Sterilization specifications

Steam (qv) sterilization specifically means sterilization by moist heat. The process cannot be considered adequate without assurance that complete penetration of saturated steam takes place to all parts and surfaces of the load to be sterilized (Fig. 1). Steam sterilization at 100°C and atmospheric pressure is not considered effective. The process is invariably carried out under higher pressure in autoclaves using saturated steam. The temperature can be as low as 115°C, but is usually 121°C or higher. 

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. 

Sterilizer engineering drawings Sterilizer operation procedure Sterilizer sanitization procedure Sterilizer maintenance procedures Sterilizer specification utilization list Distribution thermocouple location diagrams Temperature sensing unit location diagram (continuous sterilizers) Sterilizer process log sheets... 

The OQ phase of sterilizer validation shall consist of the development of an information package fulfilling the documentation requirements of the generic equipment operational qualification. The following sterilizer-specific documentation shall be incorporated in the operation qualification ... 

Unlike many dosage form specifications, the sterility specification is an absolute value. A product is either sterile or nonsterile. Historically, judgment of sterility has relied on an official compendial sterility test however, end-product sterility testing suffers from a myriad of limitations [1-4], The most obvious limitation is the nature of the sterility test. It is a destructive test thus, it depends on the statistical selection of a random sample of the whole lot. Uncertainty will always exist as to whether or not the sample unequivocally represents the whole. If it were known that one unit out of 1000 units was contaminated (i.e., contamination rate = 0.1%) and 20 units were randomly sampled out of those 1000 units, the probability of that one contaminated unit being included in those 20 samples is 0.02 [5], In other words, the chances are only 2% that the contaminated unit would be selected as part of the 20 representative samples of the whole 1000-unit lot. 

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 development of sterilization specifications differs from the development of sterilizer parameters. Both differ from validation (Fig. 2). 

Pharmaceutical Products and Materials for Aseptic Manufacture—Sterilization Specifications... 

For pharmaceutical products and materials used in connection with aseptic manufacture, sterilization specifications apply to conditions of temperature and time, or Fq, or combinations of Fq, temperature and time to which the contaminating micro-organisms themselves must be exposed over the hold period of the sterilization process. In practice, this means actually within aqueous products, on the surfaces of rubber stoppers or metal machine parts, or within the folds of cartridge filters, etc. 

The sterilizer parameters are the practical criteria that must be specified to ensure that the sterilization specification is delivered to all parts of the load. They always include specifications for temperature and time, but it is important to recognize the distinction between sterilizer parameters applying to the machine settings on the autoclave console, and sterilization specifications applying to actual conditions within the load. Essential sterilizer parameters also include other specifications, e.g., for load configuration, number and depth of prevacuums, cooling characteristics, etc. 

Sterilization specifications are product specific. Sterilizer parameters are specific to combinations of product, presentation, and autoclave. 

Sterilization specifications may be determined from theoretical considerations or from laboratory data and arewithin reason transferable from presentation to presentation, e.g., from 1 ml ampules to 5 ml vials to 50 ml bags. The sterilizer parameters required to deliver the sterilization specification to these presentations differ within the same autoclave and from one autoclave to another according to differences in load configurations, chamber size, steam entry points, control systems, etc. Sterilizer parameters are not transferable and must be developed empirically for each autoclave. 

Sterilization specifications should be easy to develop. The pharmacopeias allow sterilization specifications to be developed from a basis of no actual data concerning the numbers and thermal resistances of micro-organisms actually contaminating the items to be sterilized. Although this statement may appear initially to be barren of scientific reason, this is in fact not the case. What the pharmacopeias provide are... 

Achievement of a 10 SAL from an initial bioburden of 10 would require eight log reductions. Applying these eight log reductions to an assumed worst case thermal resistance of D i-value in water of Imin gives a sterilization specification of 121°C for 8 min. 

The range of sterilization specifications calculable by these various approaches is summarized in Table 2. It is apparent that very brief sterilization specifications (on the order of 2-3 min holding time at 121°C) are obtainable when the microbiological contamination is completely characterized in terms of numbers and thermal resistances. In practice, such limits on hold times could be difficult to control precisely, are probably insignificant in terms of thermal lethality compared with heat-up and cool-down times, and could prove difficult to sell to regulators. Without complete thermal characterization of thermal resistances, specifications calculable by the bioburden approach are hardly significantly shorter than overkill specifications. Thus, it probably makes practical sense in most cases to choose only between overkill cycles for thermally resistant products and aseptic manufacture for heat-sensitive products. 

Some products may be heat sensitive only above a threshold temperature for those that can withstand temperatures in the range of 110-118°C but cannot withstand 121°C it is possible to apply the Fq concept to the principles above and derive equivalent sterilization specifications to those given in Table 2. These specifications are summarized for 116°C in Table 3. As can be seen, if there is a requirement to sterilize at (say) 116°C, there are considerable time savings to... 

Sterilizer parameters are specific to combinations of product, presentation, and autoclave. They must be established empirically. Heat penetration studies done prior to the performance qualification phase of validation serve the purpose of determining the loading patterns, prevacuums, and temperature and pressure settings, etc.which ensure that the sterilization specification is delivered to the product and that it is delivered uniformly throughout the load. 

Table 2 The range of sterilization specifications at 121°C calculable according to various approaches...

Are they intended to apply within the media as are the sterilization specifications for pharmaceutical products and materials for aseptic manufacture Or are they sterilizer parameters There may be some indication in some of the older suppliers manuals which expand their recommendations along the lines of sterilize by autoclaving at 15psi (121°C) for 15-18min. Since pressures of 15psi are not achievable within media, it is clear that the intention was that the recommendations be applied to sterilizer parameters. 

Systems that are sterilized in-place are often immensely complex. The initial challenges to their sterilization are the removal of air and the elevation of the temperature of the pipework to prevent heat losses and condensation. As such, most work in the development of sterilization specifications for SIP systems is concerned with the heat-up phase. Appropriate questions are Is the sterilization temperature achieved throughout the system Where is the slowest location to achieve... 

The time for which the system must be held at temperature (the sterilization specification) is often relegated to a minor consideration compared with this earlier development work. Typically, it is decided arbitrarily to use, 121°C for 15, 20, or 30min, with no real scientific basis. 

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. 

If the Di2i-value in product of B. stearothermophilus is equal to or less than its D i-value in water, and the sterilization specification is based on overkill, then bio-validation must be done with spores suspended in water. However, if the sterilization specification has been tailored specifically to the resistance of micro-organisms in the product, then bio-validation must be done with the spores suspended in product. Otherwise falsely unfavorable results may occur. 

Bio-validation is usually done against a sterilization specification which delivers less lethality than the lower limit of lethality allowed by the sterilization specification defined for the material being sterilized. It is clearly intellectually flawed to choose to validate something different to that which is ever to be used in practice. So what is the reasoning behind this practice ... 

Sterilization specifications in the hold period are presented in terms of temperature and time with upper and lower tolerances set around them. The lower specification limits are critical to sterilization. 

Bio-validation cycles are therefore designed to ensure that no more lethality is delivered than that specified by the lower limits of lethality of the sterilization specification used in routine practice. Ideally this is... 

Data showing survival on some but not all of the Bis may be valuable in process development (particularly in the development of sterilization specifications and sterilizer parameters for porous and equipment loads), but would likely raise issues at regulatory inspection. The inference taken from having some survival could be that each item in the autoclave load is not being exposed to the same treatment. 

On the face of it, the implication is that this sterilization specification/sterilizer parameters combination is invalid. However, remember that this same sterilization specification/sterilizer parameter combination would have been valid if the Bis used had D i-values of 1.5 min. In practical terms the pharmacopeial specification for thermal resistance in Bis has been set naively. Many companies purchasing spores of B. stearothermophilus, either for preparing Bis or as commercial strips, order against their own specifications which... 

SIP systems range from very small systems (say, a mixing tank) where all parts may reach temperature within 2 or 3 min, to absolutely massive arrangements of vessels, valves, and pipework in which the expulsion of air, the drainage of condensate, and the attainment of the sterilization specification temperature at the slowest point can take 20 or 30 min. 

Consideration of packaging materials should be specific to particular sterilization cycles and should extend beyond primary packaging materials to include the potential effects of secondary packaging (shelf packs or shippers) and pallets on sterility assurance. In some instances these latter factors may need to be addressed on a sterilizer specific basis, where variations have been suspected of being the cause of erratic and unpredictable biological test failures. The important packaging factors to consider are... 

Empty chamber studies are sterilizer specific. Further process validation work is product specific (load specific) and may be done with dummy product if required. If this option is exercised, care must be taken to ensure that dummy loads are truly representative of genuine product. Scrap product is ideal for this purpose but may not be readily available for high cost products (e.g.. cardiac pacemakers). If good product is used in validation, it should nut be released as sterile until the validation program has been completed and signed off as satisfactory. 

Microbiological contamination of starting materials should be minimal, and the "bioburden should be monitored before sterilization. Specifications should indude... 

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