FDA Guidance on Container Closure Systems (CCS) and Out of Specification Investigations (OOS)

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“The Mystery of the Disappearing Fentanyl” case study highlights the potential impact of the container closure system on a final drug product, and the importance of having a comprehensive and robust investigation process.

To minimize issues associated with a specific CSS, a firm must go through a qualification process to determine the “Suitability” of a container closure system with their drug product.  A CCS is deemed suitable only after it has been proven to “Protect” the product, found to be “Compatible” with the product, and considered “Safe” for use with the product given the route of administration.  It is advisable to determine the suitability of a CCS prior to attempting to perform costly and time-consuming stability studies.  For more information on this important subject, please see the FDA’s Guidance for “Container Closure Systems for Packaging Human Drugs and Biologics”.

An investigation to determine the root cause of an OOS result can be a complicated, time consuming, and costly endeavor.  It is for this reason that it is important to approach the process systematically.  The first step is to look for obvious or easily identified errors in either the laboratory testing or production process.  This can be done relatively quickly (i.e. few hours to days) at minimal cost, by reviewing everything associate with the testing and production process, such as paperwork, training, equipment, materials etc.  If the issue is identified during this phase of the investigation, the cause of the issue can be corrected, after which the process can proceed.  If the root cause is not identified, a “Full-Scale” much more in-depth investigation will be required.  These investigations typically take much longer (i.e. days to weeks), and can require additional testing, and significant human and financial resources.  For more information on this important subject, please see the FDA’s Guidance for “Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production”.