Level of sterility

Because of the level of automation of the entire process, little human intervention is required during manufacture compared to traditional aseptic filling and it is considered an advanced aseptic filling process. It is therefore possible to achieve very high levels of sterility confidence with a properly configured BFS machine designed to fill aseptically. 

Extensive process simulation (broth fill) results for BFS effectively demonstrate that high levels of sterility confidence can be obtained with a properly configured and validated machine. However, in order to maintain high levels of sterility assurance, it is important that levels of microbial contamination are controlled within the filling environment. 

Sterilization by filtration is a major unit operation used in aseptic processes. Aseptic processes require the presterilization of all components of the drag product and its container. Then all of the components are brought together in a controlled aseptic environment to create the finished sterile product sealed within its container/closure system. The level of sterility attained by an aseptic procedure is a cumulative function of all the process steps involved in making the product. Therefore, the final level of sterility assurance for such a product cannot be greater than the step providing the lowest probability of sterility. Each step in the aseptic process must be validated to known levels of sterility assurance [43],... 

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. 

Information on the bioburden present in or on the product is essential to truly understanding the level of sterility assurance provided. 

Aseptic pharmaceutical BFS technology for the manufacture of sterile liquid products demonstrates high levels of sterility assurance when correctly operated and configured. The technology is continually improving as more expertise is developed. 

Bruch, C.W. Levels of sterility probabilities of survivors vs. biological indicators. Bull. Parenter. Drug Assoc. 1974, 28 (3), 105-113. 

The principles behind the sterilization processes are described in Chapter 20. The choice of method is determined largely by the ability of the formulation and container to withstand the physical stresses applied during the sterilization process. All products intended for sterilization should be manufactured under clean conditions and therefore will be of low microbial content (bioburden) prior to sterilization. Under these conditions, the sterilization process will not be overtaxed and will generally be within the safety limits needed to provide the required level of sterility assurance (Chapter 20). The next section emphasizes parenteral products, but the practices described apply to many other types of sterile product. 

A product to be labelled sterile must be free of viable microorganisms. To achieve this, the product, or its ingredients, must undergo a sterilization process of sufficient microbiocidal capacity to ensure a minimum level of sterility assurance. It is... 

Today in addition to Paris, many other cities use ozone in production of potable water. Zurich, Switzerland, Florence, Italy, Brussels, Belgium, Marseille, France, Singapore and Moscow, Russia all have ozone water treatment plants. In Europe many swimming pools, both public and private use ozone in place of chlorine. With ozone, no salts are added to the water, so that in addition to a high level of sterility, the acidity (pH) is easier to control. In the United States, ozone s use is limited, but LaSalle, Illinois has a relatively new ozone water treatment facility. ... 

According to the decision trees, where it is not possible to carry out terminal sterilisation by heating due to formulation instability, a decision should be made to utilise an alternative method of terminal sterilisation, filtration and/or aseptic processing. If this alternative route is taken, then a clear scientific justification for not using terminal heat sterilisation will be required in the NDA/MAA dossier. Commercial reasons will not be acceptable because terminal sterilisation offers the highest possible level of sterility assurance. 

Even when preservatives are included in single-dose presentations (as they often are), their efficacy against particular types of microorganisms can never be legitimately used as an excuse for tolerating in>process contamination by preservative-sensitive types. Nor can the inclusion of preservatives in products be used to shorten or reduce the intensity of sterilization processes applied to products or their containers to lower than normal levels of sterility assurance. Preservatives are supplementary, not intrinsic to industrial-scale processes of achieving sterility. 

The number of spores per strip and the number of strips per load should for validation purposes be related in some way to the bioburden of the product. What type of relationship this should be is less obvious. There are two broad approaches to this the first is to relate the microbiological challenge on each spore strip to the average bioburden on individual products and the required level of sterility assurance (SAL) the second is to relate the total microbiological challenge in the sterilizer load to the total bioburden within the sterilizer. 

It is not possible to measure levels of sterility assurance (SALs) obtained with commercial systems of achieving sterility. The expected assurance of sterility is too high to be measurable by techniques that rely on detection of nonsterility in sampled items. With processes that involve microbiological inactivation, measurements of subprocess inactivation can be extrapolated to estimate process SALs. This not possible for aseptic filling. 

The LVP sterilisation cycle employed should have been shown to deliver an F0 of 8 or more. Where an F0 of 8 is not attainable, for example because of product stability problems, an F0 of less than 8 may be approved by the licensing authority where evidence is produced to demonstrate that a high level of sterility assurance can be achieved. 

Figure 5.78 is a simple plot of cell number versus time at a given temperature according to the logarithmic death rate. To achieve a certain level of sterility (iVst) it is clear that a time t t is needed. A normal value for N t is about 10"" cells/ml. 

Commercial Sterility Level of sterility in which only one out of every 10,000 products of a certain kind can be expected to contain bacteria or other microorganisms. 

F-value The time in minutes required to bring about an acceptable level of sterilization of foods in a thermal treatment process such as canning. The F-value often has a subscript, which denotes the temperature at which it applied. For example, Fj, j is the time in minutes atl21°C. 

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