Out of specification (OOS) results are bound to occur at a testing laboratory. It is important that your contract lab investigates the unexpected results in a timely and thorough way.
An OOS result occurs when an analytical result does not meet the applicable specifications. As a cGMP compliant and ISO 17025:2017 accredited laboratory, Particle Technology Labs has established procedures dictating the actions to take upon the discovery of an unexpected result. PTL’s investigation procedures follow the FDA’s Guidance for Industry, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production (2006). The investigation process is initiated whenever an OOS test result is obtained for cGMP or ISO17025 compliant analyses. The purpose of the OOS investigation at PTL is to determine if the result was caused by the measurement process or if it genuinely represents the provided sample.
A Thorough and Timely Process That Follows FDA Guidance
Phase I: Laboratory Investigation
Immediately upon discovery of an out of specification result, laboratory staff escalate the project to investigation status. Initially, an evaluation of the analysis is conducted to verify testing was executed as required. Particle Technology Labs does this through completion of a Laboratory Investigation Checklist. The investigator verifies such things as the operation of the instrument, qualification of the chemist, execution of the analysis as compared to the test method, solution preparations and examination for any anomalies or potential improvements. Via the investigative process, three potential outcomes may arise:
- An error occurred during analysis execution.
- Further refinement of the method is advised.
- The generated result appears to be representative of the sample received.
When an out of specification result occurs, manufacturers often hope a laboratory error is discovered as it is the easiest issue to resolve. A root cause can quickly be identified, results invalidated, and samples rerun – little time is lost. In reality, laboratory errors do not occur frequently. With well trained staff, using qualified instrumentation and appropriate test methods, execution errors are rare. When an error does occur, PTL documents the issue as a nonconformance / unplanned deviation. Through this process the root cause of the issue is evaluated, the risk of the issue is determined, and appropriate corrective action is initiated. In addition, the original OOS results are considered invalid as they were caused by the laboratory error. The analysis is then repeated with a fresh sample preparation ensuring the test method is executed correctly.
Through the course of the investigation, it may become apparent that an aspect of the test method is not clear or could be refined. Alternatively, the sample may be behaving differently and the test method as written no longer provides representative results. In these cases, further evaluation is recommended to the client. If approved by the client, hypothesis testing is conducted under a second investigation stage. The results from the additional hypothesis testing will be shared and discussed with the client. This data will help to inform whether the test method should be revised as a corrective action.
The most common outcome of a laboratory investigation is confirmation that testing was executed correctly. In this case, no errors are evident and the method appears to have not caused issues. Upon approval of the laboratory investigation, the client is provided the OOS results. The need for further investigation is determined by the client.
Phase II: OOS Full Scale Investigation
It is the manufacturer/product owner’s responsibility to conduct a full scale OOS investigation into the results when a laboratory issue is not evident. Through this process the root cause of the out of specification results is determined.
As part of the full-scale investigation, additional testing can be requested of the laboratory. Ideally, this will take the form of retesting. Retesting is defined as analysis of fresh preparations from the same homogeneous material that yielded the original OOS result. In some cases, sample quantity is not sufficient for retesting. A resample of the material may be submitted for testing; however, if different results are obtained differences in sampling or shipping may be an influencing factor.
Prior to initiating additional analyses, it is critical to establish the testing plan. The number of retests must be defined in writing prior to testing initiation. PTL’s out of specification procedure requires the analysis of two additional aliquot preparations. Each retest aliquot is prepared and analyzed per the analytical test method.
The exact number of retest samples can vary from company to company or across analysis procedures. This is acceptable as long as the site defines the prescribed number of retests within an official procedure or document. It is important to not simply retest a number of undefined samples until a passing result is obtained. This is considered “testing into compliance” and is specifically deprecated by the FDA due to its unscientific nature. The point at which testing will stop and results evaluated must be clear and defined.
Three separate outcomes can potentially result from retesting at the contract laboratory:
- The retest results confirm the original, OOS results.
- The retest results are inconclusive – both OOS and passing results are obtained.
- The retest results refute the original, OOS results.
If the retest confirms the original OOS results, PTL will consider the results genuine and representative of the sample; all results will be reported. If there is not a definitive cause for the original OOS results, they cannot be invalidated. All results, both the original OOS results and the retests must be reported and used by the client in future decisions. In the case of the retest results refuting the original, the original results are marked “suspect” but must still be reported.
Throughout the investigation process, all actions must be clearly documented. The laboratory is responsible to provide the investigation documentation and the associated data to the client.
The end decision as to actions to take in regards to the sample are the responsibility of the client (manufacturer/product owner). Once the laboratory provides the testing information, the client must complete any further evaluations and investigations into the production, sampling and shipping process to determine if any issues occurred which negatively impacted the sample. The results of the investigation are critical into not only determining what to do with the sample itself but also as to if improvements are necessitated. Depending on the results, the investigation may also need to carryover to other products or lots which may have also been negatively impacted.
Throughout the investigation process, open communication between the laboratory and the client is critical. Particle Technology Labs strives to develop a trusted partnership with each client. This is accomplished through timely completion of investigations, thorough documentation, and upfront communications.