% and 3.1%, respectively. However, pharmacy technicians had a risk of 9.7%, which was much higher.²⁶ A follow-up study was carried out in 2017, to investigate the cause of this discrepancy. In addition to taking a larger number of hand-wash samples from pharmacy technicians, this study involved a further analysis of potential contamination in relation to the tasks these individuals performed. The study found that the preparation process itself resulted in low-level contamination and a low risk of exceeding the limit values. However, the preparatory tasks (collecting vials and materials in the preparation area) led to an excessively high level of contamination if gloves were not worn when performing such tasks.²⁷ In the literature, one commonly cited fact is that contaminants are present on the external surfaces of cytostatic drug vials when these products leave the factory.²⁸ Yet, the Dutch Occupational Health and Safety Catalogues do not include an obligation to wear gloves when performing preparatory tasks. These preparatory tasks involve removing cytostatic drug vials from the outer packaging. Accordingly, it is very likely that the higher value found in the hand-wash study was due to contamination of the vials’ external surface with cytostatic drugs. This exposure route can easily be eliminated by consistently wearing gloves when handling vials.

Discussion

The CM-directive (Directive 2004/37/EC of the European Parliament and of the Council on the Protection of Workers from the Risks Related to Exposure to Carcinogens or Mutagens at Work) is up for revision in 2023 or 2024. In the run-up to that process, the producers of CSTDs are lobbying strongly to get their devices included in the guidelines,²⁹ despite the lack of independent scientific evidence to support their added value compared with the method of using spikes,³⁰ the higher costs for healthcare systems when implementing CSTDs,³¹ and the emerging evidence that, in some cases, CSTDs can compromise the quality of drug products through particle formation.^{32 33} Following persistent pressure from professional associations such as the European Oncology Nursing Society (EONS), European Cancer Organisation (ECO) and ESOP, the Directorate-General of Employment, Social Affairs and Inclusion of the EU launched an investigation to study the current situation in its member states. This involved a comparison of the national guidelines used by all of the member states and visits to five of these countries (Netherlands, Spain, Portugal, Poland and Romania). Unfortunately, here too, there might be more evidence of this lobby’s power to influence events in Europe. This is because the report³⁴ makes no mention of what was discussed at the closing conference: good safety measures such as training and education, or using flushing lines, or standardising cleaning protocols, which are measures that can be installed without high costs. Furthermore, when the report was published, it transpired that the individuals it had referred to as experts had not, in fact, been consulted on its text. Finally, disclosures of the reports’ authors on financial ties with industries that have potential interests in the topic were not provided.

There is substantial variation between individual European countries, with a prominent east-west divide. In at least five eastern European countries, cytostatic drugs are prepared by nurses, in nursing wards (data on file, ESOP). Sometimes, even no use is made of protective measures, such as safety cabinets. Furthermore, these drugs are administered without adequate gloves or needleless systems. Here, there appears to be a great need for the EU to harmonise measures. Rather than tightening measures in richer countries still further, it should help less prosperous European regions to launch procedures that are already routinely used in the west, and which lead to safe working conditions. Hopefully, the recently published tender from the EU, calling for applicants who wish to be engaged in writing guidance on the safe handling of hazardous medicinal products,³⁵ will result in equal safe working conditions for all healthcare staff in all European countries.

In conclusion, recommendations based on independent scientific studies are available and have been implemented in the Dutch Safety Catalogues.^{19 20} These are summarised in box 1 and most are also described in the Quapos guidelines from the European Society of Oncology Pharmacy.³⁶ With regard to further safety improvements, the use of hand protection during preparatory procedures that include handling of cytostatic drug vials merits special attention. Independent research from the Netherlands shows that compliance with the set of measures given in box 1 is sufficient to enable cytostatic drugs to be handled safely.^{26 27} Therefore, the EU’s goal should be to bring countries with less safe working environments to the same level.

Box 1. Recommendations on safe handling of cytotoxic drugs^{19 20 36} .

Training and education

Provide training for each staff member that can come into contact with cytotoxic drugs on risks, risk management and safe handling practices

Provide training for each staff member that can come into contact with cytotoxic drugs on how to act in case of accidents and spills

Provide each area where cytotoxics are handled with a spill kit and written instructions on how to act in case of accidents and spills at hand

Receipt, transport and storage

Label all cytotoxic drugs with an adequate warning sign (the yellow hand)

Never touch primary packaging without wearing protective gloves

Transport cytotoxic drugs in a sealed secondary packaging

Compounding

Compound in a separate, dedicated room with entry through a lock

Compound in a safety cabinet or isolator with negative pressure

Do not recirculate air from the safety cabinet or isolator into the room or hospital ventilation system (0% recirculation principle)

Compound using spikes

Wear adequate gloves and gowns with full length sleeves and cuffs that have been tested and proven to protect against cytotoxic substances

Dispense compounded cytotoxic drugs with a barrier that prevents exposure of the administrating staff: a side-line or multi-way connector set filled with a neutral fluid

Administration

Use dedicated area’s for administration of cytotoxic drugs

Use multi-way infusions sets with needle-free luer lock connections

After administration: rinse and dismount the infusion set as a whole

Wear adequate gloves and gowns with full length sleeves and cuffs that have been tested and proven to protect against cytotoxic substances

Never crush oral cytotoxic drugs in an open mortar. Let oral cytotoxics dissolve in a closed compartment such as a syringe for patients who are tube-fed or have difficulty swallowing

Care for patients treated with cytotoxics

Use dedicated areas for care of patients who are treated with cytotoxic drugs

Assign dedicated toilets and sanitary areas to patients who are treated with cytotoxic drugs

Take the period in which excreta are contaminated into account:

• Wear gloves and gowns when handling excreta of patients who are still in the contaminated period

• Do not decant urine of patients who are in the contaminated period

• Use gloves and gowns when washing patients who are in the contaminated period

Cleaning and disposal

Use a written cleaning protocol that includes:

• The use of dedicated cleaning sets for all areas where cytotoxic drugs are handled

• Cleaning from the cleanest to the dirtiest spot

Check the efficacy of the cleaning protocol by taking periodic wipe samples

Use adequate personal protective equipment when cleaning: always gloves and gowns in case of wet cleaning

Dispose of any material that might be contaminated with cytotoxic drugs or residues via dedicated cytotoxic waste bins.

Data availability statement

Data are available upon reasonable request. Data are available based on the data use agreement policies of Amsterdam UMC hospital. Data from this study are available on reasonable request by sending an email message to the corresponding author.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

Not applicable.