UNDERSTAND OOS IN 10 MINUTES

Today we're diving into a topic that holds significant importance in the pharmaceutical industry: Out of Specification, or OOS results. I'll do my best to break down this complex subject in under 10 minutes.

Let's begin with a bit of history. In 1993, the Bar Laboratories sued the USFDA over ad hoc drug regulations. The issue at hand was the USFDA's reluctance to accept Bar Laboratories' practices in handling and managing out-of-specification results.

When an out-of-specification result occurred, Bar Labs would conduct testing on the same sample two more times, resulting in three sets of data: the initial OOS result and two retesting results. Bar Labs would then select two of these results. If both of the retesting results met the specification, the batch would be released. However, the USFDA had reservations about this approach. They considered it unscientific, with no clear references provided by Bar Labs to back up their methodology.

The dispute led the Bar Laboratories to file a lawsuit against the USFDA, accusing them of ad hoc drug regulations. It's worth noting that at the time, there were no clear guidelines available on how to handle out-of-specification results. As a result, the USFDA was urged to publish guidelines on OOS in 1998.

These guidelines are structured into three phases: Phase 1, Phase 2, and Phase 3.

Phase 1 primarily aims to confirm the accuracy of analytical results and determine if laboratory data is reliable.

However, within Phase 1, it's worth emphasizing a further breakdown: Phase 1A and Phase 1B. Although not officially part of the USFDA's guidance, EMA (the European Medicines Agency) has divided Phase 1 into these two sub-phases.

Phase 1A's purpose is to identify obvious errors that have direct and detectable evidence. Examples include incorrect peak integration in chromatographic analysis, varying instrument parameters in instrumental analysis, dilution errors, and weighing errors. If an obvious error is identified, corrective and preventive actions can be taken, and the OOS case may be closed with the verdict that the testing lab's result was invalid.

In cases where no obvious errors are identified—meaning errors without direct or detectable evidence—Phase 1B comes into play. Its purpose is to identify assignable causeways. Assignable causeways are deeper-seated issues that may require hypothesis testing. These hypotheses help the quality control unit either confirm or eliminate the root cause. If an assignable causeway is identified, the appropriate corrective and preventive actions can be taken, leading to the release of the batch.

However, if no assignable causeway is identified in Phase 1B, it's time to move on to Phase 2.

Phase 2 is often referred to as the full-scale investigation. Here, not only the quality control department but also manufacturing and, if needed, the vendor become part of the investigation team. Manufacturing looks into whether any problems occurred during the batch's production.

The possible outcomes in Phase 2 include identifying manufacturing deficiencies. If this happens, the batch is simply rejected (or reprocessed as per policy), and the necessary corrective actions are taken. But what if no manufacturing errors or deficiencies are observed? This presents a challenging situation. You're essentially saying there are no laboratory errors and no manufacturing errors.

In this scenario, the guideline recommends additional testing. This involves retesting the batch by two different analysts: the original analyst who reported the OOS result and a second, equivalent analyst who initiates the additional testing. If the second analyst's results all pass, then the original analyst conducts retesting. If the results of this second retesting meet the specifications, the batch can be released.

However, if one or more results from the second analyst do not meet the specifications, the original analyst's retesting is not required. In this case, the batch can be rejected based on the product's history or any previous OOS results, customer complaints, or any other valid reasons.

Let's move on to the last phase, Phase 3. Phase 3 involves reviewing the complete investigation, conducted by both the manufacturing and quality control teams. Based on the investigation's findings, Phase 3 concludes the outcome of the entire process and determines the batch's disposition.

If the decision is to reject the batch, and no root cause is identified, the guideline states that there is no provision for further investigation to find the root cause. This is a critical point to note: once the decision to reject is made, it cannot be reversed based on further testing or investigation conducted beyond Phase 3.

In summary, the investigation of OOS results involves a multi-phase process that includes laboratory investigation, identification of assignable causeways, and a thorough review. Decisions regarding batch disposition must be made carefully, and there is no room for changes after the rejection decision is finalized.

Thank you for joining me in this discussion of OOS results, a critical aspect of pharmaceutical quality control.