Wednesday, 21 February 2024 9 .00 - 17.00 h
The FDA inspection at the Swiss manufacturer has already taken place in March/April 2023. Due to the unsatisfactory response for the FDA, a Warning Letter now followed. GMP deficiencies concern the visual 100% control, the media fill, the documentation of laboratory results as well as the quality unit as a whole. In addition, the homeopathic ophthalmic preparations were distributed in the USA without medicinal product authorisation.
According to the FDA, homeopathic eye products are to be regarded as medicinal products, even if they are marketed mainly for moistening the eyes. As such, they require marketing authorisation in order to be sold. The FDA clarifies that homeopathic medicinal products are subject to the same legal requirements as other medicinal products.
The manufacturer has failed to implement the 100% visual inspection, where each container must be visually inspected (for particles e.g.). The manufacturer has limited the visual inspection to AQL sampling as an in-process inspection. The FDA clarifies that the use of AQL sampling is intended as an additional analysis that is routinely performed as part of the quality release processes after the 100% visual inspection is performed. The manufacturer had qualified and used a particle inspection system, but replaced it with AQL sampling due to insufficient speed and the high rejection rate with false positive results.
The FDA criticises the specification documents for conducting media fills, which in the FDA's view do not simulate commercial manufacturing accurately enough. The aseptic procedures simulated in the media fill are not sufficiently representative of commercial aseptic manufacturing. For example, the number of manual interventions far exceeded the number of manual interventions simulated in the Media Fill.
The FDA criticised that the laboratory records did not include complete test data to support the analysis performed. For example, negative controls for sterility tests were not documented at the time they were performed. Without negative controls for sterility tests performed at the same time, a complete evaluation of the tests performed is not possible.
According to the FDA, the responsibilities and procedures applicable to the quality organisation are not documented in writing and are not followed. For example, the quality unit has failed to establish adequate procedures to prevent microbiological contamination of sterile medicinal products. The same applies to the establishment of laboratory controls to ensure that medicinal products meet the appropriate standards for identity, strength, quality and purity. In addition, the quality organisation has not established procedures to ensure that laboratory records contain the complete data.
In addition, glycerin is an issue, as with many other Warning Letters recently. The manufacturer produces several medicinal products that contain glycerin or sorbitol solution. Identity testing for these and certain other high-risk drug ingredients includes a United States Pharmacopeia (USP) limit test to ensure they will meet specifications for diethylene glycol (DEG) or ethylene glycol (EG) content. The use of ingredients contaminated with DEG or EG has led to several fatal human poisoning cases worldwide. The FDA refers to the FDA guidance on testing e.g. glycerin and sorbitol solutions to ensure that GMP requirements are met in the manufacture of medicinal products containing ingredients at high risk of DEG or EG contamination.
The Warning Letter to the Swiss manufacturer Similasan can be found on the FDA website.