Sterility Test Failure Investigation

                      

How to Perform a Sterility Test Failure Investigation

Sterility test is a mandatory product release criteria for aseptically – filled products. Sterility test failure of a drug product/substance is a stressful event, because it will  raise concerns about manufacturers  control over the process, practices and clean room environment and finally it will landed up with customer and revenue losses.

All sterility failures in pharmaceuticals should thoroughly investigated, because inadequately investigated sterility failures can trigger regulatory action as it is evident from many of the FDA’s warning letters to the manufacturers.

Investigating a sterility failure is just like connecting the dots. The first challenge in a sterility failure investigation is to confirm the reported result is real or false positive.

As a part of investigation clean room data, such as differential pressures, microbial monitoring, videos, gowning records, cleaning records, maintenance records, sterilizer records, etc. are to be verified to find evidence of contamination. Firms should review all recent sterilization, depyrogenation, and decontamination cycle re-validations and compare them to the original qualification experiments performed.

While performing a sterility failure investigation it is important to find out how the microbes  goes in to the product rather than merely finding the source of contamination.

A sterility failure investigation must be conducted in two phases

1. Laboratory Investigation (Sterility test &testing environment)

2. Manufacturing Investigation (manufacturing & filling Process)

In the event of a sterility failure following activities to be initiated immediately parallel to the investigation program.

Immediate Action

As and when a sterility failure is reported, the batch in question must immediately be put in quarantine, and a decision must be taken to set the boundaries of the investigation and identify other batches which may also be affected.  Production activities shall be stopped in the manufacturing and filling area where the contaminated batch was manufactured until the identification of root cause and CAPA implementation.

Impact Analysis

Impact analysis is equally important as failure investigation, because regulatory inspectors pay more attention to the pitfalls in such assessments. In the event of sterility failure, a detailed impact analysis to be performed by giving consideration to other batches filled on the same filling line, filled in the same suite, using the same sterilizers, using equipment sterilized in the same manner, sharing the same air handling system, or using the same materials in formulation. A formalized risk assessment to be initiated to evaluate the impacts of sterility failure in these batches with rationale and scientific justification, because these are key area of focus in regulatory inspections. These decisions may need to be reviewed in the light of further information gained through subsequent investigation.

Investigation Procedure

1. Laboratory Investigation (Sterility test &testing environment)

·       Verify the negative control. If growth observed invalidate test and repeat the analysis. If negative control does not showing growth proceed with investigation.

·       Carry out identification of the organism. The nature of the organisms recovered in the sterility test may give some direction to potential source, but care should be taken to ensure that the investigation remains sufficiently broad to include all potential sources.

·       Verify analyst technique, If possible interview the analyst and gather the information about his knowledge and technique. Also verify the results of finger dabs and personnel monitoring of the persons involved in testing.

·       Verify autoclaving record for sterilization accessories used for the test like glass ware, garments, gloves to confirm that correct load pattern and sterilization parameters were followed.

·       Verify the deviations, which reported during the performance of sterility test.

·       Verify testing environment, be it a UDAF unit or isolator. If an isolator was used, the leak testing and gassing process should be reviewed. Validation, maintenance and cleaning status will need to be confirmed as part of this review.

2. Manufacturing Investigation (manufacturing & filling Process)

·       Review trend analysis of viable and nonviable count in the critical area immediately adjacent to it.

·       Verify if processing batches involved in any deviations.

·       Verify the trend of personnel monitoring results to find any adverse trend.

·       Verify if any untoward event occurred during processing & was not reported earlier.

·       Verify if there was any failure of utility, while batch was being processed.

·       Verify if there was any drop in differential pressure during processing.

·       Verify for the manufacturing history of the product or similar product for any changes for process, personnel and equipment.

·       Verify gowning records, cleaning records, maintenance records, sterilizer records etc. to find evidence of contamination.

·       Verify operator’s technique, If possible interview the operator and gather the information about his knowledge and technique.

·       Data from the most recent media fill to be verified. If the investigation indicates that any interventions may have been the cause, consideration should be made as to whether the interventions were included and simulated during the media fill or if there were any concerns when the intervention was simulated.

·       Cleaning & disinfection records pertaining to the filling room and filling zone to be evaluated. Such review should consider the effectiveness of cleaning techniques and the expiry time of disinfectants used for cleaning.

At the completion of the initial investigations of both the manufacturing and laboratory phases, it is not unusual to still not have identified a definitive root cause. Additional testing or monitoring may be required to do this. It certain causes investigation may conclude with more than one root cause also.Under normal conditions sterility failure can happen due to following reasons

·       Poor personnel practice

·       Loss of environmental control

·       Flawed operational design

Based up on the arrived root cause, a media fill study may required to be performed  before resuming production activities to establish that the clean room is under control.