The level of protection afforded by gloves to personnel and products when handling cytotoxic agents is complex. Nick Gardner, Shield Scientific, offers some important considerations.
With the 25% increase in cancer in Great Britain between 1977 and 20061 and chemotherapy drugs being at the forefront of our defence for tackling this disease, safety concerns regarding the preparation and handling of cytotoxic agents are likely to increase. Studies based primarily on animals have led to the International Agency for Research on Cancer classifying some cytotoxic drugs as possibly carcinogenic, mutagenic and teratogenic.2 The potentially hazardous nature of these drugs have caught the attention of the UK Health & Safety Executive (HSE), who have published two information sheets on this subject: “Safe handling of cytotoxic drugs 3 and “Handling cytotoxic drugs in isolators in NHS pharmacies 4 (latter in association with the MHRA). Of equal concern is the safety of the product and particularly with reference to microbiological contamination. Nowadays protection of the product is tightly controlled by the EC Guide to GMP5, which stipulates the precise conditions under which sterile medicinal products need to be manufactured.
The fact that many cytotoxic drugs are hazardous means that under COSHH employers are obliged to assess the risks.3 Additionally concerns regarding the possible carcinogenicity of some anti-cancer drugs means that they are subject to Appendix 1 of the COSHH Approved Code of Practice (ACOP).3 For operators engaged in the preparation and handling of chemotherapy drugs, the most common form of exposure is through dermal contact and inhalation.3 Even intact skin is potentially vulnerable4 and it is noteworthy that some chemotherapy drugs are skin irritants.3
As part of the overall risk assessment, consideration also needs to be given to the following points: • the toxicity of the cytotoxic drug • the time of exposure to the drug • the frequency of the exposure to the drug
As the gloved hand is possibly the most likely point of contact during the preparation and administration of drugs, paying particular attention to the glove specification and how it relates to personal protection seems prudent, particularly as the cumulative effect of regular exposure to small doses of cytotoxic drugs3 is not fully understood. As most production of anticancer compounds is done in an enclosed unit such as an isolator, potential exposure would appear to be limited to the barrier effectiveness of the gloving system. Away from the production unit, skin contact could result from surface residues on the packaging or on the vials themselves.
Under the Personal Protection Equipment (PPE) at Work Regulations (1992), appropriate personal protective equipment needs to be provided, when there are no other alternatives to managing the risks.3 PPE obviously includes hand protection, which gives rise to the question of how to determine the suitability of the gloves. Where the principle intended purpose is personal protection, it would seem logical to select a glove that is registered according to the PPE Directive (89/686/EEC) rather than the Medical Device Directive (MDD) 93/42/EEC where the emphasis is on patient protection.6
Similarly given the known exposure to chemical hazards, selecting only gloves that are designed to protect against the highest level of risk will be necessary. These gloves are referred to as gloves of complex design (category III) for irreversible or potentially mortal risk.6 Determining the regulatory status of a glove is simply a question of asking the manufacturer for its Declaration of Conformity (the latter is a legal obligation under the PPE Directive) and the details will often feature on the product data sheet.
The gloves’ ability to resist permeation and penetration of cytotoxic drugs are clearly important4 and requires the following considerations:
Permeation Permeation – defined as “the process by which a chemical agent migrates through the protective glove at a molecular level.”7 Those engaged in a risk assessment and thus assessing the permeation characteristics of a glove, will inevitably seek data specifically on cytotoxic drugs. However assessors may find glove manufacturers provide chemical permeation data based on three different standards: • ASTM D6978-05 “Standard Practice for Assessment of Resistance of Medical Gloves to Permeation by Chemotherapy Drugs” • ASMT F739-99a “Standard Test Method for Resistance of Protective Clothing Materials to Permeation by Liquids, Gases Under Conditions of Continuous Contact” • EN374-3:2003 “Protective gloves against chemicals and micro-organisms – Part 3: Determination of resistance to permeation by chemicals”
While all three norms provide methodologies for chemical permeation, in Europe EN374-3 is often cited as the preferred method, presumably because it is a European standard.8 However only ASTM D D6978-05 has been specifically developed for testing of gloves to permeation by cytotoxic agents. A comparison table detailing the key differences between these three standards is provided in Table 1:
Increasingly ASTM D6978-5 is specified by those engaged in risk assessments, perhaps because this methodology is more aligned with the needs of those preparing or administering cytostatics. In this respect the test temperature of 35 ºC (+/- 2 ºC) is close to that of the human hand, and it should be noted that with increasing temperature permeation accelerates. In view of the hazardousness of some chemotherapy treatments, it is reassuring to note that this standard offers the highest level of sensitivity as defined by permeation rate – in fact a hundred times more sensitive than the European norm. In addition only this standard specifically stipulates the cytotoxic agents and their concentrations. Seven are mandatory (carmustine, cyclophosphamide, doxo-rubicin HCI, etopside, fluorouacil, paclitaxel and thiotepa), while two can be selected by the user. For guidance a selection of 17 chemotherapy drugs and their concentrations are detailed for optional testing. Finally ASTM D6978-05 explicitly mentions that only the thinnest part of the glove which is likely to be exposed to chemical contact (i.e. the palm or cuff) is to be tested.
The difference between ASTM D6978-05 and EN374-3:2003 in terms of determining permeation rates is evident from the following comparison on carmustine and thiotepa in Table 2. If a risk assessment had been based on EN374-3: 2003, then it could have given the glove wearers a higher level of confidence in the glove’s resistance to permeation to carmustine and thiotepa.
As glove thickness and material type are not the only factors that governs permeation, it is suggested that when evaluating the permeation characteristics of a glove only the data for a specific formulation is considered – this can apply when looking at various formulations of gloves from the same manufacturer or when comparing similar gloves from different manufacturers.8
A further cautionary note on assessing the permeation properties of gloves is that the practice of disinfecting gloves in use will inevitably diminish their chemical resistance properties. In contrast to the guidelines in EC Guide to GMP,5 some authorities recommend not disinfecting gloves when preparing cytostatics.8
Penetration Penetration – this is described by the HSE as “the bulk flow of a chemical agent through closures, porous material, seams, pinholes and other imperfection in the protective glove”.7 The issue of penetration has been highlighted as a particular concern for operators working in isolators.4 This is especially relevant for those isolators working under positive pressure, as there is potential for leakage of the drug through holes.4
As the gloves that are being used for personal protection against cytostatics are likely to be registered as Complex Design according to the PPE Directive (89/686/EEC), part of the registration process would have entailed testing them against EN374-2: 2003.9 For disposable gloves this will invariably mean that the gloves will have undergone a watertight test and the porosity of a glove is defined by various performance levels outlined in Table 3.
According to EN374-1:200310 a glove is considered to be micro-organism resistant if it achieves a minimal Acceptable Quality Level (AQL) of 1.5 or Level 2. An AQL of 1.5 accepts the statistical probability that there are less than 1.5% defects in a batch of gloves. An AQL of 0.65 assumes a tighter quality assurance level, giving the glove wearer a reduced risk of porosity and therefore a higher level of personal protection. Given that it is recognised that harmful substances can pass through gloves by penetration8, sourcing gloves with as low an AQL as possible may be appropriate.
Other considerations for ensuring personal safety are local safety standards. Apart from the HSE, there are number of other organisations in Europe that have issued specific guidance on personal safety for the handling and preparation of cytotoxic drugs. These include the following: • Berufsgenossenschaft fuer Gesundheit und Wohlfahrt (BGW) - the professional association for the German health service and social services has produced a leaflet M620 “Safe handling of cytostatics”, which is frequently cited in the literature • TRGS 525 Technical rules for working with dangerous material • Suva (Schweizerische Unfallversicherungsanstalt): Check list PPE From. 6709/1 • Institute for Applied Healthcare Sciences (IFAHS) - Quality Standard for the Pharmacy Oncology Service in Germany • Institut National de Recherche et de Sécurité (INRS) Les médicaments cytstatiques en milieu de soins. • Toxicité et risques professionnels. Fiche Médico-Technique 33. • Recommendations pour la prévention des risques professionnels. Fiche Médico-Technique 36
Table 4 provides some insight to the guidance issued by the HSE, Berufsgenossenschaft fuer Gesundheit und Wohlfahrt or BGW (Germany) and the Institute for Applied Healthcare Sciences or IFAHS (Germany):
Glove wearing time is an area where there seems to be some variation in practice. In this respect it is noteworthy that the BGW mentions occlusion as a reason for changing gloves every thirty minutes.11 This is because the combination of perspiration and heat which is generated by occlusion may make it easier for the cytotoxic drugs to come into contact with the skin. Double-gloving in order to enjoy the additional protection afforded by a double wall system is widely practiced.8 However, the BGW recommends the use of coloured gloves in order to detect more quickly imperfections on the surface of the outer gloves.11
So far, we have looked at hand protection in enclosed units, where sterile gloves of longer length (28cm-30cm) are likely to be used. Away from the production unit, exposure could result from surface residues on the packaging or on the vials themselves. Accordingly the risk of exposure to hazardous cytotoxic agents may exist and non-sterile protective gloves will need to be worn.
Most of the criteria already discussed still apply, but noting that non-sterile gloves are often thinner and may not have been tested specifically on cytotoxic drugs.8 The most commonly encountered non-sterile gloves are shorter in length (24cm) and these may not be suitable if protection of the wrist from exposure to drugs is sought. Interestingly the BGW specifically recommends gloves with a length of 28cm for contact with cytotoxic agents.11
Other considerations may be material properties8 and their compatibility with the rigours of being left on an isolator ring. In this respect not all synthetic gloves may be as suitable as latex due to the superior elasticity of latex. Size range (particularly with reference to the smaller and larger sizes) and fit will need to be evaluated. The importance of safety in use should not be overlooked*8. Grip can be crucial for minimising spillages and yet a glove in contact with isopropyl alcohol can become very slippery.
Product protection Annex 1 to the EC Guide to GMP stipulates that “the manufacture of sterile products is subject to special requirements in order to minimise risks of microbiological contamination, and of particulate and pyrogen contamination”.5To achieve these objectives different levels of airborne particles are prescribed for various levels of cleanliness. However what about the gloved hand, which may be in direct contact with the product? Some authorities refer to the use of “clean gloves” for use in the isolator,4 without indicating what is clean.
While the glove may be terminally sterilised by gamma irradiation to Sterility Assurance Level (SAL) of 10-6 (in accordance with guidelines detailed in ANSI/AAMI/ EN ISO 11137:2006 “Sterilization of Healthcare Products – Radiation”), it could still be a source of transmission for particle and pyrogen contamination. Accordingly it seems prudent to use gloves that have been specifically developed for cleanroom use. The Product Data Sheets for these types of gloves will often provide details in terms of specification and typical levels of particles according to IEST-RP-C005.3.12 Likewise there may be a claim for low endotoxin content of less than 20 EU/pair of gloves as defined by EN455-3:2000.13
Further guarantees of the suitability of the glove for cleanroom use may come from batch specific data that is provided in the form of a certificate of analysis or certificate of conformance. An example of one such glove manufacturer’s certificate is given in Table 5:
The value of AQL: Specifically with reference to barrier defects such as pinholes, AQL or Acceptable Quality Level is an important parameter for minimising the risk of product contamination. Given that AQL represents a statistical probability of defects, a lower AQL is probably better for assuring process protection. In isolators operating under negative pressure, pinholes may increase the opportunity for air to enter the isolator thereby potentially contaminating the product.4 The value of cleanliness: Particle and extractable data are not routinely provided for surgical gloves, but are for cleanroom gloves. High particle counts on gloves may contribute to increases in bioburden. Additionally it should be noted that cleanroom gloves are typically packaged in paperless packaging to reduce the risk of particle contamination.
The value of low endotoxin content: The risks associated with endotoxin contamination is particularly relevant to aseptic processes and it has been reported that “the pyrogens that pose the most risk to the manufacture of parenteral products are endotoxins”.14 For gloves the risks of endotoxin contamination are particularly high as they are manufactured in an aqueous environment, which promotes the proliferation of Gram-negative bacteria. Also the town’s water used for washing the gloves may be laden with micro-organisms, while raw latex and powder slurries may provide a rich food source for micro-organisms. Accordingly a glove with a low endotoxin content claim and particularly if its batch tested for endotoxin is likely to be of value to protecting the product. In terms of protecting your hands, endotoxin is an inflammatory substance that is not eliminated by sterilization. It is typically associated with irritant contact dermatitis and has also been reported to accelerate the rate of sensitization to allergens.15
In summary gloves play a vital role in terms of providing personal and product protection. The different regulatory status of gloves has been outlined and it would appear that those that are registered as Complex Design (Category III) according to the to Personal Protective Equipment Directive (89/686/EEC) are most appropriate. In view of the potentially hazardous nature of some cytotoxic drugs, determining the glove’s ability to withstand exposure is important. For permeation assessing a glove on the basis of a test methodology which is significantly more sensitive and has been specifically developed for chemotherapy drugs could be beneficial (ASTM D6978-05).
In terms of penetration, selecting gloves with as low an AQL for barrier defects as possible may enhance the level of personal and process protection. Given the emphasis on product protection, consideration needs to be given to the compatibility of the gloves with the environments where cytotoxic drugs are handled and prepared. In this respect a glove specifically developed for cleanroom use may bring the benefit of reducing the risk of microbiological contamination.
Recommendations • For personal protection against exposure to cytotoxic drugs, use only gloves that are registered as Complex Design (Category III) according to Personal Protective Equipment Directive (89/686/EEC) • Use longer length gloves (>28cm) in order to allow glove wearer to roll cuff over the garment sleeve, thereby providing adequate wrist protection • In order to determine the permeation of a glove to cytotoxic agents request data based on ASTM D6978-05 • Selecting gloves with an AQL of <0.65 for pinholes may provide greater product and personal protection. • Only Cleanroom gloves should be used because they offer a higher level of cleanliness and are packed in paperless packaging. • To minimise the risk of microbiological contamination, select gloves that are batch tested for particles and endotoxin. These details are furnished on the certificate of analysis or conformance.
Contact SHIELD Scientific Nick Gardner, MBA T+44 (0)20 8647 8418 nick.gardner@shieldscientific.com www.shieldscientific.com
