Warning Letter regarding Deficiencies in Aseptic Production - Part 2: Media Fill

On 9 June, 2020, the FDA issued a Warning Letter to the Japanese company Takeda Pharmaceutical Company Limited following an inspection conducted in November 2019. Among other things, issues with the media fill, inadequate "aseptic behaviour" and inadequate controls of materials used in the aseptic area were reported. Part 2 of the News deals with the deviations in the media fill. Warning Letters of the FDA 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)).

Deficiencies found

What deficiencies were found by the inspector during the media fill?

  • Integral units were removed from the media fill run and not incubated. The company ordered the vials to be removed for a routine analytical test. From FDA's point of view, this test could have been performed after incubation.
  • The media fill did not sufficiently consider the risks of commercial production. In this case, a manual aseptic material transfer was not simulated.
  • In the case of several employees, no activities were simulated for which they were responsible in production.

The Company's Response

What was the company's response and why was this response insufficient for the FDA?

Regarding the removal of integral vials, the company stated that no critical procedures should be performed prior to vial removal. According to the FDA, this is unacceptable because such an approach undermines the sensitivity of the media fill to detect contamination risks.
The company also stated that it is revising its Media fill procedures and implementing new media fills. This was not enough for the FDA either. As usual, the FDA also expected an additional retrospective review and evaluation of the described deviations in terms of their impact on product sterility for product batches manufactured in the past.

Media Fill also mentioned in another Context

In addition to the direct deficiencies in media fills, the issue of media fill was also mentioned in another context. Reference was made to:

Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow such written procedures (21 CFR 211.22(d)).

After a comprehensive shutdown, the QU (Quality Unit) allowed the resumption of aseptic activities without defining appropriate measures. The company violated its own procedural instructions, which in this case included a media fill.

In its response, the company undertook to carry out a media fill for the line. The company also stated that it would improve its quality systems to ensure that a media fill would be carried out in any case after a shutdown. However, the company also felt that the lack of a media fill after the shutdown would not have a negative impact on product safety. The resumption of production would require the availability of environmental monitoring data prior to product release.

These statements were inadequate for the FDA because it failed to adequately assess the impact of the shutdown on the sterility of the products. Environmental monitoring data is not sufficient for this purpose! As a result, the FDA now expects a comprehensive evaluation with the aim of ensuring the functionality of the quality unit. The following was requested:

  • A determination of whether the procedures used are robust and appropriate
  • Provisions for QA oversight throughout operations
  • A complete and final review of each batch (information) before the final release decision
  • Oversight and approval of all investigations
  • A description of how top management supports quality assurance and reliable operation
  • A risk assessment of all products sold that were manufactured under unacceptable aseptic production conditions

Source: Warning Letter to Takeda Pharmaceutical Company Limited dated 9.6.2020

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