It is expected that sterilization validation will show that a particular sterilization process will be able to ensure the sterility in its intended manner and thus will ensure that the product, its package and container would not be subjected to prohibited influence. Nevertheless, during inspection reviewers rarely limit themselves only to the fact whether the validation procedure has been followed or not. They consider important factors, such as rationale of certain decisions, worst-case conditions, loads configuration, biological indicators, physical parameters, deviations and proofs that the validated process is controlled.
FDA inspection guidelines clearly state that the audit should include the analysis of bioburden, parameters of the process and its tolerances, acceptance criteria, challenge studies, biological indicators or other monitoring systems, evidence that the process really works.
There are a number of failings that recur during sterilization validation audits.
A sterilization cycle may work fine with a light loading level, but that does not necessarily prove effective performance with the highest or the most difficult routine load.
Product density, type of containers used and packing type, heat penetration, air extraction and load position can impact the efficiency of the sterilization.
A common drawback is when the given load pattern is approved in theory, yet some other pattern is used in practice.
The validation documentation has to provide sufficient information about the load configurations that were studied and give the scientific reason for choosing the maximum, minimum and difficult loads.
When using moist heat, the placement should take into account thermodynamic properties and the capability of detecting difficult-to-sterilize areas. The biological indicators should also be located in a way that would create a proper challenge to the process.
Aseptic processing guidelines issued by FDA mean that the locations of temperature sensors and biological indicators need to be recorded in validation records.
During an audit, I will compare the official scheme with the validation records and will check whether the selected locations were used while performing the validation process.
In other words, even if a particular load is frequently produced, that fact alone does not make it the worst case.
The justification should state all characteristics that pertain to the use of the specific load, including product features and properties, load intensity, size of the container, configuration of the load, heat resistance, sterilization technique, etc.
Hence, not only the ability to determine the worst-case load matters, but also the ability to explain why that load is a good load for such a study.
Audit problems may occur due to the absence of information regarding the following issues:
- the expiration date and lot of the biological indicators.
- the population and resistance properties of the indicators.
- the places of the indicator's installation.
- the control of positive and negative indicators.
- the incubation conditions for the indicators.
- the result and interpretation of the results from the indicators.
- the process of handling failed or doubtful indicators.
The results of biological indicators should always be analyzed together with the parameters of the physical cycle and the validation plan.
For sterilization processes, the connection between the metrics and the effectiveness of killing microbes is of utmost importance. It is essential to analyze process trends and patterns, rather than just verifying that some endpoint was reached.
The FDA's guidance clearly states that factual evidence should prove that preset sterilization parameters are well executed and ensure the predetermined sterility assurance level.
When I review sterilization data, I look for proof that the team understood the cycle profile and was not just satisfied with their measuring device showing acceptable parameters.
Hence, audit may evaluate whether historical data on bioburden, regular monitoring, organism attributes and controls provide sufficient support for the assumptions made during the validation process.
The most important question is not whether the deviation was closed or not.
The investigation must consider whether the event had an effect on the purpose of the validation and whether there is a need to conduct additional test work and re-run the validation.
One aspect I would always check is whether the organization has clearly related the deviation investigation to the final conclusion about the validation. "Not impacting the quality of product" statement without any evidence may not be strong enough during the audit.
Within this process, changes in sterilization equipment, software used for control, utilities involved, loading procedures, packaging, product configuration and maintenance practices may all necessitate appropriate documentation of impact assessment.
The inspection guidance provided by the FDA suggests that verifiers of sterilization processes check also adjustment of the equipment, calibration and maintenance when sterilization works beyond tolerances.
A perfect system shall link change control and validation status and define the meaning of the requalification or revalidation.
An effective audit readiness review should go beyond checking for signatures and approvals. This means that QA should challenge how the load rationale, sensor and BI positions, physical cycle data, bioburden strategy, deviations, equipment status and any changes made post-validation are linked.
When these things are scientifically linked correctly, the sterilization validation package offers much greater proof of the ability of process to guarantee sterility under real manufacturing circumstances.
There are a number of failings that recur during sterilization validation audits.
Validation Loads do not Represent Routine Production
In order to determine whether the validation load made is an accurate representation of the actual production load the first instinct would be to check.A sterilization cycle may work fine with a light loading level, but that does not necessarily prove effective performance with the highest or the most difficult routine load.
Product density, type of containers used and packing type, heat penetration, air extraction and load position can impact the efficiency of the sterilization.
A common drawback is when the given load pattern is approved in theory, yet some other pattern is used in practice.
The validation documentation has to provide sufficient information about the load configurations that were studied and give the scientific reason for choosing the maximum, minimum and difficult loads.
Inadequate Temperature Sensor and Biological Indicator Locations
The method of placing sensors involves more than the even distribution of probes throughout the chamber.When using moist heat, the placement should take into account thermodynamic properties and the capability of detecting difficult-to-sterilize areas. The biological indicators should also be located in a way that would create a proper challenge to the process.
Aseptic processing guidelines issued by FDA mean that the locations of temperature sensors and biological indicators need to be recorded in validation records.
During an audit, I will compare the official scheme with the validation records and will check whether the selected locations were used while performing the validation process.
Weak Worst-Case Justification
It is tough to justify a validation study when the company is unable to justify why it believes that the load it has chosen is a true test of the sterilization process.In other words, even if a particular load is frequently produced, that fact alone does not make it the worst case.
The justification should state all characteristics that pertain to the use of the specific load, including product features and properties, load intensity, size of the container, configuration of the load, heat resistance, sterilization technique, etc.
Hence, not only the ability to determine the worst-case load matters, but also the ability to explain why that load is a good load for such a study.
Biological Indicator Controls are Poorly Defined
Biological indicators are among the most reliable tools of sterilization, but the efficient use of these indicators requires careful choice, use, placement, incubation and analysis.Audit problems may occur due to the absence of information regarding the following issues:
- the expiration date and lot of the biological indicators.
- the population and resistance properties of the indicators.
- the places of the indicator's installation.
- the control of positive and negative indicators.
- the incubation conditions for the indicators.
- the result and interpretation of the results from the indicators.
- the process of handling failed or doubtful indicators.
The results of biological indicators should always be analyzed together with the parameters of the physical cycle and the validation plan.
Physical Data are not Properly Evaluated
Another common issue is the treatment of temperature, pressure, time, humidity and other process parameters as binary pass/fail numbers.For sterilization processes, the connection between the metrics and the effectiveness of killing microbes is of utmost importance. It is essential to analyze process trends and patterns, rather than just verifying that some endpoint was reached.
The FDA's guidance clearly states that factual evidence should prove that preset sterilization parameters are well executed and ensure the predetermined sterility assurance level.
When I review sterilization data, I look for proof that the team understood the cycle profile and was not just satisfied with their measuring device showing acceptable parameters.
Bioburden is Missing From the Validation Strategy
It is necessary to consider the microbial attributes of material subject to sterilization while validating sterilization processes. In cases where applicable/possible, the validation strategy should help understand and control bioburden prior to sterilization. FDA recognizes that bioburden determination is necessary to provide objective evidence required for sterilization process validation.Hence, audit may evaluate whether historical data on bioburden, regular monitoring, organism attributes and controls provide sufficient support for the assumptions made during the validation process.
Deviations are Closed Without Assessing Validation Impact
A sterilization validation run can have instances of unforeseen temperature spikes, pressure deviations, difficulties in managing biological indicators, missed cycles due to warning signals from equipment, etc.The most important question is not whether the deviation was closed or not.
The investigation must consider whether the event had an effect on the purpose of the validation and whether there is a need to conduct additional test work and re-run the validation.
One aspect I would always check is whether the organization has clearly related the deviation investigation to the final conclusion about the validation. "Not impacting the quality of product" statement without any evidence may not be strong enough during the audit.
Requalification and Change Control Are Weak
Validation of sterilization cannot be safeguarded indefinitely by the original qualification report.Within this process, changes in sterilization equipment, software used for control, utilities involved, loading procedures, packaging, product configuration and maintenance practices may all necessitate appropriate documentation of impact assessment.
The inspection guidance provided by the FDA suggests that verifiers of sterilization processes check also adjustment of the equipment, calibration and maintenance when sterilization works beyond tolerances.
A perfect system shall link change control and validation status and define the meaning of the requalification or revalidation.
What QA Should Review Before an Audit
Before the regulatory or customer audit, QA needs to conduct a targeted review of the sterilization validation documentation. In doing so, specific focus should be given to:- Accepted protocols and produced records
- Configuration blueprints
- Mapping of temperature and pressure
- Biological indicator documentation
- Records of the cycle and electronic data
- Data on microbial contamination
- Qualification and calibration of equipment
- Deviations and corrective actions
- Changes in control
- Records for previous validation and re-validation
- Directive and acceptance standards
An effective audit readiness review should go beyond checking for signatures and approvals. This means that QA should challenge how the load rationale, sensor and BI positions, physical cycle data, bioburden strategy, deviations, equipment status and any changes made post-validation are linked.
When these things are scientifically linked correctly, the sterilization validation package offers much greater proof of the ability of process to guarantee sterility under real manufacturing circumstances.
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