Warning Letter about Deficits in Aseptic Manufacturing - Part 1: Cleanroom Behaviour and Materials in the Aseptic Area

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 1 of the News will deal with the latter two deviations while part 2 will address media fill problems. FDA Warning Letters always refer to the 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 in Aseptci Performance, Response and FDA's Reaction

What deficiencies were identified by the inspector in aseptic performance, what was the company's response and why was this response inadequate from the FDA's perspective?

  • Employees failed to disinfect gloved hands after touching surfaces (curtains / touch screens)
  • Employees' activities in the "sterile area" were carried out with fast movements instead of a slow aseptic movement technique.

The company's response that it had trained its employees to behave adequately in an aseptic environment was not sufficient for the FDA. Rather, the company should extend this training to supervisory staff and generally demonstrate the effectiveness of the training.

Deficiencies in Review of Materials, Response and FDA's Reaction

What deficiencies were identified by the inspector in the review of materials used in the aseptic area, what was the company's response and why was this response insufficient from the FDA's perspective?

The wipes used for disinfection in the aseptic area could not be traced. The irradiation certificate of the wipes shown to the inspector did not match the material identification number. The inspector criticised the lack of adequate records in the quality unit on material reception and use.

The company replied that a risk assessment had concluded that the placing of the wipes in the clean room did not pose a risk to product quality. This risk assessment related to the use of disinfectants, environmental monitoring and a qualitative sterilisation indicator. However, the FDA expected adequate controls of material acceptance and an evaluation before entering the clean room. The company confirmed the lack of traceability of the material identification number.  

What further action does the FDA expect from the company in response to this Warning Letter?

  • A risk assessment of all contamination hazards with regard to the aseptic process, equipment and premises, including an independent evaluation which should include at least the following points
                 - A list of all activities of the employees in the respective clean room area
                 - The device positioning and the ergonomic conditions
                 - Personnel and material flows in the "sterile area"
                 - Procurement of the consumables used in the cleanroom area
                 - Acceptance, evaluation and aseptic handling of all consumables in the ISO 5 range
  • A comprehensive and retrospective review of all batches on the US market within the expiration date. In particular, the knowledge gained from the risk assessment should be incorporated and the resulting measures listed.
  • Environmental monitoring data of the last two years with details on the overall results as well as on the identification of microorganisms when limits are exceeded. In addition, a summary of the investigations performed is expected.
  • A plan to ensure appropriate aseptic and cleanroom behaviour. This should include steps to ensure routine and effective monitoring of production batches. The frequency of quality oversight measures, e.g. audits, during the aseptic processes is also required.

Source: Warning Letter to Takeda Pharmaceutical Company Limited dated 09 June 2020

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