Answers to the 10 Most Common Questions Regarding Microbial Control in Cleanrooms

Answers to the 10 Most Common Questions Regarding Microbial Control in Cleanrooms

By Elaine Kopis, ConvaTec

Q. What is the difference between a sanitizer, a disinfectant and a sterilant?

A. The Environmental Protection Agency (EPA), under the authority of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), administers the registration and regulation of chemical agents which are utilized for sanitizing, disinfecting and sterilizing hard surfaces in the United States. According to the EPA, the key differences between these agents is in terms of degree of microbial reduction. A sanitizing agent typically provides a bacterial reduction of 99.9 percent (3 log) on pre-cleaned surfaces. A disinfectant will provide 100 percent kill of bacteria, target viruses and target fungi. Depending upon the formulation, the disinfectant may or may not require that surfaces be precleaned before use. A sterilant is defined as an agent which provides 100 percent kill of all microorganisms, including bacterial spores. The key significance of a sterilant is that it is the only antimicrobial agent which has satisfactorily demonstrated the ability to destroy bacterial spores. All sterilants require that surfaces be cleaned before treatment. Oftentimes, the term “sanitizing agent” is used to describe any of these three chemical agents. The key differences between the three types of agents is the type of chemical active used in the formulation (although some chemical actives are available in all three types of agents), the concentration of the chemical actives and the contact time necessary to achieve the label-stated activity. For example, sanitizers and disinfectants typically require a 10-minute (or less) contact time to meet label-stated efficacy claims, whereas sterilants typically require 5 to 10 ten hours for full efficacy.

Q. The FDA recommends that cleaners and sanitizers introduced into the aseptic processing area be sterile. This is typically accomplished by the facility which purchases non-sterile concentrates or solutions and then processes these products through bacterial retention (0.22-&#181m) filters into a sterile container under aseptic conditions. For those products claiming to be sterilants, is it necessary to sterilize them, or are they already sterile?

A. The answer to this question may be yes or no, depending on the formulation of the sterilant. Certain sterilants are composed of strong oxidizing agents which will, after a given time period (typically less than 10 hours), destroy all microorganisms that come into contact with it. Therefore, if microorganisms are inadvertently introduced into the container during packaging, the self-sterilizing nature of these liquids would destroy the microorganisms within that 10-hour time frame. The typical time lapse from manufacture to distribution would ensure that the product would be received by the facility after a 10-hour time duration; therefore the product within the container would be sterile. Other types of EPA-registered sterilants are two-part systems, which require some form of activation prior to use as a sterilizing agent. Examples of this include glutaraldehydes and chlorine dioxide products. Because both of these products require activation prior to being considered a sterilizing solution, it may be logically argued that neither component in itself is a sterilizing agent, unless otherwise validated.

Q. Why should a facility purchase sterile concentrates when they can sterile-filter non-sterile products themselves?

A. Aseptic processing involves several sterilization steps for components and products which are later brought together under highly controlled conditions to yield a sterile product. Consequently, the possibility for contamination is much higher than that for terminal sterilization, and validation activities are more rigorous. Due to the contamination issues inherent in aseptic processing, terminal sterilization of products is preferred whenever possible. Unfor tunately, in some cases, products or components may be negatively impacted when subjected to standard sterilization techniques such as heat or radiation. In these cases, aseptic processing is the only option. Contamination control products such as phenolic germicidal detergents and 70 percent isopropyl alcohol solutions are typically purchased by a facility as non-sterile concentrates or solutions. Prior to use in an Aseptic Processing Area (APA), where critical processes take place, the pharmaceutical manufacturer will process these products by filtration through a 0.22-&#181m filter (sterilizing filter) into a sterilized container. This is a form of aseptic processing, which assumes the same level of risk and responsibility (validation) as other aseptic processing operations with regard to sterility assurance. An alternative to aseptic processing is provided to pharmaceutical facilities by those manufacturers who supply contamination control products that have been subjected to terminal sterilization. Typically, these products have been double-bagged for ease of transfer into aseptic areas, and terminally sterilized utilizing gamma radiation. The obvious advantage of this processing is that there are fewer variables in a terminal sterilization process as compared to aseptic processing. This type of processing leads to a higher sterility assurance level and a more readily validatable process. In addition, the use of terminally sterilized products transfers the responsibility for sterility validation and doc

Q. Do cleaners, disinfectants and sterilants leave residues behind on cleanroom surfaces?

A. In most cases, the answer to this question is yes. If you examine the formulations of most germicidal detergents (sanitizing agents that do not require pre-cleaning), they will contain a number of ingredients, aside from the actives, that are soluble in water, alcohol or other solvents used in the formulation. These ingredients include surfactants and dispersants (for better cleaning and soil dispersion) and buffering agents (to maintain the optimum pH range for product performance). After the product is diluted to the use concentration and applied to hard surfaces, evaporation of the solvent system occurs very quickly, leaving behind small amounts of residue from the actives and the excipients in the formulation. Additionally, in some cases, by-products of the product`s activity may leave residues. For example, sodium chloride residue may be left from the use of sodium hypochlorite (bleach). Other types of sanitizing agents may leave no residue. Examples of these products are isopropyl alcohol and hydrogen peroxide. However, both these sanitizing agents would require that the surface on which they are used be precleaned with some type of formulated cleaner, which will most likely leave a residue. The key question at this point should be, “Are residues left by sanitizing agents a concern to cleanroom users?” There are two prevailing opinions on this issue. One opinion is that the residues left behind from the use of formulated germicidal detergents may have bacteriostatic properties, in which case the residue would be beneficial. The other opinion is that no residue is acceptable in a cleanroom, in which case the residue may simply be removed with an alcohol or WFI rinse.

Q. If bleach is such a good disinfectant, why is it necessary to use anything else?

A. Sodium hypochlorite solution (bleach) has been used as an inexpensive disinfectant for over 100 years, most notably in water treatment, but also as a skin and hard surface disinfectant. There is a great deal of data supporting the efficacy of bleach as a disinfectant and a sterilant, even though bleach holds no EPA registration as a sterilant. However, there are some limitations to the use of bleach. Although, sodium hypochlorite is capable of bleaching some materials, it is not a very good cleaner in itself, as it contains no surfactants, dispersants or other ingredients necessary for soil removal. The activity of bleach is adversely affected by a number of factors, including the pH of the solution and the organic soil present. Most commercially available bleach solutions are sold at a pH above 12; however, for greater efficacy, the bleach solution should be acidified to a pH of 5-6 in order to generate a higher level of hypochlorous acid. The acidification process must be very carefully controlled to avoid the generation of chlorine gas. Storage conditions are important to preserve the activity of the product; high temperatures (> 35&#176C) and ultraviolet light exposure should be avoided. In addition to these concerns, the overuse of bleach may lead to corrosion of cleanroom surfaces, including stainless steel.

Q. In situations where more than one cleaner, disinfectant or sterilant is used in an area, will residues from these different agents interact with each other?

A. This question should be addressed on a case-by-case basis. However, typically, the use of one type of chemical agent on a dry surface which has previously been treated with another type of chemical agent will present minimal risk from interaction. The reason for this is that residue levels are very small to begin with, and in some cases, the activity of the disinfectant will have diminished from use prior to exposure to another agent. Additionally, in some cases the residues left on surfaces will include inert by-products from the reaction of the chemical agent, rather than active materials. There are some notable exceptions to this generality. Quaternary ammonium chloride compounds, which contain long chain cationic species, and phenolic compounds, which contain long chain anionic species, are innately incompatible with each other. In certain facilities where these two dissimilar antimicrobial agents have been used together on a rotational basis, the formation of sticky, dark residues on cleanroom surfaces have been reported. These residues do not appear to cause permanent damage and are readily removed by cleaning with a non-ionic surfactant-based cleaner or, in most cases, an alcohol solution. Chemical agents should never be mixed together as concentrates or use dilutions, nor used in any manner inconsistent with labeling.

Q. What is the recommended cleaning schedule for a Class 100 area?

A. The FDA published a set of recommendations in 1987 entitled, “Guideline on Sterile Drug Products Produced by Aseptic Processing.” This guideline defines aseptic processing as a process by which “the drug product, container and closure are subjected to sterilization processes separately and then brought together. Because there is no further processing to sterilize the product after it is in its final container, it is critical to the maintenance of product sterility that containers be filled and closed in an environment of extremely high quality. In addition, there are usually more variables attendant to aseptic processing than to terminal processing, a factor that can make it more difficult to attain a high degree of assurance that the end product will be sterile.” As these recommendations emphasize, the quality of the environment in which aseptic processing is performed is critical to the sterility of the product. Therefore, the cleaning of this area should be performed frequently using products which have been validated to control any environmental isolates. While the FDA guideline offers no specific cleaning frequency recommendation, typically, a Class 100 area will be cleaned daily or between shifts. Cleaning will include, floors, walls, ceilings and equipment. Supporting areas may be cleaned less frequently. However, the cleaning schedule should be supported by environmental monitoring.

Q. The FDA recommends that facilities validate that their sanitizing agent is effective against facility environmental isolates in order to support their environmental control programs. What is the best way to validate a sanitizing agent?

A. There are two approaches to validation common among pharmaceutical facilities. One is to conduct laboratory efficacy studies with the disinfectant against environmental isolates. The second is to conduct both laboratory and in situ evaluations of disinfectant efficacy. Laboratory studies generally involve an evaluation of the use-dilution disinfectant against environmental isolates either in suspension or coated onto coupons comprising the various substrates in the cleanroom. The purpose of use-dilution testing is to evaluate the performance of the disinfectant as used in the cleanroom against microorganisms isolated from the cleanroom environment. Testing is most conveniently conducted using a time-kill procedure. The primary objective is to demonstrate that the disinfectant provides a significant (3-6 log) reduction against the target organisms. After establishing via laboratory testing that the disinfectant displays sufficient efficacy, many facilities choose to conduct a trial of the disinfectant. Typically, the trial will involve a “before and after” cleaning evaluation of the facility, utilizing surface sampling procedures such as swabbing or contact plates. This type of evaluation not only provides in-use performance data, but also allows cleaning personnel to judge other characteristics of the disinfectant, such as cleaning ability and residue levels.

Q. Is fogging a good way to apply sanitizing agents?

A. In order to address this question, fogging must be clearly defined. Fogging may mean wet misting, in which case material is still in liquid form. Fogging is also used to describe a process by which the chemical agent is forced from one physical state (solid or liquid) to the vapor state. Typically, fogging (vapor state) is used to apply either formaldehyde (paraformaldehyde) or glutaraldehyde, which are chemical sterilants, by anti-infective manufacturers. The concern with manual application in these situations is that the sanitizing agent may not be able to effectively permeate all areas of the cleanroom, including HEPA filters, where viruses from the production process may be present. In this sense, fogging may be appropriate. However, fogging should not be used as a substitute for manual cleaning applications.

Q. How should sanitizing agents be prepared and stored in order to ensure the safety of personnel and the efficacy of the sanitizing agent?

A. The label for a sanitizing agent is without a doubt the best source of comprehensive infor mation regarding the use of the product. A typical label includes the following sections: Precautionary Statements (de-tails any hazards and recommended safety equipment with regard to use); Directions for Use (for each of the claims associated with the sanitizing agent); Storage and Disposal (for product and empty container); Statement of Practical Treatment (for exposure), and a summary of the active ingredients in the formulation. The label also contains the lot number and, if applicable, the expiration date of the product. The sanitizing agent should always be prepared in accordance with the label instructions. To do otherwise would be a violation of Federal Law and may lead to personnel injury. Several factors may influence the performance of a sanitizing agent. In general, concentration, water quality, temperature and contact time are the key factors. The label will address most of these factors. However, use-dilution temperature is usually not addressed. One may not assume that the use-dilution of a sanitizing agent will be stable or effective at all temperature ranges. The use of 60&#176C WFI, for example, as a diluent for the disinfectant may not be appropriate. The manufacturer of the disinfectant solution should be able to provide input on this issue. Additionally, the chemical stability of the use-dilution during extended storage may not be addressed on all sanitizing agent labeling. In general, it is recommended that use-dilution be used within a 24-hour period, even though chemical stability may be much longer, in order to minimize risk of contaminating the solution. Some facilities choose to prepare large batches of disinfectant solution, which are then stored and dispensed for use into smaller containers over a period of up to one month. In some cases, the manufacturer of the sanitizing agent will be able to provide stability information for the use-dilutio

Elaine Kopis is a Technical Service Chemist for the ConvaTec Contamin ation Control Group. Her focus area is microbial control in critical environments. She is a member of the CleanRooms Editorial Advisory Board.


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