Warning Letter for Sterile Manufacturer of Ophthalmic Drugs in the US

Recommendation

17-19 September 2024

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In May, the FDA published a Warning Letter to a US American sterile manufacturer of ophthalmic drugs which highlights serious deficiencies, especially in sterile production and the general understanding of GMP.

Ophthalmic products must be sterile - non-sterility can lead to serious issues for the patient, up to vision loss. During the inspection of the ophthalmic manufacturer, the FDA determined that the filling of the ophthalmic drugs is not only inadequate with regard to sterility, but that the products are not aseptically filled at all. Upon request, the manufacturer stated that there were no procedures in place for sterile filling of ophthalmic drugs. Products are neither sterilized before nor after filling and no aseptic filling takes place. The FDA stated that there is a lack of adequate premises (smooth walls of ceilings, floors); no adequate air quality (no filtering of the air with HEPA filters); no adequate environmental monitoring; and the required cleaning/disinfection of the premises and equipment is inexistent. The manufacturer operates as a contractor for the filling of ophthalmic preparations and was able to present a document that informed the client that the filling was not sterile. In its Warning Letter, the FDA pointed out that the responsibility for compliance with GMP in the manufacture of medicinal products cannot be waived. In their answer to FDA, the manufacturer stated that they do not manufacture pharmaceuticals, but only "repackage" them, leaving the FDA further doubting the contract manufacturer's basic understanding of good manufacturing practices. Of course, filling and packaging are also regarded as pharmaceutical manufacturing steps and are completely subject to GMP regulations.

Another inspection deficiency consisted in the release of batches of the ophthalmic preparation although a white particulate impurity was noticed. After e-mail communication with the client, the production was continued and the product was released without investigating the root cause or the possible effects. For the FDA, the client's assumption that the contamination is product precipitation is not acceptable. Neither was the contract filler's statement that the particles were not microbiologically contaminated - especially as the microbiological test methods were also found to be inadequate.

Another deficiency concerned the lack of product evaluation, i.e. the Annual Product Review. In the FDA Warning Letter, the manufacturer was not at all aware of the need to prepare such a report at least once a year.

You can find the Warning Letter for the ophthalmic manufacturer on the FDA website.