Recently, the FDA issued a Warning Letter to Corden Pharma Latina S.p.A., an Italian manufacturer, because of significant GMP violations in the manufacture of finished medicinal products and deficiencies in the production of APIs. Violations were noted in premises design and cleaning procedures with regard to the manufacture of finished medicinal products.
The FDA stated, “Your firm failed to have facilities used in the manufacture, process, packaging and holding of drug products of appropriate construction to facilitate cleaning, maintenance, and proper operations (21 CFR 211.160(b))”.
The floor tiles in the manufacturing area were filthy, even within the aseptic area. Some tiles were cracked and had been inadequately repaired, leaving dirty gaps. Promises to repair the cracked tiles and damaged seals, and to replace the flooring in the area of the aseptic filling machine, were deemed inadequate corrective action by the FDA. To ensure a GMP-compliant corrective action, the FDA required the following measures:
- A plan and a timeline of the measures taken to replace the floors with GMP-compliant floors. The plans should be submitted to the FDA before installing the new floors. The sanitisation plan should include details about the use of cleaners, sporicidal agents, and methods used to remove moisture.
- A plan for the requalification of the facility after construction, which should also contain environmental monitoring and a media fill strategy.
- Photographs of the new floors as demonstration that the facility then meets GMP standards.
In the deficiency letter, the FDA cited the cleaning procedure as inadequate and stated, “Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a))”.
This observation resulted from a poor cleaning process. Water had been sprayed throughout the aseptic area, which led to stagnant water collecting underneath the filling machine. The FDA considered this a potential source of microbiological contamination. The company’s response was to use a mop after cleaning to remove stagnant water. In addition, the company wanted to evaluate alternative disinfecting agents that would not require removal with water. However, the FDA wanted a demonstration that the use of a new disinfectant agent and the mop is adequate for cleaning and sanitising the floors.
Generally, the FDA expects the manufacturer to adapt its sanitisation and cleaning procedures to avoid microbial and particle contamination.