Process Validation and Pharmaceutical Water Deficiencies at a US Manufacturer

Back in October/November 2024, the FDA conducted an inspection at a US manufacturer of OTC products and uncovered several GMP deficiencies, including in process validation. This has now led to a warning letter.

Specifically, the FDA criticized that the available process validation reports are incomplete. For example, the complete list of equipment used, critical process parameters, sampling plans and acceptance criteria are missing. In addition, only some of the validation reports submitted were based on data from the production facility currently in use, even though, according to the FDA, batches have been commercially manufactured and shipped since May 2023. The other reports date from 2011 to 2015 and refer to a predecessor company at a different site.

The FDA is also not satisfied with the water system. According to the FDA, the production of the water used both for production and for cleaning is not adequately validated and microbiologically monitored. In the FDA's view, the specified test intervals and limits for microbiological testing are insufficient to ensure the suitability of the water for its intended use.
In its response to the inspection deficiencies (Form 483), the manufacturer stated that it had now prepared validation reports for all OTC products manufactured since 2023. However, the FDA considers this response to be inadequate because it did not explain why manufacturing was started before process validation was conducted. In addition, the subsequently submitted validation reports are also incomplete.

The FDA now requires a comprehensive, data-based validation concept. This should cover all manufacturing and packaging steps and ensure that all processes are stable, controlled and reproducible. The manufacturer also has to revise and present its procedures for process qualification (PPQ) and the ongoing monitoring of batch variations (intra- and inter-batch). For the water system, the manufacturer needs to re-describe the microbiological monitoring and provide current warning and action limits to provide water according to USP specification.

Another deficiency concerns the laboratory controls. The manufacturer could not prove that the microbiological methods used by an external testing laboratory were suitable to reliably detect relevant microorganisms.
In its response, the manufacturer submitted documents from the external testing laboratory showing that system suitability testing was performed on all liquid drug products to ensure the recovery of relevant microorganisms. The FDA judged the response to be insufficient. The documents could not confirm the suitability of the methods according to USP <60> and <62>.

The FDA has also called the quality system itself into question. The authority criticized the Quality Unit (QU) for failing to perform its duties properly. For instance, a batch was released before the microbiological test results were available. According to the FDA, releasing a batch "in quarantine" is not permitted — all tests, including microbiological tests, must be completed before a batch can be released. Additionally, the company failed to comply with its own requirement to retain reserve samples and could not provide samples of the active ingredients used.
The FDA is calling for a comprehensive review of the quality system and recommends that the company hire an independent GMP consultant.