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Drug manufacturing facilities are required to establish facility and process controls to prevent microbiological contamination (21 CFR 211.113). Bacterial endospores and fungal spores present significant contamination challenges in drug production areas due to their prevalence in the environment and inherent resistance to chemical inactivation. Spore forms of both organisms develop, in part, due to adverse environmental conditions, producing a dormancy that allows the core genetic material to survive until conditions for growth are present. While a bacterial endospore, such as Bacillus cereus, demonstrates greater resistance, fungal spores, such as Aspergillus niger, typically demonstrate more resistance to chemical inactivation than other vegetative microorganisms.
Many recent 483 observations and Warning Letters demonstrate deficiencies in addressing spore control. Control of bacterial and fungal spores requires a holistic approach to managing the environment. This approach should include examination of the contributory factors related to introduction of bacterial and fungal spores to the facility and to effective remediation, including facility design, personnel compliance, and cleaning practices.
Poor facility design is one way to assure contamination control problems. It is also very difficult to overcome after the fact. For example, controlling water through source and drainage reduces microbial contamination risk. Areas with floor drains, sinks, water drops, pooling or where water damage has occurred are breeding grounds for microorganisms. Further, uni-directional traffic control, with appropriate isolation measures, shields classified production areas from contamination from other areas. Physical barriers to introduction of contamination should be maximized. Humidity and temperature controls are another means to reduce the risk of microbial proliferation. Finally, surfaces should be selected to maximize microbial control measures (e.g., coving, chemical resistance, thermal resistance, limited obstructions).
Human beings are the most portable and proliferate source of microbial contamination, directly and indirectly. Directly, people shed particulate and accompanying this particulate are microorganisms. Although barrier apparel protects the environment to some degree, there are limits to the efficacy of barrier devices, and the efficacy is impacted by how the wearer behaves. Indirectly, through transport of equipment and supplies, people may contribute even more microbial contamination. People, are also responsible for developing and executing the processes to manage microbial risk. These processes include: development of robust standard operating procedures (SOP) for control measures, such as cleaning; development and delivery of effective training programs; and performance monitoring and feedback.
Cleaning practices in drug manufacturing areas usually involve the use of chemical agents for removal of soil and for control of microorganisms. These agents are known by many names, including, disinfectant, sanitizer, sporicide, sterilant, and detergent. A robust cleaning program for non-product contact surfaces will include multiple chemistries. Most vegetative bacteria and fungi will succumb to broad spectrum disinfectants. These products typically contain a detergent system to aid in soil removal and an active substance effective against various types of vegetative organisms and viruses. The manufacturer’s data provides guidance in these matters. Bacterial endospores are more difficult to eradicate, due to structural features such as a outer coat of keratin, and require the application of a sporicide (or sterilants) for effective eradication. There are tradeoffs in the selection and use of disinfectants and sporicides. Considerations include, efficacy against the microorganisms of concern, substrate compatibility, residue control, personnel safety and comfort, ease of use, frequency of application, and regulatory compliance.
Each facility has unique challenges and needs that must be addressed. For more information on developing an effective spore control program and on STERIS training programs, please contact the STERIS Technical Service Team.