MHRA guidance for handling OOS results was recently updated and is available on MHRA website. FDA guidance for handling of OOS was initially issued in 1998 as draft and was finally issued in 2006. MHRA guidance on handling OOS results was initially published in 2013 and was updated to add handling of microbiological OOS. MHRA guidance is complementary to FDA guidance and provides flowcharts for OOS investigations.
There are 3 phases of an OOS investigation. During Phase 1 and 2, investigation is performed to determine root cause of OOS in lab and manufacturing, respectively. During phase 3, a holistic assessment is performed to determine impact of OOS result on the impacted & other batches, stability etc. and to implement appropriate CAPA.
There are two most common regulatory observations related to OOS. (1) Inadequate justification for invalidating tests and reoccurrence of invalid tests. (2) Inadequate and inconclusive investigation with no root cause and corrective actions.
Invalid tests should be trended based on root cause to enhance assay robustness, procedures or training program, implement CAPA and to prevent reoccurrence of invalid tests. The potential or most probable root causes should be determined, where root cause cannot be determined and appropriate CAPA should be implemented for process improvements, as applicable. However, if there are numerous OOS for the same test where the root cause cannot be determined, then question arises if the specifications are adequate for the test. Is there a need to improve the process or the assay or the specification? Also, if there are numerous OOS for the different tests where root cause cannot be determined, then OOS investigation procedure and training on root cause investigation needs to be enhanced.
Therefore, a good trending program for invalid tests and OOS test is very important to implement an effective CAPA and remediate OOS issues.