Introduction
What are the expectations for industry for the inclusion of different sanitization agents within a routine sanitization program? Additionally, are there tangible benefits to routinely rotating sanitization agents? Finally, how is sanitant performance defined?
The definition of sanitant acceptability as stated in 40 CFR 156 indicates that sanitization products for use on non-food contact surfaces achieve at least a 99.9% (3-log) reduction in the number of test microorganisms over the parallel control count within 5 minutes. For the purpose of this discussion, the terms sanitization agent, sanitant, sanitizing agent, antiseptic, and disinfectant are used interchangeably as all of these agents are primarily designed to reduce microbiological bioburden on applied surfaces. The practice of rotating sanitization agents has primarily been based upon accepted wisdom that routine exposure to a single sanitization agent over time can promote the selection of microorganisms with increased resistance to antibiotic
agents. This document discusses the current argument for sanitant rotation and provides points to consider in determining when the rotation of sanitants is beneficial as part of a routine sanitization program.
Recommendations & Rationale for Recommendations
Sanitizers are defined by the Environmental Protection Agency as “pesticide products that are intended to disinfect or sanitize, reducing or mitigating growth or development of microbiological organisms including bacteria, fungi, or viruses on inanimate surfaces in the household, institutional, and/or commercial environment”.
Sanitizing agents have been used to reduce microorganisms on food and pharmaceutical processing equipment for nearly 100 years. Over this extended period of time, little data supporting the development of microbial resistance to such compounds have been observed.
The destruction and/or complete inactivation of microorganisms, accomplished by application of a sanitization agent, occur primarily through the disruption of physical properties of the bacterial cell rather than the interruption of a cellular metabolic process. Within a given microbial population, there are however natural differences in cell composition and physiology that can directly correlate to varying degrees of sensitivity to a given sanitizing agent. This “innate resistance” is a chromosomally controlled property that is naturally associated with a microorganism and is not subject to mutation as seen in acquired resistance to antibiotics.
While development of resistance to sanitization agents is not scientifically supported, differences in innate resistance is a factor to consider in a sanitization program[taz1], including rotation of sanitization agents.
Of primary importance in any sanitization program is the proper selection of a chemical agent to reduce microbial bioburden. Selection should be based upon the number and specific microorganisms present in the area where the sanitizing agent is to be routinely applied. In addition, effective cleaning should precede any application of sanitant. The condition of the surfaces that are to be sanitized require proper conditioning through cleaning, since deposits can prevent proper sanitizer contact with target microorganisms. Furthermore, residues on the surface to be sanitized have been found to inactivate or reduce the effectiveness of some types of sanitizers (e.g. hypochlorites) rendering the sanitization procedure ineffective”.
When is Sanitant Rotation Beneficial?
There are conditions when the rotation of sanitizing agents should be considered. Standard Operating Procedures (SOP) shall describe, but not be limited to, the following … Cleaning schedule and disinfectant rotation”.
The following are some useful points when considering rotation as part of a routine aseptic processing area environmental control program:
Seasonal Variation: in locations, which have significant seasonal changes, the environmental microflora can fluctuate from season to season. As a result, the anticipated bioburden that may be introduced into an area that is part of a routine sanitization program can change. This necessitates the need to assess the best chemical sanitizer to control the anticipated contaminants during each seasonal period.
Microbial Variation: it is well known that there is no single sanitant that is universally effective for all potential microbial contaminants. As a result, sanitant rotation can be a viable option to ensure that all potential environmental contaminants are controlled and not allowed to selectively proliferate in an area that is part of a routine sanitization program. The use of a single type of sanitizer may allow for selection and persistence of resistant strains. Therefore, the rotation of sanitant agents should be based on “good sense of using a medium level maintenance sanitant/cleaner with some frequent application of a sporicide that is based upon environmental data” of the varying types of micro-organisms identified.
Compatibility: the varying nature of microorganisms and their intrinsic differences may warrant the use of sanitants at some frequency that may not be compatible to area surfaces and associated equipment. By rotating sanitizing agents, the potential damage these surfaces is reduced, while still ensuring that microbial contaminants are not allowed to proliferate to an unacceptable level.
Ineffective Use: A poorly executed sanitization program or procedure that consistently results in improper application with the sanitizer (e.g. at less than manufacturers recommended concentration or insufficient contact time) can resemble the selection of resistant micro-organisms strains. Over time, the surface can become colonized with specific, hard-to-kill microorganisms, that are innately (i.e. natively) resistant to the sanitizer. In such a situation, there is a benefit to temporarily rotate to another type of sanitant in order to eliminate this residual microorganism population. Proper sanitant use is imperative as the “biocidal activity of all chemical disinfectants may be greatly reduced by errors of choice, by improper preparation, and storage of their diluted solutions, by physical or chemical incompatibilities” . Routine use of sanitants at “sub-effective dosages or sub-effective contact times”9 have promoted a false assumption of microbial resistance development.
Regulatory Expectations: Regardless of the current industry stance regarding sanitant rotation, “the regulatory authorities have in many cases spoken out in favour of this practice”. Additionally, “some employ rotation because they have been asked this question by the Food and Drug Administration investigators during GMP inspections”.
However it is important to note that there is no domestic (i.e. FDA) official requirement that indicates that sanitant rotation must be performed, rather this “regulatory opinion on rotation seems to vary from inspector to inspector”. Another supporting reference on this position concerning a preference rather than insistence on sanitant rotation can be found within the International Standards Organization (ISO) 13408-1, section 10.1.7 that states “Interchanging or rotating disinfectants should be considered due to potential changes in environmental flora/isolates”. However, internationally, the standard guide issued by the European Commission for Good Manufacturing Practices (specifically Annex 1) entitled “Manufacture of Sterile Medicinal Products” explicitly indicates that chemical agents used to reduce microbial bioburden on surfaces should include more than one type and that routine monitoring should be performed to detect the development of resistant strains.
Conclusions
The inclusion of sanitation rotation within a sanitization program within the pharmaceutical manufacturing industry is recommended under specific circumstances but it should not be rationalized from the position that such an activity prevents the development of resistant micro-organisms. Consideration for sanitant rotation may be supported by the sound scientific principles outlined herein, including such realities as a varied microbial population with different intrinsic resistance to sanitizers, season variations, surface compatibility requirements, and human error.