Steam sterilization validation

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). 

Steam sterilization validation. All autoclave operations conform to the Master Validation Plan employed at ABC Pharmaceutical Industries. The autoclave has undergone installation qualification, operational qualification, and performance qualification. The autoclave is revalidated on an annual basis. The equipment steam sterilization cycle revalidation data for the autoclave are provided in validated archives. 

Thermocouples obviously must be sufficiently durable for repeated use as temperature indicators in steam sterilization validation and monitoring. Copper-constantan wires coated with Teflon are a popular choice as thermocouple monitors, although several other types are available. 

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. 

The rules of steam sterilization are well described [2.15], including some guide-lines for the validation of the sterilization process. The special problems with the steam sterilization of closing systems for vial stoppers has been discussed above. Similar problems... 

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. 

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

The documentation (installation qualification, operational qualification, etc.) established prior to initiating validation studies provides the foundation for the subsequent validation. A comprehensive steam sterilization protocol should include the following items ... 

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

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. 

Process and equipment validation certification guideline Hot air sterilization tunnel certification/validation guideline Steam sterilization certification/validation guideline Validation and certification of hot air sterilization tunnel Validation and certification of SIP preparation/mobile vessel Validation/revalidation of sterilization cycles in sterilizer by Kaye validator... 

Perform microbiological challenge studies to determine the degree of process lethality provided by the sterilization cycle. The microorganisms most frequently utilized to challenge steam sterilizer cycles are Bacillus stearothermophilus and ATCC 7953. The Kaye validator equipped with 12 (minimum) thermocouples and biological indicators (10 ) shall be positioned in the detected cool points of the chamber and condenser. After the sterilization cycle is complete, the B.I s are recovered and subjected to microbiological test procedures. 

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. 

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

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. 

The organism most resistant to steam heat is the bacterial spore former B. stear-othermophilus. Other indicator organisms have been employed, but B. stear-othermophilus spores are by far the most commonly used Bis in validating steam sterilization cycles. 

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. 

Validation of Steam Sterilization Cycles, technical monograph no. 1. Parenteral Drug Association (1978). 

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. 

Justification of the reliable achievement of SALs of 10 for particular pharmaceutical items treated according to particular specifications of temperature and time in particular sterilizers is predicated on the regularity and predictability of steam sterilization processes. The means of justification are through scientifically based development of sterilization specifications and sterilizer parameters, and through subsequent validation of the specified processes. 

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. 

Acceptance criteria for bio-validation of steam sterilization processes are usually (but not invariably) defined along the following lines ... 

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