Alternatives to Formaldehyde Fogging of Clean Rooms
Issue
What alternative methods exist to replace formaldehyde fogging of clean rooms?
Introduction
Alternatives to formaldehyde fogging include the use of liquid sanitizers or fogging with an alternate chemical sterilant such as chlorine dioxide, vapor-phase hydrogen peroxide, or atomized peroxyacetic acid-hydrogen peroxide. For biological facilities where viral contamination is a concern, it may be a regulatory expectation to decontaminate via fogging with some frequency. The switch from one disinfectant to another involves both laboratory and facility studies. The laboratory validation should include surveying the bioburden of the facility and determining the environmental isolate that is least susceptible to the agent. The efficacy of the agent should then be tested against the least susceptible organism on representative surface materials found in the facility. The required reduction of bioburden should be proven in the laboratory with the least susceptible organism on the surface that allows for the greatest number of survivors.
Studies should then be conducted under actual conditions of use via surface monitoring of the facility both before and after application. To qualify a new fumigant it may not be necessary to include biological indicators in the facility studies if distribution of the chemical can be shown by physical means.
Recommendations & Rationales
The International Agency for Research on Cancer classified formaldehyde as carcinogenic to humans in June of 2004. It is therefore prohibited to use formaldehyde in new fogging applications. However, since many GMP facilities currently use
formaldehyde to fog clean rooms on a periodic basis, there is a need for information on the options that exist to replace it. Facilities are encouraged to actively pursue alternative sanitization methods. Feasibility studies should be completed to determine the business impacts and EHS implications of changing to a different sanitizer. If the feasibility study indicates that formaldehyde use must continue, facilities should evaluate modification of the application process to minimize amounts of formaldehyde used, the airborne concentration of formaldehyde gas, and total exposure times.
A common use of formaldehyde at GMP some facilities is to sanitize clean rooms following maintenance shutdowns. Other facilities have more established frequencies of use during routine operations that vary from daily to monthly. This good practice bulletin will discuss the options available to replace formaldehyde, some regulatory requirements for sanitization of clean rooms, and validation considerations for switching sanitizers Definitions.
Disinfectant -Substance that destroys most forms of microorganisms on inanimate objects but not necessarily spores.
Fogging -Use of a chemical, typically a sterilant, in a gaseous or vaporous state to destroy microorganisms in a facility. Also known as fumigation.
Sanitizer -Substance that significantly reduces the bacterial population on inanimate objects.
Sterilant -Substance that destroys or eliminates all forms of life on inanimate objects including vegetative bacteria, viruses, bacterial spores, fungi, and fungal spores.
Regulatory Expectations for Sanitization
There are regulatory expectations for the periodic sanitization of clean rooms to ensure conformance to expected environmental bioburden levels though none of these explicitly require the use of fogging (2), (3), (4). For biological facilities where viral contamination is a concern, there may be regulatory reasons to sanitize via fogging with some frequency as both Annex 2 of the European Commission and the World Health Organization’s GMPs for biological products mention the terms “shall” and “should” with regards to fumigation (4), (5). Many non-biologics facilities successfully meet the general regulatory expectations for sanitization through the use of only liquid sanitizers, disinfectants, and sterilants. However, fogging can be very effective and may offer advantages over the use of liquid sanitizers in certain situations (e.g. very high ceilings, inaccessible surfaces that require sanitization, etc).
Selection Criteria: The selection of a sanitizer is complex due to the number of criteria that must be considered.
- Environment, health and safety considerations of the sanitizer, including but not limited to air emissions restrictions, toxicity of the sanitizer, and potential fire implications.
- Products need to be evaluated to ensure they will not be affected.
- The number and type of micro-organisms to be controlled must be evaluated and understood.
- The sanitizer must be able to reach all of the areas that require sanitization for the required time under the required conditions.
- The chemical must be compatible with the types of materials found in the facility.
- There must be adequate ventilation to clear any vapours generated by the chemical following use.
- The product must be able to withstand exposure to the level of residual sanitizer that may remain in the facility.
- The life-cycle cost of the use of the sanitizer should be evaluated including initial capital investment in equipment, consumables, validation, and labour.
Advantages and Disadvantages of Selected Fogging Agents
Although there may be no regulatory requirement to do so, many facilities may be reluctant to eliminate fogging due to the history of acceptable data they have generated using formaldehyde. However, EHS considerations related to Formaldehyde use, i.e. carcinogenicity, are such that alternative sanitization agents should be actively pursued.
Fortunately there are other chemicals that can be used to fog clean rooms. Although there are others, three potential replacement options are listed below along with some advantages and disadvantages of each. It should be noted that what is considered an advantage is highly dependent on the specific application. These chemicals are all considered sterilants under certain conditions though the concentration of the agent that is required to achieve destruction of bacterial endospores varies greatly. With proper design and validation, all can have good distribution throughout the clean room on a consistent basis. Labor costs are still typically lower than with liquid sanitizers because the chemical can be distributed by airflow instead of by personnel.
Gases and vapors also penetrate better into enclosed spaces than liquid disinfectants. Depending on the sensitivity of the equipment to the sanitizer, this may be an advantage or disadvantage. Like liquid sanitizers, it is important that surfaces be clean prior to application of fumigants to ensure full activity.
Chlorine Dioxide
Advantages
- Effective at ambient temperatures though destruction is improved with pre-humidification
- Extremely low residuals are composed of salts
- Rapid aeration times following use
- Good material compatibility
- Good penetration characteristics since it is a true gas
Disadvantages
- Requires specialized equipment that may be costly to purchase and validate
- Strong irritant though it is a built in safety monitor, i.e. irritant properties are noted at levels below those resulting in systemic toxicity or chronic health effects
- Relatively new technology; use is not widespread in pharmaceutical industry yet
- Reagent gas contains chlorine and thus may be flammable?
Hydrogen Peroxide/Peroxyacetic Acid
Advantages- Effective at ambient temperatures
- Extremely low residuals
- Rapid aeration times following use
- Good material compatibility
Disadvantages
- Requires some specialized equipment
- Does not penetrate like a gas
- Corrodes heavy metals
- Oxidizing agent that may have fire safety implications
Vapor-Phase Hydrogen Peroxide
Advantages
- No residuals (byproducts are H2O&O2)
- Relatively rapid aeration following use
- Fair material compatibility
- Widespread use in pharmaceutical industry
Disadvantages
- Requires specialized equipment that may be costly to purchase and validate
- Requires control over temperature and humidity
- Corrodes heavy metals
- Does not penetrate like a gas
- Absorption/de-absorption issues
- Oxidizing agent that may have fire safety implications
Validation Requirements
Whether a liquid, gas, or vapor is chosen, a new sanitizer must be qualified according to Aseptic Area Environmental Control. The qualification should include an assessment of the number and types of microorganisms to be controlled. This could be determined either through historical review of environmental monitoring data or a special study. Once the types of microorganisms typically found in the facility are known, laboratory studies should be conducted to determine the environmental isolate that is the least susceptible to the chosen sanitizer.
For a liquid application, these studies typically involve inoculating a suspension of each test isolate into the use dilution of the sanitizer at expiration. After a set time period, the solutions are either neutralized or filtered to stop microbiocidal properties of the sanitizer and the number of survivors determined. It is critical to validate the neutralization or membrane filtration step to ensure organisms surviving at the endpoint will be recovered.
The isolate with the highest survival rate is assumed the least susceptible to the chosen sanitizer. Official methods for qualifying chemicals as sanitizers, disinfectants, or sterilants are available from the AOAC or European standards committee.
Although the user need not repeat these tests, they may be useful guides in designing laboratory studies.
For a fogging agent, lab studies are performed in a glove box or other suitable environment that allows exposure of inoculated carriers to the chemical for a set time period followed by prompt aeration, removal, or segregation to halt microbiocidal activity. The isolate showing the highest number of survivors following exposure to the chemical at the actual use concentration and environmental conditions is considered the least susceptible to the fumigant.
The organisms selected for screening should include representatives identified during environmental monitoring that offer the greatest resistance to the chemical; for example Gram (+) spore formers, fungal spores, viruses, etc. Additional organisms with limited susceptibility to the agent may also be included to show the relative resistance of the facility bioburden in comparison to those discussed in the literature as being difficult to destroy by the chosen agent.
The method used to apply a sanitizer and the type of surface being sanitized can have an effect on survivability of target microorganisms, so it is prudent to evaluate these variables in the lab prior to facility studies. This can be accomplished by inoculating representative carriers of the materials found in the facility with the least susceptible microorganism and exposing them to the sanitizer using the method, concentration, and conditions that are planned for routine production. Prior to inoculation, the carriers should be cleaned according to the same procedures used in the facility. The materials chosen should include the range of materials and surface finishes that will be encountered in the facility (e.g. metals, smooth and rough polymers, flooring materials, etc.). The method should be able to achieve the required bioburden reduction of the least susceptible organism on the surface material that allows for the most survivors before it is accepted for use in facility studies.
Following completion of laboratory studies, sanitizers should be qualified in the actual facility where it will see routine use. The studies should show the agent can be effectively applied to all surfaces that require sanitization and that the required conditions are met for the required contact time. For a fogging agent, if the concentration can be measured physically or chemically, distribution to all areas of the facility may be qualified without the use of biological indicators. However, biological indicators could also be used in lieu of other methods. The bioburden of surfaces should be determined during the study to ensure required bioburden levels were obtained.
In most facilities, fumigation will be used following shutdowns as part of start up activities while alternate sanitizers are applied between batches, or on a daily or weekly basis. Other facilities, particularly those that involve the use of viruses, may require more frequent fumigation. Whatever regiment is chosen, the frequency of all cleaning and sanitization activities should be based on environmental monitoring data.
The initial frequency may be chosen based on previous experience with the actual facility or other relevant experience. The adequacy of the chosen sanitization frequencies should be assessed on an ongoing basis by reviewing environmental monitoring data for trends that may signal the need for more rigorous application.