Validation of a Steam Sterilizer

To provide a written procedure to be used as a guideline for the certification/validation of a steam sterilizer 

It is the responsibility of the production manager, validation manager, and concerned departmental managers to follow the procedure. The QA manager is responsible for SOP compliance. 

Different types of sterilizers are used in the pharmaceutical industry. 

However, the following criteria are generally considered common. 

A critical part of the validation study is the temperature measurement. Several items will be required to measure and record temperature effectively. 

---

Each validation process should have a documented protocol of the steps to follow and the data to collect during the experimentation. As an example, App. I presents a protocol for the validation of a steam sterilization process. 

With the main emphasis being the validation of a steam sterilization cycle based on the achievement of a certain reproducible value at the coolest part of the full batch load, procedures for validation of a steam sterilization process will now be discussed. 

Validation of a steam sterilization process must cover the series of actions required to establish that the process is capable of doing what it is intended to do (i.e., supporting a claim of sterility) and must define a plan for maintaining the validated state of control. An overall scheme is described in Table 3. 

The lyophilizers are cleaned using a validated clean-in-place (CIP) cycle using hot WFI. After the cleaning process, a validated sterilization cycle is mn. The qualification of the steam sterilization cycle was performed during the operation qualification (OQ) of the lyophilizer. 

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. 

There are several definitions of validation but, in simple terms, the word means demonstrating that a process will consistently produce the results that it is intended to. Thus, with respect to sterile products, validation would be necessary for each of the individual aspects of the manufacturing process, e.g. environmental monitoring, raw materials quality assessment, the sterilization process itself and the sterility testing procedure. Of these, it is the sterilization process that is likely to be subject to the most detailed and complex validation procedures, and these will be used to exemplify the factors to be considered. A typical validation procedure for a steam sterilization process is likely to incorporate most, or all, of the following features ... 

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. 

Type T (copper-constant) thermocouples are most applicable in steam sterilizer validation work. Their working temperature range is wide and they are resistant to corrosion in moist environments. A high grade of thermocouple wire should be chosen. Premium grades of wire accurate to as close as 0.1°C at 121°C are recommended. These must then be calibrated against a temperature standard traceable to the National Bureau of Standards (NBS). 

Record keeping is a prime requirement of current good manufacturing practices. The records required for a validated steam sterilization cycle are listed below ... 

IV. VALIDATION OF STEAM STERILIZATION CYCLES A. General Considerations... 

Accuracy of thermocouples should be 0.5°C. Temperature accuracy is especially important in steam sterilization validation because an error of just 0.1 °C in temperature measured by a faulty thermocouple will produce a 2.3% error in the calculated F0 value. Thermocouple accuracy is determined using National Bureau of Standards (NBS) traceable constant temperature calibration instruments such as those shown in Figure 6. Thermocouples should be calibrated before and after a validation experiment at two temperatures 0°C and 125°C. The newer temperature-recording devices are capable of automatically correcting temperature or slight errors in the thermocouple calibration. Any thermocouple that senses a temperature of more than 0.5°C away from the calibration temperature bath should be discarded. Stricter limits (i.e., <0.5°C) may be imposed according to the user s experience and expectations. Temperature recorders should be capable of printing temperature data in 0.1 °C increments. 

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. 

APPENDIX I EXAMPLE PROTOCOL FOR VALIDATION OF THE STERILIZATION PROCESS IN A STEAM AUTOCLAVE... 

A. The validation of sterilization processes using saturated steam as the sterilant. 

Steam sterilization is the method mostly used to sterilize freeze-dryers. High-quality, ultra-pure steam (water for injection standard USP XXII or PhEur equivalent) is used to achieve a minimum exposure of 121 °C for 30 min or the equivalent temperature-time combination for effective sterilization (Table 2.4.1). This method is easy to validate and is recommended by regulatory authorities as being reliable. The definition of sterilization is a validated process used to render a product surface free of all forms of viable micro-organisms (EN 556-1 2001). According to the authorities, a product or surface is only sterile when a validated sterilization process has been applied (EN 550, EN 552, EN 554, EN ISO 14160 and EN ISO 14937). 

The sterilization of freeze-dryers by steam is described in [34] including a guideline for its validation. Steam sterilization is the most applied method today, because ethyleneoxide and formaldehyde have to be used with great care and residues are difficult to measure and to remove. Steam sterilization requires a vac-... 

The steam sterilization system (see Figures 5-9) used by S.G.D. Serail is designed with autoclave -type vessel construction to resist sterilization pressure combined with a control system permitting the validation of the sterilization cycles and eventual determination of the experimental FO sterilization value. 

The science that underpins steam sterilization is well known and has been long established. It is the preferred method of sterilization in the pharmaceutical industry it is used for sterilization of aqueous products in a wide variety of presentations, for sterilization of equipment and porous materials required in aseptic manufacture, in microbiology laboratories for sterilizing media and other materials, and for sterilization of massive systems of vessels and pipework [steam-in-place (SIP) systems]. Numerous rules and guidelines have been published on the topic, yet steam sterilization and particularly bio-validation of steam sterilization is still a subject for controversy and debate. 

The performance qualification (PQ) phase of validation follows the development of the sterilization specifications and of the sterilizer parameters which will deliver them. The purpose of PQ in steam sterilization of pharmaceutical products, equipment, laboratory media, and SIP systems is to confirm that the sterilization specification consistently achieves its intended purpose. The process is run using the parameters derived from process development on (usually) three separate occasions and tested for compliance with a variety of predetermined acceptance criteria. As a subset of PQ, the purpose of bio-validation is to confirm that the lethality expected from the process does not significantly deviate from what is expected. Biovalidation is a test of consistency. If the acceptance criteria are not achieved, there may be need for more process development. 

Steam sterilization in autoclaves has a long and strong scientific basis (see above). The essence of validation of steam sterilization processes is to demonstrate that temperature and time conditions are being achieved uniformly through every item included the autoclave load and that the lethality being achieved in practical situations corresponds to that which would be expected from sterilization theory. 

Parenteral Drug Association (1978). Technical Monograph No. /, Validation of Steam Sterilization Cycles. Parenteral Drug Association Washington, D.C.. U.S.A. 

An empirical rule-of-thumb is often used in the design of sterilisation processes which uses the principle of substantial overkill to design a readily validated make-safe process. The MRC Working Party reports on pressure-steam sterilizers are often quoted as the intellectual source of the much-used sterilisation standard of saturated steam at 121.1 °C for 15 minutes. This treatment is widely regarded as giving a sufficient margin of safety in yielding a sterile product irrespective of the type and initial... 

---