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Published on 1 September 2003

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The scope of validation for cleanroom disinfectants

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Andrew Davidson
Commercial Director Shield Medicare Ltd

Adaptation of a paper presented at the R3 conference in Norway, October 2002

All aspects of new disinfectant agents need to be considered right from the start. This will aid the production of quick and meaningful validation results, leading to early implementation of new disinfectants and prompt responses to audits.

There are many reasons why you may need to validate a new disinfectant:

  • New or changed standards.
  • Repeated action points.
  • Health and safety issues.
  • Corrosion concerns.

Whatever the reason, there are five key points to address when starting to validate a cleanroom ­disinfectant:

What microbiological testing is required?
Probably the most difficult requirement in a hospital pharmacy cleanroom is the control of bacterial spores, which are resistant to many standard disinfectants. Often a successful sporicide will have other drawbacks, as it can be dangerous to humans or equipment or both. Hence the search for a non-hazardous but effective sporicide is very important.

Traditional biocides, such as alcohol, quarternary ammonium compounds, phenols and amphoteric surfactants, are effective against bacteria in their vegetative state but are ineffective against spores. A key decision therefore is what level of sporicidal activity is required. For most cleanroom users a log 3 reduction is usually adequate. Check the manufacturers’ supporting data for your selected agents, including sporicidal activity, as this will identify any additional testing that is required.

Most disinfectants have BS EN 1276:1997 (bactericidal) and BS EN 1650:1998 (fungicidal) efficacy data. These standard tests are suspension tests, consideration should also be given to surface testing. A test methodology can be found in BS EN 13697:2001, with the acceptance criteria for surface testing a log 4 reduction against bacteria and a log 3 reduction for fungi. Currently, good sporicidal efficacy can be shown by a log 3 reduction in soiled conditions using a modified BS EN 1276 test and a spore suspension.

Reported success with difficult environmental isolates is invaluable. Another useful indicator is the experience of major reference sites. The commissioning of new cleanrooms is an excellent source of data as this presents a significant challenge to a disinfectant.(1) These different forms of data available from a manufacturer provide supporting evidence of effectiveness, which helps to select the agents for validation.

The next step is to determine your own sporicidal test requirements. Testing sporicides in the laboratory is very difficult for many reasons and can slow down the validation process. It can be problematic because isolates are difficult to sporilate and the neutralisation of the disinfectant being used is not always straightforward. Our company has devised a methodology that is based on a membrane filtration method and is suitable for any disinfectant. The aim was to design a test that was reliable, repeatable at an independent laboratory and inexpensive to carry out. The validated membrane test enables real situations to be tested such as spraying onto a surface.

To achieve this, we focused on the following areas:

  • Accurate quantification of the number of ­organisms to give meaningful log reduction results.
  • Uniform presentation of spores.
  • Consistent exposure of the disinfectant to the spores.
  • Wash phase to ensure full neutralisation of the agent.

We used two independent laboratories to carry out the test to investigate two strengths of our product and a peroxide/peracetic acid compound.(2) The tests were carried out at 100% concentration in clean conditions and in soiled conditions at 90% of the ready to use concentrations. This is important to note, as a ready to use concentration will always be diluted by the interfering substance and inoculum. The results were very consistent. Several large pharmaceutical companies are validating this test method for themselves with promising results.

What is the specification of the agent, and how will it be used?
While the microbiology work is in progress, it is important to widen the scope of the validation and avoid any last minute problems. The final specification of the disinfectant must be considered carefully to ensure it can be transferred easily into the cleanroom, and it meets the required standards for sterility or dilution with water for injection (WFI). Current Good Manu­facturing Practice states that disinfectants in Grade A and B cleanrooms should be sterile before use.(3)

Similarly a disinfectant may require a range of presentations and methods of application for different environments. Large areas may require concentrates for use with a mop and bucket system or a format suitable for fogging. Critical areas will need ready to use sprays or presaturated impregnated wipes.

In all cases the product must be supplied with essential batch documentation and certificates of sterility, irradiation and conformity where applicable. It is also essential to review the standard operating procedures to determine the implications a particular biocide may have.

Factors to consider include the frequency of use and the possible rotation of the agents in question. Consider the effect that contact time may have, there can be major operational considerations, for example fogging with formaldehyde has a 24-hour turnaround time. There may be a need to rinse after the use of some agents which could have consequences if overlooked. Avoiding operator error especially with bulk concentrates, ensuring the dilutions are correct, has to be considered and planned for.

Instructions for dealing with a spillage can also have a direct bearing on the choice of agent. Disinfectants are tested in soiled conditions but is powerful efficacy really required? Most procedures recognise that a spillage would be physically removed before the biocide was required.

The cleaning method itself can have an effect on disinfectant efficiency. A case study carried out in a large UK teaching hospital showed the use of a triple bucket system significantly reduced the contamination of the disinfectant solution when compared with a single bucket system.(4)

A final procedure point is; how long can you keep the disinfectant before it must be discarded? This has wide implications for wastage and auditors often ask about the in-use shelf life of a product. The two main systems of liquid application in a cleanroom environment are a trigger spray system or an aerosol can. There are benefits associated with a trigger spray system. These include an adjustable nozzle so liquid can be dispensed as a jet or a spray enabling thorough wetting of the surface so that disinfection procedures are effective, they are environmentally friendly as they contain no propellants requiring special disposal procedures, and all of the liquid can be dispensed from a trigger spray so there is no wastage making them a cost-effective solution. However, contaminated air can be drawn back into the bottle compromising the sterility of the liquid. A closed delivery system prevents air being drawn back into the bottle, eliminating the possible chance of contamination of the liquid.(5)

What are the health and safety implications?
Alongside the effectiveness and usefulness of agents, a health and safety risk assessment is required as part of the validation process. Some excellent disinfectants, particularly sporicides, are harmful and difficult to use in cleanrooms. The occupational exposure limits, the extra protective clothing or equipment required, and the cost have to be considered for each agent. Input from personnel who have to use the disinfectants can also prove invaluable in the final selection.

Similarly, practical considerations such as on site storage and increasingly, the waste disposal of chemicals or packaging materials, can have major implications resulting in additional costs.

What is the impact on the cleanroom environment?
Many disinfectants, especially sporicides, are oxidising agents and the environmental impact of using these in a cleanroom containing expensive equipment has to be taken into account. A review of the available corrosion data on materials used in cleanroom, isolators and laminar flow cabinets should be a fundamental part of every validation programme.(6)

Most cleaning agents will leave a residue but its importance will depend on the area and the operating procedures. In direct product contact areas it will probably involve rinsing and testing but elsewhere this may not be required.

What support can you expect from the manufacturer?
The final consideration is the level of support that can be provided by the disinfectant manufacturer. Auditors may challenge your validation results and much will depend on the qualities of the manufacturer to be able to respond quickly in an ever-changing regulatory environment. Check that the manufacturer can provide all the technical support you require, that they manufacture to acceptable standards and they have the production capacity to meet your needs both now and in the future. They should be willing for you to audit their manufacturing facility to your standards.

References

  1. Technical Report Number TR0012R. Evaluation of the ­efficacy of Klercide-CR Biocide B when recommissioning an aseptic facility. Based on a poster ­presentation by the Aseptic Production Dept, Colchester General Hospital. NHS QC Symposium, Grantham, October 2000.
  2. Shield Medicare. Unpublished data from work conducted at Voelker Scientific & Evans Vanodine.
  3. Eudralex. Volume 4. Good manufacturing practice. Annexe 1: Manufacture of sterile medicinal products.
  4. Smith J. The effect of different cleaning methods on ­environmental ­monitoring. Poster presentation. National QA symposium, 1999.
  5. Technical Report Number TR9903R. An investigation into the in-use shelf life of Premier Klercide™ 70 /30 Sterile Alcohol Sprays. Shield Medicare, Aug 2000.
  6. Technical Report Number TR0011R. An investigation into the effect of Klercide™ products on commonly encountered materials. Work carried out by Arnold JC, University of Wales, Jan 2001.

Resources
International Confederation of Contamination Control Societies
W:icccs.org
Association pour la prevention et l’etude de la contamination
W:www.aspec.asso.fr
Belgian Cleanroom Workclub
W:www.bcw.be
Irish Cleanrooms Society
W:www.cleanrooms-ireland.ie
Vereniging Contamination Control Nederland
W:www.vccn.nl



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