Failure of sterilization in pharmaceutical production refers to a sterilization process that either does not comply with its validated specifications or fails to give suitable guarantees of sterility. It can be either a failure in sterilization cycles, inadequate time used for contact with a sterilizing agent, having a positive biological indicator, a break in aseptic condition or finding contamination after the process.
Sterilization failure is a serious quality problem as it can lead to unsafe medicinal products and product-contact equipment, containers, closures, or any other materials used in producing sterile products. The affected product or batch needs to be controlled immediately and the incident needs further investigation with the help of a pharmaceutical quality system.
The response cannot be limited to repeating the cycle or conducting extra sterility tests. The investigation should identify reasons of failure, estimate its influence on quality of the product and explain whether the process still works as projected.
The different types of failure should be considered and understood as providing different information.
The failure of a cycle parameter means that one or more of the critical process parameters (e.g., time of exposure, temperature, pressure, humidity, or concentration of sterilant) are not met. The approved requirements. This could be, for example, failure to meet the proper exposure temperature for an autoclave cycle or the proper dwell time.
The failure of a biological indicator (BI) means that the indicator organism survives under the prescribed incubation conditions. The failure of the BI might suggest lack of microbial lethality. In addition to the biological lethality, it is important to investigate the handling, storage, incubation and validity of the BI test.
A failure of a sterility test is the detection of microbial growth in a sample tested. The failure does not necessarily mean that a sterilizer cycle failed. It could be that some contamination happened during the manufacturing process, or aseptic handling or sampling or testing in the laboratory. It is important to thoroughly investigate this type of event.
The failure of a sterile barrier/package could result in a loss of sterility after a successful process. For example, damaged packaging or a compromised container closure could allow contamination even if the sterilization cycle was successful and met the parameters of the cycle.
The responsible department should inform QA as well as the concerned staff from production, engineering, QC, microbiology and validation. The affected load must be put under the appropriate status.
Immediate actions usually include the following:
In the case of dry sterilization, on the contrary, the investigators should determine temperature uniformity, time of exposure, airflow, distribution of the load performed as well as other important parameters. If ethylene oxide sterilization was used, the most critical points to analyze are: gas concentration, humidity, temperature, etc. Finally, if radiation sterilization was applied, the investigators should study dose distribution inside the product, the volume of the load, etc.
Some possible reasons for the problem include uncalibrated temperature sensors, malfunctioning pressure keepers, improper supply of steam, leaking air, clogging of the drainage system, bad valves and improper settings. However, all of them are just possible reasons at his point of investigation.
In case the investigation has revealed that a sensor or instrument is not calibrated, the reliability of the readings should be assessed since the last calibration done.
The failure of biological indicators should be confirmed by the verification of the batch of BI, identity of microorganisms, populations and resistance characteristics, storage and handling conditions, position and incubation conditions of BI and positive and negative controls when necessary.
The result of biological indicators must be considered together with physical data, process design and should not be disregarded only because the cycle parameters are acceptable.
If the product was subjected to terminal sterilization, failure of the operation might mean that the necessary lethality was not achieved. As for the aseptic processes, the contamination might originate from the sterilized components or during the assembly of the equipment, from the technology, or due to negligence in ensuring aseptic conditions.
In addition, it is essential to investigate other batches being processed in the same equipment in case of suspicion of defect in the equipment and of any mistake made during the process.
Corrective action may include such activities as repair or replacement of defective parts of equipment, improvement of loading practices, reconnection of utilities, updating work procedures and retraining of employees. Preventive activities may include such actions as better responding to alarms, changing maintenance frequency according to statistics, making the load verification process more reliable and improving trend monitoring.
If the investigation shows that there is a flaw in the process that has been approved, the site should decide whether it is necessary to requalify or revalidate the process. The level of testing that should be conducted will depend on the results of the risk assessment.
The CAPA implementation should be evaluated against preselected important criteria. A meaningful effectiveness evaluation should include the comparison of records for future cycles, the number of alarms received, BI results and the fact that the qualification activities are performed. The completion of the training record cannot be a proof on its own that the technical failure is avoided.
A successful sterility test does not in itself confirm that the failure of the sterilization process results in the necessary level of sterility assurance. A sterility test is conducted on the sample and it cannot compensate for the failure of the process to meet the validated processing conditions.
In the same way, even a so-called successful cycle should be rejected when some critical piece of evidence is missing or not trustworthy. The investigation report should describe the failure, reason for the failure or reasonable conclusion, effect on the product, corrective and preventive actions and other necessary information.
Examination of trends can help in the identification of repeating alarms, failures of the parameters, BI positives, interruptions in the cycles and malfunction of the equipment before they become the major problem. Before any changes are made to equipment, utilities, packaging and process parameters, their approval via change control will be required.
During an inspection, the inspector may wonder how the failed cycle was investigated, what batches that could be affected by the failure were found and what conclusions were made thereafter. Every thorough and traceable investigation serves as a proof that the facility made its quality decision based on the scientific approach.
The response cannot be limited to repeating the cycle or conducting extra sterility tests. The investigation should identify reasons of failure, estimate its influence on quality of the product and explain whether the process still works as projected.
Identifying Sterilization Failures
Certain events can indicate failure. A failure could mean that a physical parameter is out of the valid range. It could also mean that a biological indicator grows. It could mean that a sterilizing load is improperly configured. It could also mean that a sterility test is positive.The different types of failure should be considered and understood as providing different information.
The failure of a cycle parameter means that one or more of the critical process parameters (e.g., time of exposure, temperature, pressure, humidity, or concentration of sterilant) are not met. The approved requirements. This could be, for example, failure to meet the proper exposure temperature for an autoclave cycle or the proper dwell time.
The failure of a biological indicator (BI) means that the indicator organism survives under the prescribed incubation conditions. The failure of the BI might suggest lack of microbial lethality. In addition to the biological lethality, it is important to investigate the handling, storage, incubation and validity of the BI test.
A failure of a sterility test is the detection of microbial growth in a sample tested. The failure does not necessarily mean that a sterilizer cycle failed. It could be that some contamination happened during the manufacturing process, or aseptic handling or sampling or testing in the laboratory. It is important to thoroughly investigate this type of event.
The failure of a sterile barrier/package could result in a loss of sterility after a successful process. For example, damaged packaging or a compromised container closure could allow contamination even if the sterilization cycle was successful and met the parameters of the cycle.
Actions to be Taken Immediately Upon Detection of Failure
The main aim of the immediate action should be preventing unauthorized use or leakage.The responsible department should inform QA as well as the concerned staff from production, engineering, QC, microbiology and validation. The affected load must be put under the appropriate status.
Immediate actions usually include the following:
- Restriction of the affected load and the linked product and/or raw materials usage.
- Batch should not be released from production, further processed, or distributed before an evaluation on the effect of the fault has been conducted.
- Storage of the information, data on cycles, alarms, BI results, test results and other data required.
- Identification of the loads, batches and raw materials that might have been processed similarly.
- Recording of the event in compliance with the approved deviation procedure.
- Determining if further equipment use should be stopped, until the investigation is completed.
Investigating the Root Cause
The root cause investigation of sterilization needs to be meticulous and should be based on actual evidence. The first task of the investigators is to clarify what has occurred and reconstruct the events of the cycle or processing operation.1. Review sterilization cycle records
For instance, if a steam autoclave has been used, the data logs of temperature, pressure, time of exposure, air removal phase, come-up time and dwell time, if they are valid for the cycle in question, should be analyzed. The alarms triggered during the cycle, phases that have been aborted, control system messages and independent monitoring should also be taken into account.In the case of dry sterilization, on the contrary, the investigators should determine temperature uniformity, time of exposure, airflow, distribution of the load performed as well as other important parameters. If ethylene oxide sterilization was used, the most critical points to analyze are: gas concentration, humidity, temperature, etc. Finally, if radiation sterilization was applied, the investigators should study dose distribution inside the product, the volume of the load, etc.
2. Examine equipment and maintenance history
The engineering department should examine the condition of the equipment, whether it has been calibrated properly, whether it has gone through any preventive maintenance, how its recent defects were fixed and how its components and control software were modified.Some possible reasons for the problem include uncalibrated temperature sensors, malfunctioning pressure keepers, improper supply of steam, leaking air, clogging of the drainage system, bad valves and improper settings. However, all of them are just possible reasons at his point of investigation.
In case the investigation has revealed that a sensor or instrument is not calibrated, the reliability of the readings should be assessed since the last calibration done.
3. Check the load and biological indicators
Wrong loading can cause a situation in which the heat or sterilizing agent will not penetrate properly. It is necessary to check the outlined load configuration, load size, position of containers, wrapping materials and the location of items.The failure of biological indicators should be confirmed by the verification of the batch of BI, identity of microorganisms, populations and resistance characteristics, storage and handling conditions, position and incubation conditions of BI and positive and negative controls when necessary.
The result of biological indicators must be considered together with physical data, process design and should not be disregarded only because the cycle parameters are acceptable.
4. Evaluate the consequence of product and process
It is necessary to check if the incident can lead to an inconsistency of sterility assurance of the product or material. Take into consideration the type of sterilization, specifications of the product, exposure conditions, load design, production technology and possible routes of contamination.If the product was subjected to terminal sterilization, failure of the operation might mean that the necessary lethality was not achieved. As for the aseptic processes, the contamination might originate from the sterilized components or during the assembly of the equipment, from the technology, or due to negligence in ensuring aseptic conditions.
In addition, it is essential to investigate other batches being processed in the same equipment in case of suspicion of defect in the equipment and of any mistake made during the process.
Corrective Action and Preventive Action
CAPA must address either the actual cause of the problem or the most probable one along with the conditions that caused or helped keep the error concealed.Corrective action may include such activities as repair or replacement of defective parts of equipment, improvement of loading practices, reconnection of utilities, updating work procedures and retraining of employees. Preventive activities may include such actions as better responding to alarms, changing maintenance frequency according to statistics, making the load verification process more reliable and improving trend monitoring.
If the investigation shows that there is a flaw in the process that has been approved, the site should decide whether it is necessary to requalify or revalidate the process. The level of testing that should be conducted will depend on the results of the risk assessment.
The CAPA implementation should be evaluated against preselected important criteria. A meaningful effectiveness evaluation should include the comparison of records for future cycles, the number of alarms received, BI results and the fact that the qualification activities are performed. The completion of the training record cannot be a proof on its own that the technical failure is avoided.
Batch Disposition and Quality Assurance Action
Quality assurance must execute proposed batch disposition action as per quality procedures of the site and applicable regulations. The batch disposition decision should be made based on documented investigation and supporting data.A successful sterility test does not in itself confirm that the failure of the sterilization process results in the necessary level of sterility assurance. A sterility test is conducted on the sample and it cannot compensate for the failure of the process to meet the validated processing conditions.
In the same way, even a so-called successful cycle should be rejected when some critical piece of evidence is missing or not trustworthy. The investigation report should describe the failure, reason for the failure or reasonable conclusion, effect on the product, corrective and preventive actions and other necessary information.
Prevention of Recurrence Through Process Control
To prevent sterilization failure, it is important to keep the validated state of the sterilization process. To this end, the facilities must use validated patterns of load, approved machines, calibrated control devices, trained staff and regular qualifications of the sterilization processes.Examination of trends can help in the identification of repeating alarms, failures of the parameters, BI positives, interruptions in the cycles and malfunction of the equipment before they become the major problem. Before any changes are made to equipment, utilities, packaging and process parameters, their approval via change control will be required.
During an inspection, the inspector may wonder how the failed cycle was investigated, what batches that could be affected by the failure were found and what conclusions were made thereafter. Every thorough and traceable investigation serves as a proof that the facility made its quality decision based on the scientific approach.
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