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.
The FDA inspected the Brazilian Company Antibioticos Do Brasil Ltda in Sao Paulo from 18 to 27 April 2016 and the inspector witnessed serious violations of GMP requirements. Because of the company's insufficient reply to the list of deficiencies, the FDA issued a Warning Letter on 8th December 2016 focussing on three main areas. In its Warning Letters, the FDA always references the deviations to the corresponding paragraphs from the 21 CFR Part 211.
1. "Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance" - 21 CFR 211.63
Regarding this point, the FDA criticised the lack of unidirectional airflow in one of the ISO 5 aseptic filling zones. The airflow was considered sufficient to protect the sterile injectable product during interventions involving operator entry. Smoke studies demonstrated that the filling line design permits turbulence above and below open vials. Besides, it was observed that vials closure caused significant airflow disruptions.
2. "Your firm failed to establish and follow appropriate 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)
Here, the design of smoke studies was criticised. The assertion couldn't thus be demonstrated that the unidirectional air stream was maintained for all aseptic operations. Moreover, the smoke volume was occasionally too low to demonstrate the unidirectional air stream. Additionally, the smoke was not injected in the areas affected by operator interventions.
3. "Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas" - 21 CFR 211.42 (c)(10)
Here, the insufficient documentation of environmental monitoring was criticised. By means of the records, it couldn't be demonstrated that samples had been collected from all locations designated in the SOP. Additionally, the records didn't clearly reconcile the samples taken with the results obtained. Moreover, according to the SOP only data >= 1 were recorded, 0-counts not.
Last but not least, the fact that the company already received a Warning Letter in 2009 with similar deficiencies was considered particularly serious. For the FDA, this aspect shows how insufficient monitoring and control are performed by the top management.