Wednesday, December 1, 2010

Basics of Isolator Cleaning


Dr. Thomas H. Treutler
Isolators are increasingly installed in pharmaceutical production laboratories due to the increased handling of hazardous drug ingredients as well as the need for smaller batches and more flexible production environments. Isolators can potentially lower the installation and maintenance costs compared to large scale cleanroom environments. While manufacturing facilities have established SOPs for isolators, this article focuses on the importance of proper cleaning and wiping procedures.
ISOLATORS AND DECONTAMINATION
Decontamination is the reduction or removal of biological or chemical agents, including non-active particles to non-hazardous levels to products, processes, or the environment by means of physical or chemical procedures.
Specifically in pharmaceutical manufacturing environments, research laboratories, and hospital pharmacies, the effective decontamination of biological agents like bacteria, viruses, fungi, protozoa, prions, and spores is essential.
Isolators like fume hoods, biosafety cabinets, and gloveboxes are used to create environments with low levels of environmental pollutants such as biological agents, aerosol particles, and dust. These separative devices have a controlled level of contamination, specified by the number of particles with a defined size per cubic meter, providing controlled environments that are specifically tailored to the needs of its operator. This classification of cleanrooms and isolators, however, is not taking into account specific requirements regarding biological contamination. In order to maintain the low levels of environmental pollutants, isolators have to be decontaminated on a regular basis.
ISOLATOR CLEANLINESS
Isolator cleanliness levels are defined by different classifications, shown in Table 1 and Table 2. These classifications are evaluating the environmental pollution by particles, however, not taking into account specific requirements regarding biological contamination. In order to maintain the low levels of environmental pollutants, isolators have to be decontaminated on a regular basis.
Quality supervisors in facilities using isolators have to determine the acceptable level of biological agents in their respective environment and decide on the method to achieve these levels. Several factors influence the choice of method and materials.
Table 1 and Table 2

POTENTIAL CONTAMINANTS
Isolators are used in a variety of industries working with different material and under different requirements. Potential contaminants in isolators can therefore range from biological contaminants (e.g. pharmaceutical industry, hospital pharmacies), radionuclides (e.g. pharmaceutical industry, research laboratories) to general particulate contaminants (e.g. semiconductor industry).
CHEMICAL AGENTS: INACTIVATION
Spills of hazardous chemical agents in isolators or potential reaction products immobilized on isolator surfaces have to be inactivated or diluted to non-hazardous levels. The chemicals and chemical processes used for inactivation depend on the contaminant.
BIOLOGICAL AGENTS: DISINFECTION AND STERILIZATION
To reduce the level of biological agents in an environment, disinfectants/sanitizers and sterilants can be used. Sanitizers and disinfectants are terms used in different industries for the same kind of product. Whereas the food and foodprocessing industry uses the term sanitizers, the pharmaceutical industry, laboratories, and hospitals are predominantly using the term disinfectant.
Disinfection describes a process that eliminates many or all pathogenic microorganisms on inanimate objects, except bacterial spores.1 On the other hand, sterilization describes a process that destroys or eliminates all forms of microbial life and is carried out by physical or chemical methods.1 Depending on the biological agent and the material or media holding it, sterilization can be achieved through the application of heat, chemicals, irradiation, high pressure, or filtration. It is essential to understand the difference between both processes to assure that contamination level requirements of work environments are met. Whereas some commercial and technical literature is confusing readers by using both terms interchangeably, it should be noted that disinfection and sterilization describe two processes with very different requirements in outcome. It is not appropriate to talk about partial sterilization or even replace the word disinfection with sterilization.
The efficacy of sterilization depends on a number of factors like:
  • prior physical cleaning (effective surface and biofilm reduction)
  • presence of organic and inorganic load-level and type of microbial contaminants
  • concentration of sterilant
  • exposure time of sterilant
  • pH, temperature, and humidity of environment
  • geometry of objects and spaces
  • physical properties of objects
Frequent application of sterilization processes is facing two major challenges; the potential build-up of resistance against the used sterilization agent as well as disadvantageous interactions with humans and surfaces that get in direct contact with these agents. The applied processes have to be well understood in order to avoid these detrimental effects.
The efficacy of different sterilization methods has been evaluated and reported by a number of publications. Tested microbial agents include bacteria, spores, and viruses.3,4,5 As discussed in these articles, microbiological agents may show a significant difference in resistance to the discussed sterilization methods. Therefore previously mentioned factors (the efficacy of sterilization depends on a number of factors such as in list one as well as the specific resistance of microbiological agents) play a vital role in the selection of the appropriate sterilization method.
Image 1
(Click Image For A Larger Version)
CLEANING OF ISOLATORS
Decontamination or cleaning, the reduction or removal of biological or chemical agents, including non-active particles is a multi-step process that depends on the contaminant and the required cleanliness level.
In isolators with processes using chemical agents the successful inactivation of these agents precedes any removal attempt in order to avoid further contamination of the environment or reaction with the isolator surfaces and cleaning materials. After successfully inactivating hazardous chemicals, high absorbency wipes are used to physically remove the reaction products.
When choosing isolator cleaning tools and materials, it is recommended that operators introduce the least amount of particle and fiber generating materials into the isolator. Typically a cleanroom laundered 100% continuous filament polyester knit material with sealed edges is recommended for use to clean surfaces inside the isolator. Additionally isolator cleaning tools with replacement covers that have been tested for particle and fiber release are appropriate to extend the reach of the cleaning area as well as providing ergonomic benefits to the operator.
One can also use cleanroom wipes with specific surface treatments to allow the wiper to capture and retain particulate contamination, resulting in more efficient cleaning and reduced likelihood of recontamination of critical surfaces.
The recommended steps to be performed when cleaning a contaminated surface do not change and are the same for all kinds of contaminants.
  1. Always clean from the cleanest to the dirtiest surface.
  2. Clean with overlapping strokes and change wiper surface with each stroke.
  3. If using an isolator cleaning tool or mop, change out cover material with each surface side of the isolator.
In the case of isolators with biological contaminants, like bacteria, spores, and viruses, regular sterilization might seem to be sufficient in killing the microbial agents. However, it is extremely important that prior to sterilization, a physical removal of these contaminants is done in order to avoid a subsequent buildup of biofilms that would increase the resistance to sterilization attempts in the future. Biofilm is composed of polysaccharides that consist of carbon, hydrogen, and oxygen. Hydrogen and oxygen are most likely to be found in most isolators with natural atmosphere, leaving killed microbial agents behind would provide the required carbon for bacteria to reproduce and form new biofilms.
CLEANING PROCESS SOP
Developing a Standard Operating Procedure (SOP) for your isolators is a difficult task and depends on the very specific requirements of a facility’s processes and regulation in its industry. As a rule of thumb, Table 3 can serve as a general guideline to develop your own SOP.6 Questions you should ask yourself are:
  • What contaminants am I concerned about?
  • Would they contaminate my processes (inside) or the environment (outside)?
  • Are these contaminants inert, chemically-, biologically-, or radio-active?
  • What contamination limits have to be considered?
The use of an isolator cleaning tool should also be considered to allow efficient cleaning6 of hard-toreach areas and guarantee an equal pressure distribution of your cleaning material (wipes/pads) on the isolator surface. The applied pressure is a determining factor in the physical removal of contaminants from a surface.
Table 3

SUMMARY
Proper decontamination and cleaning of isolators is critical to the long term success of materials produced in these environments. Reducing the risk of cross contamination starts with a full understanding of the type of potential contaminants introduced before, during, and after the production process. Sterilization and spraying with disinfectants alone are not enough to remove residual particles that could result in the buildup of biofilms. Proper wiping and rinsing protocols are needed to ensure the total removal of contaminants and the cleanliness of the isolator.
References
  1. Healthcare Infection Control Practices Advisory Committee (HICPAC), “Guideline for Disinfection and Sterilization in Healthcare Facilities,” 2008
  2. McDonnell, G.; Russell, A.D.; “Antiseptics and Disinfectants: Activity, Action, and Resistance” Clinical Microbiological Reviews, Jan. 1999, p. 147-179
  3. Mehmi, M.; Marshall, L.J.; Lambert, P.A.; Smith J.C.; “Evaluation of Disinfecting Procedures for Aseptic Transfer in Hospital Pharmacy Departments” PDA Journal of Pharmaceutical Science and Technology, Vol. 63, No. 2, p. 123-138
  4. Block, S.S. Disinfection, Sterilization, and Preservation. Philadelphia: Lea & Febiger 1991
  5. Siegerman, H. “Wiping Surfaces Clean” A2C2 Magazine, April 2003
  6. “Isolator Cleaning Guide” 01 Aug 2010 Berkshire Corporation

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