FDA Form 483 due to Particle Findings in a Product

The company Celltrion in South Korea received a so-called Form 483 report as a result of an inspection of their facility in May and June 2017. Form 483 is used by FDA inspectors to document deficiencies found during an inspection. After the inspection, this document is sent to the inspected company in order for them to comment on the deficiencies described. If the deficiencies aren't eliminated or the statement by the company is insufficient in the eyes of the FDA, a Warning Letter by the agency follows. Contrary to FDA Warning Letters, Form 483 reports are not all freely available. The FDA only publishes some selected documents on their website "Frequently requested or proactively posted compliance records". During the inspection mentioned above, several GMP violations were recorded:

There was no timely investigation of particles found in a product: a contract laboratory reported an OOS concerning particle findings on 3 February 2017. The corresponding investigation hadn't been performed until 28 February. The company received further samples on 13 April, which hadn't been investigated by 31 May, though. Furthermore, a stability study performed on 16 March found numerous particles ("too numerous to count") regarded as intrinsic protein agglomerates. It turned out however, that there were foreign particles, as well. Until 31 May, no root investigation was conducted. Further particles found during visual control hadn't been investigated, either, e.g. to determine their source. Vials which had been rejected because of particles hadn't been considered in the test kits for training or qualification.

Further deficiencies can be found in the FDA inspection review, as well: reviews about environmental monitoring hadn't been completed in a timely manner, and occurring trends hadn't been investigated. During the aseptic work, employees were observed leaning over sterile surfaces and plugs in the RABS with their arms; in another instance, the RABS had been left open unnecessarily. Deficiencies have been observed during Media Fill, also. For example, 19 vials had been rejected as "fallen from the conveyor" and not microbiologically investigated, even though they had been integral and stoppered. In routine operations and according to procedures, these vials wouldn't have had to be rejected. The FDA found further deficiencies in process validation, lab data (which didn't contain all the results of the tests performed) and equipment design. For example, identification numbers were taped to format parts inside of the RABS.

On the FDA website you can find the complete Form 483 report.

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