For a number of years, discrepancy and failure investigations within the pharmaceutical industry have been populating the Top 3 of a Food and Drug Administration (FDA) Observation list.
Unfortunately, this distinguished list depicts the top reasons why a 483 or warning letter would be issued to a company. Essentially, the FDA is stating that either companies are not investigating discrepancies and failures or their investigations are undoubtedly deficient on a consistent basis. In an earlier blog entitled Five Most Common Mistakes When Writing an Investigation, the author noted that the commonly identified mistakes for investigations are close-minded investigations, failing to identify and/or execute the appropriate CAPA, incomplete investigations, poorly written investigations, and inadequate Quality Impact Assessment.
Throughout my fairly extensive career, I've written and reviewed many investigations and, through the process, retained a few basic principles or "best practices." Whether it's investigating a roof leak into a manufacturing suite, a missed in-process time check, a differential pressure alarm, or an insect found in a lab, these same practices apply.
Here are a few of the easiest ones to adopt
Investigations should be stand-alone (not leveraging another document), thorough, and objective.
- Confirmed deviation should be investigated, even if the details are found in another investigation. Those details further establish trends and therefore pinpoint focus.
- Investigations should be thorough. In other words, the investigation should be completely written with all supporting documentation for reference. The investigation should also be clearly written so that an independent person, not familiar with the process, could follow and understand.
- Investigations should be objective. Write-ups should be without a predetermined “known” root cause. Conclusions should not be subjectively drawn based on a previous similar event or only one source of information, e.g., an interview. A systematic and objective approach instead will fully evaluate all of the investigative findings and results in identification of root cause.
Root cause and contributing factors should be identified and adequately supported.
- A singleroot cause and contributing factor(s) should be identified and substantiated with concrete evidence. Multiple causes may appear to be at the root, but further drilling will expose that one key cause which is directly related to the discrepancy and/or failure.
- Non-impacting areas (e.g., environment, materials) should be ruled out and supported with findings.
Corrections and corrective and preventive actions (CAPAs) should be aligned with the root cause identified and appropriate.
- Assigned CAPA(s) should be aligned directly with the root cause identified, e.g., if the root cause is procedure inadequacy, CAPA would be method/process related.
- Assigned CAPA(s) should be appropriate with the investigation findings identified. That’s precisely why deviations need to be fully evaluated and explained to identify and assign the right corrective and preventive actions.
- For instance, while investigating a missed time check deviation, a root cause of “personnel” was identified. Was the missed time check due to human error— operator oversight, not being trained, or confusion within the batch record or SOP? Should the resulting CAPA then include discipline to the operator, training, re-training, or revision to a procedure?
Historical searches performed should be clearly defined and include search criteria (i.e., key words).
- Investigations should include historical searches and the search criteria clearly defined in the document so that the results can be repeated.
- Search criteria should be extensive enough to establish whether a trend of the deviation is present. An investigation for a damaged elastomer should look beyond the immediate vessel and at other similar equipment. For an investigation relating to a calibration out of tolerance (OOT), the look back should be commensurate with the instrument calibration frequency.
Product quality impact should be clearly detailed, fully evaluated, and documented.
- Quality impact assessments should be clearly detailed in the corresponding SOP and define the intent of the assessment, and establish the process for evaluation.
- Assessments should be fully evaluated and documented relative to the applicable procedure, equipment, room, batch, or system to determine the quality impact, if any.
Regardless if you are writing or reviewing company investigations within the pharmaceutical or any other industry, keeping these principles in view and making them best practices will, without a doubt, remove your company from the FDAs "premier" Observation list.
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