Sterilization validation failure means the proof available does not support the idea of achievement of the given sterilization process acceptance criteria. It may include poor temperature distribution, poor heat penetration, biologic indicators (BI) failure, wrong cycle parameters, as well as inability to prove the sterilization conditions.
After failure of the validation run, there should be a scientific investigation performed before using the process on an ongoing basis, which is not only repeating the cycle until it will be passed. The investigation should clarify what is failed, how this happened, if the failure will have any effect on previously treated batches and how to demonstrate the operation of the reliable sterilization process.
For instance, a steam sterilization cycle may reach the expected temperature but fail to get sufficient temperature in some load areas. In yet another case, a steam sterilization cycle may show good results with physical indicators but produce positive results from biological indicators. Each situation calls for a specific technical assessment.
Preserve the documentation at once and determine whether this failure occurred during a validation session, standard production process, equipment qualification, or periodic requalification process.
Compare the actual cycle data with validated operating limits and accepted values. Ensure that the collected temperature is that of the location inside the object and not only that of the monitoring probe.
Heat penetration and temperature distribution are paramount. The chamber may reach the required temperature but the center of the thick object or the shape of the container may cause the product not to receive enough heat.
Review the following evidence:
To start with, check the identification of the biological indicator, including the number of the lot, the certificate received, population parameters, resistance characteristics, expiration date and storage and use history of the indicator. Make sure that it was suitable for the sterilization method and used according to the instruction given by the manufacturer.
Check its position in the load. The position should be a challenged one which is correlated with validation studies and the proper location for retrieving the indicator.
The lab investigation must include the assessment of:
The BI results need to be interpreted together with other physical parameters, load configuration, process design and other validation records. They can never substitute for critical process data and therefore must not be assessed on their own.
Analysis should differentiate the immediate cause and the real root cause. For instance, although cold point can be perceived as the immediate reason for poor lethality, the poor definition of loading scheme is the real weakness of the process.
In case nothing can be proved, record remaining uncertainties and estimate their implications, as hypothesis cannot substitute for empirical analysis.
Check the particular load, product or material, batch records, cycle history and other required monitoring data. Establish whether the problem is a single event that happened randomly or is it showing there is a serious malfunction in the process.
For terminally sterilized products, the evaluation should include the relationships between the parameters from the sterilization process, the number of microorganisms in the product and the container closure system as well as the sterilization assurance that should be followed to guarantee sterility.
When it comes to sterilizing such equipment and parts that are used during aseptic production, one should check whether these items are properly sterilized and whether using these items may touch the quality of the process after sterilization.
It is impossible to consider a failure of sterilization satisfactory after only performing a sterility test.
Preventive actions must make sure that the weak points that led to failures are taken care of. For instance, if the loading arrangement was not properly controlled, it would most probably be more reasonable to revise the loading chart and bring in the verification method rather than rely only on retraining.
Prior to the initiation of a fresh cycle of validation, verify whether:
An inspector can ask why a certain failure occurred in the cycle, if that had any effect on other cycles, how the root cause was determined and what proof of the effectiveness of the corrective action is available.
An investigation that is documented appropriately should let any competent reviewer follow the reasoning leading from failure to conclusion without any need for discussion.
First Establish the Nature and Extent of Failure
The first step in the investigation is to find out what kind of failure has occurred during the validation study. Different types of failures require different evaluations.For instance, a steam sterilization cycle may reach the expected temperature but fail to get sufficient temperature in some load areas. In yet another case, a steam sterilization cycle may show good results with physical indicators but produce positive results from biological indicators. Each situation calls for a specific technical assessment.
Preserve the documentation at once and determine whether this failure occurred during a validation session, standard production process, equipment qualification, or periodic requalification process.
In the beginning, study must determine:
- What type of sterilization means is employed and the method of sterilization or the kind of material dealt with in sterilization?
- What method of measuring effectiveness of sterilization fails?
- Was the failure identified by physical indication, chemical monitoring and biological indicators or some other means of measuring success?
- Is there a possibility of some type of alarm or abnormal events occurring?
- Is there a possibility that earlier successful sterilizations could be affected by unsuccessful sterilization of the load?
Review the Physical Cycle Data Before Drawing Conclusions
In moist heat sterilization, it is necessary to analyze the entire cycle record rather than just relying on the cycle summary presented in the device-screen. Review parameters such as temperature, pressure, exposure time, heating, equalization, etc. which are essential in terms of the approved cycle.Compare the actual cycle data with validated operating limits and accepted values. Ensure that the collected temperature is that of the location inside the object and not only that of the monitoring probe.
Heat penetration and temperature distribution are paramount. The chamber may reach the required temperature but the center of the thick object or the shape of the container may cause the product not to receive enough heat.
Review the following evidence:
- Results of temperature mapping and heat penetration study.
- Calibration status and location of temperature sensors.
- Where relevant, affect the relationship of pressure to temperature.
- Cyclic records, electronic data, alarms, logs of events.
- Load quantity, type, arrangement and packing condition.
- Where applicable, data regarding steam quality and air removal.
- Record of equipment calibration and servicing.
Investigate Biological Indicator Failures Carefully
A positive bacterial indicator result is an important impetus to investigate the matter in detail, but it cannot be interpreted without analyzing the study completely.To start with, check the identification of the biological indicator, including the number of the lot, the certificate received, population parameters, resistance characteristics, expiration date and storage and use history of the indicator. Make sure that it was suitable for the sterilization method and used according to the instruction given by the manufacturer.
Check its position in the load. The position should be a challenged one which is correlated with validation studies and the proper location for retrieving the indicator.
The lab investigation must include the assessment of:
- Results of the positive and negative controls.
- Conditions and duration of incubation.
- Growth promotion or compatibility of the recovery method.
- BI’s handling, transportation and lab record-keeping.
- Possibility of contamination in the process of collection or testing.
- Identification of the organism when applicable.
The BI results need to be interpreted together with other physical parameters, load configuration, process design and other validation records. They can never substitute for critical process data and therefore must not be assessed on their own.
Identify the Most Probable Root Cause
After gathering all of the evidence, the investigation team needs to analyze the probable root causes in a systematic manner. I would use the practical approach of classifying the investigation into equipment, process, load, measuring, material and microbial factors, so as to avoid limiting the investigation to the sterilization device even when the problem might be connected with the load preparation process or the research performance.| Area of investigation | Possible causes to analyze |
| Equipment | Hardware failure, worn trap, leakage, improper air release, maintenance problem |
| Process | Wrong cycle configurations, not enough exposure, poor equilibration |
| Load | Overloading, wrong arrangement, inappropriate containment, insufficient penetration |
| Measuring | Calibrating error, improper placement, failure to record |
| Steam quality | Presence of non-condensable vapors, too much water, poor vapor conditions |
| Microbial indicators | Wrong storing, improper handling, inappropriate BI, failure to test |
Analysis should differentiate the immediate cause and the real root cause. For instance, although cold point can be perceived as the immediate reason for poor lethality, the poor definition of loading scheme is the real weakness of the process.
In case nothing can be proved, record remaining uncertainties and estimate their implications, as hypothesis cannot substitute for empirical analysis.
Assess Product and Previously Validated Loads
The evaluation of the risk should go further than the failure of validation process if there is a risk that the same situation is present during normal operation.Check the particular load, product or material, batch records, cycle history and other required monitoring data. Establish whether the problem is a single event that happened randomly or is it showing there is a serious malfunction in the process.
For terminally sterilized products, the evaluation should include the relationships between the parameters from the sterilization process, the number of microorganisms in the product and the container closure system as well as the sterilization assurance that should be followed to guarantee sterility.
When it comes to sterilizing such equipment and parts that are used during aseptic production, one should check whether these items are properly sterilized and whether using these items may touch the quality of the process after sterilization.
It is impossible to consider a failure of sterilization satisfactory after only performing a sterility test.
CAPA and Revalidation: Demonstrating That the Problem Is Resolved
The core issue addressed by CAPA must be one that has been established as a cause of the problem or the most likely cause. That means that corrective actions could include the fixing of the equipment, replacing failed devices, modifying the load system, improving steam quality control and even making changes in the procedure or retraining the personnel.Preventive actions must make sure that the weak points that led to failures are taken care of. For instance, if the loading arrangement was not properly controlled, it would most probably be more reasonable to revise the loading chart and bring in the verification method rather than rely only on retraining.
Prior to the initiation of a fresh cycle of validation, verify whether:
- Repairs and adjustments of equipment are done and registered.
- All relevant equipment is calibrated.
- Revised procedures and load patterns are approved.
- Necessary personnel are trained properly.
- Validation plan as well as acceptance criteria is acknowledged.
- The scientific rationale for the scope of repeat testing/requalification is provided.
What QA Should Verify Before Closing the Investigation
QA needs to check whether the investigation includes original failure evidence, complete cycle documentation, technical evaluation, root cause justification, impact evaluation, CAPA and the need for revalidation or re-qualification.An inspector can ask why a certain failure occurred in the cycle, if that had any effect on other cycles, how the root cause was determined and what proof of the effectiveness of the corrective action is available.
An investigation that is documented appropriately should let any competent reviewer follow the reasoning leading from failure to conclusion without any need for discussion.
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