Sterilization, moist heat

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. 

Syringes (glass) Syringes (glass), dismantled Dry heat Moist heat Sterilization Sterilization Dry heat using assembled syringes Autoclave not recommended difficulty with steam penetration unless plungers and barrels sterilized separately... 

When drug solutions and containers can withstand autoclaving conditions, this method is preferred to other sterilization methods because moist heat sterilizes quickly and inexpensively. However, judgment must be exercised and experiments run to ensure that the solution and container are permeable to steam. Oils and tightly closed containers, for example, are not normally sterilizable by steam. 

Aseptic BPS machines are subject to steam-in-place sterilization following standard CIP cycles. The SIP cycles are routinely measured by thermocouples located in fixed positions along the product pathway. Validation of SIP cycles should be carried out to demonstrate that consistent sterilization temperatures are achieved throughout the equipment to prove that the system can be effectively sterilized. Validation should also identify suitable positions for routine use, or justify the fixed probe positions already in place. The SIP validation is generally carried out with the help of additional thermocouples and should include the use of biological indicators (appropriate for moist heat sterilization). Test locations should include areas which may be prone to air or condensate entrapment. An accurate engineering line drawing of the system to aid identification of suitable test locations and document test locations selected should be available. 

The most frequently utilized to challenge moist heat sterilization cycles are Bacillus stearothermophilus and Clostridium sporogenes, spore-forming bacteria are selected because of their relatively high heat resistance. In addition to the selection of an appropriate organism for use as a biological indicator, the concentration and resistance of the indigenous microbial population is established. 

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. 

ISO 11134. Sterilization of Health Care Products—Requirements for Validation and Routine Control—Industrial Moist Heat Sterilization. Switzerland (1998). 

Parenteral Drug Association. Moist Heat Sterilization in Autoclaves Cycle Development, Validation and Routine Operation. PDA technical report 1, revision, draft 11. Bethesda, MD, May 2001. 

PDA (2006), Technical Monograph 1, Industrial moist heat sterilization in autoclaves, draft 17. 

If an effective dry heat depyrogenation is performed, sterilization generally is achieved as well. Effective dry heat sterilization can be performed even without achieving depyrogenation. If moist heat sterilization is performed, in normal operating conditions depyrogenation is not achieved. 

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 dry-heat temperatures other than 170°C, Fh values are used. The Fh concept is comparable to the Fq concept for moist heat sterilization and references lethality to equivalent times at 170°C. Fh values are shown in units of minutes or seconds, and the calculations of Fh use the same equations as the calculations of Fq. The only difference is that a z value of 20° C is substituted for 10°C.t ... 

Moist-heat sterilization is achieved when water vapor (or, more generically, moist heat, i.e., a suitable combination of temperature and humidity) at a definite temperature is introduced or generated (even indirectly) at the level of the micro-organisms to be inactivated and is maintained in such conditions for a definite time. As explained in detail hereafter, moist-heat sterilization proceeds as an inverse logarithmic progression. Therefore, only a treatment of infinite duration provides absolute certainty that all micro-organisms have been inactivated. 

All pharmacopeias consider moist-heat sterilization as the method of choice, i.e., the method to be preferred, unless, of course, the product to be sterilized is incompatible with the characteristics of steam. The reason for this preference is the fact that moist-heat sterilization provides the best combination of flexibility, reliability, and low equipment and operating costs. 

Moist-heat sterilization is achieved when a suitable combination of temperature and humidity can be introduced (or indirectly generated) at the level of the micro-organisms to be inactivated. The classic way to achieve this is by means of pressurized saturated steam at the temperature of 121°C (250°F). However, other sterilizing media (e.g., superheated water or a steam-air mixture) are also frequently used to obviate certain problems that pure steam may pose. Sometimes the load is rotated inside the chamber of the sterilizer to achieve particular results. 

Clearly, if D is 1.0 at 121°C, it is 0.1 at 131°C and 10 at 111°C. In other words, the value of D decreases or increases by a factor of 10 when the temperature increases or decreases by 10°C. The algorithm z is defined as temperature coefficient of moist-heat sterilization, i.e., the number of degrees of sterilization temperature that causes a 10-fold variation of D or of the sterilization rate. Depending on the micro-organism... 

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... 

This is certainly the most widely used and most versatile moist-heat sterilization method. Accordingly, it is widely used not only for sterilization of pharmaceutical products but also for laboratory and hospital sterilization and for the treatment of medical devices. Nonetheless, it has significant limitations, especially in pharmaceutical use, which are described later. The sterilizing medium is obviously pure pressurized saturated steam. The word saturated means that the steam is in thermodynamic equilibrium with its liquid form (water) at the temperature being considered. 

However, the steam must entrain the smallest possible amount of condensate. The term steam dryness fraction defines the amount of condensate entrained by the moist steam. A dryness fraction of 0.95 means that lOOg of moist steam consist of 95 g of dry saturated steam plus 5 g of condensate, which is (or should be) at the same temperature the steam. A dryness fraction of 0.95 is considered the lower limit of adequacy for moist-heat sterilization. 

Gram-negative bacteria contain lipopolysaccha-rides (endotoxins) in their outer cell membranes (Chapter 19) these can remain in an active condition in products even after cell death and some can survive moist heat sterilization. Although inactive by the oral route, endotoxins can induce a number of physiological effects if they enter the bloodstream via contaminated infusion fluids, even in nanogram quantities, or via diffusion across membranes from contaminated haemodialysis solutions. Such effects may include fever, activation of the cytokine system, endothelial cell damage, all leading to septic and often fatal febrile shock. 

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. 

Syringes (glass), dismantled Moist heat Sterilization assembled syringes plungers and barrels sterilized separately... 

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. 

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