Sterilization process steam, validation

The sterilization processes described in the Ph Eur are preferred, especially terminal sterilization in the final container alternative processes have to be justified. All sterilization processes will need to be described and appropriate in-process controls and limits included. Where Ph Eur prescriptions are followed, there should be a statement to this effect in the application. Most of this information should be discussed in the development pharmaceutics section. Reference is made to the specific guidelines on ethylene oxide sterilization and irradiation sterilization, which are discussed further below. The possibility of parametric release for terminal processes such as saturated steam and irradiation is mentioned (see below). For all sterile products there should be a sterility requirement included in the finished product specification regardless of the outcome of validation studies. 

For terminal heat processes at 121°C/15 minutes (steam) or 160°C/120 minutes (dry heat), the information required includes time, temperature, and acceptance limits for in-process controls. Validation data are not normally required, but may be requested. For other process conditions, additional information will be required, such as in-process controls and acceptance limits, presterilization bioburden data, and sterility assurance level validation data. 

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... 

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... 

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. 

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. 

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). 

Sterilization by steam is a standard procedure, but can be replaced by the VHP (Vaporized Hydrogen Peroxides) process, which works at ambient temperature and without pressure. Nakahira [2.11] described the development of applicable sterilization cycles, the necessary changes in the freeze-drying plant and the sterility test necessary to validate the process. Sterilization by VHP requires certain conditions which result from the nature of the H2Oz vapor ... 

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. 

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

Pharmaceutical products can be sterilized by steam sterilization, dry-heat sterilization, filtration sterilization, gas sterilization, and ionizing-radiation sterilization. The USP provides monographs and standards for biological indicators required to test the validity of the sterilization process. These products must also be tested for pyrogens—fever-producing substances that arise from microbial contamination most likely thought to be endotoxins or lipopolysaccharide in the bacterial outer cell membrane. 

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. 

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 ... 

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. 

Utility systems such as water for injection (WFl). clean steam, clean-in-placc (CIP) solutions and sterile process air must be similarly proven. Also the building system itself has to be validated. Many bioprocess operations which contain potentially hazardous materials are operated in closely-controlled negative pressure enclosures with filtration of exhaust ventilating air. Sterile and particularly parenteral products arc processed in clean rooms which are maintained at positive pressure with filtered incoming air. Validation of building control systems and of personnel changing facilities and systems of work are necessary to meet CMP requirements. Manuals for formal test procedures are required to validate these activities. 

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. 

One can see by the complexity of these types of manufacturing procedures that much care and attention to detail must be maintained by the manufacturer. This sterile manufacturing procedure must then be validated to prove that no more than 3 containers in a lot of 3000 containers (0.1%) are nonsterile. Ultimately, it is the manufacturer s responsibility to ensure the safety and efficacy of the manufacturing process and the absence of any adverse effect on the product, such as the possible formation of substances toxic to the eye, an ever-present possibility with gas sterilization or when using ionizing radiation. For ophthalmic products sterilized by terminal sterilization (sterilization in the final sealed container, e.g., steam under pressure), the sterilization cycle must be validated to ensure sterility at a probability of 106 or greater. 

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. 

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. 

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