What does out of specification mean?
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According to the United States Food and Drug Administration (USFDA), Out of Specification results are defined as, “All test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications.”
Out of Specification results indicate a loss of control over either the manufacturing or the analytical process or both. This can result in defective products being sent out, and subsequent market complaints or product recalls, and even a threat to the life of the patients. So, it is vital to investigate Out of Specification results and identify and address the root causes responsible for the Out of Specification results.
How do you investigate out of specification?
There must be written and approved procedures to investigate any OOS results and these must be followed. OOS result investigation generally proceeds in two phases.
Phase I: Laboratory Investigation
Here, the objective is to identify the cause of the Out of Specification result. It may arise from an aberration in either the analytical process or the manufacturing process. If the Out of Specification result causes rejection of a batch of products, it is still necessary to investigate the cause and check if there may have been an impact on any other batch of the same or different products.
In this phase, the accuracy of the data collected by the laboratory is first assessed using the same samples, reagents, and standards that have been previously used. This helps to identify if any lab error or instrumental error or analyst error caused the OOS result. Common causes of the error include faulty dilutions, incorrect calculations, equipment malfunction, and error in the analytical method adopted.
If none of these are identified as the cause, the investigation moves to the second phase which is a full-scale Out of Specification investigation.
Phase II: Full-scale OOS Investigation
In this phase, a multi-department investigation committee is formed with representatives from QC, QA, Production, Stores, and Engineering. The production process is reviewed and if necessary, additional laboratory analysis is performed. Sampling procedures, production processes, storage conditions, facility environment are all reviewed to identify the cause of the OOS result. If the cause is successfully identified, the investigation is terminated, and the affected product must be rejected. Other batches of products already distributed, but which may have been affected by the OOS, must also be investigated.
In some cases, the OOS result investigation may be inconclusive – that is, either the OOS result is not confirmed or the cause of the OOS result is not detected. In such situations, the QC unit may decide to release the batch if the following conditions all exist:
- Subsequent re-test results lie within specifications, and
- No laboratory error is identified, and
- No process aberrations have been revealed by the review, and
- Results from the batch’s in-process tests, dissolution, content uniformity, and other important tests match the passing re-test results
- The process is found to be robust, and other batches have not been affected.
All findings in all stages of the investigation must be documented and stored.
Documentation of OOS result investigation:
Information to be documented for every OOS result investigation:
- Reason for investigation.
- Details of the OOS result.
- Phase I Laboratory investigation details and findings.
- Summary of Phase II analysis performed.
- Root cause identified as actual/probable cause of the OOS result.
- Description of corrective actions taken following the OOS result.
- Result from document review of previous batches to check if a similar problem has occurred before.
The flow of events in case of OOS result:
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