A review of recent Form 483s and Warning Letters shows that investigations continue to be a focus of FDA inspections, where the following citation is commonly issued: 

There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. 

It is safe to say that, during an inspection by a regulatory authority, critical investigations, such as product release, OOS, stability failures, etc., will always be examined as inspectors want to assess and gauge the firm’s Quality Unit’s ability to exercise the correct level of oversight/due diligence when faced with a situation where there is a risk that business pressures may influence the quality decision.  Quality oversight is easy when everything is going according to plan! 

When addressing an Agency citation for investigations, firms’ remediation efforts will commonly focus on actions such as implementing procedural updates, training of the investigators, etc. where the focus is, understandably, on implementing actions that will enhance the quality of the generated investigation.  However, what must not be forgotten is that the firm needs to identify the root cause(s) to ensure that a health agency review does not identify deficiencies that were not self-identified by the review and approval of the investigation by its own Quality Unit. 

In such circumstances, firms should evaluate their training and qualification of investigation reviewers, which should also include the program for continued oversight and monitoring (of said investigation reviewers).  This is where the services of a third party can prove to be beneficial as they will enable independent review of the training/qualification and oversight programs as well as provide targeted training to the Quality Unit’s investigation reviewers/approvers.  It is important that the remediation addresses the central question of why the firm’s Quality Unit failed to self-identify the deficiencies that were noted by the Agency’s investigator. 

A mistake made by some firms is focusing on the training of investigation reviewers but there is no distinct qualification step after training, which would serve as an effectiveness measure of the training.  One approach that can be employed for qualification is to have a set of mock investigations where there are known errors/issues within the investigations that need to be identified by the newly trained investigation reviewers as part of their qualification.  An investigation reviewer’s background must be such that they are familiar with the subject matter of the investigation so that they have a deep understanding of the proposed root cause and are able to challenge it when required.  This is why it is not appropriate to have an investigation reviewer review/approve investigations that are generated from all departments; rather, they should be assigned based upon expertise.  Another consideration is that the investigation reviewer should ideally maintain a level of independence and should not have been involved with the execution of the investigation.  The goal is that the investigation reviewer reviews and approves the investigation from a fresh perspective and, thus, mimics (hopefully) the review that would occur during an Agency inspection. 

Oversight of the effectiveness of the training/qualification program can occur via the firm’s internal audit/self-inspection program where internal auditors would review completed investigations that were reviewed/approved by selected Quality Unit reviewers.  The level of oversight should consider the Quality metrics for the program, which in turn consider performance based upon data from health agency and client audits, etc. 

If you have any questions relating to this topic, Lachman Consultants can help you!  Please contact LCS@lachmanconsultants.com for support with this critical undertaking.