Out of Specification Investigation Phase II (Unknown Cause / No Assignable Cause ) & Phase III
Phase II Investigation – Unknown Cause / No Assignable Cause
These are difficult to perform as the result can be 1 to 2 weeks after the analysis was performed and maybe weeks after the batch was manufactured.
It is important to evaluate the test conditions carefully and determine what the boundary of samples/products/manufacturing area is. you do not determine the boundary of the suspect results it is difficult to determine if it one or more batches impacted.
The laboratory and manufacturing investigations need to be in depth. The investigations should clearly state the hypothesis and who will be responsible for the identified tasks.
Are the organisms of an expected type, determine likely source – would it be likely to be found where it was?
Review the media – prepared in house or bought in pre-prepared, supplier history, sterilization history
Equipment/utilities used – validation, maintenance, and cleaning status. Evaluate area/environmental trends for test area and support areas.
Cleaning and maintenance of the test environment
Use appropriate root cause analysis to help brainstorm all possibilities It is likely that there may be more than one root cause
Review decisions and actions are taken in light of any new information.
Due to the variability of microbiological results don’t limit the investigation to the specific batch it should be broader to review historical results and trends
Unusual events should be included to understand potential impacts. What is the justification to perform a repeat analysis (is sample left); re-test or resample
Any identifications may need to be at DNA/RNA level (bioburden failures)
All potential sources of contamination need to be considered – process flow the issue from sample storage to the test environment.
Use scientific decisions/justifications and risk based analysis.
The investigation may include working closely with the manufacturing team
During the investigation, it is an advantage to go and look at where the contamination occurred.
Ask how relevant plant is cleaned, tested for integrity, checked for wear, checked for material suitability and maintained at the occurrence site may reveal possible causes.
Where possible talk directly to the staff involved as some information may be missed if not looked at from the chemist/ microbiologist point of view.
Look for other documentation such as deviations and engineering notifications around the area of concern (this is applicable to the laboratory as well as manufacturing).
Trending can have species drift which may also be worthy of an action limit style investigation.
Statistical analysis for microbiology can include lots of zero results so recovery rates or similar may have to be used.
If a sample is invalidated the remaining level of assurance needs to be carefully considered, is their sufficient residual information? Corrective actions may be appropriate for more than one root cause.
Stability – OOS/OOT:
Stability OOS/OOT situations should be escalated as soon as the suspect result is found. Follow the investigation as above for Phase I and Phase II. For OOS Situations Regulatory agencies will require notification within a short time point of discovery due to recall potential.
If abnormal results are found at any stability interval which predicts that the test results may be OOS before the next testing interval, schedule additional testing before the next scheduled testing interval. This will help better determine appropriate actions to be taken.
The stability OOS should link to the Product Recall procedures.
To facilitate the prompt identification of potential issues, and to ensure data quality, it is advantageous to use objective (often statistical) methods that detect potential out-of-trend (OOT) stability data quickly.
OOT alerts can be classified into three categories to help identify the appropriate depth for an investigation. OOT stability alerts can be referred to as:
–process control, and
As the alert level increases from analytical to process control to compliance alert, the depth of investigation should increase.
A compliance alert defines a case in which an OOT result suggests the potential or likelihood for OOS results to occur before the expiration date within the same stability study (or for other studies) on the same product.
The stability OOS should link to the Product Recall procedures.
Historical data are needed to identify OOT alerts.
An analytical alert is observed when a single result is aberrant but within specification limits (i.e., outside normal analytical or sampling variation and normal change over time).
If the batch is rejected there still needs to be an investigation.
– if other batches or products are affected.
– identification and implementation of corrective and preventative action.
Phase III Investigation
The phase 3 investigation should review the completed manufacturing investigation and combined laboratory investigation into the suspect analytical results, and/or method validation for possible causes into the results obtained.
To conclude the investigation all of the results must be evaluated.
The investigation report should contain a summary of the investigations performed; and a detailed conclusion.
For microbiological investigations ,where appropriate, use risk analysis tools to support the decisions taken and conclusions drawn. It may not have been possible to determine the actual root cause therefore a robust most probable root cause may have to be given.
The batch quality must be determined and disposition decision taken.
Once a batch has been rejected there is no limit to further testing to determine the cause of failure, so that corrective action can be taken.
The decision to reject cannot be reversed as a result of further testing.
The impact of OOS result on other batches, ongoing stability studies, validated processes and testing procedures should be determined by Quality Control and Quality Assurance and be documented in the conclusion, along with appropriate corrective and preventive actions.
If no laboratory or calculation errors are identified in Phase I and Phase II there is no scientific basis for invalidating initial OOS results in favor of passing retest results. All test results, both passing and suspect, should be reported (in all QC documents and any Certificates of Analysis) and all data has to be considered in batch release decisions.
If the investigation determines that the initial sampling method was inherently inadequate, a new accurate sampling method must be developed, documented, and reviewed and approved by the Quality Assurance responsible for the release. Consideration should be given to other lots sampled by the same method.
An initial OOS result does not necessarily mean the subject batch fails and must be rejected. The OOS result should be investigated, and the findings of the investigation, including retest results, should be interpreted to evaluate the batch and reach a decision regarding release or rejection which should be fully documented.
In those cases where the investigation indicates an OOS result is caused by a factor affecting the batch quality (i.e., an OOS result is confirmed), the result should be used in evaluating the quality of the batch or lot. A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in the batch’s rejection and proper disposition. Other lots should be reviewed to assess impact.
For inconclusive investigations — in cases where an investigation:-
(1) does not reveal a cause for the OOS test result and
(2) does not confirm the OOS result
the OOS result should be given full consideration (most probable cause determined) in the batch or lot disposition decision by the certifying QP and the potential for a batch-specific variation also needs considering.
Any decision to release a batch, in spite of an initial OOS result that has not been invalidated, should come only after a full investigation has shown that the OOS result does not reflect the quality of the batch. In making such a decision, Quality Assurance/QP should always err on the side of caution