FoulUp Controls

Microbiological controls are not limited in their value to the qualification of the media fill. They should also be set up to expose any problems of their own creation. Microbiological QA exists to identify production problems and to assist in their resolution — it should always be wary of creating problems of its own making. Any activities associated with microbiological control of media and any laboratory manipulations that do not exist in routine manufacturing practice should be examined critically. This is best done by detailed analysis of the ways in which particular media fills are organised. Some examples are given below.

1. Aseptic sampling from bulk media is a serious vulnerability. It is all too easy for the bulk to be contaminated when growth support samples are withdrawn. It is not inconceivable that the outcome would be for the media fill to be contaminated, probably over several filled units, as a result of the contaminants distributed throughout the bulk and possibly proliferating before all of the media are filled. If possible, the bulk vessel should be incubated at the same time as the media fill. Contamination of the bulk invalidates the media fill and creates unwanted pressure attempting to diagnose production problems that are not of production's making. Regulatory agencies would always expect a media fill in which the incubated bulk was found to be contaminated to be repeated, irrespective of the quality of the results from the filled containers.

2. In some cases, solid-dosage form media fills require the addition of the recovery medium to the placebo-filled containers (usually vials) off-line in a laboratory. This requires media in bulk, and some apparatus, most often an automatic or repeating syringe, for transfer to the placebo-filled units. The vulnerabilities are for the bulk to be contaminated when the microbiologist aseptically assembles the transfer apparatus, and for the transfer apparatus to become contaminated over the period in which it is used. In this type of media fill it is easy to retain and incubate the bulk container. A sample of the first and last media passed through the transfer apparatus before any placebo-filled units are filled should be injected into a sterile vessel and incubated. Usually the placebo-filled units are interspersed with sterile sealed containers at regular intervals. The sterile sealed containers are filled with TSB in the same way as the placebo-filled containers, intended to disclose any transfer apparatus contamination as close as possible to the stage in media transfer when it happened. The frequency of interspersion of sterile containers is a matter of judgment; it may be every third, fifth or tenth unit according to the degree of confidence in the skills of the microbiologists adding the media. Irradiation is the recommended method of sterilization because sealed empty vials are quite difficult to sterilize by autoclaving. The discolouration obtained in most grades of glass as a result of exposure to gamma radiation is a convenient feature for distinguishing sterilised from placebo-filled units.

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