Sterility assurance

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Parental products need to be sterile when they are going to be administered. The best way to obtain this is of course by applying a terminal sterilization process with an overkill approach. This will give a very high sterility assurance for the product. However, nowadays, a lot of products cannot be terminally sterilized, since they will degrade due to the high temperature, or the high level of radiation during the sterilization process. To be still able to obtain a sterile product, the final bulk is sterile filtered and the fill process is being performed aseptically. How can you then still obtain a high sterility assurance level?

First let’s start by stating that no product can be tested to be 100% sterile. Since this would mean that you have to test 100% of your product, meaning, no product left.

Sterility has to be built into the product by starting with low bioburden or sterile starting materials and taking all precautions during the manufacturing that no (microbiological) contamination can be introduced into your product. Last but not least, your container closure system needs to be tight (A presentation about this will come online in a few weeks).

Low bioburden or sterile starting materials is usually not a big issue and can be achieved by qualification of your autoclave and validation of your autoclave process. Furthermore, the final bulk that will be filled aspetically will be filtered over a 0.2 micrometer filter to remove all (if any present) micro-oragnisms. To make sure that the filter will be capable of removing all micro-organisms, a sample is taken before filtration, to determine the actual bioburden of the bulk. This, together with your filter capacity is already one level of sterility assurance. The filter will be tested for integrity after filtration to proof that indeed the filter did what it was supposed to do.

After the filtration, the bulk will be filled into vials or syringes. During this process, you do not want to contaminate the solution again with micro-organisms (since you just removed them during filtration). Therefore, the filling should be done in a class  A environment (with a class B background (see annex 1 to Eudralex vol 4 with the area classifications)). Operators should be in clean room garment, covering all parts of their skin and hair (since these are the major sources of contamination). The environment during the filling process should be monitored to make sure that indeed the environment does not contain any micro-organisms. Also the gloves and garment of the operators involved in the filling should be monitored after the filling process to make sure that they were indeed clean.

Operators should also be trained to be able to perform aseptic handlings, without contamination of product. This should be done anually by filling vials with a bacterial growth medium, which should remain clear after two weeks incubation. The filling process should be qualified twice a year by filling vials with a bacterial growth medium, which should remain clear after two weeks incubation.

When all above mentioned items are in place together with the results of the sterility test, the produced batch will have a high enough sterility assurance level for a QP to release the batch for parenteral use.