Insufficient Media Fills in FDA Warning Letter

Recommendation

5/6 July 2023

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Requirements on Aseptic Manufacturing and Approaches for Implementation

In aseptic manufacturing, media fills (process simulation) are in the scope of every FDA inspection. On August 31, 2017 FDA published a Warning Letter based on an inspection which was already performed November 03 to11, 2016 at the Korean company Firsons Co., Ltd. Amongst various other GMP violations, they criticised an insufficient media fill program.

GMP deficiencies in FDA Warning Letters are always referenced to the requirements of 21 CFR Part 211. In this case, 21 CFR 211.113(b) "Your firm failed to establish and follow appropriate procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes".

The following points are insufficient from the FDA's point of view:

• The media fills were not performed at a sufficient frequency
• Media fill did not cover worst-case production conditions
• An extra cleaning process was performed before the media fill
• Alcohol was added to the growth media
• The number of units filled and the duration of the media fill did not cover real production conditions
• The media fill program did not cover all planned and unplanned interventions and did not simulate the maximum number of persons allowed in the clean room
• The media fill records lacked basic information, such as the names of persons participating in media fills

The FDA stated once more that media fill are to simulate the exact real aseptic practices and conditions, including all possible interventions, and are to be performed at least twice a year for each shift.

The company answered to the list of deficiencies with a new media fill plan and results of newly performed media fills. The FDA regarded the answer as insufficient, though. It lacked, amongst other things, the documentation of interventions and examinations of filled units for contamination.

Regarding the deficiencies in media fill and the unsatisfactory answer, the FDA now expects, i.a., the following measures:

• A comprehensive review of the media fill program and CAPA to ensure an appropriate simulation of the worst-case conditions of commercial manufacturing. They also expect details on the examination of units for presence of growth and batch yield reconciliation.
• An overview of all media fills performed since January 01, 2015, including processing line, date of the media fill, number of units run, number of units examined and number of potentially contaminated units found.

Due to the numerous deficiencies found, and not only in regards to media fill, the FDA has recommended the employ of a consultant. The company is under an import ban since May 11, 2017 and until the deficiencies are fixed.

Source: FDA Warning Letter to Firsons Co., Ltd.