Out of Specification (OSS) Investigations

1. Definition of OOS and OOT
Out of specification (OOS) is defined as a result that falls outside the predetermined specifications or established acceptance criteria set by the manufacturer and/or the laboratory. In simple terms, the result of a stability test conducted by a Quality Analyst (QA) should always adhere to the previously established specifications or criteria. The Quality Control (QC) declares the result as OOS if it doesn’t comply or agree with the given test result criteria. Similarly, out of trend (OOT) is defined as a result that falls outside the trend. QC compares the result of the current test with a set of previous results to check with the on-going trend.

2. Reason for OOS
A. Laboratory Related (Testing Error) OOS
i. Method of Analysis
ii. Non- Calibrated Instruments Used
iii. Calculation Error
iv. Analyst Error
v. Instruments Failure

B. Process Related OOS
i. Operator Error
ii. Equipment Error
iii. Deviation from Validated Procedure
iv. Quality of RM/Intermediates Used
v. In-process Control During Manufacturing

C. Sample Homogeneity (Sampling Error & Handling) OOS
i. Sampling Error
ii. Handling of Sample
iii. Pooling of Sample

3. Phase of Investigation of OOS as per MHRA
– Phase I Investigation – Laboratory Investigation
Phase IA: Primary Laboratory Investigation
Phase IB: Extended Laboratory Investigation
– Phase II Investigation – Manufacturing Investigation
– Phage III Investigation – Extended Manufacturing Investigation

Phase IA Investigation
This phase of investigation are for obvious error such as calculation or power outage, testing errors such as spillages or incorrect setting of equipment parameters. It is expected that these issues are trended even if a laboratory investigation lb or II was not raised.

Phase IB Investigation
This is an initial investigation conducted by the analyst and supervisor using the laboratory investigation checklist covering the pertinent areas for investigation.

Phase II Investigation
This phase of investigation is conducted when the phase I investigations did not reveal an assignable laboratory error. Phase II investigations are driven by written and approved instructions against hypothesis and should always commence with a manufacturing investigation to determine whether there was a possible manufacturing root cause.

Phase III Investigation
If the batch is rejected there still needs to be an investigation to determine whether other batches or products are affected and to identify and implement corrective and preventative actions.

4. Some important definition related to OSSS
Assignable Cause / Conclusive Error: A cause, which is identified as the reason to invalidate a test result. The
assignable cause as conclusion derived from direct or indirect evidence found during the investigation process.

Non- Assignable Cause / Inconclusive Error: JA cause, which is other than assignable cause and cannot be assigned to any finding.

Retest: Performing the test over again using material / product from original composite sample, if it has not been compromised and / or is still available. If not, a new sample to be used.

Re-dilution: The act of repeating test method dilution(s) from the original stock sample and / or standard solution and measuring the final dilution.

Re-sample: A new sample from the original container where possible, required in the event of insufficient material from the original composite sample or proven issue with original sample integrity.

Obvious error: An event / apparent / clear reason for obtaining an Out of Specification (00S) result (but not limited to). Example of obvious error like Calculation error, Spillage of sample solution, incomplete transfer of sample, incorrect instrument parameters, Sample preparation etc.

Hypothesis / Investigative testing: It is the testing performed to help confirm or discount a possible route cause i.e. what might have happened that can be tested? For example, it shall include further testing regarding sample filtration / centrifugation, sonication / extraction, dilution and potential equipment failure etc. multiple hypothesis can be explored. This is applicable to Phase-Ib investigation.

Outlier Tests: To find our outlier results a predetermined experimental plan shall be worked out involving QA and other concerned department (if any) on case to case basis.

Value may be obtained that is markedly different from the others in a series obtained using a validated method.

Such a value may qualify as a statistical outlier. An outlier may result from a deviation from prescribed test methods, or it may be the result of variability in the sample. It should never be assumed that the reason for an outlier is error in the testing procedure, rather than inherent variability in the sample being tested.

Averaging: The validity of averaging depends upon the sample and its purpose. Using averages can provide more accurate results. For example, in the case of microbiological assays, the use of averages because of the innate variability of the microbiological test system. The kinetic scan of individual wells, or endotoxin data from a number of consecutive measurements, or with HPLC consecutive replicate injections from the same preparation (the determination is considered one test and one result), however, unexpected variation in replicate determinations should trigger investigation and documentation requirements.

5. General Investigation Steps for OOS:

Phase III Investigation
The phase III 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 the batch is rejected there still needs to be an investigation. To determine:
– if other batches or products are affected.
– identification and implementation of corrective and preventive action (CAPA).

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