9-11 April 2024
The frequent occurrence of particles in sterile injection solutions and the inadequate investigation of the cause led to a Warning Letter to a sterile manufacturer in Japan. In addition, data integrity breaks and falsifications had occurred in the environmental monitoring. The Warning Letter was preceded by an eight-day inspection in February 2021 and a review of the letter the manufacturer had sent as a response to the deficiency list.
In 2019 and 2020, the Japanese manufacturer was found to have many batches of a sterile injection solution with significant particulate contamination. The particles were judged by the manufacturer to be extrinsic (or foreign particles). [Note: these are particulate contaminants that do not originate from the process or the immediate process environment]. According to the FDA, when foreign particles were found, no timely investigation of the cause and no evaluation of the impact on the product were initiated. Furthermore, there was no adequate differentiation between intrinsic and extrinsic particles. The manufacturer claimed that these are most likely particles that cannot be removed from vials or stoppers by washing and sterilization processes. The FDA lacked an adequate root cause investigation on the source of the particles in upstream processes as well as appropriate CAPA measures. In addition, an iron complex was found in several cases. Again, the root cause investigation was lacking as well as an evaluation of potential side effects from a patient immune response. Particulate contaminants such as cellulose and glass fibers, black & white particles as well as color particles of different colors were found in 12 batches. Extending the investigation to additional batches that were still within the shelf life yielded additional extrinsic particulate findings. Again, the FDA lacked a determination of appropriate CAPA measures. According to the FDA, extrinsic particles should only be found sporadically and should always be subjected to a full investigation.
Following, the FDA imposed some measures on the manufacturer. Thus, an independent evaluation of the overall system for deviations, complaints, OOS results and malfunctions is to be prepared. In addition, a risk assessment is to be carried out for all batches on the market with regard to extrinsic particles and the above-mentioned iron complex. Further, the authority asked for an independent review of the defect limits in the visual 100% and AQL control. Finally, an update of the investigations on the extrinsic particle findings including root cause analysis is supposed to be performed.
Further serious inspection deficiencies were assigned to the area of "data integrity". For instance, the Japanese manufacturer was accused of breaches within the data integrity chain. The cases mentioned relate to environmental monitoring and manipulations in the performance of smear tests and particle monitoring.
During surface testing, employees had first wiped the surfaces before the sample was taken by means of a swab. The manufacturer itself had discovered that employees of the microbiological contact plate measurement as well as employees of the particle measurement were involved in the manipulation of data. The swabbing of equipment in Zones A and B, as well as of personnel in Zone B, was not carried out with complete certainty. In addition, employees had not reported the readings for particulates in Zone A (determined via a mobile instrument) but had repeated the measurements. FDA inspectors also found other weaknesses in the reliability of records, such as uncontrolled worksheets and weaknesses in the reconciliation of laboratory data. From the FDA's perspective, the sterility of the products is thus in question.
The manufacturer now has to submit a plan on how they will ensure aseptic conditions and correct behavior in the cleanroom as well as quality oversight in the future. In addition, a risk assessment is required that provides information about the product risk due to inadequate aseptic conditions. This should include at least: all human interventions in the process, equipment set-up and ergonomics, air quality in the A zones and their surroundings, facility layout, personnel and material flows. The FDA recommends the involvement of a GMP consultant.
For further information please see the FD Warning Letter issued to Toyobo Co.