Expert opinion: Isolators vs Class II cytotoxic cabinets vs CSTDs for cytotoxic handling

Cytotoxic chemotherapy is synonymous with a narrow therapeutic index, severe adverse effects for patients and occupational exposure risks for pharmacy and nursing staff.

 

The majority of cytotoxic drugs are administered as sterile injections or infusions, which means asepsis must be maintained during the preparation and administration of chemotherapy, particularly because many patients are immunocompromised. Protecting healthcare staff from occupational exposure, ensuring sterility of parenteral chemotherapy and complex clinical management issues all combine to present a multidimensional challenge to pharmacy staff and specialist chemotherapy nurses.

 

This opinion piece considers the different technologies used for the preparation of cytotoxic injections and infusions: pharmaceutical isolators, Class II cytotoxic cabinets (also erroneously referred to as vertical laminar flow cabinets), and closed system transfer devices (CSTDs). The attributes and limitations of each technology are considered in terms of the maintenance of infusion/injection sterility (protection of the product from the environment), containment of the cytotoxic medicine (protection of staff from the product), conserving the pharmaceutical integrity of the product and issues around the incorporation of these technologies into oncology pharmacy practice.

 

Protection of the product

For simple aseptic manipulations involving reconstitution of vials, withdrawal of liquid and dilution to prepare pre-filled syringes or infusion bags, both the class II cabinet and the isolator offer critical zone environments corresponding to EUGMP Grade A. This is conditional upon maintenance, monitoring, testing and validation for both types of device, the details of which are available elsewhere. In theory at least, the Class II cabinet is more vulnerable to changes in airflow in the vicinity of the cabinet caused, for example, by personnel moving around in the aseptic suite.¹ This can disrupt the laminar airflow at the open face and draw in air from outside the critical zone. Conversely, a pharmaceutical isolator should, if properly maintained and validated, sustain the Grade A environment against such challenges. The isolator offers potential design advantages in that materials are introduced into the critical zone via flushed hatch systems with interlocking doors. This enables the implementation of a time delay between the closing of the outer hatch door and opening of the inner hatch door to the Grade A work zone, which, in turn, enforces a minimum contact time for surface disinfectants sprayed, or wiped onto the surface of in-bound materials or packaging to exert a bactericidal effect. Isolators, either connected in series or used singly, offer the potential for gaseous sterilisation of consumables introduced into the isolator prior to aseptic manipulation. This approach, which is best applied to batch-scale preparation for applications such as dose-banding, requires rigorous validation and systems to ensure there is no ingress of sterilising gas (usually powerful oxidising agents) into the product. The main disadvantage of isolators when compared with Class II cabinets is that they are more difficult to clean and to sanitise internal surfaces.²

 

There has been much debate over the use of positive- or negative- pressure isolators for cytotoxic manipulation; the former, in theory, is more likely to maintain the aseptic environment in the event of a leak in the isolator, but the latter provides a higher level of operator protection in the same scenario. Guidance based on a limited study conducted by the UK Health and Safety Executive was inconclusive and suggested either positive or negative isolators were acceptable providing they were properly maintained and operated.³

 

Unlike isolators and Class II cabinets, which provide an aseptic environment and containment, CSTDs provide a closed, sterile fluid path for aseptic manipulation, with either an expansion chamber or a filtration system to permit displacement of air by liquid. In most cases, the CSTD accesses the drug vial or the infusion bag via a spike or retractable needle system. When deployed in a non-aseptic environment there must be the potential risk of microbial inoculation into the vial or the infusion. In an uncontrolled environment the manipulation of CSTD connectors and docking devices may also carry a risk of microbiological contamination, even when sophisticated valve systems are used to mitigate this risk. Additionally, the integrity of the seal between the drug vial or infusion bag septum and the CSTD spike or needle is not only dependent in the design of the CSTD, but also on the material and design of the vial septum and this can vary significantly between manufacturers.

 

In recent years, CSTDs have been used for drug reconstitution in clinical areas outside the pharmacy, particularly for monoclonal antibodies. While this practice is undoubtedly an improvement over the use of open systems in an uncontrolled environment, it should not be assumed that product sterility is automatically guaranteed. There is huge variation in the environmental quality of clinical areas in oncology units, variation in cleaning and sanitisation practices, differences in staff training and competency assessment and, subsequently, the potential for significant variation in the bioburden that challenges the integrity of the CSTD in different centres. In the opinion of the author, the use of CSTDs in this type of environment requires careful validation and control for each individual area in which infusions are prepared to ensure sterility is not compromised. Closed systems are increasingly deployed in infusion/injection administration sets to minimise the exposure of chemotherapy nurses to cytotoxic drugs in outpatient clinics. There is currently much debate concerning whether pharmacy should provide infusion bags and syringes of cytotoxic drugs with CSTD devices already fitted. The aim is to avoid compromising sterility or risking cytotoxic contamination when nurses spike infusion bags or connect syringes, but in solving these issues other problems around product integrity are created. Progress on these matters will require much more ‘joined-up’ thinking between nursing and pharmacy staff.

 

Protection of staff

In the pharmacy setting, mechanical ventilation in the form of Class II cytotoxic cabinets and isolators are at the top end of the controls designed to protect staff from occupational exposure to cytotoxic drugs. The hierarchy beneath this includes staff training, safe systems of work, personal protective equipment and environmental monitoring. Both Class II cabinets and pharmaceutical isolators discharge air outside of the isolator through one or two HEPA filters, and ideally to the outside of the building via fan-assisted external ducting. As with product protection, above, the open face of the Class II cabinet presents a potential weakness in that disturbance of the air flow in the ‘protective curtain’ of air directed vertically from the top of the open face into the plenum at the base of the work area might permit air currents to drift from the cabinet to the outside. The author has seen smoke tube experiments where a combination of overloading the cabinet with equipment (syringe filling pump) and movement in the aseptic room in front of the cabinet have resulted in trails of smoke tracking along the operator’s arms, through the protective curtain and into the proximity of the operators face. 

 

Isolators provide a physical barrier between the cytotoxic manipulation area and the operator. After initial resistance from UK pharmacy staff in the 1980s, most technicians and pharmacy assistants prefer isolators because they ‘feel safer’. There may, however, be an element of a ‘false sense of security’ about this. In the case of a positive pressure isolator, leaks in the isolator chamber, gloves or sleeves, exhaust HEPA filters or the external ducting could result in contaminated air being pumped into the outside environment. As with Class II cabinets, isolators (whether operated under positive or negative pressure) must be validated, monitored, tested and fully maintained to work effectively.

 

A less obvious problem with isolators relates to the fact they are containment devices, and also difficult to clean and remove cytotoxic drug residues.² This means that the inside of isolators and transfer hatches can become contaminated with cytotoxics, even when regular cleaning routines are deployed. This issue has been demonstrated in the ‘real-life’ setting⁴ where cytotoxic contamination was not only found on wipe samples from the inside of the isolator, but also on the external surfaces of pre-filled syringes and infusion bags passed out of the isolator and into the aseptic room. When these are then taken to clinical areas for administration to patients, the cytotoxic contamination is transferred with them, potentially contaminating clinic and patient areas and exposing nursing staff, non-cancer patients and patient carers to risk. It would therefore be erroneous to think of isolators as a ‘single and final solution’ for reducing cytotoxic contamination in the pharmacy and the clinic.

 

CSTDs are designed to contain cytotoxic residues and aerosols within the device itself. There has been debate over which CSTDs on the market are ‘genuine’ closed systems. Manufacturers of devices with air-displacement chamber technology argue that devices where displaced air is exhausted through hydrophobic filters and activated charcoal are not closed systems amid concern that not all cytotoxic molecules are trapped by the filter system and that repeated use may saturate the filter. Reference to studies published on these devices tends to show that they all reduce contamination on workplace surfaces when tested in the field using cytotoxic drugs, irrespective of the CSTD design, albeit with some variation in effectiveness.^5,6 In one study,⁴ the CSTD significantly reduced cytotoxic contamination on the external surfaces of pre-filled syringes and infusion bags leaving the isolator when compared with standard needle and venting pin techniques. Even with these encouraging findings, CSTDs should not be considered a ‘panacea’ for eliminating cytotoxic contamination and some devices exhibit residual droplets of liquid on docking valves after disconnection. Also, contamination may arise from multiple sources and some of these are not mitigated by the use of CSTD technology, for example contamination on the outside of drug vials. The cost of implementing CSTDs may also prove challenging.

 

There seems to be a developing argument for combining the use of CSTDs and isolators, with the intention of reducing cytotoxic contamination inside the isolator and minimising the transfer of cytotoxic residues to the outer surface of syringes and infusion bags leaving the isolator. The key question then would be whether this measure, when combined with the use of closed-system infusion administration sets, can reduce cytotoxic contamination in clinical areas and reduce the occupational exposure risk to nursing and clinic staff. There is a clear need for research in both pharmacy and clinical areas to evaluate this approach. The paucity of evidence on the effectiveness of CSTDs was highlighted in a recent Cochrane Review⁷ commissioned by the UK Oncology Nursing Society. Some experts in the field consider this review to be poorly conducted and unhelpful,^8,9 but it does serve to highlight the need for well-designed studies to evaluate new technologies or combinations of technologies.

 

The current interest in robotic chemotherapy compounding systems may present another opportunity for combining isolator/Class II cabinet and CSTD technology. With the cleaning and decontamination issues presented by complex robotic systems, this combination offers the potential for environment and product protection together with reduced cross-contamination between batches of different products.

 

Regulatory controls and microbiological considerations restrict the re-use of part-used vials of chemotherapy drugs. This results in considerable drug wastage which is unacceptable in the challenging economic conditions of modern cancer care. The use of CSTDs has been proposed as a potential option to effectively replace a multiple needle-entry vial septum with a syringe docking device to maintain vial integrity and permit multiple or extended use.¹⁰ However, as discussed above, there is still the integrity of the seal between the CSTD spike or needle and the vial septum over prolonged time-periods to consider. Use of CSTDs in this context would need extensive microbiological validation and also an assessment of materials leaching from the device fluid path when in prolonged contact with cytotoxic drug infusions, some of which are formulated with aggressive co-solvent systems which could attack plastic and metal components of the device.

 

Conclusions

It seems likely that optimal cytotoxic containment and maintenance of infusion sterility requires a combination of current technologies. The implementation of CSTDs in pharmaceutical compounding units when used in combination with isolators, and their use in clinics for chemotherapy administration, may be the way forward. This would require a joined-up approach by pharmacy and nursing staff, and careful evaluation in terms of cost and benefit.

 

References

 

Note: As an opinion piece, this article is not extensively referenced. If additional reference sources are required, please contact the author.