In case of serious violations of GMP requirements, the American FDA issues a Warning Letter to the company in question. The company must react to this within 15 working days and submit a corrective action plan to the FDA. In its Warning Letter, the FDA always references the deviations to the corresponding paragraphs from the 21 CFR Part 211.
The FDA inspected the Japanese company Sato Pharmaceutical Co. Ltd from 8 to 12 February, 2016 and the inspector (investigator) witnessed serious violations of GMP requirements. Because of insufficient answers from the company, a Warning Letter was issued.
Deviation 1 "Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42 (c)(10)(iv))"
Here, the inspector criticised the lack of routine personnel monitoring. This was the state before a successful renovation. In the draft of a new SOP on that topic too, the inspector considered that not all the aspects had been addressed. For example, there was no description of appropriate measures to be taken when personnel monitoring yields results outside of action and alert limits. Regarding the action and alert limits, the lack of a scientific rationale was also criticised.
Furthermore, routine surface sampling of the cleanroom environment as well as data about the air quality were inexistent. From the FDA's point of view, the monitoring frequencies and the sampling locations weren't sufficiently described.
In the response to this Warning Letter, the FDA is expecting a reassessment and CAPA measures with regard to the monitoring programme, including:
Deviation 2 "Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113 (b))"
The main critic here was that no smoke studies under "at rest" and "dynamic" conditions had been performed to evaluate air flow characteristics of an open RABS. In the meantime, the RABS has been renovated and a closed design established. Nevertheless, the FDA expected in the company's response an assessment of the deficits observed with regard to the quality of the products manufactured for the U.S. market on the "old" open RABS design. In the response to this Warning Letter, the FDA is also expecting a risk assessment including all the possible process failures and the sterility history (sterility testing, media fills). Furthermore, all measures taken should be described addressing the acceptability of the products manufactured on the open RABS that were distributed to the U.S. market.