Sterilization heating cycle

A review of all sterilization specifications assigned to the sterilizer under consideration shall be made, with the specifications cycle requiring the maximum peak dwell temperature and heating rate to be selected for the empty sterilizer heat distribution runs. During the empty sterilizer heat distribution runs, sterilizer parameters and equipment component status shall be visually monitored to confirm applicable control operations. 

Dry heat sterilization validation. The tunnel operations conform to the master validation plan employed at ABC Pharmaceutical Industries. The sterilizing tunnel has undergone installation qualification, operational qualification, and performance qualification. The sterilizing tunnel is revalidated on an annual basis. The sterilization/depyrogenation cycle revalidation data for the tunnel are provided in validation archives. Sterilization validation reports are provided in validation archives. 

The sterile solutions are filled in different sizes of vials and ampoules. One dosage form is lyophilized injection and filled in A-ml vials. To ensure the sterility during the aseptic processing, it was decided to revalidate the A-ml vials sterilization/depyrogenation cycle once in a year by one heat penetration study and endotoxin challenge test. 

The goal of the biological validation procedure depends on the nature of the process. If the process is intended to sterilize only, the probability of survival approach is used. In this case, validation studies must determine a dry-heat cycle that will assure that the probability of survival of the microbial indicator is not greater than 10 If the process is intended to sterilize and depyrogenate, which occurs when the materials can withstand excessive heat, the overkill approach is used. The goal here is to validate a heating cycle that can produce a 12-log reduction in the biological indicator population. 

Akers, M. J., Ketron, K., Thompson, B. F value requirements for the destruction of endotoxin in the validation of dry heat sterilization/depyrogenation cycles. J Parenter Drug Assoc 36 23-27 (1982). 

Product Heat Treatment. Equivalent heat treatment for destmction of microorganisms or inactivation of enzymes can be represented by plotting the logarithm of time versus temperature. These relationships were originally developed for sterilization of food at 121.1°C, therefore the time to destroy the microorganism is the V value at 121.1°C (250°F). The slope of the curve is and the temperature span is one log cycle. The heat treatment at 131°C for one minute is equivalent to 121.1°C for 10 minutes (Fig. 10). 

Dry-heat sterilization is generally conducted at 160—170°C for >2 h. Specific exposures are dictated by the bioburden concentration and the temperature tolerance of the products under sterilization. At considerably higher temperatures, the required exposure times are much shorter. The effectiveness of any cycle type must be tested. For dry-heat sterilization, forced-air-type ovens are usually specified for better temperature distribution. Temperature-recording devices are recommended. 

Great care is needed in the design of autoclaves and sterilization cycles because of the requirement for the presence of moisture. The autoclave must be loaded to allow complete steam penetration to occur in all parts of the load before timing of the sterilization cycle commences. The time required for complete penetration, the so-called heat-up time, varies with different autoclave constmction and different types of loads and packaging materials. The time may not exceed specific limits in order to guarantee reproducibility and, for porous loads, saturated steam. The volume of each container has a considerable effect on the heatup time whenever fluids are sterilized. Thermocouples led into the chamber through a special connector are often employed to determine heatup times and peak temperatures. The pressure is refleved at the end of each sterilization cycle. Either vented containers must be used or... 

Once a plant is built, the conditions of agitation, aeration, oxygen transfer, and heat transfer are more or less set, and sterilization cycles are defined. Those environmental conditions achievable in plant-scale equipment should be scaled down to the pilot plant and laboratoiy equipment (shaken flasks) to insure that results can be translated. 

Relative thermal resistance for the different types of microorganisms encountered in typical environments associated with fermentation broths is shown in Table 24-3. Bacterial spores are far more resistant to moist heat than are any other type oi microbial contaminants thus, a sterilization cycle based on the destruction of bacterial spores should destroy all life. 

The resistance of an organism to a sterilizing agent can be described by means of the D-value. For heat and radiation treatments, respectively, this is defined as the time taken at a fixed temperature or the radiation dose required to achieve a 90% reduction in viable cells (i.e. a 1 log cycle reduction in survivors Fig. 20.2k). The calculation of the D-value assumes a linear type A survivor curve (Fig. 20.1), and must be corrected to allow for any deviation from linearity with type B or C curves. Some typical D-values for resistant bacterial spores are given in Table 23.2 (Chapter 23). 

Dry heat sterilization is usually carried out in a hot air oven which comprises an insulated polished stainless steel chamber, with a usual capacity of up to 250 litres, surrounded by an outer case containing electric heaters located in positions to prevent cool spots developing inside the chamber. A fan is fitted to the rear of the oven to provide circulating air, thus ensuring more rapid equilibration of temperature. Shelves within the chamber are perforated to allow good air flow. Thermocouples can be used to monitor the temperature of both the oven air and articles contained within. A fixed temperature sensor connected to a chart recorder provides a permanent record of the sterilization cycle. Appropriate door-locking controls should be incorporated to prevent interruption of a sterilization cycle once begun. 

Dry-heat processes kill microorganisms primarily through oxidation. The amount of moisture available to assist sterilization in dry-heat units varies considerably at different locations within the chamber and at different time intervals within the cycle. Also, the amount of heat available, its diffusion, and the environment at the spore/air interface all influence the microorganism kill rate. Consequently, cycles tend to be longer and hotter than would be expected from calculations to ensure that varying conditions do not invalidate a run. In general, convection dry-heat sterilization cycles are run above 160°C [37],... 

In addition to normal compression set test conditions, usually 22 hours at 70 °C in a hot air oven, pharmaceutical elastomeric closures may be subjected to compression set conditions simulating steam sterilization cycles in an autoclave for 30 minutes at 121 °C. Also, sterilizing cycles employing ETO, radiation, or dry heat are used. Comparison data between formulations are used to develop compression set values that will identify potentially acceptable compounds under these conditions. 

Dry heat is used to sterihze and depyrogenate components and drug products. The definition of dry heat sterilization is 170 °C for at least 2 hours and a depyrogenation cycle at 250 °C for more than 30 minutes. Typical equipment includes tunnel sterilizers (force convection, infrared, fiame) and microwave sterilizers. An important aspect is the need to ensure air supply is filtered through HEPA filters. Biological indicators such as Bacillus subtilis can be used to gauge the performance of sterilization. 

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. 

Heat penetration studies are also employed to determine points within a load configuration that achieve higher temperatures and consequently greater Fq values. The temperature data obtained may be significant when heatable products are involved in the sterilization process and the potential for product degradation exists. The cool points established for a specified load and configuration will eventually be utilized to control the exposure time in subsequent routine production runs. The temperature sensors that control sterilization-cycle-exposure time at process temperature may be positioned within the load at the previously detected cool point. Consequently the entire load is exposed to sufficient heat lethality and achieves the desired Fq value. 

Biological castles are employed during heat penetration situations in order to demonstrate the degree of process lethality provided by the sterilization cycle. Calibrated biological indicators utilized for this purpose function as bioburden models providing data that can be utilized to calculate Fq or substantiate and supplement physical temperature measurements obtained from thermocouples. 

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. 

Confirm that established sterilization cycles deliver a uniform and reproducible heat input to products assigned to each cycle... 

---