Sterility assurance level

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. 

For sterile products, particular attention should be paid to the choice of an appropriate method of sterilization. Wherever possible a terminal sterilization process should be applied to the product in its final container-closure system, as suggested in the Ph Eur. The preferred options include steam sterilization, dry heat sterilization, and irradiation using the Ph Eur listed conditions (saturated steam at 121°C for 15 minutes dry heat at 160°C for 120 minutes irradiation with an absorbed dose of not less than 25 kGy). Where these cannot be used, the application must include justification for the alternative procedure adopted on the understanding that the highest achievable sterility assurance level should be achieved in conjunction with the lowest practicable level of presterilization bioburden. There is guidance in the form of decision trees as to the preferred options for sterilization method to be applied ... 

Aqueous products moist heat at 121°C/15 minutes then moist heat to achieve a F0 value of not less than 8 minutes to achieve a sterility assurance level of 10 6 then aseptic filtration and aseptic processing then the use of presterilized components and aseptic compounding and assembly... 

Justifications for the use of nonstandard (i.e., nonpreferred or nonpharmacopeial) methods of sterilization may include the heat instability of the active ingredient or an essential excipient. The choice of a method based on filtration through a microbial retentive filter and/or aseptic assembly should be justified, and the appropriate in process controls (including bioburden controls on active ingredients, excipients, bulk solutions, process time constraints etc) discussed in detail in the application. Commercial considerations should not form part of the argument for the application of a nonstandard sterilization process. The highest possible sterility assurance level should be achieved. 

Currently the main application of interest for parametric release is to replace the sterility test as a control method in appropriate cases (given the limited value of that test to predict sterility assurance due to statistical considerations, although it is also pointed out that a sterility test provides a final opportunity to identify a major failure, although other means should provide a more reliable way of detecting such failures). The concept is applicable to well-founded methods of sterilization where the product stability is known and development data have identified the critical process parameters. The measured parameters should be such as to ensure that correct processing of the batch provides sufficient assurance that the sterility assurance level intended has been achieved. 

There is no appropriate defined sterility confidence level which can be translated directly into acceptance criteria for broth fill contamination for BFS processes. The most commonly recognized acceptance criterion is a sterility assurance level (SAL) of 10 although modem aseptic filling techniques such as BFS can achieve a higher SAL. This should be reflected by broth fill results and acceptance criteria for this advanced technology. 

Also, validated reduced bioburden (e.g., 0-1 colony-forming units (CFU) per unit surface area or mL) would allow for a reduction in the radiation dose required to achieve a sterility assurance level of 10A... 

Table 4 Sterility assurance levels indicated by inactivation of 10 spores of B. stearothermophilus...

This raises a second question of how much confidence must one have to claim sterility The answer to this question, for terminally sterilized products, is that there must be no more than one chance in a million that viable contaminants survive in any one unit. This is called a sterility assurance level (SAL) of 10 . The answer for aseptically filled products is that the SAL must be as close to 10 as is technically possible, with the proviso that thedegree of protection given to the process must afford no more than one chance in a thousand of any one unit becoming contaminated. This is called a contamination rate of 10 , and unlike the SAL it relates only to the protection given to the process and not to the potential for contaminants surviving or proliferating in actual products. ... 

Even though the definition of sterility is an absolute condition, the effectiveness of the sterilization process can be determined by measuring the reduction of microbial population. Such measurements reveal the kinetics of microbial inactivation, and it is from the exponential nature of inactivation that the concept of sterility assurance level (SAL) is derived. This value... 

In pharmaceutical technology, to define an item as sterile, one must be able to demonstrate that on a statistical basis related to the processing conditions, no more than 1 in 10 units subjected to sterilization may be non-sterile. Therefore, the SAL (Sterility Assurance Level) of the product must be greater than (or equal to) 10 . The obvious consequence of this situation is that although the word sterile expresses an absolute concept, the word sterilized, understood as the result of an adequate sterilization process, has a probabilistic meaning. 

Underestimating the level of microbial contamination prior to the terminal sterilization process will lead to a miscalculation of the sterilization dose requirements to achieve the desired sterility assurance level. The bioburden must be maintained within certain limits to justify the chosen sterilization process. When a higher number of organisms or... 

Greater stringency is required for terminally sterilized products. Such environmental and process controls might seem overzealous, but it is better to minimize risk at all stages rather than to rely on final product testing (section 1). The lower the bioburden the easier it is to achieve the required sterility assurance level in the terminal sterilization process (Chapter 20). It is also important to exclude pyrogens and particulate matter that would not be removed by sterilization. 

Sterility Assurance Level Structure Activity Relationship Summary Basis of Approval Small Business Innovative Research Program (USA) Subcutaneous... 

The protocol will include acceptance criteria for sterility assurance level and growth promotion. 

Photochemical reactivity of drug formulations is an important aspect to consider during development, production, storage, and use of pharmaceutical preparations. However, photochemical stability of drug substances is rarely as well documented as thermal stability of the compounds. For instance, in order to obtain a high sterility assurance level of the product, a parenteral preparation is sterilized in its final container if possible. Steam sterilization at minimum temperature of 121°C for... 

In summary, there is always a finite probability of a survivor occurring, no matter the strength or duration of a sterilization process. In other words, absolute sterility, in the sense of total freedom from all viable life forms, can never be achieved in practice. The acceptance of exponential inactivation lunetics has led to two different approaches to the establishment of standards of satisfactory sterilization treatment, the inactivation factor approach and the sterility assurance level (SAL) approach. 

Sterility Assurance Levels The concept of the sterility assurance level (SAL) not only considers the kinetics of inactivation of microbial populations but also addresses the numbers of contaminants on product items prior to sieril-... 

If the number of spores per spore strip and the number of spores per validation load is to be related to the individual product item and a sterility assurance level of 10. h is first necessary to know the average number of contaminants per product item. In the interests of conservatism this number may be rounded up or supplemented by a safety factor. The target is to use as many spore strips as is necessary to provide assurance that this bioburden is being inactivated to an SAL of 10 This can be calculated from... 

In making this proposal, the FDA recognizes that a dual standard of sterility a iunmee has been in operation. Terminal sterilization processes for parenteral pharmaceutical products are currently required to be validated to sterility assurance levels of 10 aseptic processes can only be demonstrated to achieve sterility assurance levels of 10. This is clearly an example of dual standards. Fuithefmore, to the FDA it appears to be fundamentally wrong for products that are quite capable of tolerating terminal sterilization to be manufactured asepti-cally. 

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