Moist-heat sterilization processes

Current pharmaceutical production practice uses substantially three moist-heat sterilization processes 1) pressurized saturated steam 2) superheated water and 3) steam-air mixture. Process 1 is the traditional multipurpose process, which obviously uses pure pressurized saturated steam as sterilizing medium. Processes 2 and 3 are so-called counterpressure processes they were introduced in pharmaceutical production practice approximately 20 years ago and, respectively, use a spray superheated water and a homogeneous... 

Sterilization processes are discussed in detail in Chapter 20. However, it is axiomatic that whatever method is chosen, the process should not cause damage to the product. By reference mostly to moist heat sterilization processes (the reader should remember that there are parallel approaches to other methods of sterilization) this section illustrates the factors that must be considered in the design of a sterilization process. 

An inherent problem is the location of the sensors. It is not possible to locate the sensors inside the packages which are to be sterilized. Electromechanical instmmentation is, therefore, capable of providing information only on the conditions to which the packages are exposed but cannot detect failures as the result of inadequate sterilization conditions inside the packages. Such instmmentation is considered a necessary, and for dry and moist heat sterilization, a sufficient, means of monitoring the sterilization process. 

Steam (qv) sterilization specifically means sterilization by moist heat. The process cannot be considered adequate without assurance that complete penetration of saturated steam takes place to all parts and surfaces of the load to be sterilized (Fig. 1). Steam sterilization at 100°C and atmospheric pressure is not considered effective. The process is invariably carried out under higher pressure in autoclaves using saturated steam. The temperature can be as low as 115°C, but is usually 121°C or higher. 

In step 5, the qualification stage, the critical issue is that the protocol for IQ/OQ of the equipment and the facility include the established method and acceptance criteria. The IQ/OQ report should include the maintenance program to keep the equipment in good condition for reproducibility of the product. For qualification of the equipment and process for terminal sterilization, the following standards should be referred to ISO 13408-1 [6] and 11138-1 [7] for general issues, ISO 11134 [8] and 11138-3 [9] for moist heat sterilization, ISO 11135 [10] and 11138-2 [11] for ethylene oxide sterilization, and ISO 11137 [12] for radiation sterilization. 

The kinetics of dry-heat treatments is comparable to that of moist heat sterilization. The organisms that are considered to be representatives for dry-heat sterilization processes are spores of Bacillus subtilis var. nigerP ... 

For heat treatment, a D-value only refers to the resistance of a microorganism at a particular temperature. In order to assess the influence of temperature changes on thermal resistance a relationship between temperature and log D-value can be developed, leading to the expression of a z-value, which represents the increase in temperature needed to reduce the D-value of an organism by 90% (i.e. 1 log cycle reduction Fig. 20.2B). For bacterial spores used as biological indicators for moist heat (B. stearotbermopbilus) and dry heat (B. subtilis) sterilization processes, mean z-values are given as 10°C and 22°C, respectively. The z-value is not truly independent of temperature but may be considered essentially constant over the temperature ranges used in heat sterilization processes. 

Sterilization by moist heat usually involves the use of steam at temperatures in the range 121-134°C, and while alternative strategies are available for the processing of products unstable at these high temperatures, they rarely offer the same degree of sterility assurance and should be avoided if at all possible. The elevated temperatures generally associated with moist heat sterilization methods can only be achieved by the generation of steam under pressure. 

In heat sterilization processes, a temperature record chart is made of each sterilization cycle with both dry and moist heat (i.e. autoclave) sterilizers this chart forms part of the batch documentation and is compared against a master temperature record (MTR). It is recommended that the temperature be taken at the coolest part of the loaded sterilizer. Further information on heat distribution and penetra-... 

Clearly, physical stability is of critical importance for emulsion formulations, and care must be taken to ensure not only that the product itself is physically stable but that any infusion solutions which may be prepared by dilution of the emulsion are also physically stable over the required period of time. In addition, parenteral emulsions should be able to withstand the stresses associated with moist heat sterilization. Alternatively, if this cannot be achieved, it may be possible to prepare an emulsion aseptically from sterile components, provided the process can be suitably validated. For a good introduction to the formulation and preparation of IV emulsions, the reader is referred to Hansrani et al. (1983). 

As with sterilization by saturated steam, thermal damage to biological systems as a result of dry heat sterilization processes is a function of absorbtion of heat energy. Inactivation of microorganisms is by oxidation. The kinetics of oxidation and population death approximate to first-order reactions, but they are significantly different from the processes of coagulation of cellular proteins found with moist heat sterilization in that they require far higher temperatures and proceed more slowly. 

Moist heat sterilization is achieved by exposure to saturated steam under pressure in a suitably designed chamber. In these circumstances there is an exact relationship between the steam temperature and pressure, but the pressure is used solely to obtain the temperature required and otherwise contribute nothing to the sterilization process. The time, temperature and pressure must be used to control and monitor the process. 

The most widely used sterilization method ia the food industry is moist heat. The heat is usually suppHed by high pressure steam, but because most foods already contain moisture the role of steam is to heat the food to the required temperature. The cooking and sterilization processes can frequendy be combined into one. The food may be sealed into impervious containers of glass, metal, or plastic film and undergo terminal sterilization, or it may be presterilized in batches or in a continuous operation and then filled into a presterilized container. The latter process is called sterile filling. 

The F-value concept which was developed for steam sterilization processes has an equivalent in dry heat sterilization although its application has been limited. The Fh designation describes the lethality of a dry heat process in terms of the equivalent number of minutes exposure at 170°C, and in this case a z value of 20°C has been found empirically to be appropriate for calculation purposes this contrast with the value of 10°C which is typically employed to describe moist heat resistance. 

Aqueous products moist heat at 121°C/15 minutes then moist heat to achieve a F0 value of not less than 8 minutes to achieve a sterility assurance level of 10 6 then aseptic filtration and aseptic processing then the use of presterilized components and aseptic compounding and assembly... 

Medium for use in a process simulation test can be rendered sterile using either moist heat (autoclaving) or filtration. The method chosen depends on the availability of suitable equipment and the information desired from the study. 

The predominant method for terminal sterilization is moist heat, and a substantial percentage of sterile products are processed in this manner. (Estimates range from 5 to 15% of all sterile products are terminally sterilized.) The sterilization often requires the attainment of a balance between sterility assurance and degradation of the material s essential properties [42],The overkill sterilization method is preferred for heat-resistant materials, and may be usable for terminal sterilization where the formulation can tolerate substantial heat input. The bioburden/biological indicator approach uses less heat input but requires increased control over the titer and resistance of the bioburden organisms present. 

Terminal sterilization is most commonly accomplished by moist heat. Terminal sterilization by other means is certainly possible, and a very limited number of parenteral drugs are treated with dry heat or radiation after filling. There is growing interest in the use of radiation, including low-energy E-beam, as a terminal treatment suggesting more products will be processed in this manner. 

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