Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119): Quality control

There should be personnel available with appropriate training and experience in microbiology and sterility assurance and with knowledge of the processes. Trained and experienced personnel are needed to support the design of manufacturing activities, environmental monitoring regime and any investigation assessing the impact of microbiologically linked events to the safety of the sterile drug.

Specifications for raw materials, components and products should include requirements for microbial, particulate and endotoxin/pyrogen limits when monitoring and/or the contamination control strategy (CCS) have indicated the need.

The bioburden assay should be performed on each batch for both aseptically filled product and terminally sterilized products. The results should be considered as part of the final batch review.

There should be defined limits for bioburden immediately before the final sterilizing grade filter or the terminal sterilization process, which are related to the efficiency of the method to be used. Samples that represent the worst-case scenario (such as at the end of hold time) should be taken. Where overkill sterilization parameters are set for terminally sterilized products, bioburden should be monitored at suitable scheduled intervals.

For products authorized for parametric release, a supporting pre-sterilization bioburden monitoring program for the filled product prior to initiating the sterilization cycle should be developed. The bioburden assay should be performed for each batch. The sampling locations of filled units before sterilization should be based on a worst-case scenario and be representative of the batch. Any organisms found during bioburden testing should be identified and their impact on the effectiveness of the sterilizing process determined. Where appropriate, the level of endotoxin/pyrogen should be monitored.

A sterility test conducted on the finished product should be viewed as the last in a series of critical control measures taken to assure sterility. A sterility test cannot be used to assure sterility of a product that does not meet its design, procedural or validation parameters. The test should be validated for the product concerned.

The sterility test should be performed under aseptic conditions. Samples taken for sterility testing should be representative of the whole of the batch. In particular samples should be taken from parts of the batch considered to be most at risk of contamination, for example:

• For products that have been filled aseptically, samples should include containers filled at the beginning and end of the batch. Additional samples, such as those taken after critical interventions, should be considered based on risk.
• For products that have been heat sterilized in their final containers, samples should represent the worst-case locations (for example, the potentially coolest or slowest to heat part of each load).
• For products that have been lyophilized, samples should be taken from different lyophilization loads.

Note: Where the manufacturing process results in sub-batches (for example, for terminally sterilized products), sterility samples from each sub-batch should be taken and a sterility test conducted for each sub-batch. Other finished product tests should be done separately.

It may not be possible to obtain a sterility test result for some products before they are released because the shelf life is too short to allow a sterility test to be completed. In these cases, the additional process design considerations as well as additional monitoring and/or alternative test methods required to mitigate identified risks should be assessed and documented.

Any process (for example, vaporized hydrogen peroxide, ultraviolet) used to decontaminate the external surfaces of sterility samples before testing should not negatively impact the sensitivity of the test method or the reliability of the sample.

Media used for product testing should be quality control tested according to the related Pharmacopeia before use. Media used for environmental monitoring and APS should be tested for growth promotion before use, using a scientifically justified and designated group of reference microorganisms and including suitably representative local isolates. The end user should perform media quality control testing. Outsourced testing or supplier testing of media should be justified and transportation and shipping conditions should be thoroughly considered.

Environmental monitoring data and trend data generated for classified areas should be reviewed as part of the product batch certification/release. There should be a written procedure describing the actions to be taken when data from environmental monitoring are found out of trend or exceed established limits. Environmental data for the time of manufacture may not be available for products with a short shelf life. In these cases, the compliance should include a review of the most recent available data. Manufacturers of these products should consider using rapid/ alternative methods.

Rapid and automated microbial methods used for general manufacturing purposes should be validated for the product(s) or processes concerned.