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FDA Releases Final Guidance on Handling OOS Test Results

On October 12, 2006, the FDA announced the release of the final Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production (1). A draft with the same title was published in 1998 and although it was only a draft it was one of the most important FDA guidance documents. This article describes differences to the eight years old draft guidances, key requirements, strategies for implementation and how Agilent can help to avoid OOS test results.

Difference Between Old and New Guidance

The basic principles are the same but there are also some differences in three areas:

• Scope: Whereas the previous guidance was mainly focusing on testing of active pharmaceutical ingredients (APIs) and finished drugs, the final guidance makes it clear that it also applies to raw materials, in-process materials and stability studies.
• Involvement of QCU: The new guidance puts more responsibility on the quality control unit for full investigation including production review.
• Examples: The final guidance has more and very specific examples for situations where retesting is required and for appropriate and inappropriate uses of averaging. It also has an example for a situation when the root cause for an initial OOS could not be found the batch could be released.

Key Requirements

The key points of the Guidance are

• For each test, there should be clear specifications and acceptance criteria
• If for a specific test acceptance criteria are not met, further tests should be stopped until the failure has been investigated and resolved.
• The investigation occurs in two phases: Initial laboratory investigation (phase one) and full investigation (phase II).
• Phase two is managed by the QCU and may involve production, engineering and additional laboratory tests.
• In case of a full investigation, QCU evaluates the results and decides to either reject or release the batch.
• The investigations should follow a written procedure that defines responsibilities and steps for handling OOS test results.
• Part of the investigation is to find the root cause for a failure. Once the root cause is known, a preventive action plan should be developed to prevent occurrence of the same or similar problem.

Recommendations for Implementation

• Develop an SOP for OOS situations. The SOP should clearly describe responsibilities - who does what when an OOS situation occurs.
• Define acceptance criteria for each test.
• When acceptance criteria are not met, initiate failure investigation following the SOP for OOS situations.
• Identify the root cause of each failure.
• Develop a corrective and preventive action for each OOS situation.
• Verify effectiveness of preventive actions.
• Include OOS procedures in internal audit program. On a few examples, check if the procedures were followed.
   

Agilent's Offering

By far the best approach to deal with OOS is to avoid them, to the highest extent possible. Reliable and well-calibrated, qualified and maintained instrument hardware together with validated computer systems help to reduce the number of OOS situations. Agilent Technologies offers a large variety of equipment hardware and software for pharmaceutical QC analysis. Examples are industry leading HPLCs and GCs. The products are well known for their high performance, outstanding reliability and convenient maintenance. This together with Agilent's qualification services for hardware and computer systems, the extensive training offering and complemented by preventive maintenance services will significantly reduce the number of OOS test results caused by equipment.
And should an OOS situation occur, Agilent has more sophisticated instruments to investigate and diagnose the failure, for example, GC/MS, LC/MS or ICP-MS. For more information on Agilents Solutions for QA/QC see reference 2. For a free Compendium CD with a video and 150 applications see reference 3.

References

1. United States Food and Drug Administration, Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, 2006, available on the FDA website.
2. Agilent Drug Manufacturing/QAQC website
3. Pharmaceutical Applications Compendium CD for routine pharmaceutical development and QA/QC