Media Fill and Aseptic Behaviour in Focus of FDA Warning Letter

Following a first Warning Letter dated 4 February 2019, the FDA issued a second Warning Letter within half a year to the American company Akorn on 13 June 2019. The 10-page Warning Letter is unusually extensive. In this news, we compiled the deficiencies identified regarding the media fill and the aseptic behaviour of the employees. FDA Warning Letters always refer to corresponding chapters of 21 CFR Part 211.

"Your firm failed to follow appropriate written 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 (21 CFR 211.113(b))."

"Poor Aseptic Behavior."

Regarding this, the FDA criticized several bad aseptic practices in the setup and filling of a lidocaine hydrochloride solution. Among others, the following deficiencies were listed:

  • An operator made an aseptic connection without first sanitizing his/her hands.
  • An operator bent over to wipe the soles of his/her shoes. Without disinfecting his or her hands, the operator connected a new tank to the filling line.
  • Sterile lidocaine hydrochloride solution leaked to the soil during setup and filling. Filling was not interrupted while the operators wiped up the leaked solution. Aseptic connections were made directly above the leaking product.
  • The inspector criticised the complete aseptic filling; both the machine design and the spatial situation in the area where aseptic connections were made as well as the personnel situation were insufficient.

Inadequate Media Fills

Regarding media fill, the insufficient simulation of interventions was criticized. Among other things, a cutting device in aseptic filling was replaced about 15 times during the past six months without being included in the media fill programme. The company's solutions to these issues - including the product recall of the batch affected, the involvement of a third party to improve the media fill programme, as well as the plan to adjust procedures and revalidate, were not satisfactory to the FDA.

Measures required

The company's proposed actions regarding the inspection report were not sufficient for the FDA. Rather, the following measures are expected:

  • A comprehensive and independent identification of all contamination risks with regard to the aseptic process, equipment and premises. An independent risk assessment should pay particular attention to the following points:
    - All human interactions with the ISO 5 area
    - Ergonomics and setup of the facilities
    - Layout of the site
    - Personnel and material flow
    - Available space
  • A CAPA plan including deadlines, taking into account the results of the contamination risk assessment.
  • Improvement of the operational management to ensure good aseptic practices and appropriate cleanroom behaviour. 
  • A complete investigation of the leakage during the filling of the lidocaine hydrochloride solution.
  • A risk assessment of the poor cleanroom performance and inadequate aseptic practices in terms of product quality and sterility.
  • An update of the third-party assessment of the media fill programme including a plan on how the resulting recommendations should be implemented.
  • A description of the improvements implemented in the last media fill with regard to the inclusion of interventions

FDA Warning Letter to Akorn Inc. dated June 13, 2019

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