Heat sterilization monitoring

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. 

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. 

As with any sterilization process, the first step in dry-heat sterilizer validation involves qualification of all the equipment and instrumentation used. This step includes examination and documentation of all utilities, ductwork, filters, and control valves or switches for the oven or tunnel unit, and the calibration of the instrumentation used in validating and monitoring the process. The instruments used are as follows ... 

Case, L., and Heffernan, G. (1998), Dry heat sterilization and depyrogenation Validation and monitoring, in Agalloco, J., and Carleton, F. J., Eds., Validation of Pharmaceutical Processes Sterile Products, Marcel Dekker, New York. 

The physical parameters of the process are monitored in normal production runs to obtain additional information on the process and its reliability. Extra temperature-sensitive devices installed in an autoclave or dry-heat sterilizer (in addition to probes used routinely) will permit an in-depth study of the heat distribution for several loads. Heat-penetration measurements are recommended for injectable products of higher viscosity or with volumes larger than 5 ml. A tableting press equipped with pressure-sensitive cells will be helpful in collecting statistical data on the uniformity of die-fill and therefore on mass uniformity. 

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. 

Pharmaceuticals for injection must be presented in a sterile form. Sterility may be achieved by filtration through 0.22 pm filters under aseptic conditions, or by steam, dry heat, radiation or gas sterilisation methods, which may be applied to packaged products. Irrespective of the method, the process must be validated and monitored to assure its effectiveness. As discussed in Chapter 2, this is an example of a process that cannot be assured by verification testing because of its destructive nature. 

The Ph Eur mentions the possibility of parametric release for certain terminal sterilization processes (saturated steam, dry heat and irradiation) where sterilization parameters can be accurately monitored and recorded and controlled. Much of the information in the two draft documents relates to parametric release of sterile products, but the possibility of parametric... 

Figure 4.11. a so liter bench fermenter that can be scaled for production of recombinant proteins. The bench-top scale configuration contains all the control valves and ports necessary to monitor and control cell cultivation while maintaining sterility of the culture. The stainless steal reaction vessel allows easy cleaning and permits heat and pressure sterilization in place by connecting the vessel to a steam supply. (New Brunswick Bioflo-4500, adapted from the manufacturer s literature with permission)... 

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. 

The final step in steam sterilization validation is the establishment of a monitoring program to ensure that the validated cycle remains essentially unchanged in the future. Cycle monitoring usually involves the use of thermocouples to measure heat penetration at the cool spot location and to verify that the design F0 value has been reached. 

Do a series of repetitive runs for each sterilization cycle in an empty vessel in order to verify the accuracy and reliability of the sterilizer controls and monitoring equipment. Thermocouple locations should be basically the same for all the heat-distribution studies. 

The complexity of the sterile filtration operation and the CGMP regulations require the validation of sterilizing filter systems. The validation of a sterile filtration operation can be complex, with many operational parameters and their interactions needing to be identified, controlled, and predicted for each end product to demonstrate that sterility is adequately achieved by the filtration process. In the commonly used steam sterilization process, the heat parameters are identified and in-process controls specified such that a level of sterility assurance can be reproducibly obtained. In steam sterilization, the important parameter of heat, measured by temperature, can be accurately measured and continuously monitored to ensure the operational integrity of the autoclave however, unlike steam sterilization, filtration sterilization cannot be monitored on a continuous basis throughout the process. 

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