Terminal sterilisation methods

Components of parenteral solutions (active substances, excipients, intermediates and packaging material) should be routinely tested for bioburden and bacterial endotoxin level to ensure they are not adding an excessive microbial load. Bioburden is usually determined on the unfiltered bulk solution. Testing of filtered bulk parenteral solution either before or after filling into the final container may be done by comparison to the previously tested unfiltered bulk solution. Initial bioburden and endotoxin monitoring should be conducted to establish appropriately designed and sized terminal sterilisation methods such as filtration/aseptic filling or terminal heat treatment (see Sects. 30.5 and 30.6). Bioburden is also used as a parameter to evaluate process control. 

The sterilisation methods (methods of preparation of sterile products) described in the Ph. Eur. are terminal sterilisation methods and filtration [1]. See for filtration Sect. 30.6. In this section an overview of terminal sterilisation methods is given. 

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. 

It will be necessary to conduct preliminary feasibility studies to establish an acceptable and effective method for sterilisation of the product. There is a clear responsibility with the manufacturer to provide evidence to the regulatory agencies that the product can or cannot be terminally sterilised. Preformulation studies will indicate whether the candidate drug and proposed formulation can withstand the sterilisation process using small samples of product. 

Process development studies showed that terminal sterilisation of the gel was not possible. Heat sterilisation and gamma irradiation methods both caused unacceptable physical degradation of the gel and also caused chlorbutol hydrolysis. Aseptic filtration was not possible because the drug was suspended in the gel vehicle and viscosity would also have been a problem. The process described below was therefore developed with consideration of the sterilisation of the product components and the maintenance of asepsis throughout manufacture. 

Sterilisation is the finite method for microbial control and can be achieved either by sterilising each component (product and packaging materials) followed by assembly, i.e. aseptic processing, or by a terminal sterilising process which involves both product and pack. The latter is the preferred method as it entails less risk of a non-sterile product being produced. 

Moist heat sterilisation at 121 °C for 15 min is the method of choice for terminal sterilisation of finished products. 

What is the best sterilisation method for your product Is terminal sterilisation better than aseptic processing See references [17, 18]. The objective of aseptic processing in general is to maintain the sterility of a product that is assembled from components, each of which has been sterilised. Sterile medicinal products should be manufactured using aseptic processing only when terminal sterilisation is not possible. Some types of final packaging and some medicinal products do not withstand the temperatures and/or pressure of a terminal sterilisation process. In such cases a... 

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