Environmental monitoring programmes must be in place for both uncontrolled and controlled processing facilities and must meet the requirements of appropriate regulatory bodies. They must form part of the quality management system ensuring that products are processed to the highest possible standards. Uncontrolled facilities include blood-processing laboratories and controlled facilities include cleanrooms used for the aseptic processing of tissues and stem cells.
The main aim of microbiological environmental monitoring is to provide a means of monitoring trends over time thereby ensuring that processing facilities continue to operate within acceptable bioburden levels. Individual test results, whether high or low counts, are rarely significant.
The monitoring programmes must define and document:
Monitoring must be performed using standardised techniques and the main areas of sampling should include:
In controlled facilities, monitoring for fungal in addition to bacterial contamination must, as a minimum, be achieved through the use of settle plates with media specific for each type of contamination.
Culture media used for environmental monitoring must be appropriate for the type of environment in which it is to be used, i.e. irradiated and triple wrapped media for use in cleanrooms, and for the range of organisms likely to be isolated. Media used for post-disinfection monitoring must contain agents, either individually or in combination, that will neutralise any residual surface disinfectant. Neutralising agents must be validated against the disinfectant(s) in use within the facility. Media storage must be in compliance with the manufacturer’s recommendations and the monitored facility must be able to provide monitoring data to show that these storage requirements are met.
In cleanroom facilities, limits must be set for the results of both particulate and microbiological monitoring. These limits are specified in Annex 1 of the EC Guidelines to GMP (Manufacture of Sterile Medicinal Products7).
The action levels for microbiological monitoring in controlled rooms are taken as the limits given in the EU Guide. Alert levels must also be set in order to provide a warning of a possible deviation from normal operating conditions that may not require direct action but may need to be monitored more closely.
In uncontrolled facilities, action levels must be established using historical data. The monitoring programmes must define how the alert levels in controlled rooms and the action levels in uncontrolled rooms are to be determined.
Monitoring results must be entered on a suitable database to allow data and trend analysis. The results must be reviewed by staff of the monitored facility on a regular basis with a formal documented review being held at a minimum of four times a year. This formal review must involve senior cleanroom/processing staff and representatives from the quality and microbiology departments.
Environmental monitoring programmes for controlled rooms also need to include procedures for:
Gowning qualification and exit suit monitoring should be performed for each cleanroom operator on a regular basis with the frequency, sampling method(s) used and monitoring sites clearly defined in the procedures.
Validation of aseptic processing should include a process simulation test using a nutrient medium. The process simulation test should imitate as closely as possible the routine process including all critical subsequent manufacturing steps. It should also take into account various interventions known to occur during the routine process as well as worst-case situations. Process simulation tests should be performed as initial validation with three consecutive satisfactory tests and repeated at defined intervals and after any significant modification to the heating, ventilation and air conditioning (HVAC) system, equipment or process.
Normally process simulation tests should be repeated twice a year (per shift and process). Alert and action levels should be defined and documented and any contamination investigated.
Cleaning/disinfection validation should be performed in order to confirm the effectiveness of a cleaning/disinfection programme. As part of the validation, pre- and post-cleaning/disinfection environmental monitoring should be used to verify the acceptability of the frequency and efficiency of the programme in terms of microbiological contamination. Pre- and post-limits should be established and documented within the cleaning/disinfection programme. The monitoring results should be reviewed and, where limits have been exceeded, the contamination investigated and corrective action implemented.
Typically, three consecutive applications of the cleaning/disinfection procedure should be performed and shown to be successful in order to prove that the method is validated.
The cleaning and disinfection of controlled rooms is particularly important and should be performed in accordance with a written programme. Where disinfectants are used, more than one type should be employed on a rotational basis. Detergents and disinfectants should be monitored for microbial contamination and, when used in grade A and B areas, should be sterile prior to use.