Deviations in Aseptic Manufacturing: Warning Letter to a Japanese Pharmaceutical Manufacturer

The FDA inspected the Tokyo site of a Japanese pharmaceutical manufacturer in November 2025 and found, among other things, fundamental deficiencies in the aseptic manufacturing processes. Due to the severity of the violations, a Warning Letter has now been issued.

The FDA criticises the manufacturer for failing to establish and follow appropriate written procedures to prevent microbial contamination of products declared as sterile, including the validation of aseptic processes. According to the FDA, the ISO-5 area (Zone A) and the design of the filling line are not suitable for aseptic filling. The FDA cites the repeated failure of aseptic process simulation (APS, media fill) as a major deficiency: between November 2022 and February 2025, at least six media fills failed during validation trials. Furthermore, significant microbiological contamination and contamination by foreign particles were detected on the line. The FDA considers the corrective measures implemented by the company to be insufficient because they do not address fundamental factors of the aseptic process design. According to the FDA, the protection concept based on unidirectional airflow in the critical area is inadequate. The FDA states that during certain operations (in the context of a RABS), the first-air principle is violated, thereby exposing sterile products. The FDA describes the current design as fundamentally faulty.

The airflow visualisation studies (smoke studies) carried out are also described as inadequate. Among other things, the FDA cites excessively rapid manual movement of the smoke source and a positioning of the smoke source that does not allow for an assessment of the airflow across the entire working area. At times, visibility was also restricted by the technician's position. In the FDA's view, the required unidirectional airflow was therefore not sufficiently demonstrated.

The FDA also considers the company's response to be inadequate. Although the company plans to update the line prior to media fills in October 2026 and to resume commercial production only after successful media fills, the measures described are not suitable for rectifying the fundamental design flaws. The announced changes (e.g. replacement of components and revision of smoke study procedures) would not address the systemic weaknesses of the aseptic process design.

The FDA requires a comprehensive risk analysis of all sources of contamination, taking into account aseptic processes, equipment and facilities. This should include, amongst other things, human interactions in the ISO-5 area, gowning, plant layout/ergonomics of the equipment, air quality, and personnel and material flows across all rooms relevant to sterile operations. Building on this, the FDA requires a detailed remediation plan with timelines setting out how improvements to the design of the facilities, rooms and processes will be implemented, qualified and validated.

The FDA also objects to the inadequate stability programme and the absence or inadequacy of stability-indicating test methods. As a result, important quality attributes had not been considered in the studies. For example, tests for viscosity and degradation products were missing. Furthermore, additional peaks were visible in the stability data within HPLC chromatograms, which had not been identified or evaluated against acceptance criteria.

The FDA also criticises the manufacturer for releasing products for the US market without the required microbiological testing; specific mention is made of testing for Burkholderia cepacia complex in products containing a particular excipient.

The response was deemed insufficient, partly because, according to the FDA, no reliable data or results from retained sample testing had been provided. The FDA also noted the absence of risk assessments for batches released without the required microbiological testing, as well as any recall actions that might have been necessary as a result.

The FDA notes that the manufacturer has suspended the production of sterile products for the US market and demands that production not be resumed until appropriate corrective actions have been implemented, successful media fills are available and the CAPA plan has been discussed with the authority - alternatively, the company should provide a written statement if it no longer intends to manufacture sterile products for the US market. In addition, the FDA recommends engaging a qualified GMP consultant, including a comprehensive Six-System audit.

The full text of the Warning Letter can be found on the FDA website.