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Ethylene oxide gas is an agent in the sterilization of medical devices due to its effectiveness and compatibility with most materials. The advantages and disadvantages, as well as its recommended uses, are explored in this review article. The variables and their relevance on process optimization are described, the types of processing cycles are detailed and emphasis is given to the design and validation of the sterilization process.

There are several rapid microbiological methods becoming available that have useful applications in pharmaceutical and medical devices. They are ATP bioluminescence, fluorescent labeling, electrical resistance, and nucleic acid probes. In choosing to employ rapid methods, the microbiologist should examine their prospective performances against the specific requirements for that sector. Some methods may require expensive equipment and offer full automation, and others represent only a small investment. The regulatory view of these methods is changing and they still officially have not been approved in medical and pharmaceutical area, but it will still be up to the microbiologist to demonstrate that the method chosen is fit for the purpose intended.

Water for injection (WFI) and purified water are the most widely used and stringently regulated raw material in pharmaceutical manufacturing. WFI is utilized for a parenteral drug product. Water system is monitored at frequent and routine frequency for demonstrating the overall system control and stability of performance. The critical ports demonstrating systemic control should be monitored more frequently. For reducing the overall risk of microbial contamination or microbial build-up, it is important to develop appropriate alert and action levels. The assignment of alert and action levels should be performance-based, derived from the historic data and well below water specifications. These levels and overall excursion rates should be assessed annually. An action level should not be established at a level equivalent to the specification. Consecutive or multiple alert level excursions and each action level excursion should be comprehensively investigated with appropriate corrective and preventive action. It is important to analyze the efficacy of the corrective and preventive action to reduce the overall excursion rates.

Microbial testing performed in support of pharmaceutical and biopharmaceutical production falls into three main categories: detection (qualitative), enumeration (quantitative), and characterization/identification. Traditional microbiological methods are listed in the compendia and discussed by using the conventional growth-based techniques, which are labor intensive and time consuming. In general, such tests require several days of incubation for microbial contamination (bioburden) to be detected, and therefore management seldom is able to take proactive corrective measures. In addition, microbial growth is limited by the growth medium used and incubation conditions, thus impacting testing sensitivity, accuracy, and reproducibility. 　For more than 20 years various technology platforms for rapid microbiological methods (RMM) have been developed, and many have been readily adopted by the food industry and clinical microbiology laboratories. Their use would certainly offer drug companies faster test turnaround times to accommodate the aggressive deadlines for manufacturing processes and product release. Some rapid methods also offer the possibility for real-time microbial analyses, enabling management to respond to microbial contamination events in a more timely fashion, and can provide cost savings and higher efficiencies in quality control testing laboratories. Despite the many proven business and quality benefits and the fact that the FDA's initiative to promote the use of process analytical technology (PAT) includes rapid microbial methods, pharmaceutical and biopharmaceutical industries have been somewhat slow to embrace alternative microbial methodologies for several reasons. The major reason is that the bioburden counts detected by the incubation method and rapid assay are greatly divergent. 　The use of rapid methods is a dynamic field in applied microbiology and one that has gained increased attention nationally and internationally over time. This topic has been extensively addressed at conferences and in published documents around the world. More recently, the use of alternative methods for control of the microbiological quality of pharmaceutical products and materials used in pharmaceutical production has been addressed by the compendia in an attempt to facilitate implementation of these technologies by pharmaceutical companies. The author presents some of the rapid method technologies under evaluation or in use by pharmaceutical microbiologists and the current status of the implementation of alternative microbial methods.

This review discusses the application of several sorts of non-equilibrium gas plasma discharges for sterilization and disinfection treatments against spores or bioburden on/in the healthcare products or biological indicators. The basic properties of electrical discharges are briefly reviewed and thereafter the paper discusses the interactions of gas plasma with several sorts of biological systems such as bacteria, bacterial spores, endotoxins, lipid A and normal and abnormal prion proteins.

A new low-temperature sterilization method to replace the ethylene oxide gas sterilization is needed. Strong bactericidal effects of OH and O2H radicals are well known. The purpose of this study was to evaluate the sterilization effect of wet oxygen ("O2+H2O") plasma in the bubbling method, confirming the effect of humidity. Sterility assurance was confirmed by using a biological indicator (Geobacillus stearothermophilus ATCC7953, Namsa, USA). One hundred and eight samples (10(5) spores/carrier) were divided into three groups of 36 in each for treatment with a different type of gas (O2, O2+H2O, Air+H2O). Plasma processing was conducted using a plasma ashing apparatus (13.56 MHz, PACK-3(®), Y. A. C., Japan) under various gas pressures (13, 25, 50 Pa) and gas flows (50, 100, 200 sccm). Fixed plasma treatment parameters were power at 150 W, temperature of 60 ℃, treatment time of 10 min. The samples after treatment were incubated in trypticase soy broth at 58 ℃ for 72 h. The negative culture rate in the "O2+H2O" group was significantly (Mantel-Haenszel procedure, p<0.001) higher than in the other gas groups. It is suggested that the significant sterilization effect of the "O2+H2O" group depends on the bubbling method which is the method of introducing vapor into the chamber. The bubbling method seems able to generate OH and O2H radicals in a stable way.

No formation of N,N'-methylene dianiline (MDA) was observed in chain-extended thermoplastic polyurethane (PU) when sterilized by autoclaving or γ-ray irradiation. No formation of MDA was observed in nonchain-extended thermoplastic PU when sterilized by γ-ray irradiation. Less than 1 ppm of MDA was produced in nonchain-extended thermoplastic PU subjected to autoclave sterilization. Autoclave sterilization did not produce MDA in thermosetting PU potting material. MDA formation in potting material was promoted by γ-ray irradiation and increased with increasing irradiation doses at a quadratic equation of regression. MDA formation at 100 kGy irradiation amounted to a few ppm and less than one ppm at 25 kGy irradiation: therefore, the potential risk to human recipients was not significant. The elution of compounds other than MDA from potting material was more problematic. Solvent extracts from potting material showed mutagenicity in the absence of metabolic activity (S9Mix). MDA showed mutagenicity in the presence of metabolic activity, therefore MDA was not the major mutagenic candidate. The chemical and biological characteristics of the specific mutagens should be identified in a further study. The lack of MDA formation and a smaller presence of mutagens in autoclave-sterilized potting material indicated that autoclave sterilization was preferable if the material is able to tolerate heating.

Microbiological control is a regulatory requirement and one that can be defined as the continued interaction of science and applied technology with products, processes, materials, equipment, and personnel entering the manufacturing areas. In the ISO 14644-1, control of microbial contamination is addressed. A good microbiological control program starts with understanding the risks for microbial contamination in the manufacturing process and identification of possible types of contaminants. The results obtained from such risk assessment can be used in the design of facilities and equipment as well as when establishing protocols regarding equipment and personnel. Once possible sources of contamination have been identified, control and preventative measures can be implemented and qualified/validated.

Every person involved in pharmaceutical product manufacturing has the responsibility to assure the quality of the product being produced. The aim of this paper is to validate quality assurance throughout the process of manufacturing pharmaceutical products. Additionally, within aseptic manufacturing, certain monitoring and information needs to be collected on a routine basis to continually assess the state of control of the complete operation. The basis for assessing the state of control is to have rigorous and defined information flow processes. Once the information is collected, quality assurance involves the ability to assess, evaluate, and make appropriate decisions to ensure the product has the required safety, identity, strength, quality, and purity. Quality assurance study is the process of bringing all of the information together, evaluating the information, making decisions, refining systems, and applying process knowledge. This process begins in the early stages of drug development when not a lot of specific process information about the process is known, but it is important to allow for development to progress, building knowledge about process. However, even in early development, sterility assurance requirements should be largely the same at all stages of development and routine commercial manufacturing.

A high-level aseptic environment must be maintained in bio-cleanrooms used for the manufacture of sterile products. In the past, formaldehyde gas was most commonly used to sterilize bio-cleanrooms, but due to strict residual limitations there has been a need to develop a less toxic alternative choice. The authors have developed a revolutionary new sterilization system using a high concentration of ozone gas and used this system to sterilize an actual bio-cleanroom. This system integrates the ozone gas generator with the air conditioning system by proper control. The design specifications for the system included an ozone gas concentration of 200 ppm or more, relative humidity of 80% or more, and a sterilizing time of 120 min. Blow vents and suction ports were placed to ensure a uniform airflow which would extend through the entire room during ozone gas sterilization. Tests regarding long-term material exposure to ozone gas were conducted when the system was introduced to distinguish usable and unusable materials. In an actually constructed cleanroom, simulations were used to predict the evenness of the diffusion of ozone gas concentration and relative humidity during ozone gas sterilization, and measurements of the actual indoor ozone gas concentration, temperature and relative humidity during sterilization revealed that the ozone concentration and relative humidity needed for sterilization had been achieved generally throughout the entire environment. In addition, the CT value (mg/m(3) (=ppm) × min) , derived by multiplying the ozone gas concentration during ozone gas sterilization by the sterilization time, was equal to or greater than the target value of 24 × 10(3) (ppm·min) . When the results of sterilization in a cleanroom were confirmed using a biological indicator (BI) , negative results were obtained at all measurement points, demonstrating that sterilization was being performed effectively in the actual factory at which the ozone gas sterilization system had been introduced.

The proposed approach to validation of steam sterilization in autoclaves follows the basic life cycle concepts applicable to all validation programs. Understand the function of sterilization process, develop and understand the cycles to carry out the process, and define a suitable test or series of tests to confirm that the function of the process is suitably ensured by the structure provided. Sterilization of product and components and parts that come in direct contact with sterilized product is the most critical of pharmaceutical processes. Consequently, this process requires a most rigorous and detailed approach to validation. An understanding of the process requires a basic understanding of microbial death, the parameters that facilitate that death, the accepted definition of sterility, and the relationship between the definition and sterilization parameters. Autoclaves and support systems need to be designed, installed, and qualified in a manner that ensures their continued reliability. Lastly, the test program must be complete and definitive. In this paper, in addition to validation study, documentation of IQ, OQ and PQ concretely were described.

Healthcare product manufacturers strive to provide safe, sterile products by validating and controlling manufacturing procedures. Validation study is the result of a multidisciplinary team effort. This successful effort relies on each discipline understanding the fundamentals of each technical disciplines and applying those fundamentals in terms of their own technical background. This paper is to introduce the basic concepts of sterilization methodology which are involved in validating various technical methods of sterilization and biological indicators (BIs). These will mainly address sterilization procedures in general terms and highlight on their microbiological aspects. The proper starting point is defining what sterility is and how it can be achieved through the validation studies by using BI.

There are several well-developed rapid microbiological methods now becoming available that may have useful applications in pharmaceutical and medical devices. They are ATP bioluminescence, fluorescent labeling, electrical resistance, and nucleic acid probes. In choosing to employ rapid methods, the microbiologist should examine their prospective performances against the specific requirements for that sector. Some methods may require expensive equipment and offer full automation, and others represent only a small investment. The regulatory view of these methods is changing and they still officially have not been approved in medical and pharmaceutical area, but it will still be up to the microbiologist to demonstrate that the method chosen is fit for the purpose intended.

An advantage of vapor phase hydrogen peroxide (VPHP) is that it can readily react to form reactive free radicals, which perform the sterilization and form water and hydrogen by catalyst. Absorptive hydrophilic materials such as cellulosics hinder penetration due to hydrogen bonding and necessitate the use of hydrophobic materials, i.e., polyethylene or polypropylene, as packaging materials. The 8h TWA (time-weight-average) is 1 ppm. Hydrogen peroxide sterilization is now being used for the sterilization of gloveboxes, freeze dryers, isolators and endoscopes and so on. This paper focuses on the application of VPHP to the sterilization of the endoscopes.

The plasma of several different gases has shown a sporicidal activity. From these gases, nitrogen gas was most difficult to produce atomic nitrogen radicals. However, these radicals have a high energy, indicating that nitrogen gas plasma could be used to sterilize microorganisms and inactivate endotoxins. The sterilization mechanism of nitrogen gas plasma is the synergistic effect of a high rising-up voltage pulse, UV irradiation and atomic nitrogen radicals. Thus, the target cells were damaged by degradation, which resulted in death. The biological indicator (BI) used in this study was Geobacillus stearothermophilus ATCC 7953 at a population of 1 x 10(6) CFU/sheet. Sterility assurance was confirmed by using the BI. Moreover, endotoxins were successfully inactivated. More than 5 log reduction of endotoxins could be attained with 30 minutes of nitrogen gas plasma exposure. Material functionality influenced by nitrogen gas plasma presented a satisfactory result. No deterioration of polymers could be observed by nitrogen gas plasma exposure.

Disinfection or sterilization treatment by heating, irradiation, or chemicals can cause injury to microorganisms at sublethal levels. Microbial injury is the inability to grow under conditions suitable for the uninjured microorganisms. This inability of injured microorganisms to grow is explained in terms of more complex or different nutritional requirements or in terms of increased sensitivity to environmental conditions such as incubation conditions (time or temperature) or to chemical agents such as halogen compounds. Injured microorganisms can be distinguished from those that are dead or mutated by their ability to regain normal physiological activity when placed in appropriate conditions for cultivation. The return to normal physiological function has been termed repair. The extent and severity of sublethal injury, the mechanisms of injury, and the mechanisms and degree of recovery vary with the sterilization procedures, the species, the strains, the condition of the microorganism, and the methods of repair. Injury to spore formers has been detected at different stages of the spore cycle. The sites of injury include damage to enzymes, membrane disruption, and/or damage to DNA or RNA. Information on the sublethal injury and recovery of microorganisms is very important in evaluating sterilization/disinfection procedures. This paper supplies academic as well as practical information dealing with the repair, and detection of injured microorganisms for performing reproducible sterilization validation.

The photocatalyst equipment consists of a titanium dioxide membrane and an ultraviolet lamp. The authors studied if the photocatalyst equipment is practically useful in sterilizing environmental microorganisms in the health care facility. The number of microorganisms was compared in the cases of no sterilization (control) and the photocatalyst sterilization. As a result, a statistical difference was observed between control and the photocatalyst sterilization against airborne microorganisms (p < 0.01), but not against surface microorganisms (p > 0.2). The photocatalyst uses an air sucking system, so it may be ineffective against microorganisms tightly attached to surfaces. However, the effectiveness of the photocatalyst to sterilize airborne microorganisms in the health care facility was successfully confirmed. Concerning the humidity effect on the photocatalyst sterilization, the authors compared the number of airborne microorganisms in cases of the control, UV alone and photocatalyst sterilization when humidity was changed. A statistical difference was observed between UV and the photocatalyst sterilization (p < 0.01) when humidity was increased to 60-70%, but not observed between UV and the photocatalyst sterilization (p > 0.2) when humidity was not controlled and was around 10-20%. This indicates that maintaining high humidity levels will present satisfactory sterilization results due to a greater production of OH radicals. From data obtained, no effect of the adsorption on the TiO2 membrane could be observed.

Nosocomial infections are a great problem in the health care facilities. The white uniforms of nurses are often washed to keep them clean, but the nurse's caps are not washed as frequently in comparison. It could be that the importance of these caps is being overlooked. If these caps are providing a residence for microorganisms causing nosocomial infection in the health care facility, then they should be washed as frequently as the uniforms. So far, the relationship between the contamination of the nurse's caps and nosocomial infection has not yet been studied. Therefore, this study was conducted to confirm if relationships exist among factors regarding the number of microorganisms on the nurse's caps, the period in which caps were used without being washed, and the individual characteristics of nurse wearing the caps. Results showed that the degree of contamination of the nurse's caps depended on individual characteristics and the period of use. Finally, results led to the conclusion that the nurse's caps should not be worn if their only purpose is to symbolize female workers in the health care facilities because, in actually, they provide a resistance for microorganisms causing nosocomial infections.